Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:68][CH2:69][C@H:70]1[O:74][C:73](=[O:75])[NH:72][C@@H:71]1[C:76]1[CH:81]=[CH:80][C:79]([F:82])=[C:78]([F:83])[CH:77]=1>ClCCl.C(=O)(O)[O-].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:22])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:68][CH2:69][C@H:70]4[O:74][C:73](=[O:75])[NH:72][C@@H:71]4[C:76]4[CH:81]=[CH:80][C:79]([F:82])=[C:78]([F:83])[CH:77]=4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: NC[C@H]1OC(=O)N[C@@H]1c1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4OC(=O)N[C@@H]4c4ccc(F)c(F)c4)cc3)oc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
A suspension of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2, 67 mg, 0.219 mmol), o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (166 mg, 0.438 mmol), 1-hydroxybenzotriazole hydrate (50 mg, 0.327 mmol), and diisopropylethylamine (0.2 ml, 1.145 mmol) in dichloromethane (1 ml) was stirred for 5 min at room temperature, and then a solution of (4R,5R)-5-(aminomethyl)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one in dichloromethane (1 ml) was added. The mixture was stirred overnight at 25° C. The mixture was diluted with 10 ml of saturated sodium bicarbonate solution and 10 ml of dichloromethane. The phases were separated and the aqueous phase was extracted with 2×10 ml of dichloromethane. The combined organics were washed with 10 ml of brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes, to provide the title compound (51 mg, 0.099 mmol, 45.1% yield). Mass spectrum (ESI) 517.2 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.36 (d, J=8.5 Hz, 2H), 8.05 (d, J=8.5 Hz, 2H), 7.95 (s, 1H), 7.52 (s, 1H), 7.35 (m, 1H), 7.23 (m, 2H), 6.02 (s, 1H), 4.79 (d, J=7.5 Hz, 1H), 4.48 (m, 1H), 3.05 (m, 1H), 3.83 (m, 1H), 3.49 (m, 2H), 1.47 (d, J=7.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:19])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1.C(Cl)Cl.C(N)CN>[CH3:19][C:13]1[C:12]([C:9]2[C:8]3[N:7]=[CH:6][CH:5]=[N:4][C:3]=3[C:2]([C:20]#[N:21])=[CH:11][CH:10]=2)=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=1
Reactant: Cc1cnc(C)c(-c2ccc(Br)c3nccnc23)c1
Reactant: N#C[Cu]
Solvent: NCCN
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1cnc(C)c(-c2ccc(C#N)c3nccnc23)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
A mixture of 5-bromo-8-(2,5-dimethyl-pyridin-3-yl)-quinoxaline (Step 99.4) (189 mg, 0.60 mmol) and CuCN (70 mg, 0.78 mmol, 1.3 equiv) in NMP (2 mL) was stirred for 6 h at 160° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with DCM/10% aqueous solution of ethylenediamine (25 mL), extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 150 mg of the title compound as a yellow solid. Title compound: ESI-MS: 261.2 [M+H]+; tR=1.92 min (System 1); TLC: Rf=0.68 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([N:9]3[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]3)=[C:7]([N+:23]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C([O-])=O.[NH4+].[Br:30][C:31]1[S:32][C:33]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:34]([C:36](O)=[O:37])[N:35]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.[Pd].O>[Br:30][C:31]1[S:32][C:33]([NH:39][C:40](=[O:41])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[C:34]([C:36](=[O:37])[NH:23][C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[N:9]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]2)[N:35]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2C2CC2)CC1)C(F)(F)F
Agent: [Pd]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(C2CC2)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of (R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide (0.725 g, 2.00 mmol) in MeOH (20 mL) was added 10% palladium on carbon (0.75 g, 7.07 mmol) and ammonium formate (0.507 g, 8.03 mmol). The mixture was heated at 80° C. for 3 hr. The mixture was filtered through Celite® and the filtrate concentrated under reduced pressure. The residue was re-dissolved in DCM (20 mL) and 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (0.74 g, 2.29 mmol), PyBOP (1.57 g, 3.01 mmol) and DIPEA (1 mL, 5.6 mmol) were added. The reaction mixture was stirred at room temperature for 18 hr. Water (20 mL) was added and stirring continued for 10 min. The layers were separated and the aqueous extracted with DCM (2×20 mL). The combined organic layers were passed through a phase separation cartridge and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to afford (R)-tert-butyl 2-bromo-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a pale brown solid (0.98 g, 77% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.43 (s, 1H), 7.71 (s, 1H), 6.47 (d, J=8.3 Hz, 1H), 4.25-4.15 (m, 1H), 3.47-3.35 (m, 3H), 3.29-3.13 (m, 2H), 2.46-1.57 (m, 6H), 1.52 (s, 9H), 1.23-1.17 (m, 2H), 1.12-0.96 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]12[CH2:11][CH2:10][N:7]([CH2:8][CH2:9]1)[CH2:6][C:5]2=[O:12])[CH:2]=[CH2:3].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:4]12[CH2:9][CH2:8][N:7]([CH2:10][CH2:11]1)[C:6](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:12])[CH:2]=[CH2:3]
Reactant: O=Cc1ccccc1
Reactant: C=CCC12CCN(CC1)CC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCC12CCN(CC1)C(=Cc1ccccc1)C2=O
Yield: 98 %

Procedure:
4-Allyl-1-azabicyclo[2.2.2]octan-3-one, 57 (17.66 g, 107 mmol), benzaldehyde (12.49 g, 117 mmol) and sodium hydroxide (0.46 g, 11.5 mmol) were dissolved in 80 ml of ethanol, and the resultant mixture was heated at reflux for 1 hour. After the mixture was cooled down, yellow solids were collected to provide 4-allyl-2-benzylidene-1-azabicyclo[2.2.2]octane-3-one (26.66 g, 98%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>C(Cl)Cl.CO>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCN(c2ncc(N)cn2)CC1
Reaction time: 1.5 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 33.1 but using 2-(4-isopropyl-piperazin-1-yl)-5-nitro-pyrimidine (Step 35.2) and stirring the reaction mixture for 1.5 h. The title compound: ESI-MS: 222.1 [M+H]+; TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:39]1[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[N:40]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([CH3:36])([CH3:37])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[N:40]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nccc(Cl)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Product: Cc1nccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)C#N)(c4ccc(F)cc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 4-chloro-2-methylpyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 1 tR=1.55, m/z=473 (M+1); 1H NMR (CDCl3) 8.96 (s, 1H), 7.98 (d, 2H), 7.84 (s, 1H), 7.29 (m, 2H), 7.10 (m, 4H), 5.72 (d, 1H), 3.05 (d, 1H), 2.97 (s, 3H), 2.91 (m, 1H), 2.51 (d, 1H), 1.61 (d, 3H), 1.38 (d, 3H), 1.27 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([OH:27])=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:41][C@@H:42]([C:46]([NH2:48])=[O:47])[CH:43]([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:48][C:46]([C@H:42]([NH:41][C:25]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:12][CH2:13]2)=[C:2]([Cl:1])[CH:3]=1)=[O:27])[CH:43]([CH3:45])[CH3:44])=[O:47]
Reactant: CC(C)[C@@H](N)C(N)=O
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)[C@@H](NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
The product of step (i) (0.14 g) was dissolved in 1-methyl-2-pyrrolidinone (4 ml) and to this solution was added carbonyldiimidazole (0.064 g) the mixture was stirred at room temperature for 1 h and then treated with D-valinamide hydrochloride (0.11 g) and N,N-diisopropylethylamine (0.10 g). After stirring for 18 h at room temperature the mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate, the organic layer was washed with water, dried and evaporated under reduced pressure. The resultant solid was washed with ethyl acetate to yield 0.06 g of product.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31].C(=O)([O-])[O-].[Cs+].[Cs+]>>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:3]1[C:4]2=[N:9][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:7][C:6](=[O:16])[N:5]2[CH2:17][C@@:2]1([CH3:1])[C:18]([F:21])([F:19])[F:20]
Reactant: Fc1cccc(CBr)c1F
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1Cc1cccc(F)c1F

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 82 mg of 1-(bromomethyl)-2,3-difluorobenzene, replacing the sodium hydride with 214 mg of caesium carbonate. After purification by preparative HPLC/MS (method C), 90 mg of (2S)-1-(2,3-difluorobenzyl)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one are obtained in the form of a white semi-solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9]([O:11]CC)=O)(=[O:3])[NH2:2].[NH2:17][CH2:18][CH:19]([OH:31])[CH2:20][N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1>CCO>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[CH2:20][CH:19]([OH:31])[CH2:18][NH:17][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[C:4]([CH:16]=[CH:15][CH:14]=1)[C:1]([NH2:2])=[O:3]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc(C(N)=O)c1
Solvent: CCO
Product: NC(=O)c1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
To a stirred mixture of ethyl 2-(3-carbamoylphenoxy)acetate (150 mg, 0.673 mmol) in EtOH (1 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (138.6 mg, 0.673 mmol). The mixture was stirred at 120° C. for 0.5 hour under mediated heating. After evaporation of the solvent, the residue was purified by prep-HPLC to afford the desired title product (64 mg, Yield 25%). 1H NMR (400 MHz, MeOD) δ 7.53 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.39 (dd, J1=J2=7.9 Hz, 1H), 7.12-7.00 (m, 5H), 4.60 (s, 2H), 4.04-4.01 (m, 1H), 3.74-3.65 (m, 2H), 3.47-3.39 (m, 2H), 2.95-2.87 (m, 2H), 2.85-2.77 (m, 2H), 2.58 (d, J=6.0 Hz, 2H). LCMS (m/z): 384.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][C:29]=3[S:36](=[O:48])(=[O:47])[NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]>[Pt]=O.C(OCC)(=O)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([Cl:19])=[C:10]([N:8]2[C:7](=[O:20])[N:6]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][C:29]=4[S:36](=[O:47])(=[O:48])[NH:37][C:38](=[O:46])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[Cl:45])=[CH:26][CH:27]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9]2)[CH:15]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reaction time: 24 h
Yield: 62.5 %

Procedure:
A mixture of 135 mg (0.191 mmole) of 5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]-5'-ethylbiphenyl-4-yl]methyl]-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C), 10 mg of platinum oxide, and 2 mL of ethyl acetate was stirred under an atmosphere of hydrogen (balloon) for 1 day and then then filtered through Celite. The crude product was chromatographed on a column of silica gel (gradient elution with 0.5-4% MeOH in CH2Cl2) to give 81 mg (63%) of the title compound; homogeneous by TLC in 9:1CH2Cl2 --MeOH; m/e 678 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:31]([CH2:30][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=CCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(CC3CCOCC3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (250 mg, 0.808 mmol) in dimethylformamide (3 mL) was added (4-tetrahydropyranyl)acetaldehyde (114 mg, 0.889 mmol) and oxone (323 mg, 0.525 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (197 mg, 58% yield) as light brown crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[C:15]1=O)([O-])=O.[H][H]>[Pd].C(O)(=O)C>[F:13][C:10]([F:12])([F:11])[C:8]1[CH:7]=[CH:6][C:5]2[N:14]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][C:20]5[C:21]4=[C:16]([CH:17]=[CH:18][CH:19]=5)[C:15]3=[N:1][C:4]=2[CH:9]=1
Reactant: [H][H]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1c2cccc3cccc(c32)c2nc3cc(C(F)(F)F)ccc3n12
Reaction time: 1.5 h
Yield: 59 %

Procedure:
2-[2-nitro-4-(trifluoromethyl)phenyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, 134.3 g. (0.347 m.), was hydrogenated at 55° C. in 600 ml. of glacial acetic acid with 15 g. of palladium-on-carbon (5 percent) at 60 psi. The temperature rose to about 100° C., and after 1.5 hours, three equivalents of hydrogen were absorbed with the temperature returning to room temperature. The reaction mixture was heated to boiling and filtered to remove the catalyst. Upon cooling, the precipitated product was collected and washed with 2B ethanol. Recrystallization from N,N-dimethylformamide yielded about 69.2 g. (59 percent yield) of 11-(trifluoromethyl)-7H-benzimidazo[2,1-a]benz[de]isoquinoline-7-one, m.p. about 212°-214° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=1.[ClH:13]>COC(=O)C>[Cl:13][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: Cl
Reactant: COC(=O)c1ccnc(CO)c1
Solvent: COC(C)=O
Product: COC(=O)c1ccnc(CCl)c1
Reaction time: 3 h

Procedure:
A solution of the product of stage (ii) in methylacetate (5 ml) was treated with ethereal hydrogen chloride (5 ml). The resulting solid was collected by filtration and added to thionyl chloride (7.5 ml) at 0°-5°. The mixture was stirred at 0°-5° for 3 h and then at ambient temperature for 1 h. Diethyl ether (100 ml) was added and the resulting solid was collected by filtration and washed with diethylether (2×50 ml), to give the title compound as a solid (1.7 g) T.l.c. Silica dichloromethane/methanol/ammonia 75:10:2 Rf 0.8.
Reaction SMILES: [CH2:1]([C:4]1([CH2:18][CH:19]=[CH2:20])[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]1=[O:17])C=C>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[O:17]=[C:5]1[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][CH2:9][C:4]21[CH2:1][CH:20]=[CH:19][CH2:18]2
Reactant: C=CCC1(CC=C)CCCN(C(=O)OC(C)(C)C)C1=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CC=CC2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of tert-butyl 3,3-diallyl-2-oxopiperidine-1-carboxylate (4.74 g, 16.9 mmol) in dichloromethane (20 mL) was added Grubbs first generation catalyst (711 mg, 0.85 mmol). The reaction mixture was stirred at rt for 4 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/9) to give the title compound as a white solid (3.61 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=O)[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]#[N:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C#N
Yield: 84.2 %

Procedure:
The title product of Example 10 (10.81 g, 50.45 mmol) and cyanuric chloride (5.58 g, 30.3 mmol) was stirred in DMF (30 mL) for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic extracts were washed with aq. sodium carbonate, water, brine dried over sodium sulphate, filtered and concentrated to afford the title product (8.34 g, 84%) as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([O:27][CH:28]([F:30])[F:29])[C:8]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[C:9]([F:14])[CH:10]=2)[N:5]([CH2:31][CH3:32])[CH:4]=1)#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.Cl>C1(C)C(C)=CC=CC=1>[CH2:31]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:14])=[C:8]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[N:22]=[CH:23][CH:24]=[CH:25][N:26]=4)[CH2:19][CH2:20]3)[C:7]=2[O:27][CH:28]([F:30])[F:29])[C:12](=[O:13])[C:3]([C:1]2[NH:35][N:34]=[N:33][N:2]=2)=[CH:4]1)[CH3:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1cc(C#N)c(=O)c2cc(F)c(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCn1cc(-c2nnn[nH]2)c(=O)c2cc(F)c(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21
Temperature: 25 °C
Yield: 69 %

Procedure:
To 25 ml of xylene were added 0.5 g (0.0011 mole) of 3-cyano-1-ethyl-6-fluoro-8-difluoromethoxy-7-[4-(2-pyrimidinyl)piperazin-1-yl]-1,4-dihydro-4-oxoquinoline obtained as described above, 0.21 g of (0.0033 mole) of sodium azide and 1.07 g (0.0033 mole) of tributyltin chloride, and the mixture was stirred under reflux by heating for 9 hours. After the mixture was cooled to room temperature, 7 ml of a 1N hydrochloric acid aqueous solution was added thereto, and the mixture was stirred. Then, crystals precipitated were collected by filtration, washed with ethanol and toluene, and applied to silica gel column chromatography (the eluent used was a mixture of chloroform:methanol=9:1) to obtain 0.37 g of the title compound as pale yellow powder.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:16]=1[C:30]1[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH:11]([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:17][C:16]=1[C:30]1[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)c1ccn2c(Br)cnc2n1
Product: CC(C)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-isopropylimidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-isopropylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white powder: δH (360 MHz, CDCl3) 1.38 (6H, d, J 7), 3.15 (1H, septet, J 7), 6.87 (1H, d, J 7), 7.39 (1H, t, J 9), 7.52-7.63 (4H, m), 7.71 (1H, dd, J 8 and 1), 7.83 (2H, dd, J 8 and 7), 8.74 (1H, d, J 7); m/z (ES+) 357 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][C:22]1[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=1)=[N:8][CH:7]=[CH:6]2.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([C:22]1[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=1)=[O:39])=[N:8][CH:7]=[CH:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2ccnc(-c3ccccc3Sc3nc4ccccc4[nH]3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2ccnc(-c3ccccc3S(=O)c3nc4ccccc4[nH]3)c2cc1OC

Procedure:
The product of step (f) above was dissolved in 1:1 CH2Cl2 -CHCl3 (10 ml), treated with 85%m-Chloroperbenzoic acid (24 mg) at -5°, and worked up in aqueous NaHCO3 to give the title compound. NMR (CDCl3)d, 8.5 (d,1H), 8.35 (dd,1H), 7.26 (1H,s), 7.21 (1H,s), 7.7-7.2 (complex,8H), 4.30 (s,3H), 3.85 (s,3H)ppm, mp 250° (d).