Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3[C:15](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]2=[O:23])[CH2:5][CH2:4]1
Reactant: COC1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A suspension of 4-methoxypiperidine (286) (4.1 g, 35.3 mmol), N-(3-bromopropyl)phthalimide (9.0 g, 33.6 mmol) and K2CO3 (7.0 g, 50.4 mmol) in DMF (80 mL) was stirred at 50° C. for 16 h. The solution was cooled, the solvent evaporated and the residue partitioned between water (150 mL) and EtOAc (150 mL). The organic fraction was washed with water (2×50 mL) and brine (50 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give phthalimide 305 (6.0 g, 59%) as a white solid: 1H NMR δ 7.81-7.86 (m, 2H, Harom), 7.67-7.73 (m, 2H, Harom), 3.75-3.79 (t, J=7.0 Hz, 2H, CH2N), 3.28 (s, 3H, OCH3), 3.09-3.17 (m, 1H, CHO), 2.63-2.70 (m, 2H, CH2N), 2.39 (t, J=7.0 Hz, 2H, CH2N), 2.01-2.08 (m, 2H, CH2N), 1.85 (p, J=7.0 Hz, 2H, CH2), 1.74-1.81 (m, 2H, CH2), 1.37-1.46 (m, 2H, CH2). Anal. calcd for C17H22N2O3: C, 67.5; H, 7.3; N, 9.3. Found: C, 67.3; H, 7.4; N, 9.3%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:44])([F:43])[CH2:38][C:39]([NH:41][NH2:42])=O>CC1C=CC(C)=CC=1>[C:29]1([C:19]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)=[N:28][C:22]3[O:23][CH2:24][C:25]4[N:26]([C:39]([CH2:38][C:37]([F:44])([F:43])[F:36])=[N:41][N:42]=4)[C:21]=3[CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NNC(=O)CC(F)(F)F
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3CC(F)(F)F)CO4)cc2)CCC1
Temperature: 150 °C
Yield: 12.8 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (250 mg, 0.513 mmol) and 3,3,3-trifluoropropanehydrazide (145 mg, 1.205 mmol) in p-xylene (2 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (38 mg, 13%). LCMS (Method D): RT=1.499 min, M+1=578. 1H NMR (500 MHz, CDCl3): 7.84 (1H, s), 7.36-7.32 (5H, m), 7.31-7.28 (2H, m), 7.23-7.18 (2H, m), 5.60 (2H, s), 4.12 (2H, q), 2.52-2.42 (4H, m), 2.12-2.01 (1H, m), 1.87-1.78 (1H, m), 1.44-1.26 (9H, bs).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC(=C)CCO.Cl[C:19]1C=C[CH:22]=[C:21]([C:25]([O:27]O)=O)[CH:20]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH2:19][CH2:20][C:21]3([CH3:22])[CH2:25][O:27]3)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2cccc(O)c2s1
Agent: C=C(C)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc2cccc(OCCC3(C)CO3)c2s1
Temperature: 25 °C
Yield: 63 %

Procedure:
2-Methyl-7-hydroxybenzothiazoie was alkylated with 3-methyl-3-buten-1-ol according to Method VI. The product of this alkylation (0.30 g, 1.28 mmol) was dissolved in CH2Cl2 at about 0° C. to which was then added a solution of m-chloroperbenzoic acid (0.95 g, 5.53 mmol) in CH2Cl2. The reaction was allowed to warm to room temperature and after about 0.5 h the reaction was complete. 1N NaOH was added, the layers separated and the organic layer was washed with additional 1N NaOH and H2O. The organic layer was then dried over MgSO4 and the solvent was removed by rotary evaporation to give the title compound (0.20 g, 63%) as a yellow oil which was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][CH:12]([CH3:35])[CH:13]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)[N:25]=1)=[O:20])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:24]3[N:25]=[C:21]([C:19]([NH:18][C@@H:13]([CH:12]([CH3:35])[CH3:11])[C:14]([O:16][CH3:17])=[O:15])=[O:20])[S:22][CH:23]=3)=[CH:27][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3cccc(Cl)c3)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 3-chlorophenyl isocyanate and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 8.959 (s, 1H), 8.940 (s, 1H), 8.826-8.798 (d, J=8.4 Hz, 1H), 8.325 (s, 1H), 8.058-8.030 (d, J=8.4 Hz, 2H), 7.734 (s, 1H), 7.596-7.567 (d, J=8.7 Hz, 2H), 7.318-7.294 (m, 2H), 7.046-7.023 (m, 1H), 4.395-4.343 (t, J=7.8 Hz, 1H), 3.700 (s, 3H), 2.320-2.274 (m, 1H), 1.001-0.953 (t, J=6.9, 7.5 Hz, 6H); MS (ESI) m/z 485 (M−H), 487 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1N.N(OCCC(C)C)=O.[CH3:18][S:19]SC>>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[S:19][CH3:18]
Reactant: Nc1cc(F)ccc1Br
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1cc(F)ccc1Br
Temperature: 75 °C
Yield: 76 %

Procedure:
Dissolve 2-bromo-5-fluoroaniline (25 g, 131 mmol) in methyldisulfide (220 mL) and heat to 75° C. under nitrogen. Add isoamyl nitrite (46 mL, 342 mmol) dropwise via an addition funnel trough a reflux condenser (˜1 drop/sec). Large exotherm may occur if addition is too fast. After addition is complete heat the reaction to 95° C. for 1 hour and cool to room temperature and concentrate in vacuo. Purify residue twice via silica gel chromatography eluting with hexanes to yield 22 g of 1-bromo-4-fluoro-2-methylsulfanyl-benzene (76%).
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][N:19](C)CC1C=CC=CC=1.C#N.[C-]#N.[K+]>C(Cl)Cl.O>[Cl:1][C:2]([Cl:17])([Cl:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:11]=1)[C:6]([C:18]#[N:19])=[O:7]
Reactant: CN(C)Cc1ccccc1
Reactant: O=C(Cl)c1cc(C(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)c1
Agent: C#N
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CC(=O)c1cc(C(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)c1

Procedure:
78 g of 3,5-bis-(trichloromethyl)-benzoyl chloride and 0.4 g of dimethylbenzylamine are dissolved in 500 ml of methylene chloride and, at -15° C., first a solution of 10 ml of hydrogen cyanide in 50 ml of methylene chloride and then a solution of 12.4 g of potassium cyanide in 20 ml of water are added dropwise. After 11/2 hours, the mixture is dried by means of sodium sulfate stirred in, the inorganic salts are filtered off with suction and the solvent is stripped off in vacuo. On addition of ether, 14 g (18% of theoretical) of dimeric 3,5-bis-(trichloromethyl)-benzoyl cyanide crystallize out from the remaining viscous residue. The remaining monomeric product is purified by double distillation in a bulb tube.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[F:10][C:11]([F:20])([F:21])[O:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([O:12][C:11]([F:10])([F:20])[F:21])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2cccc(OC(F)(F)F)c2)nc1Nc1cccc(OC(F)(F)F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-trifluoromethoxyaniline were reacted to yield N2,N4-bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.03 (bd, 1H), 7.62 (bs, 2H), 7.48 (bd, 1H), 7.39 (t, 1H, J=8.1 Hz), 7.34 (m, 1H), 7.29 (t, 1H, J=7.5 Hz), 7.01 (m, 2H), 6.88 (m, 2H); 19F NMR (CDCl3): −16447 (s, 3F), −16459 (s, 3F), −46738 (s, 1F); LCMS: ret. time: 33.77 min.; purity: 93%; MS (m/e): 449 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17](O)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:10][CH2:11][C:12]([C:17]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[CH:27][C:21]=3[CH3:20])=[O:18])([CH2:15][CH2:16]1)[CH2:13][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(F)(F)F)ccc1N
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Product: Cc1cc(C(F)(F)F)ccc1NC(=O)C12CCC(NC(=O)OC(C)(C)C)(CC1)CC2

Procedure:
In a similar manner to Example 133, 4-tert-butoxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (150 mg) and 2-methyl-4-trifluoromethylaniline (2152 μL) were used to obtain 4-tert-butoxycarbonylamino-N-(2-methyl-4-trifluoromethylphenyl)bicyclo[2.2.2]octane-1-carboxamide (92.5 mg).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: NCC1CCOCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1NCC1CCOCC1
Yield: 93 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (tetrahydro-2H-pyran-4-yl)methanamine gave 1-methyl-4-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-5-amine as an off-white solid (277 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=1.6 Hz, 1H), 6.75 (s, 1H), 4.01 (dd, J=11.6, 4.3 Hz, 2H), 3.85 (d, J=1.0 Hz, 3H), 3.44-3.32 (m, 4H), 1.90-1.76 (m, 1H), 1.75-1.68 (m, 2H), 1.38 (qd, J=12.4, 4.4 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:20]([O:11][C@H:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:6][CH2:7]2)=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: O[C@@H]1CCc2ccc(Cl)cc21
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(O[C@@H]2CCc3ccc(Cl)cc32)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of (R)-6-chloroindan-1-ol (0.45 g, 2.67 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (112 mg, 2.8 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (0.41 g, 2.94 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed-ice water, stirred, filtered, and dried to yield 450 mg of 2-fluoro-5-((R)-6-chloroindan-1-yloxy)benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.Cl[CH2:11][CH:12]=O.C([O-])(=O)C.[Na+].CN(C=O)C>O>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[C:5]2[CH:12]=[CH:11][NH:8][C:6]=2[N:7]=1
Reactant: O=CCCl
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2[nH]ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.3 %

Procedure:
A mixture of 2,4-diamino-6-hydroxypyrimidine (300 g, 2.37 mol), chloroacetaldehyde (50% aq. solution, 382 g, 2.43 mol, 303 mL, 1.02 eq.), sodium acetate (195 g, 2.37 mol), DMF (2.5 L), and water (360 mL) was stirred mechanically at rt for 2 days. The resulting solid was collected by filtration, and washed with water (50 mL×3). The mother liquor was concentrated to give additional material which was washed with water (50 mL×3). The combined solid materials were recrystallized from MeOH to give the title compound as a white powder (186 g, 52% yield, HPLC purity: 100%). tR: 2.21 min. 1H-NMR (DMSO-d6) δ 11.00 (br. s, 1H), 10.33 (br. s, 1H), 6.63 (q, 1H), 6.21 (q, 1H), 6.12 (br. s, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)[OH:12])=[CH:9][N:10]=3)[N:7]=2)[CH:26]=[N:25]1
Reactant: OC(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
A microwave tube was charged with rac-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-ylmethanol (Stage 1.1, 1.12 g, 3.60 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (789 mg, 3.60 mmol), tetrakis-(triphenylphosphine)palladium (210 mg), 2M Na2CO3 (6.5 mL) and DME (11 mL). It was heated at 150° C. under microwave irradiation for 10 min. The RM was taken up with EtOAc and washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The reside was purified by MPLC eluting with a DCM/MeOH gradient to afford the title compound as a brown solid (tR 1.0 min(conditions 1), MH+=357).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.OC1CCN(S(C2C=CC(OCC)=C(C3NC(=O)C4=CN=C(CCC)N4N=3)C=2)(=O)=O)CC1>ClCCl.CO>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:14]3[NH:19][C:18](=[O:20])[C:17]4=[C:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]4[N:15]=3)[CH:6]=2)(=[O:12])=[O:11])[CH2:32][CH2:31]1
Reactant: OC1CCNCC1
Reactant: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Agent: CCCc1ncc2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(O)CC4)ccc3OCC)nn12
Solvent: CO
Solvent: ClCCl
Product: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(O)CC4)ccc3OCC)nn12

Procedure:
By the same method, starting with 640 mg (1.5 mmol) of 4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 460 mg (45 mmol) of 4-hydroxypiperidine, 485 mg (66%) of 2-[5-(4-hydroxy-piperidine-1-sulphonyl)-2-ethoxyphenyl]-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained. Rf=0.37 (dichloromethane/methanol=19:1)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH3:12])=[O:10].C([Li])CCC.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.O>[O:3]=[C:4]1[C:8](=[CH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)C1CCCC1=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCC(=CCCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.9 %

Procedure:
To a suspension of 60% NaH (1.2 g, 30 mmol) in anhydrous THF (30 mL) in an ice bath is added a solution of methyl 2-oxocyclopentanecarboxylate (4.26 g, 30 mmol) in 10 mL of THF dropwise over 5 minutes. The mixture is stirred at room temperature for 20 minutes. The mixture is cooled to -25° C. and 2.5 M n-butyllithium is added over 5 minutes (12 mL, 30 mmol). After stirring for 5 minutes, 1-bromo-3-phenylpropane (4.6 mL, 30 mmol) is added. The mixture is stirred at room temperature for 3 hours. The mixture is poured into water and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (6:1 hexane:ethyl acetate) to afford methyl 2-oxo-3-(3-phenylpropyl-1-yl)cyclopentanecarboxylate (1 g, 13%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.22-1.50 (m, 2H), 1.62-1.90 (m, 4H), 2.12-2.38 (m, 4H), 2.58-2.69 (m, 2H), 3.75 (s, 3H), 7.10-7.32 (m, 5H); MS (EI) m/e 260 (M+).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:16])[O:15][C:13](=[O:14])[CH2:12][C:10](=[O:11])[O:9]1.[C:17](Cl)(=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C>C(Cl)Cl>[OH:31][C:17](=[C:12]1[C:13](=[O:14])[O:15][C:8]([CH3:16])([CH3:7])[O:9][C:10]1=[O:11])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
14.3 mL of pyridine is added at 0° C., to a solution of Meldrum's acid (10.60 g, 73.5 mmol) in 70 mL of anhydrous CH2Cl2. After stirring for 15 min at this temperature, commercial tetradecanoyl chloride (18.16 g, 73.5 mmol) is added dropwise, so that the temperature remains below 10° C. After stirring for 2 h at 0° C. and for 1 h at ambient temperature, the reaction medium is washed with 50 mL of a 2N solution of HCl then 2×50 mL of water. After a last washing with a saturated aqueous solution of NaCl, the organic phase is dried over MgSO4, filtered and concentrated under vacuum. The oil obtained is crystallized by the addition of absolute ethanol then left overnight in the refrigerator. The solid is then filtered then rinsed with cold absolute ethanol before being dried in order to produce compound 17 (21.25 g, 59.9 mmol, 81%) in the form of a white solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=3)[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:29]=[C:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>>[CH3:24][C:19]1[CH:18]=[C:17]([CH:15]2[CH2:14][CH:13]([C:25]3[O:26][N:34]=[C:30]([CH:31]([CH3:33])[CH3:32])[N:29]=3)[CH2:12][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:16]2)[CH:22]=[CH:21][C:20]=1[CH3:23]
Reactant: CC(C)C(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1C
Product: Cc1ccc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCC(C#N)CC3)C2)cc1C

Procedure:
80 mg (0.210 mmol) of the compound from Example 132A and 33 mg (0.315 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 47 mg (51% of theory)
Reaction SMILES: [O:1]=[C:2]([CH2:13][CH2:14][CH3:15])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].CN(C)N>C1(C)C=CC=CC=1>[CH3:15][C:14]1[O:1][C:2]([CH2:13][CH2:14][CH3:15])=[C:3]([C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])[C:2](=[O:1])[CH:13]=1
Reactant: CCCC(=O)CC(=O)Nc1ccccc1
Agent: CN(C)N
Solvent: Cc1ccccc1
Product: CCCc1oc(C)cc(=O)c1C(=O)Nc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A mixture of 2.05 g (10 m mol) of 3-oxo-N-phenylhexanamide (m.p. 77.0°-78.5° C.), 0.9 g (15 m mol) of N,N-dimethylhydrazine and 15 ml of toluene was stirred for 8 hours at 60° C. Then, unreacted N,N-dimethylhydrazine and the resulted water, together with about 2 ml of toluene were distilled off outside the reaction system. A solution of 3.90 g (25 m mol) of 2-ethyl-2,6-dimethyl-4H-1,3-dioxin-4-one in 8 ml of toluene was dropwise added to the remaining solution over a period of 30 minutes, while refluxing. The mixture was further refluxed for 2.5 hours and 3 ml of toluene was distilled off outside the reaction system. The reaction mixture was cooled to room temperature. The resulted crystals were filtered off, washed and dried to obtain 1.32 g (Yield: 49%) of the title compound.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>COCCOC>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: c1c[nH]cn1
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: COCCOC
Product: Cc1cc2nc(-n3ccnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 95 °C
Yield: 19.2 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (200 mg, 0.332 mmol) in 1,2-dimethoxyethane was added imidazole (226 mg, 3.32 mmol) and the reaction was sealed and heated to 95° C. overnight. The crude reaction mixture was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (33.2 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H35ClN3O3: 520.23. found: 520.35.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][CH:29]=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(C)Oc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OC(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 58.1.1) to give the title compound as a white solid. (HPLC: tR 2.30 min (Method A); M+H=429 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.33-8.28 (m, 1H), 8.28-8.23 (m, 1H), 8.16-8.08 (m, 2H), 8.02-7.96 (m, 1H), 7.61-7.55 (m, 1H), 7.38-7.33 (m, 1H), 4.84-4.73 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H), 1.33 (d, 6H))
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([F:21])([F:22])[F:23])[C:13]=1[CH3:12])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Cc1c(N)cccc1C(F)(F)F
Product: Cc1c(NC(=O)c2cc(Cl)ccc2O)cccc1C(F)(F)F
Yield: 14.5 %

Procedure:
Using 5-chlorosalicylic acid and 2-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.