Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[CH3:25][O:26][CH2:27][C:28](Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:28]2[CH2:27][O:26][CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Solvent: C1CCOC1
Product: COCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in Tetrahydrofuran (THF) (8001) at 0° C. was added methoxyacetyl chloride (49.7 μl, 0.545 mmol). The mixture was stirred at room temperature overnight, then quenched with methanol and concentrated. The residue was purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-5-[(methyloxy)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (16 mg, 14%); LC/MS: MS (ES+) m/e 421 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H), 3.23 (s, 3H), 3.49-3.54 (m, 4H), 3.57-3.65 (m, 4H), 4.36 (s, 2H), 5.54 (s, 2H), 6.54 (d, J=7.6 Hz, 1H), 7.14 (m, 1H), 7.37 (d, J=7.8 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[ClH:25]>CO>[ClH:25].[NH:16]1[CH2:15][CH:14]([O:13][C:8]2[C:7]([C:4]3[CH2:5][CH2:6][O:1][CH2:2][CH:3]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ncccc2C2=CCOCC2)C1
Agent: Cl
Solvent: CO
Product: C1=C(c2cccnc2OC2CNC2)CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To tert-butyl 3-((3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)azetidine-1-carboxylate (see PREPARATION P25.1; 2.3 g, 6.9 mmol) was added 4 M HCl in MeOH (100 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed to give the title compound (1.5 g, 6.5 mmol, yield 95%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:23]1([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:29]([C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=2[OH:11])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: C=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)c1ccc(O)c(C(C)(c2ccccc2)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 4.5 h

Procedure:
To a 500 mL three-necked flask equipped with a mechanical stirrer, 40 g of 4-tert-butylphenol, 40 g of hexanes and 1.9 g of p-toluenesulfonic acid are charged. The slurry is heated to 60° C. at which time 62 g of 1,1-diphenylethylene is added. The temperature is increased to 110° C. and the hexanes are removed by distillation. After 4.5 hours, the reaction mass is cooled to ambient temperature and purified by silica gel chromatography using heptane/ethyl acetate as the eluent. Sixty (60) grams of the title compound is obtained whose structure is confirmed by 1H nmr.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]=3[CH2:25][CH2:26][CH3:27])=[O:19])[CH:12]=2)[C:7]=1[Br:34].[OH-].[Na+].O>CO>[Br:34][C:7]1[C:8]2[C:13](=[CH:12][C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:24]=3[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][CH2:4][C:3]([OH:35])=[O:2]
Reactant: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC(=O)OC)ccc3c2)cnn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC(=O)O)ccc3c2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.7 %

Procedure:
A mixture of (1-bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (0.20 g, 0.373 mmol), prepared in the previous step, 1N NaOH (373 μL, 0.373 mmol), 5 mL of water and 60 mL of methanol was stirred at room temperature for 20 h. Starting material was present by TLC. An additional 186 μL (0.186 mmol) of 1N NaOH was added and the reaction stirred at room temperature for 18 h. The reaction was filtered to remove trace solids and acidified with 1N HCl until pH 1 by litmus paper. The methanol was removed under reduced pressure. The solid formed was collected by filtration and dried under reduced pressure to give the title compound (0.13 g, 67%) as an off-white solid, mp 140-145° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][NH2:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][NH:23][CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccc(C2CO2)cc1
Product: COc1ccc(CCNCC(O)c2ccc(C)cc2)cc1OC
Temperature: 100 °C

Procedure:
Similarly a mixture of 10.6 g. (0.0789 mol) of p-methylstyrene oxide and 14.3 g. (0.0789 mol) of 3,4-dimethoxyphenylethylamine is stirred under argon and heated at 100° C. for 18 hours to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-methylphenyl)ethylamine, m.p. 99°-100° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:23][CH2:24][OH:25])[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:45].O1CCOCC1>C(Cl)Cl>[ClH:45].[ClH:45].[ClH:45].[NH2:37][C:33]1([C:30]2[CH:31]=[CH:32][C:27]([N:26]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([NH:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NCCO)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(NCCO)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.6 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[(2-hydroxyethyl)amino]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (73.0 mg, 0.123 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the minute and stirred at room temperature for 3.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (61.2 mg, 82.6%) as yellow solid.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.BrC(Br)C1C=CC([O:32]C(F)(F)F)=CC=1>C(O)C.O>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[O:32])=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: FC(F)(F)Oc1ccc(C(Br)Br)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(OC(F)(F)F)cc1

Procedure:
To a solution of hexamethylenetetramine (300 g; 2.14 mole) in ethanol (900 ml) and water (600 ml) a mixture of α-bromo-4-trifluoromethoxytoluene and α,α-dibromo-4-trifluoromethoxytoluene (300 g; 1.11 mole; 76:24 mixture) is added. The reaction mixture is stirred and heated at reflux for 3 hours under a nitrogen atmosphere, and then stirred overnight at room temperature.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[Br:1][C:2]1[C:3]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2Br)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Bromo-2-chloropyridine (10.3 g, 53.4 mmol), 4-aminophenol (7.00 g, 64.1 mmol), cesium carbonate (34.8 g, 107 mmol), and DMSO (53 ml, 53.4 mmol) were added into a pressure tube. The tube was capped and placed in a preheated oil bath at 130° C. After 16 h, the reaction mixture was stirred and cooled in ice-water. Water was added slowly to the mixture and the product precipitated out as a gray solid. The solids were washed with water, dried under vacuum at RT to afford 4-(3-bromopyridin-2-yloxy)benzenamine. MS Calcd for C11H9BrN2O: [M]+=264. Found [M+H]+=265.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[CH:19]1([C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25])[CH2:21][CH2:20]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:19]1([C:22]([C:23]2[C:24]([CH3:25])=[N:1][C:2]3[S:10][C:5]4[CH2:6][O:7][CH2:8][CH2:9][C:4]=4[C:3]=3[C:11]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:27])[CH2:21][CH2:20]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCOC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1C(=O)C1CC1)CCOC3
Temperature: 70 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a stirred solution of 100 mg (0.38 mmol) (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)-phenyl-methanone in 5 ml acetic acid was added 73 mg (0.57 mmol) of 1-cyclopropyl-butane-1,3-dione (prep. described in the patent DE 94-4404059) and one drop of sulfuric acid. The mixture was then stirred at 70° C. for 2 hours and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 3:1) afforded 50 mg (37%) cyclopropyl-(2-methyl-4-phenyl-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl)-methanone as a yellow solid. ES-MS m/e (%): 350 (M+H+, 100).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[ClH:25]>CN(C)P(N(C)C)(N(C)C)=O.CO.CCOCC>[ClH:25].[C:18]1([CH2:17][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[OH:11])[CH2:4][CH2:3][CH2:2]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1cccc2c1NCCC2
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Oc1cccc2c1N(Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2.00 g (13.4 mmol) of 1,2,3,4-tetrahydro-8-quinolinol (see Example 7A), 1.69 g (20.0 mmol, 1.5 eq.) of finely powdered sodium bicarbonate and 1.75 ml (14.7 mmol, 1.1 eq.) of benzyl bromide in 40 ml of hexamethylphosphoramide was stirred for 24 hours at room temperature under argon. The following work-up was carried out under conditions of minimum air exposure. Solvents and solutions were bubbled with nitrogen prior to use. The reaction mixture was diluted with 300 ml of 1:1 ether:petroleum ether and washed with five 100 ml portions of water and 100 ml of brine, dried over sodium sulfate and evaporated to obtain a tan solid. The solid was immediately dissolved in 10 ml of methanol, treated with 10 ml of hydrogen chloride-saturated methanol and diluted with 200 ml of ether. The precipitate was filtered, washed with ether, and dried under vacuum for 20 hours to afford 3.19 g of the title compound as an ivory solid; melting point 192°-194° C. (decomposition from 175° C.). 1H NMR indicated that this material contained 0.16 equivalents of methanol.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1.[OH-].[Li+].Cl>C1COCC1>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@H](C)O)[C@H](O)C[C@H]2Cl)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](O)CCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)O)s2)[C@H](Cl)C[C@H]1O
Yield: 60.1 %

Procedure:
A solution of 40 mg of ester 16 (0.09 mmol) in 0.72 mL of THF was hydrolyzed with 360 uL of aqueous lithium hydroxide (0.5M, 0.18 mmol)) at 23° C. for 16 h. The mixture was acidified by addition of 1N HCl and then extracted with EtOAc (2×). The combined organic portions were washed with brine (2×), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 23.3 mg (60%) of the free acid 17.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[H-].[Na+].[CH3:27]I.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:27])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C

Procedure:
To an ice-cooled and stirred solution of 4.0 g (12 mmol) of the above prepared 2-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester in 37 ml DMF was cooled (0° C.), and treated with 0.78 g (55% in oil, 18 mmol) of sodium hydride and, after 30 min, with 5.93 ml (95 mmol) of CH3I. The reaction was stirred at 0° C. to room temperature for 16 h. Subsequently, the solution was poured onto ice water, adjusted to pH 1 (with aqueous 1N HCl) and extracted with ether (two times). The organic layers were washed with water, dried (MgSO4), evaporated and purified by flash chromatography (SiO2, heptane/AcOEt=9:1) to finally give 3.68 g of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.S(=O)(=O)=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cl)cc1
Temperature: 89 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
A suspension of 50 mmol of 4-chlorobenzamide and 125 mmol of triethylamine-sulphur trioxide in 75 ml of triethylamine was stirred at 89° C. for 6 hours. The working up was effected as described under Example 1a). Yield: 92% of theory.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH2:6]1.[N+]([O-])(O)=O.C(Cl)Cl.[NH4+].[OH-]>C(Cl)Cl>[N+:1]([C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][O:5][CH2:6]2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16](=[O:18])[CH3:17])([O-:4])=[O:2]
Reactant: CC(=O)Nc1ccc(C2COC2)cc1
Reactant: O=[N+]([O-])O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2COC2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The organic phase (upper phase) was isolated and the process was repeated with an additional 20 ml CH2Cl2. The organic extracts were combined, it was assumed the organic phase contained about 5 g (−80 mmol) of anhydrous HNO3. Using a 50 fold excess, this required about 25 ml of solution. The nitric acid solution was cooled in a ice bath. The N-(4-oxetan-3-ylphenyl)acetamide (21 0 mg, 0.70 mmol) was treated with 25 ml of the chilled HNO3/CH2Cl2 solution and was allowed to stir about 30 minutes. The reaction mixture was carefully poured into 45 ml 1 0% NH4OH solution and carefully shaken. The phases were separated and the aqueous phase was washed with 20 ml CH2Cl2. The combined organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1noc2ccccc12

Procedure:
A mixture of 5.3 g of 3-ethyl-1,2-benzisoxazole, 6.4 g of N-bromosuccinimide and 50 ml of carbon tetrachloride is refluxed for 1 h. Afterwards c. 50 mg of α,α-azoisobutyro-nitrile are added and the mixture is refluxed for a further 1 h. After cooling and filtering the mixture, the filtrate is concentrated under vacuum. The crude product is purified by chromatography over silica gel with ethyl acetate/hexane (1:1) to give 3-(1-bromoethyl)-1,2-benzisoxazole as an oil.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH2:33])=[O:32].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:1]([S:19][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH2:33])=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NC(=O)CCCCCCCCCCBr
Reactant: CCCCCCCCCCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCCCSCCCCCCCCCCC(N)=O
Temperature: 100 °C

Procedure:
13.2 Grams of octadecanethiol, 14.3 g of 11-bromoundecanamide, 1.7 g of potassium iodide, 20.7 g of potassium carbonate and 100 ml of N,N-dimethylacetamide were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with heating at 100° C. for 5 hours. The reaction mixture was cooled to room temperature and, then, introduced into ice water, and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 16.4 g of the desired product. m.p. 108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[NH3:30]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH2:30])=[O:13])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Solvent: C1CCOC1
Product: NC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure I, the coupling of {6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) ammonia in THF gave the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cu][C:13]#[N:14]>CN(C)C=O>[CH3:11][O:10][C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([CH:3]=1)[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: COc1cc(Br)cnc1OC
Solvent: CN(C)C=O
Product: COc1cc(C#N)cnc1OC
Temperature: 18 °C

Procedure:
To a solution of 5-bromo-2,3-dimethoxypyridine (4-2, 0.300 g, 1.38 mmol, 1.0 equiv) in dimethylformamide (3.9 mL) was added copper (I) cyanide (0.15 gL, 1.65 mmol, 1.2 equiv) and the reaction mixture was heated for 40 minutes at 18° C. in a microwave reactor. The reaction mixture was cooled and partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (2×30 mL) and brine (1×30 mL), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (0 to 40% EtOAc in hexanes, silica) to afford the desired product (4-3) as white solid after concentration. ESI+MS[M+H]+C8H8N2O2 calc'd 165.1. found 165.1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[Cl:22][CH2:23][C:24](Cl)=[O:25].C(#N)C>CO>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)=[O:25]
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)CCl
Solvent: CO
Solvent: CC#N
Product: Cc1nc2cccc(NC(=O)CCl)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 100 °C
Yield: 88.6 %

Procedure:
The stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (4.0 g, 14 mmol) and chloroacetyl chloride (7.7 mL, 98 mmol) was heated in a 100° C. oil bath for 15 minutes. The mixture was allowed to cool to room temperature. Acetonitrile (5 mL) was added to the mixture. The suspension was filtered and washed with ethyl acetate (2×10 mL) to give a white solid. The solid was stirred in methanol (50 mL) overnight. The suspension was filtered and washed with methanol (20 mL) to give 2-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide as a white solid (4.5 g, 90% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 12.79 min (97.6%); mp: 275-277° C.; 1H NMR (DMSO-d6) δ 2.18-2.25 (m, 1H, CH2), 2.61-2.80 (m, 5H, CH3, 2CHH), 2.86-2.91 (m, 1H, CHH), 4.48-4.53 (m, 2H, CH2), 5.36 (dd, J=6, 11 Hz, 1H, NCH), 7.39 (dd, J=1, 8 Hz, 1H, Ar), 7.83 (t, J=8 Hz, 1H, Ar), 8.57 (dd, J=1, 8 Hz, 1H, Ar), 10.7 (brs, 1H, HCl), 11.11 (s, 1H, NH), 12.26 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.66, 23.10, 30.60, 43.56, 56.84, 107.89, 115.65, 120.87, 135.77, 138.87, 147.17, 155.49, 162.67, 165.55, 169.14. 172.60; LCMS: MH=363, 365; Anal Calcd for C16H15N4O4Cl+1.05HCl: C, 47.92; H, 4.03; N, 13.97; Cl, 18.12. Found: C, 48.24; H, 3.79; N, 13.84; Cl, 18.27.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2.[C:32]12([C:42](Cl)=[O:43])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2.O>N1C=CC=CC=1>[C:32]12([C:42]([O:1][C:2]3[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]4[C:3]=3[C:4](=[O:31])[O:5][CH2:6]4)=[O:43])[CH2:39][CH:38]3[CH2:37][CH:36]([CH2:35][CH:34]([CH2:40]3)[CH2:33]1)[CH2:41]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Solvent: O
Solvent: c1ccncc1
Product: COc1c(C)c2c(c(OC(=O)C34CC5CC(CC(C5)C3)C4)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (10.0 g) was dissolved in pyridine (50.0 ml) followed by the addition of 1-adamantanecarbonyl chloride (10.0 ml). The mixture was stirred at room temperature for 90 minutes, then poured into water and extracted with ethyl acetate. The organic solution was dried and evaporated to give morpholinoethyl E-6-[1,3-dihydro-4-(1-adamantoyloxy)-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl]-4-methyl-4-hexenoate.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][CH2:28][C:29](O)=[O:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:28](=[O:27])[CH2:29][OH:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)CO
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (65 mg, 67%), MS (ISP) m/z=387.4 [(M+H)+], mp 154.5° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-hydroxy-acetic acid.