Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]([Mg]Br)[CH3:18].[Mg].C(Br)C.[Cl-].[NH4+]>CCOCC>[CH2:17]([C:6]1([OH:16])[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH3:18]
Reactant: CC[Mg]Br
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Product: CCC1(O)c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5H-dibenzo[a,d]cyclohepten-5-one (15.5 g., 0.075 mole) is added in portions to a solution of ethyl-magnesium bromide, prepared from 3.64 g. (0.15 mole) of magnesium and 16.4 g. of ethyl bromide in ether. After stirring for one hour at room temperature, the mixture is heated to refluxing for 15 minutes, then cooled, and the Grignard adduct is hydrolyzed by cautiously adding ammonium chloride solution. The crude 5-ethyl-5-hydroxy-5H-dibenzo[a,d]cycloheptane is recovered from the ether layer in a yield of 16.78 g. (95%), m.p., 63°-65° (clearing at 70°C.). After recrystallization from petroleum ether, hexane and finally isopropyl alcohol, an analytical sample melted at 63°-65°C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH3:39])=[CH:33][C:32]=1[N+:40]([O-:42])=[O:41])[C:16]1[N:21]=[CH:20][N:19]=[C:18]([N:22](C)[C:23](=O)OC(C)(C)C)[CH:17]=1)=O)(C)(C)C>C(Cl)Cl>[CH3:39][O:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([NH:15][C:16]2[CH:17]=[C:18]([NH:22][CH3:23])[N:19]=[CH:20][N:21]=2)=[C:32]([N+:40]([O-:42])=[O:41])[CH:33]=1
Reactant: COCc1ccc(N(C(=O)OC(C)(C)C)c2cc(N(C)C(=O)OC(C)(C)C)ncn2)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(Nc2ccc(COC)cc2[N+](=O)[O-])ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 139.4 %

Procedure:
TFA (5 mL) was slowly added to a stirred solution of tert-butyl (6-((tert-butoxycarbonyl)(4-(methoxymethyl)-2-nitrophenyl)amino)pyrimidin-4-yl)(methyl)carbamate (0.85 g) in dry DCM (10 mL) under argon atmosphere at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 h. After completion of the reaction, excess solvents were removed under reduced pressure and washed with ether to afford the title compound (0.7 g crude) as a solid. MS (ESI): 290.2 [M+H]+.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]2.[Cl-].[NH4+].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([CH:1]1[CH:6]([OH:7])[CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]1)=[N+:16]=[N-:17]
Reactant: CCOC(=O)C1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O)C(N=[N+]=[N-])C1
Temperature: 76 °C
Reaction time: 13 h

Procedure:
A mixture of Racemate-ethyl 7-oxa-bicyclo[4.1.0]heptane-3-carboxylate (24.0 g, 140 mmol), ammonium chloride (13.6 g, 210 mmol) and sodium azide (13.7 g, 210 mmol) in N,N-dimethylformamide (120 mL) was stirred at 76° C. for 13 hours. After any insoluble matter was collected by filtration, the filtrate was concentrated under reduced pressure while not allowing the solvent to evaporate to dryness. The residue was combined with the solid matter collected by the previous filtration, and the thus-obtained mixture was dissolved in water (500 mL). The solution was extracted with ethyl acetate (500 mL). The extract was washed with water (500 mL×5) and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the tile compound (28 g, crude) as an yellow oil. MS (ES+) C9H15N3O3 requires: 213, found: 214 [M+H]+, 236 [M+Na]+.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17]COC)=[C:8](/[CH:21]=[C:22](\[CH2:28][C:29]2[C:37]([O:38][CH3:39])=[CH:36][C:32]3[CH2:33][CH2:34][O:35][C:31]=3[CH:30]=2)/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].Cl>CCO>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[OH:17])=[C:8](/[CH:21]=[C:22](\[CH2:28][C:29]2[C:37]([O:38][CH3:39])=[CH:36][C:32]3[CH2:33][CH2:34][O:35][C:31]=3[CH:30]=2)/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)OCC)c1-c1ccc(Cl)cc1OCOC
Agent: Cl
Solvent: CCO
Product: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)OCC)c1-c1ccc(Cl)cc1O
Yield: 64 %

Procedure:
To a solution of Ethyl (E)-3-[1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate (4.50 g, 8.10 mmol) in EtOH (60 mL) was added 0.6 mL of conc. HCl. After heating at reflux for 3 h, the mixture was concentrated and then diluted with EtOAc. The resulting mixture was washed with 5% NaHCO3, brine and dried (Na2SO4). After removing the solvent, column chromatography of the residue with 25% EtOAc in hexane gave 2.65 g (64%) of the title compound as a solid: m.p. 158-160° C.; MS (ESI) m/z 511 (M+H)+; 1H NM (400 MHz, CDCl3) d 7.58 (s, 1H), 7.47 (s, 1H), 7.02 (d, 1H), 6.78 (s, 1H), 6.62 (dd, 1H), 6.59 (d, 1H), 6.48 (s, 2H), 5.50 (bs, 1H), 4.48 (t, 2H), 4.12 (m, 2H), 3.85-3.95 (m, 4H), 3.83 (s, 3H), 3.81 (s, 3H), 3.16 (t, 2H), 1.67 (m, 2H), 1.20 (t, 3H), 1.17 (m, 2H), 0.80 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[F:17])(=[O:26])=[O:25])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1F

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 2-fluoro-benzenesulfonyl chloride. 1H NMR (CDCl3): δ (ppm): 6.88-6.93 (m, 1H), 7.16-7.20 (m, 1H), 7.38 (d, J=6.4 Hz, 1H), 7.41-7.46 (m, 4H), 7.52 (m, 2H), 7.58-7.62 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.81-7.85 (m, 1H), 10.10 (s, 1H). MS: m/z 390.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:11][CH2:10][C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: Nc1ccccc1F
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccccc1F
Yield: 11.4 %

Procedure:
To a solution of 2-fluoroaniline (22.06 g, 0.198 mol) and freshly distilled tert-butyl acrylate (25.45 g, 0.198 mol) in dry benzene (250 ml) was added tin tetrachloride (1 ml) and the mixture was refluxed for 60 h. The resulting suspension was filtered and the filtrate was evaporated to give a semisolid which was chromatographed on silica gel eluting with 25/75 ethyl acetate/hexane to give the title compound (5.4 g, 11%). Anal calcd for C13H18NO2F: C, 65.25; H, 7.58; N, 5.85. Found: C, 65.49; H, 7.75; N, 5.80.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:18]=[C:19]=[S:20])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:19](=[S:20])[N:18]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][O:17]1)[C:4]2=[O:6]
Reactant: S=C=NCC1CCCO1
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1c2cc(Br)ccc2[nH]c(=S)n1CC1CCCO1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 2-amino-5-bromobenzoic acid (8.0 g, 37.0 mmol), tetrahydrofurfuryl isothiocyanate (5.0 g, 34.9 mmol) and triethylamine (5.0 mL, 3.6 g, 35.6 mmol) in ethanol (48 mL) was heated at reflux for 2 h. The reaction mixture was then allowed to cool to room temperature and filtered. The resulting filter cake was washed with 50 mL of cold ethanol, followed by 50 mL of hexanes to provide 10.8 g of the title compound of Step A as a solid melting at 230-232° C. 1H NMR (400 MHz, Me2SO-d6): δ 1.63-2.0 (m,4H), 3.58-3.68 (m,1H), 3.74-3.82 (m,1H), 4.32 (dd,1H), 4.39-4.50 (m,1H), 4.58 (dd,1H), 7.37 (d,1H), 7.91 (d,1H), 8.02 (s,1H), 13.1 (br s,1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11](O)[CH2:10][CH2:9]2.Cl>O1CCCC1.O>[CH2:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:7]=2)[CH:11]=[CH:10]1
Reactant: OC1CCc2cc(-c3nccs3)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C1=Cc2ccc(-c3nccs3)cc2C1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a solution of 5-(1,3-thiazol-2-yl)indan-1-ol (900.00 mg, 0.0041420 mol) in tetrahydrofuran (20.00 mL) was added a 1.0 M solution of hydrogen chloride in water (20.00 mL). The reaction mixture was heated to reflux overnight. After cooling down to room temperature, the reaction was quenched with 30 mL of 1 N NaOH aqueous solution. The organic layer was separated and the aqueous phase was extracted with EtOAc (3×30 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure to afford the desired product (381 mg, 46%). LC-MS [M+H]=200.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18]Br>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([Br:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(N)n1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1nc(N)ccc1Br
Temperature: 25 °C
Reaction time: 7 h
Yield: 29.3 %

Procedure:
To a suspension of methyl 6-aminopyridine-2-carboxylate (5.98 g, 39.5 mmol) and sodium carbonate (2.64 g, 24.9 mmol) in acetic acid (150 mL) was added bromine (7.89 g, 49.4 mmol), and the mixture was stirred at room temperature for 7 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. This was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (2.67 g, yield 29%).
Reaction SMILES: [N:1]1(S(N)(=O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:14]C1C=CC=CC=1[N+]([O-])=O>>[Br:14][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: NS(=O)(=O)n1ccc2ccccc21
Product: Brc1cccc2cc[nH]c12

Procedure:
Similarly, the route shown in Scheme 2 below exemplifies synthesis of certain 7-aryl(heteroaryl)-indoline(indole)-1-sulfonamide compounds of the present invention. To synthesize indole-1-sulfonamide compound (9), 1-bromo-2-nitrobenzene (6) is reduced to afford 7-bromo-1H-indole (7), which reacts with 4-methoxyphenylsulfonyl chloride to provide 7-bromo-1-(4-methoxyphenylsulfonyl)-1H-indole (8). The sulfonamide (8), is then treated with an aryl or heteroaryl boronic acid, Pd(PPh3)4, and K2CO3 in toluene/EtOH to afford final compound (9). To synthesize indoline-1-sulfonamide compound (12), 7-bromo-1H-indole (7) is further reduced (with NaCNBH3 and CH3COOH, at room temperature) to afford 7-bromoindoline (10), which reacts with a substituted phenylsulfonyl chloride to provide bromo-indoline-sulfonamide (11). The bromo-indoline-sulfonamide (11) is then treated with an aryl or heteroaryl boronic acid, Pd(PPh3)4, and K2CO3 in toluene/EtOH to afford final compound (12), which can be further modified to obtain compound (13).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]([O:28][CH3:29])=[CH:20][C:21]=3[O:26][CH3:27])[N:16]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)=[N+]=[N-].[C:30]([OH:33])(=S)[CH3:31]>>[CH3:27][O:26][C:21]1[CH:20]=[C:19]([O:28][CH3:29])[CH:18]=[C:17]2[C:22]=1[C:23](=[O:25])[NH:24][C:15]([C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1)[O:6][CH2:5][CH2:4][NH:1][C:30](=[O:33])[CH3:31])=[N:16]2
Reactant: CC(O)=S
Reactant: COc1cc(OCCN=[N+]=[N-])cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Product: COc1cc(OCCNC(C)=O)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[3-(2-Azido-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (90 mg, 0.22 mmol) was taken in thioacetic acid (2 mL) and the reaction mixture was stirred at room temperature for 2 hours. Thioacetic acid was removed under reduced pressure, and the residue was purified by column chromatography (silica gel 230-400 mesh; 3.5% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 45 mg (49%). MP 264-265° C. 1H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.13 (t, J=5.86 Hz, 1H), 7.39 (d, J=1.56 Hz, 2H), 6.76 (d, J=2.34 Hz, 1H), 6.69 (t, J=2.15 Hz, 1H), 6.55 (d, J=2.34 Hz, 1H), 4.07 (t, J=5.67 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.43 (q, J=5.47 Hz, 2H), 1.84 (s, 3H). MS (ES+) m/z: 414.11 (M+1).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([Cl:14])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC(Br)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCC(Br)C(=O)Cl
Yield: 63.5 %

Procedure:
To a solution of 20 g (90 mmol) 2-bromooctanoic acid in 100 mL toluene was added 13.2 mL (180 mmol) thionyl chloride. The solution was heated at reflux under nitrogen for 3 hours. The excess thionyl chloride and toluene were distilled at atmospheric pressure under N2. The yellow residue was purified by kugelrohr distillation (bp=60°-65° C./0.1 mm Hg) and 13.8 g (64%) of the 2-bromooctanoyl chloride as a colorless oil was isolated.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]>O1CCCC1.CCCCCC>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)#[N:30]
Reactant: Cc1cccc2cncn12
Reactant: N#CCCCCBr
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCCCCCc1cccc2cncn12
Temperature: 0 °C

Procedure:
A solution of 5-methylimidazo[1,5-a]pyridine (4.0 g) and tetramethylethylene diamine (4.9 g) in 100 ml of tetrahydrofuran is cooled to 0° under nitrogen and 26.5 ml of 1.6 N n-butyllithium in hexane is added dropwise maintaining the temperature below 2°. After 30 minutes this solution is transferred under nitrogen over 45 minutes to an ice-cold solution of 5-bromovaleronitrile (4.86 g) in 80 ml of tetrahydrofuran. After 15 minutes the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is reextracted with 2 N hydrochloric acid (3×15 ml). Basification of the aqueous phase to pH=10 with 50% sodium hydroxide, extraction with ethyl acetate (2×75 ml), drying over magnesium sulfate, evaporation and chromatography (SiO2, ethyl acetate) yields 5-(5-cyanopentyl)-imidazo[1,5-a]pyridine.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:40]=[C:23]4[C:24]([C:28]5[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=5[O:35][CH2:36][CH:37]([F:39])[F:38])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([O:35][CH2:36][CH:37]([F:39])[F:38])=[C:28]([C:24]2[C:23]3[N:22]([N:21]=[C:20]([NH:19][C:17]4[CH:16]=[CH:15][C:12]5[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=5[CH:18]=4)[N:40]=3)[CH:27]=[CH:26][CH:25]=2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(Cl)ccc5OCC(F)F)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)COc1ccc(Cl)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12

Procedure:
{8-[5-Chloro-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine was prepared from 7-{8-[5-chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.117 g, 205 mmol) and trifluoroacetic acid (0.5 mL) in a manner analogous to Example 312 to give product (0.045 g, 47%). MP=102-105° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.52 (s, 1H), 8.78 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.50 (d, 1H), 7.40 (m, 2H), 7.30 (d, 1H), 7.05 (t, 1H), 7.00 (d, 1H), 6.25 (br m, 1H), 4.35 (m, 2H), 3.10 (br m, 1H), 2.79 (br m, 8H). MS=470 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:36][CH2:37][CH3:38]>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH:8]([CH2:36][CH2:37][CH3:38])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CCCI
Reactant: COC(=O)Cc1c(C)nc(-c2ccccc2)nc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
A solution of methyl 2-(4-methyl-2,6-diphenylpyrimidin-5-yl)acetate (150 mg; 0.471 mmol) in dry DMF (2.5 mL) was cooled to −15° C. LHMDS (0.518 mL; 0.518 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (0.069 mL; 0.707 mmol), after stirring for 2 h at −15° C. the mixture was allowed to warm to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine and dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (1-10%) in heptane to give 94 mg (54%) of the title compound as a colorless oil. ESI/APCI(+): 361 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[CH:14][C:15]4[C:16](=[O:33])[NH:17][C:18]([C:22]5[CH:27]=[CH:26][C:25](Br)=[CH:24][C:23]=5[O:29][CH2:30][CH2:31][CH3:32])=[N:19][C:20]=4[CH:21]=[C:12]3[N:11]=[CH:10]2)=[CH:4][CH:3]=1.[Cu][C:35]#[N:36].N>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[CH:14][C:15]4[C:16](=[O:33])[NH:17][C:18]([C:22]5[CH:27]=[CH:26][C:25]([C:35]#[N:36])=[CH:24][C:23]=5[O:29][CH2:30][CH2:31][CH3:32])=[N:19][C:20]=4[CH:21]=[C:12]3[N:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: CCCOc1cc(Br)ccc1-c1nc2cc3ncn(Cc4ccc(F)cc4)c3cc2c(=O)[nH]1
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: CCCOc1cc(C#N)ccc1-c1nc2cc3ncn(Cc4ccc(F)cc4)c3cc2c(=O)[nH]1
Temperature: 25 °C
Yield: 91 %

Procedure:
1-(4-Fluorophenylmethyl)-6-(4-bromo-2-propoxyphenyl)-1H-imidazo[4,5-g]quinazolin-8(7H)-one (507 mg, 1 mmol) was dissolved in 6 mL N-methyl-2-pyrrolidinone containing copper (I) cyanide (178 mg, 2 mmol). The reaction was heated to reflux overnight, then cooled to room temperature and poured into 100 mL of 2N aqueous ammonia solution. The solid that precipitated was collected by filtration and washed first with 2N aqueous ammonia, then water and dried in a vacuum oven at 45° C. overnight to afford the title compound as a yellow solid (464 mg, 0.91 mmol, 91% yield). HPLC: (YMC S5 ODS 4.6×50 mm column, 4 minute gradient-0% B to 100% B, 4 mL/min flow, solvent A: 10% MeOH-90% H2O-0.2% H3PO4, solvent B: 90% MeOH-10% H2O-0.2% H3PO4) retention time 3.65 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([OH:19])=O.[CH:20]([NH:23][NH:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[O:26])=[O:19]
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Reactant: CC(C)NNC(=O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccsc2)C(C)C)c1C
Yield: 50.5 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (207 mg, 0.81 mmoles) and thiophene-3-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.81 mmoles) in DMF (8 mL) was treated with triethylamine (0.34 mL, 2.44 mmoles), HOBT (132 mg, 0.98 mmoles) and EDCI (156 mg, 0.98 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (172 mg, 50%). LC-MS m/e 421.46 (M+H+)
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:6][C:7](Cl)=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35]1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[C:43]([O:42][C:41]([NH:40][C@@H:36]1[CH2:37][CH2:38][CH2:39][N:34]([C:7]2[N:6]=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=2)[CH2:35]1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)n2)C1
Temperature: 100 °C
Yield: 87.2 %

Procedure:
A mixture of benzyl 4-(4-(3-carbamoyl-6-chloropyridin-2-ylamino)phenyl)piperazine-1-carboxylate (4 g, 8.58 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (2.58 g, 12.88 mmol), and DIEA (3.00 mL, 17.17 mmol) in N-methyl-2-pyrrolidinone (6 mL) was placed in two capped scintillation vials and heated at 100° C. overnight. The reaction mixtures were quenched with water and filtered. The solid was purified by MPLC chromatography (ISCO, 6% NH4OH/MeOH/CH2Cl2, two 40 g stacked silica gel columns) to give 4.71 g of ((R)-benzyl 4-(4-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:22]1([C:25]2[O:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31](O)=[O:32])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C.CCCP(=O)=O>C1COCC1>[CH:22]1([C:25]2[O:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]4[C:14]5[CH:15]=[N:16][CH:17]=[CH:18][C:13]=5[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=4)=[O:9])[CH:3]=3)=[O:32])[N:29]=2)[CH2:24][CH2:23]1
Reactant: Cc1oc(C2CC2)nc1CC(=O)O
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1oc(C2CC2)nc1CC(=O)Nc1cncc(C(=O)c2cn(C(C)C)c3ccncc23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
To a mixture of (5-aminopyridin-3-yl)(1-isopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 19, 80 mg, 0.285 mmol) and (2-cyclopropyl-5-methyl-1,3-oxazol-4-yl)acetic acid (Preparation 87, 52 mg, 0.285 mmol) in THF (5 mL) was added triethylamine (138 uL, 0.997 mmol) and propylphosphonic anhydride (429 uL, 0.712 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated to dryness and purified using preparative HPLC to afford the title compound as a white solid (50 mg, 39%).