Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:21]([CH3:23])[CH3:22])=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:7]=2)=[CH:9][C:10]=1[C:24]([F:27])([F:26])[F:25])([CH3:23])[CH3:22]
Reactant: C1COCCN1
Reactant: CC(C)c1ccccc1Sc1ccc(-c2cc(Cl)ncn2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1Sc1ccc(-c2cc(N3CCOCC3)ncn2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 72 %

Procedure:
To a solution of compound 47 (0.015 g, 0.0367 mmol) in DMF (1.0 mL) was added morpholine followed by potassium carbonate (0.015 g, 0.109 mmol). The reaction mixture was heated at 80° C. for 16 hours. The solid was removed through filtration, and the filtrate was directly purified by preparative HPLC, to give a yellow solid, 43 (0.012 g, 72%). 1H-NMR (CDCl3, 400 MHz) δ 1.19 (d, J=6.8 Hz, 6H), 3.51 (heptet, J=6.8 Hz, 1H), 3.69 (t, J=4.9 Hz, 4H), 3.81 (t, J=4.9 Hz, 4H), 6.80 (s, 1H), 6.90 (d, J=8.5 Hz, 1H), 7.20–7.24 (m, 1H), 7.43 (s, 1H), 7.44 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 8.26 (s, 1H), 8.67(s, 1H). MS (APCI) m/z 460 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([N:25]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH:26]2[C:32](=[O:41])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:4][C:5]1[N:6]=[C:7]([N:25]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH:26]2[C:32](=[O:41])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: COc1ccc(-c2ccc3nc(NC(C)=O)nc(N4CCCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc3nc(N)nc(N4CCCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Yield: 77.9 %

Procedure:
A solution of 2-acetamido-4-[(N-3-methylphenylcarbamoyl)-homopiperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine (110 mg, 0.24 mmol) and potassium carbonate (83 mg, 0.6 mmol) in methanol (10 ml) and water (5 ml) was heated at 50° C. for 2 hours. The solvents were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a MeOH/CH2Cl2 mixture in a volume ratio of 1:30, resulting in the pure title compound (96 mg, yield: 93%) which was characterised as follows:
Reaction SMILES: [Si:1]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19]Cl)=[O:16])([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[C:21]([O-])(=[S:23])C.[K+]>C(O)C>[Si:1]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19][S:23][CH3:21])=[O:16])([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CC([O-])=S
Reactant: CCO[Si](CCCNC(=O)NCCCl)(OCC)OCC
Agent: [K+]
Solvent: CCO
Product: CCO[Si](CCCNC(=O)NCCSC)(OCC)OCC
Temperature: 25 °C
Yield: 96.5 %

Procedure:
(EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—Cl (81.52 g, 0.25 mol, 1.00 eq) is initially charged in ethanol (85 ml) in a 500 ml three-neck flask with stirrer, reflux condenser and internal thermometer. Potassium thioacetate (28.48 g, 0.25 mol, 1.00 eq) is added and the mixture is heated to reflux. After a reaction time of 3.5 h, the mixture is cooled to room temperature and the suspension is filtered. The filtrate is freed of the solvent on a rotary evaporator and dried under reduced pressure. The (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—S—CH3 product (81.64 g, 89% of theory) is obtained as a light brown solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:16]=1)=O)C>C1COCC1>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:12]([CH2:10][OH:9])[S:13][CH:14]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To an ice-cold suspension of LAH (0.056 g, 1.40 mmol) the 8 ml of anhydrous THF was added dropwise a solution of 4-(4-Trifluoromethyl-phenyl)-thiazole-2-carboxylic acid ethyl ester (0.21 g, 0.71 mmol) in the 5 ml of THF. The reaction mixture was stirred at 25° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), cooled the reaction mixture to 0° C. and quenched with 2.5 ml of water followed by the addition of 15% NaOH solution (2 mL) and finally 4 ml of water. The resulting solution was filtered through celite bed and the filtrate was concentrated under reduced pressure. Water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to give the desired product (0.13 g, 70%). The other derivatives were also prepared by the same general method.
Reaction SMILES: [F:1][C:2]([F:35])([CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][CH2:4][C@H:5]1[C@H:9]([O:10]C2CCCCO2)[CH2:8][C:7](=[O:17])[C@@H:6]1[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>C(O)(=O)C.O.C1COCC1>[F:1][C:2]([F:35])([CH2:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:3][CH2:4][C@H:5]1[C@H:9]([OH:10])[CH2:8][C:7](=[O:17])[C@@H:6]1[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](OC2CCCCO2)[C@@H]1CCC(F)(F)COc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1CCC(F)(F)COc1ccccc1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,3R)-2-(3,3-Difluoro-4-phenoxybutyl)-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid, prepared in Step H, is dissolved in a (4:2:1) solution of acetic acid-water-THF (0.5 M). The solution is stirred for several days at room temperature until the reaction is complete, as judged by TLC. The crude product is purified by flash chromatography on regular silica gel using ethyl acetate-hexane-acetic acid as eluent to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)=O>CN(C)P(N(C)C)(N(C)C)=O>[C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCc2ccccc2)cc1

Procedure:
A solution of 34.9 g. of ethyl p-aminobenzoate, 26.9 g. of 6-phenylhexanol O-methanesulfonate (prepared as described in Example 47) and 200 ml. of hexamethylphosphoramide is heated at 110° C. in an oil bath for 20 hours. The mixture is cooled, diluted with 100 ml. of water and filtered. The solid is washed with 60 ml. of ethanol-water (1:1) to give crude ethyl 4-(6-phenylhexylamino)benzoate. Purification gives the product as crystals, m.p. 69.5°-72.5° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1.[C:16](Cl)(Cl)(Cl)Cl>>[CH3:5][O:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ncccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (50 ml.) was added to 2-methoxypyridine-3-carboxylic acid (5 g.) in 50 ml. of carbon tetrachloride and the mixture refluxed for 2 hours. The reaction mixture was cooled, evaporated to solids and chased with multiple portions of fresh carbon tetrachloride. The resulting acid chloride hydrochloride was dissolved in excess methanol (50 ml.), stirred for 16 hours at room temperature, then evaporated an oil and taken up in chloroform. The chloroform solution was washed with two portions of saturated sodium bicarbonate and then one portion of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [4.63 g.; pnmr/CDCl3 /delta (ppm): 3.9 and 4.1 (2s, 6H), 6.9 (m, 1H), 8.2 (m, 2H)].
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]1[CH3:33])=[O:4].[CH3:34][CH:35]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])=[N:42][CH:43]=1)[CH3:36]>>[F:24][C:22]([F:25])([F:23])[C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:41]4[CH:40]=[CH:39][C:38]([O:37][CH:35]([CH3:34])[CH3:36])=[CH:43][N:42]=4)([CH3:51])[NH:48][C:47]3=[O:49])[C@@H:6]([CH3:33])[CH2:7]2)=[C:12]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([OH:26])[C:18]([F:19])([F:21])[F:20]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@@H](C)C1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)nc1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)[C@@H](C)C1

Procedure:
(S)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propyl phenyl}-2-methylpiperazin-1-yl)ethanone and 5-[5-(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8].BrCCCCC(OCC)=O>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:17]=[CH:2][CH:3]=[CH:4][C:5]=1[O:18][CH2:19][C:20]([F:22])([F:23])[F:21]
Reactant: O=C(NCc1ccccn1)c1cc(O)ccc1OCC(F)(F)F
Agent: CCOC(=O)CCCCBr
Product: O=C(NCc1ccccn1)c1ccccc1OCC(F)(F)F

Procedure:
Using the method of Example I Part A, 13.1 g (0.04 mole) of 5-hydroxy-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide was reacted with 11.7 g (0.056 mole) of ethyl 5-bromovalerate to give 13.7 g of white 5-(4-ethoxycarbonylbutoxy))-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide, m.p. 83°-84° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Oc1ccccc1)c1cc(F)c(F)cc1F
Reaction time: 2 h

Procedure:
A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL) was cooled in ice bath and treated with N,N-diisopropylethylamine (34 mL, 193 mmol) followed by dropwise addition of 2,4,5-trifluorobenzoyl chloride (25 g, 129 mmol) over a period of 15 minutes. The ice bath was removed, stirring was continued for two hours at room temperature and the solution was then transferred to a separatory funnel and the organic layer was washed successively with hydrochloric acid solution (2N, 150 mL), saturated aqueous sodium bicarbonate solution (150 mL), and brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and the resulting solid product was purified on silica in portions by eluting successively with hexane, and then 0-5% ether in hexane in a gradient fashion to yield phenyl 2,4,5-trifluorobenzoate as white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:19]([CH2:28][C:29]([O-:31])=O)[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:10]2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:54][C:55]1[CH:60]=[C:59]([CH3:61])[CH:58]=[CH:57][C:56]=1[NH2:62]>C(OCC)(=O)C.O.CN(C=O)C>[Cl:54][C:55]1[CH:60]=[C:59]([CH3:61])[CH:58]=[CH:57][C:56]=1[NH:62][C:29]([CH2:28][CH:19]([C:5]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:8]([CH:9]2[CH2:10][CH:11]([CH2:13][CH:14]([CH2:15][CH3:16])[CH2:17][CH3:18])[CH2:12]2)[O:7][N:6]=1)[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[O:31]
Reactant: CCC(CC)CC1CC(c2onc(C(CC(=O)[O-])CC(=O)OC(C)(C)C)c2C2CC2)C1
Reactant: Cc1ccc(N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)CC1CC(c2onc(C(CC(=O)Nc3ccc(C)cc3Cl)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mono-tert-butyl 3-{4-cyclopropyl-5-[3-(2-ethylbutyl)cyclobutyl]isoxazol-3-yl}glutarate (150 mg) and DMF (1.5 mL) were mixed. To the mixture were added HOBt.H2O (63.5 mg), WSC.HCl (79.6 mg) and 2-chloro-4-methylphenylamine (0.0512 mL). The mixture was stirred at RT overnight. To the reaction mixture was added ethyl acetate. The mixture was washed with aqueous 10 w/v % citric acid, water, saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: ethyl acetate/hexane=1/6) to give the title compound (122 mg).
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[CH:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:42])[NH:20][CH2:21][C:22]([N:24]([CH2:31][C:32]([N:34]([CH3:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH:15]=[CH:16][CH:17]=1)=O>O.CO>[OH:9]/[N:8]=[CH:10]/[C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:42])[NH:20][CH2:21][C:22]([N:24]([CH2:31][C:32]([N:34]([CH3:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH:15]=[CH:16][CH:17]=1
Reactant: NO
Reactant: CN(C(=O)CN(C(=O)CNC(=O)Nc1cccc(C=O)c1)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CN(C(=O)CN(C(=O)CNC(=O)Nc1cccc(/C=N/O)c1)c1ccccc1)c1ccccc1
Yield: 48.4 %

Procedure:
0.18 g of pyridine and then 0.17 g of hydroxylamine hydrochloride in solution in 3 cm3 of water are added to a solution of 1 g of 2-{2-[3-(3-formylphenyl)ureido]-N-phenylacetamido}-N-methyl-N-phenylacetamide in 6 cm3 of methanol. The mixture is heated under reflux for 3 hours. After cooling, the insoluble product is separated off by filtration, washed with 3 times 3 cm3 of water and air-dried. After recrystallization from a dimethylformamide/water mixture (50/50 by volume), 0.5 g of (E)-2-{2-[3-(3-hydroxyiminomethylphenyl)ureido]-N-phenylacetamido}-N-methyl-N-phenylacetamide melting at 219° C is obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=O)=[CH:20][C:19]=3[CH:30]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:53][C:54]1[CH:59]=[CH:58][C:57]([C@@H:60]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=2)[OH:61])=[CH:56][CH:55]=1>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:53][C:54]4[CH:59]=[CH:58][C:57]([C@H:60]([OH:61])[C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=5)=[CH:56][CH:55]=4)=[O:29])=[CH:20][C:19]=3[CH:30]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc([C@H](O)c2ccccn2)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4ccccn4)cc2)CCN3C=O)cc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (280 mg) and 1-hydroxybenzotriazole (0.14 g) in DMF (10 ml), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g) was added at room temperature, and the mixture was stirred for 1 hour. To the reaction solution, a solution of (S)-(4-aminophenyl)-(2-pyridyl) methanol (150 mg) and triethylamine (0.28 ml) in DMF (10 ml) were added dropwise. The mixture was stirred for 4 days at room temperature, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 75) (247 mg) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([O:5][C:6]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([C:19](=O)[NH2:20])=[CH:17][C:16]([Cl:22])=[C:15]([Cl:23])[N:14]=2)[CH2:8][CH2:7]1)=[O:4].O=P(Cl)(Cl)Cl.N1C=CC=CC=1>CC#N.[OH-].[Na+]>[F:24][C:2]([F:1])([F:25])[C:3]([O:5][C:6]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][C:16]([Cl:22])=[C:15]([Cl:23])[N:14]=2)[CH2:8][CH2:7]1)=[O:4]
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1OCCCC1(OC(=O)C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)c(Cl)nc1OCCCC1(OC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To the crude 1-(3-(3-carbamoyl-5,6-dichloropyridin-2-yloxy)propyl)cyclopropyl 2,2,2-trifluoroacetate in MeCN (20 mL) was added POCl3 (700 mg, 4.6 mmol) and pyridine (720 mg, 9 mmol) at room temperature. After being stirred for 2 h at room temperature, the mixture was diluted with 30 mL of sodium hydroxide solution, then extracted with ethyl acetate (2×50 mL), the combined organic layers were washed with brine twice, dried over Na2SO4, concentrated and purified by column chromatography (silica gel, Petroleum ether:EtOAc=1:0 to 10:1) to give the product 1-(3-(5,6-dichloro-3-cyanopyridin-2-yloxy)propyl)cyclopropyl 2,2,2-trifluoroacetate (0.87 g, 97%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.68 (s, 1H), 4.39 (t, 2H, J=6.4 Hz), 1.90 (m, 4H), 1.05 (t, 2H, J=6.8 Hz), 0.84 (t, 2H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:31][C:32]4[N:33]=[C:34]([CH3:37])[S:35][CH:36]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1csc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (448 mg, 1.4 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (676 mg, 4.9 mmol) in DMF (10 ml) was stirred at ambient temperature for 10 minutes. 4-Chloromethyl-2-methylthiazole hydrochloride (310 mg, 1.68 mmol) was added and the mixture was heated at 70° C. for 3.5 hours. The reaction mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by column chromatography eluting with a mixture of methylene chloride/acetonitrile/methanol (50/45/5 followed by 50/40/10). The resulting purified solid was dissolved in methylene chloride/methanol and a solution of 5M hydrogen chloride in isopropanol (1 ml) was added. Partial evaporation led to the precipitation of a white solid. This solid was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline hydrochloride (240 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][N:20]3[C:24](=[O:25])[CH2:23][O:22][C:21]3=[O:26])[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[NH3:27]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:26])[O:22][CH2:23][C:24]([NH2:27])=[O:25])[CH2:16][CH2:17]1)[CH:6]=[CH:5]2
Reactant: N
Reactant: O=C1COC(=O)N1CCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Solvent: CO
Product: NC(=O)COC(=O)NCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 3 (step 3.4). Starting with 1.28 g (3.42 mmol) of 3-{2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 10.3, and 22.10 ml (154.08 mmol) of a solution (7M) of aqueous ammonia in methanol, and after crystallization from ethanol, 0.64 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=3[CH:12]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:11]([CH2:28][CH:29]3[CH2:33][CH2:32][O:31][CH2:30]3)[C:10]2=[O:34])[CH:6]=[CH:7][CH:8]=1.ClCC1C=[CH:43][N:42](C)[C:41](=O)C=1>>[F:1][C:2]([F:35])([F:36])[C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=3[CH:12]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:11]([CH2:28][C:29]3[CH:30]=[CH:41][N:42]([CH3:43])[C:32](=[O:31])[CH:33]=3)[C:10]2=[O:34])[CH:6]=[CH:7][CH:8]=1
Reactant: Cn1ccc(CCl)cc1=O
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC2CCOC2)cc1
Product: Cn1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C2c2ccc(C#N)cc2)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound is prepared in analogy to 4-(1-(3-(trifluoromethyl)phenyl)-2,5-dioxo-3-((tetrahydrofuran-3-yl)methyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)benzonitrile (example 25), using 4-(chloromethyl)-1-methylpyridin-2(1H)-one as alkylating agent and stirring the reaction mixture at room temperature for 24 h. Yield: 60 mg; ESI mass spectrum [M+H]+=533; Retention time HPLC: 0.84 min (Z011_S03).
Reaction SMILES: [NH:1]([C:37](OC(C)(C)C)=[O:38])[C@H:2]([C:6]([N:8]1[CH2:36][CH2:35][CH2:34][C@H:9]1[C:10]([NH:12][C@H:13]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4].Cl.CCOC(C)=O.[NH:51]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[C@H:52](C(O)=O)[CH2:53][C:54](=[O:56])[NH2:55].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:51]([C:60]([O:62][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)=[O:61])[C@H:52]([C:37]([NH:1][C@H:2]([C:6]([N:8]1[CH2:36][CH2:35][CH2:34][C@H:9]1[C:10]([NH:12][C@H:13]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4])=[O:38])[CH2:53][C:54](=[O:56])[NH2:55]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared from 3.0 g of Boc-Thr-Pro-Arg(NO2)-OBzl, 15 ml of 4N HCl-AcOEt, 1.2 g of Z-Asn-OH, 1.2 g of HOBt and 1.1 g of DCC in the same manner as in Example 7-(3).