Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([N:23]([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:27])([CH3:26])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:25][N:23]([CH3:24])[C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:27])([CH3:26])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N(C)C)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1cc(F)cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 34.1 %

Procedure:
A mixture of 2-(3-dimethylamino-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.11 g, 0.3 mmol), lithium hydroxide hydrate (0.12 g, 3.0 mmol), water (2 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-dimethylamino-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (35 mg, 30%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C20H23FN2O2 (M+H)+: 343.2, observed: 343.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[CH:17][C:16]=2[NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[C:35]([O:37]CC4C=CC=CC=4)[CH:34]=[N:33][C:32]=23)=[O:27])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:45])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[CH:17][C:16]=2[NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[C:35]([OH:37])[CH:34]=[N:33][C:32]=23)=[O:27])[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cc3ncccc3cc2NC(=O)c2cnn3cc(OCc4ccccc4)cnc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc3ncccc3cc2NC(=O)c2cnn3cc(O)cnc23)CC1
Reaction time: 48 h
Yield: 64.6 %

Procedure:
A mixture of (1-{6-[(6-benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (0.4 g) and palladium on carbon (10%, 50 mg) in ethanol (20 mL) was stirred under hydrogen atmosphere (balloon pressure) for 2 days. The resulting mixture was filtered over a CELITE™ pad and the filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography to afford 0.220 g of (1-{6-[(6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]([CH3:14])[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21]O)=[C:17]([CH3:23])[CH:16]=3)=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:30])=O>ClCCl.CN(C)C=O>[Cl:30][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[N:12]([CH3:14])[O:13][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[CH:16][C:17]=1[CH3:23]
Reactant: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
690 mg of {4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-methanol was dissolved in 20 ml dichloromethane and one drop of N,N-dimethylformamide was then added. Thionylchloride (216 mg) was then added very slowly at room temperature. The mixture turned slight yellow before the end of the addition. The mixture was stirred for 3 hours at ambient temperature and then evaporated to dryness. The residue was dissolved in diethylether, washed with aqueous sodium bicarbonate, then with water and finally dried over anhydrous sodium sulfate. The organic phase was then evaporated to dryness affording 3-(4-chloromethyl-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole as a resinous product (99% yield), which was used immediately for the further step without purification. 1H-NMR (CDCl3, δ in ppm): 7.29-7.44 (m, 6H), 5.36 (s, 1H), 4.60 (s, 2H), 2.99 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:3]=1[O:4][CH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[OH:9].[CH3:25]N(C)C=O.CI.[H-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:3]=1[O:4][CH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[O:9][CH3:25]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)c(OCc2ccccc2C(O)c2ccccn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: COC(c1ccccn1)c1ccccc1COc1cc(C)ccc1C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a mixture of 0.42 g (1.3 mmol) of 2-[2-(2,5-dimethylphenoxymethyl)-α-hydroxybenzyl]pyridine, 4 ml of N,N-dimethylformamide and 0.12 ml (2 mmol) of methyl iodide was added 0.07 g (1.7 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-[2-(2,5-dimethylphenoxymethyl)-α-methoxybenzyl]pyridine (0.40 g, 92.3%) as colorless oil.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27][CH3:28])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:29].Cl[O-].[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27]([CH3:28])=[O:29])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1Cl
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1Cl
Reaction time: 2 h
Yield: 71 %

Procedure:
3-butyryl-4-(2-chlorophenylamino)-8-(2-methylthioethoxy)quinoline (0.34 g, 0.82 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.37 ml) were added and the mixture was stirred for 2 h. Another portion of sodium hypochlorite (0.5 ml) was added and the stirring was continued for 2 h. The organic layer was dried over sodium sulfate and evaporated. The residue crystallized from a mixture of ethyl acetate and isopropyl ether and 0.25 g (71%) of the title compound was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][O:4][CH:3]1[C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[CH3:1][CH:2]1[CH:3]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:4][CH2:5][C:6]2([CH3:8])[CH:7]1[O:26]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CC(C)C(c2c([N+](=O)[O-])cnn2C)OC1
Solvent: ClCCl
Product: CC1C(c2c([N+](=O)[O-])cnn2C)OCC2(C)OC12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-(6-methoxy-3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole (100 mg, 0.38 mmol) in DCM (1 mL) cooled to −78° C. was added boron trifluoride diethyl etherate (0.14 mL, 1.13 mmol) and triethylsilane (0.36 mL), 2.68 mmol). After stirring at −78° C. for 1 hr, the reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Saturated aqueous NaHCO3 (5 mL) and DCM (5 mL) were added and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave 5-(3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole as a yellow oil. The reaction was repeated to provide more material. To a solution of 5-(3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole (305 mg, 1.29 mmol) in DCM (6.5 mL) cooled to 0° C. was added m-CPBA (70-75%, 382 mg, 1.54 mmol) and the mixture was stirred at 0° C. for 90 min. More m-CPBA (70-75%, 191 mg, 0.774 mmol) was added and the mixture was slowly warmed to room temperature over 6 hr. The mixture was filtered through Celite® washing with DCM (15 mL) and the filtrate washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave 5-(2,6-dimethyl-4,7-dioxabicyclo[4.1.0]heptan-3-yl)-1-methyl-4-nitro-pyrazole as a single diastereomer as an off-white solid (189 mg, 53% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 5.32-5.28 (m, 1H), 4.15-4.08 (m, 1H), 4.06 (s, 3H), 3.78 (d, J=12.9 Hz, 1H), 3.30 (d, J=5.6 Hz, 1H), 2.71-2.61 (m, 1H), 1.38 (s, 3H), 0.92 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:29](Cl)(Cl)=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][C:29]2=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2N)C1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2c(=O)[nH]c3ccccc32)C1
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 3(R)-(2-Amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (52 mg, 0.18 mmol), Et3N (1.0 ml) in CH2Cl2 (1 ml) at 0° C. was added a solution of phosgene (20% in toluene, 0.1 ml). After stirring for 2 hr and evaporation of solvent, the residue was purified by chromatography (1%-2% MeOH in CH2Cl2) to give a colorless oil (34 mg, 60%). 1H-NMR (300 MHz, CDCl3) δ 7.80 (d, 1H), 4.20 (m, 3H), 3.50 (m, 1H), 2.75 (m, 1H), 2.65 (m, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.70 (m, 1H), 1.50 (s, 9H) ppm; IR (film) 3067, 2975, 2935, 2858, 1745, 1692, 1612, 1487, 1423, 1383, 1347, 1266, 1246, 1158 cm−1; LRMS (calculated for C17H23N3O3-BOC)+ 217, found 217.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][OH:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:45][C:46]4[CH:53]=[CH:52][C:49]([CH2:50][OH:51])=[CH:48][CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: Nc1ccc(CO)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5ccc(CO)cc5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminobenzyl alcohol as the aniline component. (15%, MS=613.3 (M+H))
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[N:12])[N:5]=1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH2:12])[N:5]=1
Reactant: N#CCc1cccc(CC#N)n1
Agent: [Ni]
Solvent: CO
Product: NCCc1cccc(CCN)n1
Reaction time: 48 h
Yield: 82.9 %

Procedure:
To a solution of 2,6-bis(cyanomethyl)pyridine (4.3 g, 27 mmol) in methanol (75 ml, saturated with ammonia) was added Raney nickel (10.0 g, excess) and the mixture hydrogenated at 45 psi and room temperature for 48 hours. The catalyst was filtered off and the solvent evaporated in vacuo to give 2,6-bis(2-aminoethyl)pyridine as a brown viscous oil (3.7 g, 83%). This was used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 48 (363 mg, 1 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 332 mg (73%) of white solids. M.P. 209° C. 1H NMR (DMSO-d6): δ 3.69 (m, 4H), 3.97 (m, 4H), 5.49 (s, 2H), 6.66 (m, 1H), 7.09 (d, J=3.3 Hz, 1H), 7.22 (m, 3H), 7.32 (m, 2H), 7.45 (dd, J=4.7, 9.5 Hz, 1H), 7.55 (m, 1H), 7.69 (dd, J=2.8, 9.7 Hz, 1H), 7.88 (s, 1H). EIMS m/z 479 (M+23). Anal. (C26H21FN4O3) C, H, N.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[N:16][O:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1(C)C(C)(C)OB(C=C)O1.C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[N:16][O:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22]([CH:26]=[CH2:27])=[CH:21][CH:20]=3)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cnoc1-c1ccc(I)cc1)N1CCC(c2ccccc2)C1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 4-[(3-phenylpyrrolidin-1-yl)carbonyl]-5-(4-iodophenyl)isoxazole (50 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (50 μL, 0.78 mmol), sodium bicarbonate (20 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (2 mg, 0.002 mmol) in 1,2-dimethoxyethane/water (5 mL) was stirred at 60° C. for 1 h. The residue was purified on SiO2 (2:1 hexane/ethyl acetate) to afford the title compound (25 mg). HRMS (ESI, pos. ion) m/z calcd for C22H20N2O2: 344.1525, found 344.1521.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:48]=[CH:47][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=2[NH2:46])=[O:36])=[CH:33][CH:32]=1>>[NH2:46][C:39]1[CH:40]=[C:41]([O:44][CH3:45])[CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:47]=[CH:48][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:32][CH:33]=1)=[O:36]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: COc1ccc(NC(=O)c2ccc(CN)cc2)c(N)c1
Product: COc1ccc(NC(=O)c2ccc(CNC(=O)c3cccc4cc(Oc5ncnc6cc(OC)c(OC)cc56)ccc34)cc2)c(N)c1
Yield: 81.9 %

Procedure:
The title compound (51.6 mg, 82% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-methoxyphenyl)benzamide (32.5 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 630 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9](=[O:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+]>CCO>[CH2:1]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9](=[O:29])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN(CCc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCN(CCc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 30.3 %

Procedure:
Methyl 2-[(4-{2-[heptyl(2-phenylethyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (0.146 g, 0.291 mmol) was dissolved in EtOH (5 ml, 95%), potassium hydroxide (0.025 g, 0.437 mmol) was added. The reaction was performed in an single node microwave oven (7 min, 150° C.). Work-up was by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water-phase was extracted with two portions of EtOAc (20 ml) and the organic phase was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation to give 0.043 g of 2-[(4-{2-[heptyl(2-phenylethyl)amino]-2-oxoethyl}-phenoxy)methyl]benzoic acid (yield 30.3%).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[H-].[Na+].CS(C)=O.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1.O>[C:2](=[N:4][O:5][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([CH3:3])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)=NO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=NOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of propanone oxime (30 g, 0.4 mole) in dry tetrahydrofuran (300 ml) was added slowly to a suspension of sodium hydride (10.8 g, 0.45 mole) in dry tetrahydrofuran (50 ml). After gas evolution was complete, dimethylsulphoxide (100 ml) and 4-fluoronitrobenzene (57.85 g, 0.41 mole) were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted three times with ether. The combined ether extracts were washed with water, dried (MgSO4) and evaporated to give the title compound which was granulated in hexane and filtered, yield 67 g. A sample (7 g) was recrystallised from ethanol, yield 5 g, m.p. 104°-106°.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[OH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:32]3[CH2:33][CH2:34][C@H:30]([OH:29])[CH2:31]3)[CH2:26][CH2:27]2)=[O:21])[CH2:2][CH2:3]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Reactant: O[C@H]1CCNC1
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CC[C@H](O)C2)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (S)-3-hydroxyl-pyrrolidine in direct analogy to the general procedure used in example 129. MS: 463.3 (MH+).
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:4]1[C:5]2[S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2c1sc1ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1ncnc2c1sc1ccccc12
Temperature: 110 °C
Yield: 169.7 %

Procedure:
Benzo[4,5]thieno[3,2-d]pyrimidin-4(3H)-one (10.78 g, 26.7 mmol) was treated with pyridine (2.68 mL, 33.3 mmol) and phosphoryl trichloride (53.4 mL, 573 mmol), then heated to reflux at 110° C. for 1 hr. Excess POC3 was removed and cautiously quenched with ice water in an ice bath. The pH was adjusted to ˜5 with ammonium hydroxide. Solid was collected by filtration washed with water. The solid was dried to give 4-chlorobenzo[4,5]thieno[3,2-d]pyrimidine (10 g, 85% yield).
Reaction SMILES: [C:1]1(=[CH:5][C:6]([OH:8])=O)[CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[C:11]([O:18][CH3:19])=[CH:12][CH:13]=[C:14]([C:16]=1[CH3:17])[NH2:15].CN(C)CCCN=C=NCC.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.C(N(CC)CC)C>[C:1]1(=[CH:5][C:6]([NH:15][C:14]2[CH:13]=[CH:12][C:11]([O:18][CH3:19])=[C:10]([CH3:9])[C:16]=2[CH3:17])=[O:8])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)C=C1CCC1
Reactant: COc1ccc(N)c(C)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C=C2CCC2)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Cyclobutylideneacetic acid (3.8 g), 5,6-dimethyl-4-methoxyaniline (5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (4.7 g), 1,3-dicyclohexylcarbodiimide (DCC) (2.4 g), 4-dimethylaminopyridine (DMAP) (805 mg) and triethylamine (TEA) (7.3 g) were dissolved in dichloromethane (80 mL). The mixture was stirred at room temperature overnight, concentrated, and the residue dissolved in ethyl acetate. The organic phase was washed with water (3×20 mL) and 1M HCl (3×20 mL), and a white solid was filtered out. The organic solution was then dried out by evaporation giving 2-cyclobutylidene-N-(4-methoxy-2,3-dimethylphenyl)acetamide as a brown solid (5.3 g). The product was used in the next step without further purification. MS: (m/z)=246 (100, M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]([C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)#[N:14]>>[C:13]([C:15]1[CH:16]=[C:17]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)#[N:14]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(C#N)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-cyanobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (39.4 mg) with purity >90%. MS (pos) m/z 352.3.