Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[C:13]1[C:22]2[C:17](=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:13]1[C:22]2[C:17](=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Product: Cc1[nH]c2ccc(F)cc2c1-c1ccnc2c(C(F)(F)F)cccc12

Procedure:
The sub-title compound was prepared from 5-fluoro-2-methylindole and 4-chloro-8-trifluoromethylquinoline by the method of Example 31, step a).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:15]=[CH:14][NH:13][N:12]=3)=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].Br[C:33]1[CH:34]=[CH:35][C:36]([Cl:45])=[C:37]([CH2:39][NH:40][C:41](=[O:44])[O:42][CH3:43])[CH:38]=1>O1CCOCC1.[Cu]I>[Cl:45][C:36]1[CH:35]=[CH:34][C:33]([N:13]2[CH:14]=[CH:15][C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][CH2:4][C:5]=4[CH:10]=3)=[N:12]2)=[CH:38][C:37]=1[CH2:39][NH:40][C:41](=[O:44])[O:42][CH3:43]
Reactant: c1cc(-c2ccc3c(c2)CCCO3)n[nH]1
Reactant: COC(=O)NCc1cc(Br)ccc1Cl
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)NCc1cc(-n2ccc(-c3ccc4c(c3)CCCO4)n2)ccc1Cl
Temperature: 95 °C

Procedure:
To a solution of 3-(3,4-dihydro-2H-1-benzopyran-6-yl)-1H-pyrazole (i.e. the product of Step A) (600 mg, 3 mmol) in dioxane (50 mL) under nitrogen atmosphere, was added trans-N,N′-dimethylcyclohexane-1,2-diamine (86 mg, 0.6 mmol), followed by the addition of copper(I) iodide (114 mg, 0.6 mmol) and potassium carbonate (2.48 g, 18 mmol) to form a dark green-colored reaction mixture. To this reaction mixture was added methyl N-[(5-bromo-2-chlorophenyl)methyl]carbamate (1.2 g, 4.5 mmol; prepared according to U.S. Pat. No. 6,313,071), and the reaction mixture was heated at 95° C. under nitrogen overnight. The reaction mixture was then concentrated and purified by silica gel column chromatography using 20% ethyl acetate in petroleum ether as eluant to provide the title product, a compound of the present invention, as a solid (110 mg).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][NH:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:20][C:21]2[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35]([C:24]2[N:23]=[CH:22][C:21]([O:20][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:29])=[O:28])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:26][CH:25]=2)=[CH:34][CH:33]=1
Reactant: CCCCCC(Oc1ccc(Cl)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCCCCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 62 starting from 3-{4-[1-(6-chloro-pyridin-3-yloxy)-hexyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS: 513.3 [M−H]−; Isomer 2 MS: 513.3 [M−H]−.
Reaction SMILES: O[C:2]([CH:11]([CH3:13])[CH3:12])([CH:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3](O)=[O:4].CCCCCC.C(OCC)(=O)C>C(OC(=O)C)(=O)C>[CH:11]([C:2]1[C:3]([O:8][C:7](=[O:9])[C:6]=1[CH3:10])=[O:4])([CH3:13])[CH3:12]
Reactant: CC(C)C(O)(C(=O)O)C(C)C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC1=C(C(C)C)C(=O)OC1=O
Temperature: 110 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
The 2-hydroxy-2-isopropyl-3-methylsuccinic acid thus obtained was dissolved in acetic anhydride (30 mL), and stirred at 110° C. for 15 h. The acetic anhydride was evaporated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 19:1) to give 203 mg of the title compound as oil (yield: 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1>C(CN)O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:9][CH2:4][CH2:3][OH:2])[C:12]=2[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Solvent: NCCO
Product: COc1ccccc1N1CCc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Temperature: 190 °C
Yield: 165.3 %

Procedure:
1-(2-methoxyphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.5 mmol) was dissolved in ethanolamine(6 ml) in the pressure tube, then refluxed at 190° C. for 3 hours. The solvent was removed by distillation under reduced pressure, then the residue was diluted in dichloromethane(20 ml), and washed with water (15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 520 mg of desired compound as solid in 83% of yield.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14]>Cl>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:10]1[CH2:11][CH2:12][CH2:13][OH:14]
Reactant: O=C(O)CCCCl
Reactant: Nc1ccccc1N
Agent: Cl
Product: OCCCc1nc2ccccc2[nH]1
Yield: 42.6 %

Procedure:
A mixture of 1,2-Phenylenediamine (1.0 g, 12.0 mmol) and 4-chlorobutyric acid (1.5 mL, 15.17 mmol) were refluxed in 4N HCl (13 mL) for 16 hours under N2 to give the title compound as white solid (900 mg, 50%). 1H NMR (CD3OD) □ 2.04-2.08 (m, 2H), 2.97 (t, 2H, J=7.8 Hz), 5.64 (t, 2H, J=6.6 Hz), 7.15-7.21 (m, 2H), 7.47-7.49 (m, 2H); ES-MS m/z 177.1 (M+H).
Reaction SMILES: C(N(CC)C(CCCC(NF)C)CC)C.CCN([C:21]1[CH:26]=[CH:25][C:24]2[C:27]3([C:37]4[CH:43]=[C:42](Cl)[CH:41]=[CH:40][C:38]=4[O:39][C:23]=2[CH:22]=1)OC(=O)C1C3=CC=CC=1)CC.CC1C=C2OC3C=C(N4CCCCC4)C=CC=3C3(OC(=O)C4C3=CC=CC=4)C2=CC=1NC1C=CC=CC=1.CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=O)C1C3=CC=CC=1)C1C=CC(C)=CC=1>>[CH:43]1[C:37]2[CH2:27][C:24]3[C:23](=[CH:22][CH:21]=[CH:26][CH:25]=3)[O:39][C:38]=2[CH:40]=[CH:41][CH:42]=1
Reactant: CCN(CC)c1ccc2c(c1)Oc1ccc(Cl)cc1C21OC(=O)c2ccccc21
Agent: CCC(CCCC(C)NF)N(CC)CC
Agent: CCN(c1ccc(C)cc1)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Agent: Cc1cc2c(cc1Nc1ccccc1)C1(OC(=O)c3ccccc31)c1ccc(N3CCCCC3)cc1O2
Product: c1ccc2c(c1)Cc1ccccc1O2

Procedure:
Rhodamine B aniline lactam, rhodamine B-p-chloroanilino lactam, 3-diethylamino-7-dibenzylaminofluoran, 3-diethylamino-7-octylaminofluoran, 3-diethylamino-7-phenylfluoran, 3-diethylamino-7-chlorofluoran, 3-diethylamino-6-chloro-7-methylfluoran, 3-diethylamino-7-(3,4-dichloroanilino)fluoran, 3-diethylamino-7-(2-chloroanilino)fluoran, 3-diethylamino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tolyl)amino-6-methyl-7-anilinofluoran, 3-piperidino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tolyl)amino-6-methyl-7-phenethylfluoran, 3-diethylamino-7-(4-nitroanilino)-fluoran, 3-dibutylamino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-propyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-isoamyl)amino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-cyclohexyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tetrahydrofuryl)-amino-6-methyl-7-anilinofluoran, 3-dipentylamino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-p-tolyl)amino-6-methyl-7-anilinofluoran, and so on.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[CH3:36][N:37]1[C:41]([CH3:42])=[CH:40][C:39]([CH2:43]O)=[N:38]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:14](=[O:23])[N:13]([CH2:43][C:39]3[CH:40]=[C:41]([CH3:42])[N:37]([CH3:36])[N:38]=3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NC(=O)N2c1ccccc1Cl
Reactant: Cc1cc(CO)nn1C
Product: Cc1cc(CN2C(=O)N(c3ccccc3Cl)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)nn1C

Procedure:
The title compound, MS: m/e=627.1 (M+), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 1,5 -dimethylpyrazole-3-methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(OC)N(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12](=[CH:6][N:8]([CH3:13])[CH3:9])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: COC(OC)N(C)C
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (10 g, 50 mmol) was dissolved in dimethyl formamide dimethylacetal (50 mL) and heated to reflux for 1.25 h. The solution was cooled, concentrated, and purified by flash chromatography to give 2.55 g (19%). Mass spec.: 255.16 (MH)+.
Reaction SMILES: C1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([SH:22])[CH:19]([SH:21])[CH3:20].[C:23]1([CH2:29][CH:30]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:29]([CH:30]1[S:21][CH:19]([CH3:20])[CH2:18][S:22]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=CCc1ccccc1
Reactant: CC(S)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC1CSC(Cc2ccccc2)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100 cc reaction flask equipped with reflux condenser, magnetic stirring bar and thermometer and hot plate equipped with magnetic stirring apparatus is placed 5 ml cyclohexane, 0.2 grams of para-toluenesulfonic acid and 5.4 grams (0.05 moles) of 1,2-propanedithiol. With stirring, over a period of 30 minutes, 6 grams (0.05 moles) of phenylacetaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and refluxed for a period of 8 hours. During the refluxing period, water of reaction is removed. At the end of the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The resulting filtrate is distilled on a Microvigreux column yielding the following three fractions:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH2:19][CH2:20][CH3:21]>C(C(C)=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)[CH2:19][CH2:20][CH3:21]
Reactant: Oc1cccc2cc[nH]c12
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1cccc2cc[nH]c12
Temperature: 55 °C
Yield: 90 %

Procedure:
To a stirred solution of 7-hydroxyindole and potassium carbonate (325 mg, 2.35 mmol) in methyl ethyl ketone (2.4 mL) was added iodobutane (1.24 mL, 10.8 mmol) at room temperature. After the mixture was heated at 55° C. for 12 h the solvent was removed and water was added. The mixture was extracted with EtOAc (3 times), dried over anhydrous MgSO4, filtered and evaporated. After chromatographic purification on silica gel, 7-n-butoxyindole was obtained in 90% yield (310 mg). 1H NMR (500 MHz, CDCl3) δ 8.39 (1H, brs), 7.23 (1H, d, J=8.0 Hz, 7.17 (1H, t, J=3.0 Hz), 7.01 (1H, t, J=7.5 Hz), 6.63 (1H, d, J=7.0 Hz), 6.53 (1H, t, J=2.5 Hz), 4.14 (2H, t, J=5.2 Hz), 1.88-1.80 (2H, m), 1.59-1.50 (2H, m), 1.00 (3H, t, J=7.0 Hz).
Reaction SMILES: [C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>>[C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15]([NH:21][NH2:22])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A suspension of 21.6 g of 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 80 cc of hydrazine hydrate is boiled at reflux at an oil bath temperature of 110° for 1 hour. After a reaction time of approximately 15 minutes the material dissolves completely. The crude title compound resulting after cooling the mixture, is washed with a small amount of absolute ethanol and dissolved in 60 cc of dimethyl formamide. 60 cc of absolute ethanol are added to the solution, whereupon the title compound crystallizes. M.P. 220°-223° (decomp.).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17](O)=[O:18].C([N:23](CC)CC)C.C(Cl)(=O)OCC.N>C(Cl)(Cl)Cl.O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([NH2:23])=[O:18]
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1S2
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C(N)=O)c1ccc2c(c1)CCc1ccccc1S2
Reaction time: 0.17 h

Procedure:
An amount of 55 mg of 2-(10,11-dihydro dibenzo[b,f]thiepin-2-yl)-propionic acid was dissolved in 0.5 ml of chloroform solution containing 0.02 ml of triethylamine and the resulting mixture was added dropwise with ice-cooling over a period of 5 minutes to 0.5 ml of chloroform solution containing 0.02 ml of ethyl chlorocarbonate. The mixture was stirred for 10 minutes at the same temperature, then at room temperature for 30 minutes after introduction of ammonia gas. After the completion of the reaction, to this was added water and the resulting mixture was extracted with chloroform. The extract was washed with dilute sodium hydroxide solution, then saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale brown crystals, which were chromatographed over silica gel, eluted with chloroform, and there were obtained pale yellow crystals. These were recrystallized from benzene-n-hexane to give 26 mg of 2-(10,11-dihydro dibenzo[b,f]thiepin-2-yl)-propionamide as colorless crystals having a melting point of 135°-135.5° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[CH3:23][CH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=O>>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][N:18]([CH:25]4[CH2:26][CH2:27][CH2:28][CH:24]4[CH3:23])[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reactant: CC1CCCC1=O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCCC2C)CC3)nc1

Procedure:
Example 224 (E224) was prepared from N-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) and 2-methyl cyclopentanone using the method described for Example 223; MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:49])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([N:38](C=O)[CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:25](=[O:37])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)(C)(C)C.Cl>CO>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:49])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:25](=[O:37])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(C(=O)Nc2ccc(C(F)(F)F)cc2)N(C=O)CCN2CCOCC2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccccc1NC(=O)/C=C/c1ccc(C(NCCN2CCOCC2)C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Yield: 23.7 %

Procedure:
(E)-[2-(3-{4-[[Formyl-(2-morpholin-4-yl-ethyl)-amino]-(4-trifluoromethyl-phenylcarbamoyl)-methyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (300 mg, 0.432 mmol) was treated with 1.25M HCl in methanol (2.6 mL) at room temperature overnight. The reaction was quenched slowly with solid sodium bicarbonate until the pH was 6-7. The mixture was diluted in acetonitrile with a small amount of dimethylsulfoxide, passed through a 40 μm pipette filter, and then purified by preparative HPLC to obtain the desired product (58 mg, 24%). MS: calc'd 568 (MH+) exp 568 (MH+). 1H NMR (d6-DMSO, 400 MHz) δ 10.6 (broad s, 1H), 9.40 (s, 1H), 7.84 (d, 2H, J=8.4 Hz), 7.69 (d, 2H, J=8.4 Hz), 7.62 (d, 2H, J=8.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 7.53 (d, 1H, J=15.6 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.91 (t, 1H, J=7.6 Hz), 6.89 (d, 1H, J=15.6 Hz), 6.75 (d, 1H, J=7.2 Hz), 6.58 (t, 1H, J=7.2 Hz), 4.94 (broad s, 2H), 4.51 (broad s, 1H), 3.59 (m, 4H), 3.45 (m, 2H), 2.66 (m, 2H), 2.33 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][N:29]=1.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:28]2[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]3[CH:42]=[CH:41][N:40]=[N:39]3)=[CH:30][N:29]=2)[N:18]=1
Reactant: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2F)n1
Reactant: Clc1ncc(CCCCn2ccnn2)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(COc2ncc(CCCCn3ccnn3)cn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.100 g, 0.35 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by the addition of sodium tert-butoxide (NaOtBu) (0.041 g, 0.42 mmol). After stirring for 15 min at r.t. 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.075 g, 0.32 mmol) is added slowly and stirred for further 3 h at r.t. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 97:3) 2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine is obtained as a colorless solid. Yield 0.104 g (75%).
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.[NH:9]1[CH2:13][CH2:12][C:11]2([N:18]3[CH:19]=[N:20][CH:21]=[C:17]3[CH2:16][CH2:15][CH2:14]2)[CH2:10]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[O:1]1[C:5]([C:6]([N:9]2[CH2:13][CH2:12][C:11]3([N:18]4[CH:19]=[N:20][CH:21]=[C:17]4[CH2:16][CH2:15][CH2:14]3)[CH2:10]2)=[O:8])=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1cnco1
Reactant: c1ncn2c1CCCC21CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cnco1)N1CCC2(CCCc3cncn32)C1
Temperature: 25 °C

Procedure:
1.5 mmol of oxazole-5-carboxylic acid [118994-90-4] are dissolved in 5 ml of dichloro-methane and the solution is admixed at 0° C. with 1.6 mmol of chlorenamine. The reaction solution is subsequently stirred at room temperature for an hour and then added dropwise at 0° C. to a solution of 1 mmol of 7,8-dihydro-6H-spiro[imidazo[1,5-a]pyridine-5,3′-pyrrolidine] (Example 3a) and 2 mmol of triethylamine in 5 ml of dichloromethane. The reaction mixture is subsequently stirred at room temperature for 3 hours, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3×). The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(O)(=O)C>[Fe].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)ccc1Br
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of 1-bromo-2-methoxy-4-nitrobenzene (3.0 g, 12.9 mmol) and glacial acetic acid (25 ml) was heated at 100° C. under an atmosphere of nitrogen. Iron powder (2.2 g, 38.8 mmol) was added and the mixture was stirred for one hour at a temperature of 100° C. The mixture was cooled to ambient temperature, water (100 ml) was added and the mixture was then extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3×25 ml) and then brine. The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (6:4) as an eluent yielded 4-bromo-3-methoxyaniline (1.22 g): 1H NMR (DMSO-d6, 400 MHz) δ 7.1 (d, 1H), 6.31 (s, 1H), 6.1 (d, 1H), 5.27 (bs, 2H), 3.72 (s, 3H); TLC (heptane/ethyl acetate 1:1) Rf 0.33; RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=11.05 min.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6]=2[C:5]([CH:11]=O)=[C:4]([CH3:13])[C:3]=1[CH3:14]>CC(C)=O>[CH3:1][C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6]=2[C:5]([CH:11]=[CH:5][C:6](=[O:7])[CH3:10])=[C:4]([CH3:13])[C:3]=1[CH3:14]
Reactant: Cc1c(C)c(C=O)c2c(c1C)CCO2
Solvent: CC(C)=O
Product: CC(=O)C=Cc1c(C)c(C)c(C)c2c1OCC2

Procedure:
1-(2,3-Dihydro-4,5,6-trimethylbenzo[b]furan-7-yl)but-1-en-3-one was prepared from 2,3-dihydro-4,5,6-trimethylbenzo[b]furan-7-carboxaldehyde and acetone following essentially the same procedure as that described in Example 1 part (i), and was obtained as a pale brown solid, mp 116° C.
Reaction SMILES: C([O:4][C:5](=[O:52])[C@H:6]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][P:33]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])=[C:28]([N:49]=[N+:50]=[N-:51])[CH:27]=1)[NH:7][C:8]([O:10][CH2:11][CH:12]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])C=C.CNC1C=CC=CC=1.CCOC(C)=O.OS([O-])(=O)=O.[K+]>C1COCC1>[C:8]([NH:7][C@H:6]([C:5]([OH:52])=[O:4])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][P:33]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:34])=[C:28]([N:49]=[N+:50]=[N-:51])[CH:27]=1)([O:10][CH2:11][CH:12]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OP(=O)(Cc2ccccc2)Cc2ccccc2)c(N=[N+]=[N-])c1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CNc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)ccc1OP(=O)(Cc1ccccc1)Cc1ccccc1
Yield: 44.1 %

Procedure:
Fmoc-3-azido-O-(dibenzylphosphoryl)tyrosine allyl ester 11 (969 mg, 1.30 mmol) was dissolved in dry THF (10 mL), after which N-methylaniline (0.42 mL, 3.9 mmol) and tetrakis triphenylphosphine palladium (75 mg, 0.065 mmol) were added. After stirring for 2 h at room temperature under a N2-atmosphere in the dark, EtOAc (30 mL) and 1M KHSO4 (30 mL) were added. After drying on Na2SO4 and column chromatography (3% MeOH in DCM), the product (386 mg, 42%) was obtained as a white foam.