Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:28][CH:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37](Cl)[C:32]=2[CH2:31][CH2:30]1)(=O)C.Cl.C[O-].[Na+].CO>C(O)C>[OH:28][CH:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([NH:22][C:21]3[CH:20]=[CH:19][C:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]4[CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:9][CH2:10]4)=[CH:24][CH:23]=3)[C:32]=2[CH2:31][CH2:30]1
Reactant: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3O)cc1
Yield: 57.7 %

Procedure:
To 15 ml of ethanol were added 0.60 g of 4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.51 g of 7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, then 3 ml of an ethanol solution of hydrochloric acid (containing 0.19 g of hydrochloric acid) was added to the mixture and the mixture was reacted under reflux for 30 minutes. After cooling, a 28% sodium methylate-methanol solution was added to the reaction mixture to make it alkaline, and the mixture was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.49 g of the title compound as white crystal.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([O:14][C:15](=[O:31])[CH2:16][C@H:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29]Br)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:29][CH2:28][CH2:27][O:26][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[C@H:17]([CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:31])[CH2:18][CH2:19]3)=[C:3]([O:10][CH3:11])[CH:4]=1)#[N:7]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: COc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cc3OC)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a mixture of 4-hydroxy-3-methoxybenzonitrile (2.6 g, 17.6 mmol), ethyl [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45) (6 g, 17.6 mmol), and Cs2CO3 (6.9 g, 21.1 mmol) in DMF (30 mL) was added water (15 drops). The reaction mixture was stirred at 40° C. for 16 h and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. Recrystallization from MeOH (5 mL) gave 4.9 g (68%) of the title compound as an off-white solid. LC-MS: RT=3.59 min; (M+H)+ 410.0.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([SH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]>>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[S:7][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: Cc1ccccc1S
Product: CC(C)=CCCC(C)=CCSc1ccccc1C

Procedure:
thio-o-cresol is reacted with 1-bromo-3,7-dimethyl-octa-2,6-diene to produce 3,7-dimethyl-octa-2,6-dienyl o-tolyl sulphide (boiling point = 125° C/0.08 mmHg);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[N:11]=1)[C:5]([O:7]C)=[O:6].C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cc(C(=O)O)cc(Cl)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinate (2 g, 7.18 mmol) in 1:1 THF:MeOH (60 mL) added a NaOH (9.3 mL, 9.3 mmol, 1N). The reaction mixture was stirred at rt for 0.5 h, acidified to pH 3-4 with 1N HCl, extracted with dichloromethane (×2), dried over sodium sulfate and concentrated in vacuo to provide 2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinic acid as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.88 (s, 1H), 7.63 (s, 1H), 3.39 (s, 3H), 3.13 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:6]=1[NH2:7].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CC(N(C)C)=O>[O:18]1[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][O:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:6]=2[NH2:7])[CH2:16][CH2:17]1
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: Nc1c(OCCN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
2-(2-Chloroethoxy)-6-nitroaniline (1.9 g, 4.63 mmol), morpholine (0.5 mL) was dissolved in 5 mL of DMA. The mixture was heated at 110° C. in a pressure bottle overnight, and then cooled to room temperature. The reaction mixture was separated between ethyl acetate and water, the combined organic layers were washed with water, brine, dried, and concentrated to get 1.3 g of 2-(2-Morpholinoethoxy)-6-nitroaniline, which was used without any further purification. 1H-NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 6.95 (d, 1H), 6.72 (b, 2H), 6.61 (dd, 1H), 4.16 (t, 2H), 3.75 (t, 2H), 2.82 (m, 2H), 2.58 (m, 4H), 2.10 (m, 2H). MS (EI): 263 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[N:24]=[CH:23][CH:22]=[CH:21][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:11])([O-])=O.[H][H]>CO.O1CCCC1.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[N:24]=[CH:23][CH:22]=[CH:21][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:11]
Reactant: O=C(NCc1ccccc1Cl)c1cccnc1Oc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(Oc2ncccc2C(=O)NCc2ccccc2Cl)c1

Procedure:
To a solution of 2-(3-Nitro-phenoxy)-N-(2-chloro-benzyl)-nicotinamide (0.530 g 1.38 mmole) in methanol (15 ml) and tetrahydrofuran (20 ml) was added 10% PtO2 (0.0.50 g). This was shaken under 35 psi hydrogen for 1 hour 40 minutes. The catalyst was removed by filtration, and the solution was concentrated to give an oil that was purified by chromatography on silica gel eluting with 2.5% methanol/methylene chloride. Recrystalization from ethyl acetate/hexane gave crystals. (0.327 g). M.P. 101-103° C.; Anal. calcd. for C19H16N3O2Cl: C, 64.5; H, 4.56; N, 11.88. Found: C, 64.15; H,4.07; N, 11.80.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC(=O)c1cccc(N)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-n2cccc2)c1

Procedure:
The mixture of methyl 3-aminobenzoate (110.0 g) and 2,5-dimethoxytetrahydrofuran (141.4 ml) in acetic acid (330 ml) was heated under reflux for 50 minutes under stirring and the solvent was removed by concentration in vacuo. To the residue was added a mixture of ethyl acetate and water, and adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with water and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with chloroform. The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(pyrrol-1-yl)benzoate (112.84 g) as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28]([O:30]C)=O)[O:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1.[NH3:33].CO>CO>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28]([NH2:33])=[O:30])[O:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1
Reactant: N
Reactant: COC(=O)c1nc(-c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)no1
Solvent: CO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(N)=O)n3)c1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Methyl (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazole-5-carboxylate (320 mg, 0.71 mmol) obtained in Step 1 of Example 80 was dissolved in methanol (3.0 mL), and the mixture was stirred at room temperature for 3 hours after adding a 2.0 mol/L ammonia/methanol solution (3.50 mL, 7.07 mmol). The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazole-5-carboxamide (300 mg, 96%).
Reaction SMILES: [N:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:25]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCN(C2=Nc3ccccc3Oc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine (0.28 g, 1.00 mmol) in DMF (10 mL) was added sodium hydride (0.056 g, 60% in oil, 1.40 mmol) at 0° C. under argon. The mixture was stirred at 0° C. for 10 min at room temperature for 20 minutes, and then treated with 1 -bromohexane (0.198 g, 1.2 mmol). The resulted mixture was stirred at room temperature overnight and quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate/hexane (1/2) as the eluent. The desired compound, 11-(4-hexyl-1-piperazinyl)dibenz[b,f][1,4]oxazepine, was obtained in 0.167 g (46%) as a light yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1.N1C=CC=CC=1>ClCCl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[S:34]([C:32]1[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=1)(=[O:36])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNc2ccc(CN3CCN(c4ccccc4)CC3)cc2)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N(Cc2ccccc2)c2ccc(CN3CCN(c4ccccc4)CC3)cc2)c1
Temperature: 25 °C

Procedure:
A solution of benzyl-[4-(4-phenyl-piperazin-1-yl methyl)-phenyl)-amine (30 mg, 0.08 mmol), 1-methylimidazole-4-sulfonyl chloride (51 mg, 0.27 mmol) and pyridine (24 μl, 0.30 mmol) in dry dichloromethane (2 ml) were heated to reflux for 15 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by column chromatography (5% methanol in dichloromethane) to afford the title compound as an off white solid (22 mg, 55%). HPLC retention time 7.04 min. Mass spectrum (ES+) m/z 502 (M+H). 1H-NMR (CDCl3) δH 2.54 (4H, m, 2×CH2), 3.16 (4H, m, 2×CH2), 3.45 (2H, br s, CH2), 3.71 (3H, s, CH3), 4.99 (2H, s, CH2), 6.84 (1H, t, J=7.3 Hz, ArH), 6.89 (2H, m, 2×ArH), 7.10 (2H, m, 2×ArH), 7.17-7.30 (10H, m, 10×ArH), 7.55 (1H, m, ArH).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:15](=[O:18])[NH:16][CH3:17])[CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)(C)(C)C.[ClH:20].O1CCOCC1>>[ClH:20].[NH2:7][C@@H:8]([CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)[C:15]([NH:16][CH3:17])=[O:18]
Reactant: CNC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](N)Cc1cscn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-(1-Methylcarbamoyl-2-thiazol-4-yl-ethyl)-carbamic acid tert-butyl ester (248 mg, 0.87 mmol) was dissolved in 4 M HCl-dioxane at 0° C. The resulting mixture was stirred for 1 hour at 25° C., concentrated and the residue triturated with ether. Yield, 202 g, 102%; HPLC (70/30) 2.41 minutes (96%);
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])[O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[S:4][N:3]=1.O[C@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]([C:8]([O:9][CH2:10][C:11]([Cl:12])([Cl:14])[Cl:13])=[O:15])[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22][CH:23]([CH3:25])[CH3:24])[S:4][N:3]=1
Reactant: COC(=O)[C@H](O)CC(C)C
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)sn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1cc(C)ns1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 2,2,2-trichloroethyl 3-methylisothiazol-5-ylcarbamate (20.6 g, 71.1 mmol), methyl (2R)-2-hydroxy-4-methylpentanoate (15.9 g, 109 mmol) and triphenylphosphine (28.9 g, 110 mmol) in DMF (260 mL) was slowly added over 15 min diisopropylazodicarboxylate (21.7 mL, 110 mmol). The resulting brown solution was stirred at room temperature for 30 min and then heated to 60° C. for 18 h. The reaction mixture was allowed to cool to room temperature and it was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified twice by flash chromatography using EtOAc in hexane to afford methyl N-(3-methylisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]-L-leucinate as a yellow syrup.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:24])/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21]>CS(C)=O.O1CCOCC1>[N+:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[O:1][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]2=[O:24])([O-:10])=[O:9]
Reactant: O=C(/C=C/c1ccccc1C(F)(F)F)c1cccc([N+](=O)[O-])c1O
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=c1cc(-c2ccccc2C(F)(F)F)oc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one 9 (1.4 g, 4.2 mmol) and SeO2 (1.4 g, 12.5 mmol) in DMSO/dioxane (35 ml, 1:15) was heated at reflux for 12 h. After cooling to room temperature, the reaction mixture was passed through a filter and the filtrate was concentrated to dryness. The crude residue was suspended in H2O and collected by filtration to give 10 as a yellow solid (1.3 g, 92% yield).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Cl:23])([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Cl:23])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(Br)CBr
Reactant: CC(C)(CNc1cc(F)ccc1Cl)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(CN(C(=O)CBr)c1cc(F)ccc1Cl)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
2.2 ml of bromoacetyl bromide (25.2 mmol) was added to a solution of 5.3 g of [2-(2-chloro-5-fluorophenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester obtained in Example (62a) (16.8 mmol) in N,N-dimethylacetamide (170 ml) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 5.8 g of the title compound (yield: 80%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O>[CH:24]1([O:10][C:5]2[CH:6]=[C:7]([C:2]([F:1])=[CH:3][C:4]=2[O:11][CH3:12])[CH:8]=[O:9])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrC1CCCC1
Reactant: COc1cc(F)c(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)c(C=O)cc1OC1CCCC1

Procedure:
A mixture of 6-fluoro-3-hydroxy-4-methoxybenzaldehyde (2 g), potassium carbonate (1.66 g) and anhydrous dimethylformamide (20 mL) is treated with cyclopentyl bromide (1.62 mL) and heated on a steam bath for 43 hours. The mixture is cooled, poured into water (200 mL) and extracted with diethyl ether (3×100 mL). The combined ethereal extracts are washed with sodium hydroxide solution (2×50 mL; 2 N), and brine (2×50 mL), dried over magnesium sulphate and concentrated. The residual brown oil is subjected to flash chromatography [a solvent gradient of 9:1 to 4:1 v/v petroleum ether (b.p. 60-80° C.) and ethyl acetate is used as eluent on a silica gel column] to give 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.42 g) in the form of a yellow oil. [NMR (CDCl3):—10.22 (s, 1H), 7.27 (d, 1H, J=8 Hz), 6.63 (d, 1H, J=16 Hz), 4.81-4.76 (m, 1H), 3.91 (s, 3H), 2.01-1.57 (m, 8H)].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@H:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C@@H:22]([C:27](O)=[O:28])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:34][NH2:35]>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@H:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C@@H:22]([C:27]([NH:35][CH3:34])=[O:28])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C)[C@@H](C(=O)O)C1
Reactant: CN
Agent: Cl
Product: CNC(=O)[C@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C

Procedure:
(2R,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylic acid (20) was coupled with methylamine hydrochloride analogously as for the equivalent step in Example 7 to give the title compound (2R,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N,1-dimethylpiperidine-2-carboxamide: 1H NMR Spectrum: (DMSO-d6) δ1.63-1.72 (2H, m), 2.15-2.21 (6H, m), 2.55-2.62 (4H, m), 2.93-2.98 (1H, m), 3.94 (3H, s), 4.43-4.51 (1H, m), 7.23 (1H, s), 7.28-7.33 (1H, m), 7.49-7.56 (2H, m), 7.68-7.72 (1H, m), 7.86 (1H, s), 8.39 (1H, s), 9.57 (1H, s); Mass Spectrum: (M+H)+ 474.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH2:46][CH2:45][C:44]=3[N:43]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=3)[C:42](=[O:61])[N:41]2[CH2:62][C:63](O)=[O:64])=[CH:36][CH:35]=1)#[N:33].N>CN(C)C=O>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH2:46][CH2:45][C:44]=3[N:43]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:59])([F:60])[F:58])[CH:52]=3)[C:42](=[O:61])[N:41]2[CH2:62][C:63]([NH2:8])=[O:64])=[CH:36][CH:35]=1)#[N:33]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38 mg, 100 μmol) and triethylamine (70 μL, 500 μmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetic acid (example 32, 47 mg, 100 μmol) in N,N-dimethylformamide (0.5 mL). After 20 min ammonia (0.5 M in 1,4-dioxane, 200 μL, 100 μmol) is added, and the mixture is stirred at room temperature for 2 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 29 mg; ESI mass spectrum [M+H]+=469; Retention time HPLC: 0.84 min (Z018_S04).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][N:11]=[C:5]2[N:4]2[CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=[C:3]12.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:10]2[CH:9]=[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3]4[N:4]([CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=4)[C:5]3=[N:11]2)=[CH:20][CH:21]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc(CBr)cc1
Reactant: CN1C(=O)c2c[nH]nc2N2CC(C)(C)N=C12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cn2cc3c(n2)N2CC(C)(C)N=C2N(C)C3=O)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A suspension of 7,8-dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (438 mg, 2.0 mmol), 1-(4-(bromomethyl)phenyl)ethanone (520 mg, 2.4 mmol) and K2CO3 (828 mg, 6.0 mmol) in DMF (18 mL) is stirred at room temperature over a weekend. Solvent is removed under reduced pressure. The obtained residue is purified on a basic alumina oxide column to give 634 mg of product (yield: 90%). MS (ESI) m/z 352.2 [M+H]+.
Reaction SMILES: CC1C=[C:5](C)[N:4]([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH3:24][O:25][CH2:26][CH2:27][C:28]1[O:32]C(N)=[N:30][N:29]=1>>[CH3:24][O:25][CH2:26][CH2:27][C:28]1[O:32][C:5]([NH:4][C:8]([CH:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:9])=[N:30][N:29]=1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Reactant: COCCc1nnc(N)o1
Product: COCCc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 204° C. and MS: m/e=351.1 (M+H+) was prepared in accordance with the general method of example 44a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and [5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-amine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2].[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=3)=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([CH:28]2[CH2:29][CH2:30]2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(=O)C2CC2)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 5, using the following starting materials: (3-{4-amino-2-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester and 4-chlorobenzoyl chloride.