Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:25](=[O:26])[N:24]([CH3:27])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:28]CN(CCOC1C=CC(NC2N=C3C(C=C(C4C(Cl)=CC=CC=4Cl)C(N3C)=O)=CN=2)=CC=1)CC.C1COCC1.[Br:68]C[C:70]1[N:71]([CH3:78])[CH:72]=[C:73]([N+:75]([O-:77])=[O:76])[N:74]=1>CN1C(=O)CCC1>[Br-:68].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:25](=[O:26])[N:24]([CH3:27])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][N+:21]([CH2:28][C:72]4[N:71]([CH3:78])[CH:70]=[N:74][C:73]=4[N+:75]([O-:77])=[O:76])=[CH:20][CH:19]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1cc([N+](=O)[O-])nc1CBr
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccncc3)nc21
Reactant: CCN(CC)CCOc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cn1cnc([N+](=O)[O-])c1C[n+]1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Product: [Br-]
Yield: 65 %

Procedure:
To a stirred solution of 6-(2,6-dichlorophenyl)-8-methyl-2-(4-pyridinylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD166285 analogue A; Klutchko et al, J Med Chem, 1998, 41(17), 3276-3292) (200 mg, 0.50 mmol) in dry NMP (3 mL)/THF (200 mL) was added 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole (105) (133 mg, 0.60 mmol). The resulting solution was then stirred at room temperature for 25 days before THF was removed. The resulting solution was partitioned between EtOAc/water. The aqueous portion was subjected to freeze drying and the resulting gum was triturated with Et2O/EtOAc/CH2Cl2 to give 4-{[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-1-[(1-methyl-4-nitro-1H-imidazol-5-yl)methyl]pyridinium bromide (142) (200 mg, 65%) as a pale yellow powder, m.p. 252° C. (dec). 1H NMR [(CD3)2SO] δ 11.83 (bs, 1H), 9.08 (s, 1H), 8.68 (d, J=7.0 Hz, 2H), 8.21 (bs, 2H), 8.09 (s, 1H), 8.05 (s, 1H), 7.61 (dd, J=8.1, 0.6 Hz, 2H), 7.5 (dd, J=8.9, 7.4 Hz, 1H), 6.00 (s, 2H), 3.84 (s, 3H), 3.73 (s, 3H). Analysis found: C, 44.33; H, 3.42; N, 17.00. C24H19BrCl2N8O3.2H2O requires: C, 44.06; H, 3.54; N, 17.13.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([S:16][C:17]1[CH:18]=[C:19]([C:23]2[O:28][C:27](=[O:29])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=2)[CH:20]=[CH:21][CH:22]=1)([F:15])[F:14]>C(Cl)Cl>[F:15][C:13]([F:12])([F:14])[S:16]([C:17]1[CH:18]=[C:19]([C:23]2[O:28][C:27](=[O:29])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=2)[CH:20]=[CH:21][CH:22]=1)=[O:9]
Reactant: O=c1oc(-c2cccc(SC(F)(F)F)c2)nc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=c1oc(-c2cccc(S(=O)C(F)(F)F)c2)nc2ccccc12
Reaction time: 22 h

Procedure:
8.85 Parts by weight of m-chloroperbenzoic acid in 150 parts of methylene chloride are added to a mixture of 16.2 parts of 2-(m-trifluoromethylmercapto-phenyl)-3,1-benzoxazin-4-one and 130 parts of methylene chloride at room temperature. The mixture is then stirred for a further 22 hours. The precipitate which has formed is dissolved by adding 100 parts of methylene chloride and the solution obtained is extracted twice with 0.3 N sodium hydroxide solution and with water. It is then dried over magnesium sulfate and chromatographed over aluminum oxide, giving 12.4 parts of 2-(m-trifluoromethylsulfinyl-phenyl)-3,1-benzoxazin-4-one, of melting point 106°-108° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([NH2:29])[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].CN(C)[C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][C:52]=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[C:36]1([CH2:35][O:34][C:32](=[O:33])[CH2:31][N:29]([C:14]2[CH:13]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=2)[CH2:31][C:32](=[O:33])[O:34][CH2:44][C:53]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCCCCCCCCOc1cc(N)cc(OCCCCCCCCCC)c1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: O=C(CBr)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Yield: 45.4 %

Procedure:
A mixture of 20.0 g (0.0493 mol) of 3,5-bis(decyloxy)benzenamine, 23.6 ml (0.148 mol) of benzyl bromoacetate, 26.4 g (0.123 mol) of 1,8-bis(dimethylamino)naphthalene and 2.1 g of sodium iodide in 300 ml acetonitrile and 65 ml of DMF was stirred at reflux for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with 0.5N HCl, with saturated NaHCO3, dried and concentrated under reduced pressure to an oil. Purification by HPLC using 10% ethyl acetate-hexane gave 15.7 g(45% yield, mp 55°-57°) of N-[3,5-bis(decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)=[O:31]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH:16]([CH3:20])[C:17]([O:19][CH2:29][C:30](=[O:31])[C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:37]=2)=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)C1(NC(=O)OCc2ccccc2)COC1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C(=O)OCC(=O)c1ccc(C(F)(F)F)cc1)C1(NC(=O)OCc2ccccc2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
2-(3-{[(Benzyloxy)carbonyl]amino}oxetan-3-yl)propanoic acid (Preparation 28, 1.5 g, 5.37 mmol) and triethylamine (1.12 mL, 8.06 mmol) were stirred in ethyl acetate (50 mL). 2-Bromo-1-[4-(trifluoromethyl)phenyl]ethanone (1.51 g, 5.64 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound as an oil (2.19 g, 88%).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][CH:27]([CH3:31])[CH2:28][NH:29]N.CCN(CC)CC>C(O)C.Cl>[CH3:26][CH:27]([CH3:31])[CH2:28][N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)CNN
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)Cn1nccc1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 53.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (500 mg, 1.5 mmol) in ethanol (10 mL) were added 2-methylpropylhydrazine hydrochloride (274 mg, 2.2 mmol) and Et3N (0.41 mL, 3.0 mmol). The mixture was stirred at 100° C. for 5 h. The mixture was diluted with 1N HCl aqueous solution, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=10/90 to 0/100) and recrystallized with AcOEt/i-Pr2O to yield the title compound as a pale yellow solid (289 mg, 54%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=[C:2]12.[NH2:12][C@@H:13]([CH3:30])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[C:26]([F:28])[C:23]([C:24]#[N:25])=[C:22]([Cl:29])[CH:21]=2)=[N:16]1.CN(C=O)C>O.C(OCC)(=O)C>[Cl:29][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[N:8]=[C:2]4[N:3]([CH:6]=3)[CH:4]=[CH:5][S:1]4)=[O:11])[CH3:30])[N:16]=2)[CH:27]=[C:26]([F:28])[C:23]=1[C:24]#[N:25]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2ccsc2n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2ccsc2n1
Reaction time: 48 h
Yield: 41.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from imidazo[2,1-b]thiazole-6-carboxylic acid (1.041 mmol, 0.175 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.041 mmol, 0.290 g). DMF (10 ml) was used as the solvent and the reaction time was 2 days. The work up was done by diluting the reaction mixture with water and ethyl acetate and washing it with 2M Na2CO3, water and brine. The combined organics were dried, filtered and eveaporated. The crude product was purified by flash chromatography. 0.186 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.24 (d, 3H), 4.32-4.39 (m, 1H), 4.40-4.47 (m, 1H), 4.53-4.61 (m, 1H), 6.79 (d, 1H), 7.20 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.77-7.81 (m, 1H), 7.89-7.91 (m, 1H), 8.10 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:27]2[CH:28]=[C:29](OS(C(F)(F)F)(=O)=O)[CH:30]=[CH:31][CH:32]=2)([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][N:42](C=O)C>C(OCC)C.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:26])=[CH:18][CH:19]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:41]#[N:42])[CH:28]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(C2(c3cccc(OS(=O)(=O)C(F)(F)F)c3)CCCN(Cc3ccccc3)C2)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccc(C2(c3cccc(C#N)c3)CCCN(Cc3ccccc3)C2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-[1-benzyl-3-(4-diethylcarbamoyl-phenyl)-piperidin-3-yl]-phenyl ester (0.40 g, 0.69 mmol) in DMF (8 mL) was added zinc cyanide (0.057 g, 0.49 mmol) and tetrakis triphenylphosphine palladium (0.16 g, 0.14 mmol). The reaction was stirred under a nitrogen atmosphere at 90° C. for 5 hours. The mixture was cooled to room temperatures and it was diluted with diethyl ether (30 mL). The organic layer was washed with brine (5x 10 mL), dried (MgSO4) and concentrated. Purification with hexanes/EtOAc (1:1) afforded 0.28 g of 4-[1-benzyl-3-(3-cyano-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide. 1HNMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.69-7.20 (comp, 10H), 7.15-7.13 (comp, 2H) 3.60-3.38 (comp, 4H), 3.31-3.19 (comp, 2H), 3.09-2.94 (m, 1H), 2.58-2.45 (comp, 2H), 2.22-2.17 (comp, 3H), 1.71-1.61 (m, 1H), 1.28-1.16 (comp, 3H), 1.17-1.08 (comp, 3H); MS (M+1) 452.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:13]=1[C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N(C(OC(C)(C)C)=O)C1SC=C(CC(C)C)C=1C(OCC)=O)=O)(C)(C)C.[OH-].[K+].C(O)(=O)C>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(CC(C)C)csc1NC(=O)OC(C)(C)C
Agent: CCOC(=O)c1c(CC(C)C)csc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Cc1csc(NC(=O)OC(C)(C)C)c1C(=O)O

Procedure:
A solution of crude ethyl 2-t-butoxycarbonylamino-4-isobutylthiophene-3-carboxylate and ethyl 2-bis(t-butoxycarbonyl)amino-4-isobutylthiophene-3-carboxylate in methanol (1200 ml) was stirred and a solution of potassium hydroxide (44.8 g, 800 mmol) in water (450 ml) was added. The mixture was heated at 80° C. for 6h and left at room temperature over night. The reaction mixture was diluted with water and the pH adjusted to pH 4-5 with glacial acetic acid under cooling on ice. The product was extracted with ether and after drying with Na2SO4 the ether phase was concentrated in vacuo. The residue was suspended in petroleum ether and 2-t-butoxycarbonylamino-4-isobutylthiophene-3-carboxylic acid (75.2 g) was isolated by filtration. M.p. 154°-155° C. 1H-NMR (CDCl3, δ): 0.95 (d, 6H), 1.55 (s, 9H), 1.9 (m, 1H), 2.7 (d, 2H), 6.35 (s, 1H), 9.3 (br.s, 1H), 10.2 (s, 1H).
Reaction SMILES: N(OCCCCC)=O.N[C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:18]#[N:19].[I:20]CI>>[I:20][C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:18]#[N:19]
Reactant: ICI
Reactant: CC(C)n1ncc(C#N)c1N
Agent: CCCCCON=O
Product: CC(C)n1ncc(C#N)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Amyl nitrite (13.00 g, 111.0 mmol) was added to a suspension of 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (1.77 g, 11.8 mmol) in Diiodomethane (56.0 mL, 695 mmol) at −10° C. in 30 min. The mixture was stirred for 30 min at room temperature and then heated at 100° C. for 2 hours. The mixture was then cooled and concentrated in high vacuum to give a residue which was partitioned between ethyl acetate and 5% Na2S2O5. The organic layer was washed with water, 0.1% of aq HCl, water, brine, dried and concentrated in vacuum. The residue was purified on silica column eluting with 20-30% ethyl acetate in heptane. Yield 1.68 g (55%). MS (ESI+): 262.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl.[I-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13]
Reactant: Nc1cc(Cl)c(N)c(C(F)(F)F)c1
Reactant: ClCCOCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1c(Cl)cc(N2CCOCC2)cc1C(F)(F)F
Temperature: 165 °C
Yield: 24 %

Procedure:
2-Chloro-6-trifluoromethyl-benzene-1,4-diamine (2.9 g), bis-(2-chloroethyl)ether (1.7 mL) and sodium iodide (516 mg) were mixed in acetonitrile (45 mL) and heated to 165° C. for 1 hour in a sealed microwave process vessel. The crude mixture was concentrated in vacuo, redissolved in ethyl acetate (100 mL) and washed with water (2×100 mL) and brine (1×100 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 940 mg (24%) of the title compound as a black oil. 1H NMR (500 MHz, CDCl3): 3.02 (m, 4H), 3.84 (m, 4H), 4.30 (b, 2H), 6.97 (d, 1H), 7.06 (d, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:14]1[CH2:13][CH2:12][N:11]([C:9](=[O:10])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15]1)[CH3:29]
Reactant: O=C(CC(c1ccccc1)c1ccccc1)N1CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Temperature: 70 °C
Yield: 60 %

Procedure:
To a solution of 3,3-diphenyl-1-piperazin-1-yl-propan-1-one (2.0 g, 6.79 mmol) and ethyl bromoacetate (0.94 ml, 8.49 mmol) in dry DMF (15 ml) was added K2CO3 (2.7 g, 19.53 mmol) and the mixture was heated to 70° C. overnight. Reaction mixture was cooled and water (32 ml) was added. The product was extracted with ether, dried and evaporated. The residue was purified by column chromatography using hexane:ethyl acetate (1:4) to give the desired product in 60% yield.
Reaction SMILES: Br[C:2]12[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][CH:17]=1.Cl>[N+](C1C=CC=CC=1)([O-])=O.ClCCl.[Fe](Cl)(Cl)Cl>[F:22][C:21]1[C:16]([F:15])=[C:17]([C:2]23[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][CH2:7]2)[CH2:4][CH2:3]3)[CH:18]=[CH:19][C:20]=1[O:23][CH3:24]
Reactant: COc1cccc(F)c1F
Reactant: CCCCCC12CCC(Br)(CC1)CC2
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCC12CCC(c3ccc(OC)c(F)c3F)(CC1)CC2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
A solution of 1-bromo-4-pentylbicyclo[2.2.2]octane (6 g, 23 mmol) in sieve-dried nitrobenzene (100 cm3) is added dropwise to a stirred solution of 2, 3-difluoro-4-methoxybenzene (6 g, 23 mmol) and anhydrous iron(III)chloride (1.2 g, 9 mmol) in sieve-dried nitrobenzene (100 cm3) maintained at 80° C. throughout the addition and overnight. The cooled solution is added to a small volume of hydrochloric acid and stirred for 20 min. The organic layer is separated off and steam-distilled to yield a solid residue. This is taken up in dichloromethane and dried (MgSO4). The raw product is crystallised from ethanol to yield the desired 2, 3-difluoro-1-methoxy-4-(4-pentylbicyclo[2.2.2]octyl)benzene (3.2 g, 44%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]1[C:12]([CH3:15])=[N:13][N:14]=[C:9]1[CH2:8][CH2:7]2.Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:34])[C:31]=1[CH2:32][CH3:33].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:34])[C:31]=2[CH2:32][CH3:33])[CH:5]=[C:6]2[C:11]=1[N:10]1[C:12]([CH3:15])=[N:13][N:14]=[C:9]1[CH2:8][CH2:7]2
Reactant: Cc1nnc2n1-c1c(Cl)cc(B3OC(C)(C)C(C)(C)O3)cc1CC2
Reactant: CCc1c(F)cncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCc1c(F)cncc1-c1cc(Cl)c2c(c1)CCc1nnc(C)n1-2
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 9-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (80-4; 0.717 g, 0.0020 mol) and 3-bromo-4-ethyl-5-fluoropyridine (0.423 g, 0.0020 mol) in the mixture of 1,4-dioxan (5 mL) and water (5 mL) was added sodium carbonate (0.66 g, 0.0062 mol). Reaction mass was purged with argon for the next 20 min. Catalyst Pd(dppf)2Cl2.dichloromethane (0.084 g, 0.0001 mol) was added and again purged with argon for 10 min and allowed to stirred at 90° C. for 4 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic parts was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography followed by preparative HPLC (analytical conditions; column: ZORBAX XDB (150 mm×4.6 mm×3.5 μm), mobile phase (A): water, Mobile phase (B): MeOH, flow rate: 1.0 mL/min, gradient T/% B:0/20,6/25,25/75,27/20,30/20) to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ: 8.55 (s, 1H), 8.32 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 2.94 (bs, 4H), 2.65-2.59 (m, 2H), 2.56 (s, 3H), 1.09-1.05 (t, J=7.6 Hz, 3H). MS (M+1): 343.2.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:19][C:20]1[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=1[O:31][CH2:32][CH2:33]I>>[C:15]([C@@:5]1([C:3]([OH:2])=[O:4])[CH2:9][C:8]2[CH:10]=[C:11]([O:14][CH2:33][CH2:32][O:31][C:21]3[CH:22]=[CH:23][C:24]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:25][C:20]=3[Cl:19])[CH:12]=[CH:13][C:7]=2[O:6]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)C1(C(C)(C)C)Cc2cc(O)ccc2O1
Reactant: FC(F)(F)Oc1ccc(OCCI)c(Cl)c1
Product: CC(C)(C)[C@@]1(C(=O)O)Cc2cc(OCCOc3ccc(OC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the phenol prepared in Example 21, Step 1 and the iodide prepared in Example 23, Step 1.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6](Cl)[N:5]=[C:4]([CH3:14])[N:3]=1.C(C1C=C(O)C=CC=1)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:31][NH:32][CH3:33]>CN(C)C=O.O>[CH3:31][N:32]([CH3:33])[N:5]1[CH:6]=[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:2]=[N:3][CH:4]1[CH3:14]
Reactant: CNC
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Agent: CC(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1=CN(N(C)C)C(C)N=C1
Reaction time: 16 h

Procedure:
Methyl 4,6-dichloro-2-methyl-pyrimidin-5-yl-acetate (23.5 g, 0.1 mol), 3-isopropylphenol (13.6 g, 0.1 mol) and potassium carbonate (20.7 g, 0.15 mol) are heated in dimethylformamide (30 ml) at 100° C. for 45 minutes. The mixture is cooled and an aqueous solution of dimethylamine (50 ml of a 40% solution) is added. Stirring is continued for 16 hours at room temperature. Addition of water, filtering and drying gives the methyl 1-dimethylamino-2-methyl-pyrimidin-5-yl-acetate as a brownish solid (28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)c1ccc(O)cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1Cl
Reaction time: 24 h

Procedure:
A solution of 2-chloro-4-hydroxy-benzoic acid (3.70 g, 21.4 mmol)) in methanol (50 ml) was treated with thionyl chloride (2.4 ml, 32 mmol) dropwise and stirred for 24 hours and the solvents were removed in vacuo. The residue was dissolved in ethyl acetate and washed with sat. sodium hydrogen carbonate, dried and solvents were removed in vacuo. The residue was purified by column chromatography on silica gel (eluant with 30% EtOAc:70% cyclohexane) to yield the desired product as a yellow solid, 3.68 g, 92%.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22]O)[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)CC)=[O:5].NC1C=CC(Br)=CC=1[C:27](NC)=[O:28].CC1(C)C(C)(C)OB(C2C=NN(CCCCO)C=2)O1>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:27][OH:28])[CH:19]=2)=[CH:11][C:3]=1[C:4]([NH:6][CH3:9])=[O:5]
Reactant: CNC(=O)c1cc(Br)ccc1N
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Agent: CC1(C)OB(c2cnn(CCCCO)c2)OC1(C)C
Product: CNC(=O)c1cc(-c2cnn(CCCCO)c2)ccc1N
Yield: 17 %

Procedure:
Prepared analogously to Compound 3C using 2-amino-5-bromo-n-methyl-benzamide (Compound 8D, 300 mg, 1.31 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-1-ol (Compound 14C, 383 mg, 1.44 mmol) to afford 64 mg of the title compound (17%). 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.32 (dd, J=2.0, 8.6 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.13 (br. s., 1H), 5.43 (br. s., 2H), 4.20 (t, J=6.9 Hz, 2H), 3.65-3.72 (m, 2H), 3.01 (d, J=5.1 Hz, 3H), 2.01 (quin, J=7.3 Hz, 2H), 1.58-1.67 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:18][CH:17]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:15][C:16]1[C:21]([C:22]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[N:7]=[CH:6][N:5]=[C:4]3[O:3][CH2:1][CH3:2])=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:18][CH:17]=1
Reactant: CCOc1ncnc2c(N)cccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 17.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-ethoxyquinazolin-8-amine (Intermediate-38, 140 mg, 0.80 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 323 mg, 1.12 mmol), oxalyl chloride (141 mg, 1.12 mmol), DMF (1 drop) and DIPEA (310 mg, 2.40 mmol) in CH2Cl2 (4 mL) to afford 65 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.79 (m, 2H), 8.13 (t, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.69 (t, 1H), 7.36-7.31 (m, 2H), 4.62 (m, 2H), 4.29 (d, J=6.0 Hz, 2H), 1.44 (t, J=7.5 Hz, 3H), 1.12 (s, 9H); MS (m/z): 459.20 (M+H)+.