Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]([CH:14]1[N:19]([CH3:20])[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]1)(=[S:13])[NH2:12]>CCO>[CH3:20][N:19]1[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:15][CH:14]1[C:11]1[S:13][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1C(N)=S
Solvent: CCO
Product: CN1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccccc2)cs1
Temperature: 70 °C
Yield: 64.2 %

Procedure:
A mixture of 2-bromoacetophenone (130 mg, 0.65 mmol) and tert-butyl 3-carbamothioyl-4-methylpiperazine-1-carboxylate (170 mg, 0.65 mmol) in EtOH (15 mL) was heated to 70° C. for 4 h. The reaction mixture was cooled to room temperature and solvent was evaporated under reduced pressure. The residue was diluted with water and the organic product was extracted with EtOAc. The combined extracts were washed with H2O and brine, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 4-methyl-3-(4-phenylthiazol-2-yl)piperazine-1-carboxylate (150 mg, yield 64%). 1H NMR (300 MHz, CDCl3) δ 7.92-7.90 (m, 2H), 7.49 (m, 1H), 7.46-7.41 (m, 2H), 7.37-7.34 (m, 1H), 4.03-3.98 (m, 1H), 3.67-3.64 (m, 2H), 3.23-3.15 (m, 2H), 2.97-2.93 (m, 2H), 2.26 (s, 3H), 1.46 (s, 9H). MS (ESI) m/z: Calculated for C19H25N3O2S: 359.17. found: 360.2 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:12]=[C:13]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(Br)cc(OCc2ccccc2)c1=O
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccc(Cl)c(C(F)(F)F)c2)cc(OCc2ccccc2)c1=O
Yield: 113.3 %

Procedure:
3-(Benzyloxy)-5-bromo-1-(propan-2-yl)pyridin-2(1H)-one (58 mg, 0.180 mmol), 4-chloro-3-(trifluoromethyl)phenylboronic acid (49 mg, 0.218 mmol), and Pd(dppf)Cl2—CH2Cl2 (8 mg, 9.80 μmol) were combined in THF (1 mL) in a microwave vessel. To this was added 1 M Cs2CO3 (0.540 mL, 0.540 mmol). The vessel was sealed then irradiated to 150° C. for 20 min. The layers were separated and the aqueous extracted with EtOAc (3×). The combined organic layers were filtered through a pad of silica gel washing with EtOAc. The filtrate was concentrated to give 3-(benzyloxy)-5-[4-chloro-3-(trifluoromethyl)phenyl]-1-(propan-2-yl)pyridin-2(1H)-one (86 mg) which was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:27])=O>CN(C)C=O.ClCCl>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([Cl:27])=[O:23])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One drop of N,N-dimethylformamide (DMF) was added to a solution of 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyric acid (3.53 g, 11.3 mmol, 1.0 eq) in dichloromethane (55 mL). Oxalyl chloride (3.0 mL, 33.9 mmol, 3.0 eq) was added dropwise over 5 minutes to the reaction mixture, which was subsequently stirred for 2 hours at ambient temperature. The mixture was concentrated under reduced pressure to provide 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyryl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)=[O:4].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21])[CH2:9][CH2:8]2)=[O:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CCN2
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Yield: 79.8 %

Procedure:
To a solution of 10 (0.28 g, 1.58 mmol) in pyridine (2 mL), benzenesulfonyl chloride (0.40 ml, 3.16 mmol) was added. The reaction mixture was refluxed overnight. The mixture was then purified by silica gel chromatography (EtOAc:n-hexane=1:3) to afford 11 (0.40 g). 1H NMR (500 MHz, CDCl3): δ 2.99 (t, J=8.6 Hz, 2H), 3.87 (s, 3H), 3.97 (t, J=8.6 Hz, 2H), 7.45-7.48 (m, 2H), 7.56-7.59 (m, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.75 (s, 1H), 7.82 (d, J=7.7 Hz, 2H), 7.90 (d, J=7.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=3)[C:10]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[N:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[C:38](=[O:40])[CH3:39]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:38]([OH:40])([C:33]4[N:34]=[CH:35][CH:36]=[CH:37][N:32]=4)[CH3:39])[CH:15]=3)[C:10]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ncccn1
Reactant: C#Cc1ccc2c(C(=O)N(C)C)nn(-c3ccnc(N)n3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ncccn3)ccc12
Temperature: 25 °C

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide (80 mg, 0.217 mmol) in THF (1.0 mL) at −78° C. under nitrogen was added 2M LDA in THF (0.27 mL, 0.54 mmol). After 5 minutes 1-pyrimidin-2-yl-ethanone (79 mg, 0.65 mmol) in THF (0.5 mL) was added and the reaction was allowed to warm to RT after 20 minutes. After a further 30 minutes the reaction mixture was quenched by addition of saturated aqueous NH4Cl (0.5 mL). The volatiles were removed in vacuo and the mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 0-2% methanol in DCM). Trituration of the partially purified product from EtOAc-heptane gave the title compound: 1H NMR (250 MHz, MeOD) delta 1.93-2.02 (3H, m), 3.22 (3H, s), 3.41 (3H, s), 7.24 (1H, d, J=5.79 Hz), 7.40-7.55 (2H, m), 7.97 (1H, d, J=8.38 Hz), 8.29 (1H, d, J=5.79 Hz), 8.88 (2H, d, J=5.03 Hz), 9.12 (1H, s); LC-MS: m/z=+429.45 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]=[C:7]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].Cl[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29]([S:31]([NH:34][CH2:35][C:36]([NH2:38])=[O:37])(=[O:33])=[O:32])[CH:30]=1.[Li+].[Br-].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]=[C:7]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29]([S:31]([NH:34][CH2:35][C:36]([NH2:38])=[O:37])(=[O:33])=[O:32])[CH:30]=3)[CH2:18][CH2:17]2)[O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: COc1ccc(CCCl)cc1S(=O)(=O)NCC(N)=O
Reactant: CCOCc1nc(C2CCNCC2)oc1-c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOCc1nc(C2CCN(CCc3ccc(OC)c(S(=O)(=O)NCC(N)=O)c3)CC2)oc1-c1ccccc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
4-(4-ethoxymethyl-5-phenyl-oxazol-2-yl)-piperidine (450 mg, 1.4 mmol), prepared as in Intermediate 4, and 2-[5-(2-chloro-ethyl)-2-methoxy-benzenesulfonylamino]-acetamide (644 mg), prepared as in Intermediate 6, LiBr (182 mg), and diisopropyl ethylamine (0.73 mL) in dioxane (15 mL) is stirred at 100° C. for 18 h. The solvent is evaporated and the residue purified by chromatography on silica using 3% MeOH:CHCl3 as eluent to afford the product as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(B(CC)[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)C.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(c1ccc(I)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: CCB(CC)c1cccnc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2cccnc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
1-(6-Chloronaphth-2-ylsulphonyl)-4-(4-iodobenzoyl)piperazine (920 mg, 1.7 mmol), diethyl 3-pyridylborane (250 mg, 1.7 mmol), tetrabutyl ammonium bromide (110 mg, 0.34 mmol), tetrakis(triphenylphosphine) palladium (0) (69 mg, 0.06 mmol) and potassium hydroxide (286 mg, 5.1 mmol) were refluxed in dry tetrahydrofuran (100 mL) for two hours under an atmosphere of nitrogen. The reaction mixture was allowed to cool to room temperature then concentrated in vacuo. The resulting solid was subjected to flash chromatography (SiO2: 100% CH2Cl2, 50% EtOAc/Hexane, 100% EtOAc) to yield an oil. The oil was dissolved in EtOAc (100 mL) and washed with saturated sodium hydrogen carbonate solution (100 mL). The EtOAc layer was separated, dried over MgSO4, filtered and concentrated in vacuo to yield an off white foam which was triturated with hexane. This solid was subjected to chromatography (SiO2: 40%, 50% 60%, 70% EtOAc/Hexane) to yield 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(3-pyridyl)benzoyl]piperazine as a white solid (322.4 mg); 1H NMR (DMSO-d6) δ=3.1 ppm (s,4H), δ=3.6 ppm (s,4H), δ=7.46 ppm (d,2H), δ=7.5 to 7.67 ppm (m,1H), δ=7.70 to 7.79 ppm (m,3H), δ=7.83 pmm (dd,1H), δ=8.09 ppm (dt,1H), δ=8.15 ppm to 8.31 ppm (m,3H), δ=8.50 ppm (s,1H), δ=8.60 ppm (dd,1H), δ=8.90 ppm (d,1H); MS (M+H)+ 492.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.[NH3:12].C(O)C.O>C(O)C>[NH2:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Solvent: CCO
Solvent: O
Product: Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of 2,6-dibromo-3-nitropyridine (5.00 g) in ethanol (10 ml) was added an ammonia/ethanol solution (6.8 M, 15 ml) at room temperature, and the mixture was placed in a closed reaction vessel and stirred at room temperature for 19 hr. To the reaction mixture was added water (25 ml), and the precipitate was collected by filtration. The precipitate was washed with ethanol, suspended in ethanol (55 ml), heated and cooled. The precipitate was collected by filtration to give the objective compound (3.19 g) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH3:11][Si:12]([CH3:21])([CH3:20])[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>O1CCCC1>[CH3:11][Si:12]([CH3:21])([CH3:20])[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:10])[F:1])=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCCC=C(F)F
Reactant: C[Si](C)(C)c1ccc(N)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(NC(=O)CCCC=C(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With cooling at 10°, 1.0 g of 6,6-difluorohex-5-enoic acid chloride is added to 1.0 g of 4-trimethylsilylaniline, 0.73 g of trithylamine and 10 mg of 4-N-pyrrolidinopyridine in 25 ml of tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and then concentrated by evaporation in vacuo. The residue is taken up in toluene, the toluene phase is washed with water, dried over sodium sulfate and concentrated to dryness by evaporation. The residue is taken up in hexane:ethyl acetate (9:1) and filtered over silica gel. Evaporation of the filtrate yields the title compound having a melting point of 50°-51° (compound no. 1-1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.[N:16]1[N:17]([CH:21]([CH3:26])[C:22](OC)=[O:23])[N:18]=[N:19][CH:20]=1.Cl>O1CCCC1.O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:22]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=2)([OH:23])[CH:21]([N:17]2[N:18]=[N:19][CH:20]=[N:16]2)[CH3:26])=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: COC(=O)C(C)n1ncnn1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(n1ncnn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of 4-trifluoromethoxybromobenzene (45.79 g) in dry tetrahydrofuran (200 cm3) was added carefully to a stirred mixture of magnesium turnings (4.56 g), iodine (1 crystal) and dry tetrahydrofuran (70 cm3). The reaction commenced after about 20 cm3 of the solution had been added, and the reaction was maintained at the reflux temperature whilst the remainder of the solution was added, and thereafter for a further 1 hour. The mixture was cooled to the ambient temperature and a solution of methyl 2-(1,2,3,4-2H-tetrazol-2-yl)propionate (13.95 g), in dry tetrahydrofuran (60 ml) added dropwise, after which the mixture was heated at the reflux temperature for 30 minutes. The mixture was cooled and poured into water (500 cm3) and acidified with 2N hydrochloric acid (250 cm3). The aqueous mixture was extracted with diethylether (3×400 cm3), the ethereal extracts combined, dried over anhydrous magnesium sulphate, and concentrated by removal of the solvent by evaporation under reduced pressure. The residual oil (30.5 g) was subjected to purification by chromatography using a silica gel column eluted with a mixture of hexane (4 parts by volume) and ethylacetate (1 part by volume), and by hplc to yield 1,1-bis(4-trifluoromethoxyphenyl)-2-(1,2,3,4-2H-tetrazol-2-yl)propan-1-ol as a colourless oil (10 g) which crystallized on standing (mp. 55°-58° C.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][CH2:30][C:3]1=2.[ClH:38]>ClCCl>[ClH:38].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)nc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)nc4=O)cc31)CNCCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H) carboxylate (25 mg, 0.068 mmol) in dichloromethane (4.0 mL) was added HCl (2M in diethyl ether, 4.0 mL). The resulting slurry was stirred at room temperature for 2 days and then concentrated under reduced pressure. The resulting residue was purified by semi-preparative HPLC. The clean fractions were combined and concentrated under reduced pressure. The resulting trifluoroacetate salt was treated with aqueous sodium carbonate and extracted with EtOAc (2×). The combined organic extract was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The free base was converted to its HCl salt using HCl in methanol and lypholized to provide the title compound (18.0 mg, 60%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.17 (d, J=6.5 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.32-7.26 (m, 4H), 7.22-7.18 (m, 1H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 6.64 (d, J=6.5 Hz, 1H), 4.56 (s, 2H), 3.79 (s, 3H), 3.60-3.57 (m, 2H), 3.27-3.20 (m, 2H), 3.14-3.06 (m, 4H), 2.23-2.18 (m, 2H); ESI MS m/z 399 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[N:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:39][CH3:40])[CH:32]=1.C(N(CC)CC)C>C(O)CO>[CH3:38][O:37][C:35]1[N:36]=[C:31]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:32]=[C:33]([O:39][CH3:40])[N:34]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: COc1cc(Cl)nc(OC)n1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: COc1cc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)nc(OC)n1
Temperature: 100 °C
Yield: 43.2 %

Procedure:
A mixture of 3.70 g (0.00924 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 1.61 g (0.00924 mol) of 6-chloro-2,4-dimethoxypyrimidine, 1.29 ml (0.00924 mol) of triethylamine and 125 ml of ethylene glycol is heated at 100° C. for 6 hours. After cooling, the precipitated solid is collected on a sintered glass funnel and dried in the air over the weekend. The solid is chromatographed on silica gel, eluting with 6% methanol/methylene chloride, to give 2.15 g (43%) of 1-(2,6-dimethoxy-4-pyrimidinyl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 260°-262° C., after crystallization from methanol/methylene chloride.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C:6]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[N:26]1([C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:8]2[C:6]3[CH2:7][C@H:2]([NH:1][S:38]([C:35]4[CH:34]=[CH:33][C:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:37][CH:36]=4)(=[O:39])=[O:40])[CH2:3][O:4][C:5]=3[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NS(=O)(=O)c2ccc(N4CCOCC4)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (120 mg, 0.485 mmol) in anhydrous methylene chloride (10 mL) were added triethylamine (81 μL, 0.582 mmol) and 4-(4-morpholinyl)benzenesulfonyl chloride (140 mg, 0.534 mmol; described in: Galliani, G. Eur. Pat. Appl. EP 335,758, 1989, Chem. Abstr. 1990, 112, 98374d [125393-22-8]). The reaction mixture was stirred at room temperature for 4 h, washed with a 2 M NH3 solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica (eluent: chloroform/ethanol, 90:10+0.5% conc. NH3) affording 141 mg (61% yield) of the title compound as a white solid: mp sinters>100° C.; [α]22D+10° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 472 (56, M30 ).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]([F:51])([F:50])[F:49])[CH:42]=3)=[CH:37][CH:36]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]([F:51])([F:49])[F:50])[CH:42]=3)=[CH:37][CH:36]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3cccc(OC(F)(F)F)c3)cc2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3cccc(OC(F)(F)F)c3)cc2)cn1
Temperature: 25 °C

Procedure:
A 4M HCl solution in 1,4-dioxane (3 mL, 12 mmol) was added to a tert-butyl 3-(5-(5-chloro-2-(((3′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (49 mg, 0.08 mmol) and the resulting mixture was stirred at room temperature. After 1.5 h the resulting mixture was concentrated in vacuo, triturated with MeOH (0.5 mL) and diethyl ether (5 mL), and filtered to yield the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:15][CH2:14][C:13]2([CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16]2)[CH2:12]1.Cl.N1CCC2(CC3C=CC=CC=3O2)C1.C(N(CC)CC)C>C(Cl)(Cl)Cl.O>[C:1]1([CH2:7][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[O:16]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CC1(CCNC1)O2
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)N1CCC2(Cc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.0 g of phenylacetyl chloride in 10 ml of chloroform is added dropwise to a stirred solution of 4.0 g of 2,3-dihydrospiro[benzofuran-2,3'-pyrrolidine], free base of Example 8, and 3 ml of triethylamine in 40 ml of chloroform. After total addition, the reaction mixture is stirred successively at ambient temperature for 18 hours and at reflux for 3 hours and then permitted to cool to ambient temperature before being poured into 100 ml of water. The organic layer is collected and then washed sequentially with dilute acid, dilute base, a saturated sodium chloride solution and dried. Thereafter, the solvent is evaporated off, leaving a dark oil which is chromatographed through a silica gel column with a 5% methyl alcohol in chloroform eluant, leaving a light yellow oil. This oil is triturated with boiling hexane, the triturant is decanted and allowed to cool, which causes a precipitate to appear. The precipitate is collected and recrystallized twice from hexane to give the pure product, 2,3-dihydro-1'-(phenylacetyl)spiro[benzofuran-2,3'-pyrrolidine], mp 98°-99° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:2]=1.Cl.[CH3:18][C:19]([CH3:21])=O>>[CH2:21]([N:10]([CH2:9][CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH:19]=[CH2:18]
Reactant: O=C(NCC=Cc1cccnc1)C(F)(F)F
Reactant: CC(C)=O
Agent: Cl
Product: C=CCN(CC=Cc1cccnc1)C(=O)C(F)(F)F
Yield: 42 %

Procedure:
14.0 g (51.8 mmol) of N-allyl-N-[3-(3-pyridyl)[-allyl]-2,2,2-trifluoroacetamide were dissolved in 1.40 ml of acetone, and 30 ml of 10% strength aqueous hydrochloric acid were added and the mixture was irradiated under nitrogen in a boro-silicate glass apparatus at room temperature with a 150 watt high-pressure mercury lamp for 48 h. The reaction solution was then concentrated, taken up in 150 ml of water and adjusted to pH 8-9 with aqueous ammonia solution. The aqueous phase was extracted twice with tert-butyl methyl ether, and the combined organic phases were dried over sodium sulfate and concentrated. The residue was fractionated by column chromatography (silica gel, methylene chloride+2% methanol) to yield 6.2 g (42%) of unchanged N-allyl-N-[3- (3-pyridyl)allyl]-2,2,2-trifluoroacetamide and 3.7 g (26%) of 2,2,2-trifluoro-1-[exo-6-(3-pyridyl) -3-azabicyclo[3.2.0]hept-3-yl]ethanone as a dark oil.