Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.CC[N:23]([CH:27]([CH3:29])C)[CH:24]([CH3:26])C.[OH2:30]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:26][C@H:29]([OH:30])[CH2:27]2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(Cl)nc32)cc1
Reactant: O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5,7-Dichloro-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 109, b) (2.95 g), (S)-pyrrolidinol (1.82 g, 20.9 mmol) and DIPEA (9.83 g, 76.1 mmol) in DCM was stirred at room temperature for 30 min. The mixture was poured into water, extracted with DCM and the combined organic layers were dried with MgSO4, filtered and evaporated to yield the crude title compound which was used in the consecutive step without further purification. MS (m/e): 361.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])C=O>N1CCCCC1>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:21]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C=O)cc1OC
Solvent: C1CCNCC1
Product: COc1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1OC
Yield: 33.6 %

Procedure:
The title compound was prepared from p-nitrophenylacetic acid (25.0 g, 0.14 mol), and 3,4-dimethoxybenzaldehyde (21.0 g, 0.14 mol) in piperidine (5 mL) using the procedure described in Example 1, Step A, to yield a yellow solid, 13.4 g (0.047 mol, 34%) of the desired product. mp: 133-134° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:36]=[CH:35][C:17]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH:27]C(=O)OC(C)(C)C)=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[C:4]([CH3:37])=[N:3]1.Cl.[OH-].[Na+]>O1CCOCC1.O.C(OCC)C>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[C:17]1[CH:35]=[CH:36][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[C:4]([CH3:37])=[N:3][N:2]([CH3:1])[CH:6]=3)[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
tert-Butyl (2-{[4-(1-{1,3-dimethyl-1H-pyrazol-4-ylmethyl}piperidin-4-yl)benzoyl]amino}phenyl)carbamate (prepared as described in Method 6 below; 7.61 g, 15.11 mmol) was dissolved in 1,4 dioxane (70 ml) and cooled to 0° C., using an ice-water bath. A 4M solution of hydrogen chloride in 1,4 dioxane (150 ml, 600 mmol) was then added slowly. The resultant suspension was allowed to warm to room temperature and lumps broken up by agitation with a glass rod. The reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered, under suction. The solid obtained was dissolved in water (200 ml), and the solution adjusted to pH 12 by slow addition of a 2M aqueous solution of sodium hydroxide. The mixture obtained was extracted with dichloromethane (300 ml) and the organics separated. The aqueous phase was further extracted with dichloromethane (200 ml) and the combined extracts washed with brine, dried over magnesium sulphate, filtered and evaporated to give a clear gum. The gum was taken up in diethyl ether and re-evaporated to dryness to afford the title compound (5.69 g, 93%); NMR Spectrum (CDCl3) δ 1.81 (m, 4H), 2.07 (m, 2H), 2.25 (s, 3H), 2.56 (m, 1H), 3.04 (m, 2H), 3.39 (s, 2H), 3.81 (s, 3H), 3.85 (s, 2H), 6.84 (m, 2H), 7.08 (m, 1H), 7.24 (s, 1H), 7.33 (m, 3H), 7.82 (m, 3H).
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH2:16][O:17]C(C=C)=O)([CH2:10][O:11]C(C=C)=O)[CH2:4][O:5][C:6]([CH:8]=[CH2:9])=[O:7].C(S)(=S)C1C=CC=CC=1>C(Cl)Cl>[C:6]([OH:7])(=[O:5])[CH:8]=[CH2:9].[C:6]([OH:7])(=[O:5])[CH:8]=[CH2:9].[C:6]([OH:7])(=[O:5])[CH:8]=[CH2:9].[CH2:4]([C:3]([CH2:16][OH:17])([CH2:10][OH:11])[CH2:2][CH3:1])[OH:5]
Reactant: C=CC(=O)OCC(CC)(COC(=O)C=C)COC(=O)C=C
Agent: S=C(S)c1ccccc1
Solvent: ClCCl
Product: C=CC(=O)O
Product: CCC(CO)(CO)CO
Temperature: 25 °C

Procedure:
Trimethylolpropane triacrylate was purified by passing it trough a pipette packed with hydroquinone inhibitor remover (Sigma-Aldrich cat. no. 311332) and then through a pipette filled with activated alumina. TMPTA (2.03 g, 6.8 mmol) and an excess of freshly prepared dithiobenzoic acid (6.97 g, 45.3 mmol) were dissolved in 40 mL of methylene chloride. The pink solution was allowed to reflux for 6 hours. The solution was cooled to room temperature and the solvent was evaporated off under vacuum. The dark red crude material was dry mounted on a silica column and eluted with a 10% ether:hexanes solution. A purple band and then a pink band were eluted. After all the pink compound was removed, the product began to elute as an orange band. The mobile phase was changed to 50% ether:hexanes and the product was collected. The solvent was removed under vacuum to give the product as a viscous red oil. This material was stored in the freezer at 0° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10](S(C)=O)[N:9]=[C:8]([NH2:15])[N:7]=1.[OH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:9]=[C:8]([NH2:15])[N:7]=1
Reactant: CS(=O)c1cc(-c2ccco2)nc(N)n1
Reactant: OCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OCCc2ccccn2)cc(-c2ccco2)n1
Temperature: 100 °C
Yield: 34.8 %

Procedure:
To a stirred suspension of 500 mg (2.24 mmol) 4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine in 20 ml DME was added 0.50 ml (4.48 mmol) 2-(2-hydroxyethyl)pyridine and 0.84 ml (5.60 mmol) DBU and the mixture heated at 100° C. for 72 hours. The reaction mixture was then cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in ether afforded 220 mg (35%) 4-furan-2-yl-6-(2-pyridin-2-yl-ethoxy)-pyrimidin-2-ylamine as a white crystalline solid. ES-MS m/e (%): 283 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32]#[N:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34].[ClH:35].[NH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C>[Cl:35][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32](=[NH:33])[NH:36][OH:37])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34]
Reactant: Cc1cc(C#N)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Reactant: NO
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C(=N)NO)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)phenyl]-5-cyano-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.13 g) in ethanol (4 mL) were added hydroxylamine hydrochloride (91 mg) and potassium carbonate (0.2 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=4/1), and collected by filtration. The collected solids were dried under reduced pressure to give the title compound (0.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]2[C:39]3[C:31](=[C:32]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]([C:40]([O:42]C)=[O:41])[CH2:33]4)[CH:30]=[CH:29]2)=[O:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[CH2:13])[CH:11]=[CH2:12])=[CH:5][CH:4]=1.C1COCC1.[Li+].[OH-]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]2[C:39]3[C:31](=[C:32]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]([C:40]([OH:42])=[O:41])[CH2:33]4)[CH:30]=[CH:29]2)=[O:27])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10](=[CH2:13])[CH:11]=[CH2:12])=[CH:5][CH:4]=1
Reactant: C=CC(=C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)OC)C3)(c1ccccc1)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(=C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)O)C3)(c1ccccc1)c1ccc(OC)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of 8 (0.47 g, 0.78 mmol), THF (9 ml), MeOH (6 ml) and 4M LiOH (3 ml) was stirred at 55° C. for 1 h. The resultant solution was cooled to give a white precipitate, the Li salt of the product. The solid was triturated with a small amount of cold 10% citric acid and filtered off. Washing with water and drying under vacuum gave 0.43 g (94%) of 9 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>CCCCCCC.CCOC(C)=O>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: COc1ccc2c(c1)NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(CCCCl)C(=O)CO2
Yield: 42.1 %

Procedure:
6-Methoxy-4H-benzo[1,4]oxazin-3-one (81MF2249a) (0.212 g, 1.18 mmol), Cs2CO3 (0.578 g, 1.77 mmol) and 3-chloro-1-iodopropane (0.265 g, 1.3 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 10:1-2) gave the title compound (81MF2249b) (0.127 g, 42%). 1H-NMR (CDCl3) δ 6.88 (d, J=8.8 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.50 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 4.50 (s, 2H), 4.05-4.01 (m, 2H), 3.76 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 2.16-2.09 (m, 2H); 13C NMR (CDCl3) δ 164.8, 155.5, 139.3, 129.2, 117.4, 107.8, 101.9, 67.8, 55.8, 42.4, 38.9, 30.0.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[CH:13]1.Cl>O>[CH3:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH:13]1[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S([O-])c1ccccc1
Reactant: CC1C=CC(=O)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1CCC(=O)CC1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium benzenesulfinate (3.0 g) was added to a solution containing 1.52 g of 4-methyl-2-cyclohexen-1-one and 9 ml of water. 1N Hydrochloric acid (18 ml) was added dropwise to the resulting solution. After stirring at room temperature for 24 hours, the crystals so precipitated were filtered and washed with water, isopropanol and cold ether. After recrystallization from isopropanol, 4-methyl-3-(phenylsulfonyl)-cyclohexan-1-one was obtained in the form of white crystals (yield: 72%).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][N:4]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[C:32]([F:35])([F:34])[F:33])[CH2:3]1.[N-:36]=[N+:37]=[N-:38].[Na+]>C1(C)C=CC=CC=1>[F:19][C:18]([F:21])([F:20])[C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:8]([N:7]2[CH2:6][CH2:5][N:4]([C:24]3[CH:31]=[CH:30][C:27]([C:28]4[NH:38][N:37]=[N:36][N:29]=4)=[CH:26][C:25]=3[C:32]([F:35])([F:33])[F:34])[CH2:3][C@H:2]2[CH3:1])(=[O:9])=[O:10])[CH:12]=1)([OH:23])[CH3:22]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C(C)(O)C(F)(F)F)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(-c3nnn[nH]3)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C(C)(O)C(F)(F)F)c1
Temperature: 100 °C

Procedure:
The compound of Example 29U, 4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]sulfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile, was used as starting material to make the title compound. A mixture of 4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]sulfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile (300 mg, 0.58 mmol), NaN3 (112.5 mg, 1.73 mmol), Et3NHCl (238.1 mg, 1.73 mmol) were charged to a microwave vial. Toluene (3 mL) was introduced under nitrogen atmosphere and the reaction mixture was heated at 100° C. over night in an oil bath. Reaction was complete as determined by TLC. Reaction mixtures was diluted with EtoAc, washed with 10% HCl until pH=6-7. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified via prep HPLC under acidic condition to yield 1,1,1-trifluoro-2-[3-({(2R)-2-methyl-4-[4-(1H-tetrazol-5-yl)-2-(trifluoromethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white solid (111.2 mg, 34.3 yield %). HRMS: calcd for C22H22F6N6O3S+H+, 565.14510. found (ESI-FTMS, [M+H]1+), 565.14524.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2ccc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A suspension of sodium hydride (60% oil dispersion, 112 mg, 2.81 mmol) in THF (12 mL) was stirred at rt and treated with a solution of 4-bromo-1H-indole (500 mg, 2.55 mmol) in THF (3 mL). After 1-2 min, the mixture was treated with 4-fluorobenzyl bromide (0.318 mL, 2.55 mmol) and the slightly cloudy solution was stirred at rt. After 20 h, the mixture was concentrated. The residue was partitioned between EtOAc and 0.1 M hydrochloric acid, and the aqueous phase was again extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) to provide 4-bromo-1-(4-fluorobenzyl)-1H-indole as a colorless oil (461.4 mg, 85% purity, 51%) contaminated by ca. 15% by weight of 4-bromo-1,3-bis(4-fluorobenzyl)-1H-indole. 1H NMR (400 MHz, chloroform-d) δ 7.28 (1H, dd, J=7.6, 0.8 Hz), 7.19 (1H, d, J=8.4 Hz), 7.16 (1H, d, J=3.3 Hz), 6.94-7.09 (5H, m), 6.60 (1H, dd, J=3.1, 0.9 Hz), 5.28 (2H, s). Mass spectrum m/z 304, 306 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:21]1[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: N#Cc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C#N)n2)cc1
Yield: 44.8 %

Procedure:
Using a method similar to Example 381 Part A, using [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (0.140 g, 0.588 mmol), NaH (80% in mineral oil) (0.194 g. 0.647 mmol) and 6-bromopyridine-2-carbonitrile (0.107 g, 0.588 mmol) gives the title compound (0.0895 g, 44.8%): MS ES+ 340.2 (M+H)+, base peak MS ES+ 284.0 (M+2H—C(CH3)3)+, MS ES− 338.3 (M−H)−; TLC [silica gel 60 F254, 40% ethyl acetate in hexanes] Rf=0.24.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:11]=2[CH:12]=1
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)cc(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3cc(Cl)cc(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 90 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) was added to a solution of tert-butyl 8,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.30 g, 0.84 mmol) in DMF (5 mL). After 25 min, β-bromophenetole was added (0.23 mL). The reaction was quenched with saturated aqueous NH4Cl after 18 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (9:1) to give 0.36 g (90%) of a white solid: mp 131.5-133.0° C.; 1H NMR (300 MHz, CDCl3) δ 7.04 (d, J=1.7 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 6.77 (m, 2H), 4.41 (m, 2H), 4.16 (m, 2H), 3.76 (m, 2H), 3.65 (m, 2H), 3.45 (m, 2H), 3.11 (m, 2H), 1.48 (s, 9H); IR (diffuse reflectance) 2974, 2929, 1691, 1600, 1496, 1459, 1413, 1393, 1365, 1348, 1303, 1243, 1170, 1114, 754 cm−1; MS (EI) m/z 474 (M+), 420, 419, 418, 417, 344, 334, 332, 57, 56; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.19; H, 5.99; N, 5.89.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:19](Cl)(=O)/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[N:4]1[C:3]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:2]=2[N:1]=[C:19]1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 2-amino-N-(2-pyridyl)-4-trifluoromethylaniline and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[S:6](Cl)([CH3:9])(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[F:1][CH:2]([F:5])[CH2:3][O:4][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 2,2-difluoro-ethanol (6 g, 73.12 mmol) and mesyl chloride (6.26 ml, 80.43 mmol) in CH2Cl2 (40 ml) was added triethylamine (12.66 ml, 87.74 mmol) dropwise at 0° C. After the addition was completed, the mixture was allowed to warm to room temperature and was stirred for 1 h. The reaction mixture was then washed two times with water and with brine and dried with Na2SO4. Evaporation of the solvent yielded the title compound (10.7 g, 92%) as yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][C:12]([CH:14]2[CH2:18]CO[CH2:15]2)=[O:13])=[O:10])[CH:5]=[CH:4][C:3]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:21]=1.[C:32](Cl)(=O)C(Cl)=O.N1C=CC=CC=1.Cl[CH2:45][CH2:46]Cl>C1COCC1>[CH3:32][C:45]1([CH3:46])[CH2:15][CH:14]([C:12]([NH:11][C:9](=[O:10])[NH:8][C:6]2[CH:5]=[CH:4][C:3]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:21]=3)=[C:2]([CH3:1])[N:7]=2)=[O:13])[CH2:18]1
Reactant: ClCCCl
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(NC(=O)NC(=O)C2CCOC2)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)NC(=O)C2CC(C)(C)C2)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 83 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A suspension of Example B (0.054 g, 0.427 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.037 mL, 0.427 mmol), heated at 83° C. for 2 h, cooled to RT and added drop-wise to a solution of Example A6 (0.1 g, 0.355 mmol) in THF (4 mL) and pyridine (0.144 mL, 1.777 mmol). The mixture was stirred at RT for 2 h, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over MgSO4, concentrated to dryness, triturated with MeCN, and the solid collected via filtration and dried to afford 3,3-dimethyl-N-((6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclobutanecarboxamide (134 mg, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 10.69 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.24 (m, 1H), 2.26 (s, 3H), 2.02-1.87 (m, 4H), 1.13 (s, 3H), 1.05 (s, 3H); MS (ESI) m/z: 435.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH:7]([C:9]1[N:14]=[N:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:11][CH:10]=1)[CH3:8])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]1[N:14]2[C:9]([CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:13]2)=[C:7]([CH3:8])[N:6]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3F)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccccc4F)n3n2)cc1
Yield: 37.1 %

Procedure:
Applying the Cyclization Procedure 1, using 2-fluoro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 64) (100 mg, 0.27 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 7-(2-fluorophenyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (35 mg) as a yellow solid. MS m/z 350 (M+1).
Reaction SMILES: ClCC[C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][N:13]([CH3:14])[C:7]2=[N:6][C:5]=1[CH3:15].C([O:18]CCN1C2=NC=CC=C2N=C1CN1CCNCC1)C.[C:37](=[O:40])([O-:39])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[C:9]([OH:10])(=[O:18])/[CH:4]=[CH:5]/[C:37]([OH:39])=[O:40].[CH3:14][N:13]1[C:7]2=[N:6][C:5]([CH3:15])=[CH:4][C:9](=[O:10])[N:8]2[CH:11]=[CH:12]1
Reactant: CCOCCn1c(CN2CCNCC2)nc2cccnc21
Reactant: Cc1nc2n(C)ccn2c(=O)c1CCCl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cc1cc(=O)n2ccn(C)c2n1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 44 h

Procedure:
A mixture of 2.7 parts of 6-(2-chloroethyl)-1,7-dimethyl-1H,5H-imidazo[1,2-a]pyrimidin-5-one, 2.9 parts of 3-(2-ethoxyethyl)-2-(1-piperazinylmethyl)-3H-imidazo[4,5-b]pyridine, 1.06 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone was stirred first for 44 hours at reflux temperature and then over weekend at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extracted was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the (E)2-butenedioate salt in 2-propanol. The salt was filtered off and dried, yielding 3.36 parts (47.3%) of 6-[2-[4-[3-(3-ethoxyethyl)-3H-imidazo[4,5-b]-pyridin-2-yl]methyl]1-piperazinyl]ethyl]1,7-dimethyl-1H,5H-imidazo[1,2 a]pyrimidin-5-one (E)-2-butenedioate(1:2); mp. 162.5° C. (compound 81).