Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](OC)=[O:10]>C(O)C>[Cl:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([NH:2][NH2:3])=[O:10]
Reactant: NN
Reactant: COC(=O)C(CCCCl)c1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)C(CCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl phenylacetate (2.0 g) in DMF (5 mL) was added to a solution of sodium hydride (containing mineral oil at 40%, 590 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (2.99 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product of methyl 5-chloro-2-phenylpentanoate. Hydrazine monohydrate (8 mL) was added to a solution of the resulting crude methyl 5-chloro-2-phenylpentanoate (3.279 g) in ethanol (20 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 730 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1>>[OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([N:11]([CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[CH3:10])=[O:9])[CH:3]=1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1cc(O)[nH]n1
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1cc(O)[nH]n1

Procedure:
The title compound was prepared from commercially available 5-hydroxy-1H-pyrazole-3-carboxylic acid and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) analogously to Example 15 step 3;
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C(O)=O.[OH-].[Li+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: O=CO
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 99.7 %

Procedure:
In a nitrogen atmosphere under normal pressure, 2,4-di-tert-butylphenyl methanesulfonate (500 g, 1.76 mols), formic acid (162 g, 3.52 mols), lithium hydroxide (84 g, 3.52 mols) and methanol (3000 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass % water-containing product) (100 g) (as metal palladium; 1 mass % relative to 2,4-di-tert-butylphenyl methanesulfonate) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) was put into it. With stirring, the reaction liquid was reacted at the same temperature for 2 hours. Water (100 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (500 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (334 g, yield 100%, by mass). The result is shown in Table II-2.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9](O)=[O:10])=[C:7]([CH3:12])[N:6]=[C:5]2C2C=CC(OC(F)(F)F)=CC=2)[CH2:3][CH2:2]1.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)C(Cl)=O.[N:38]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:1]1([N:4]2[C:8]([C:9]([N:46]3[CH2:47][CH2:48][CH:43]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:44][CH2:45]3)=[O:10])=[C:7]([CH3:12])[N:6]=[C:5]2[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([O:26][C:25]([F:24])([F:36])[F:37])[CH:28]=2)[CH2:3][CH2:2]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)n(C2CC2)c1C(=O)O
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: Cc1nc(-c2cccc(OC(F)(F)F)c2)n(C2CC2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 2, the title compound has been obtained by coupling of 3-cyclopropyl-5-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (prepared in analogy to the sequence described for the preparation of intermediate 7, but using 3-trifluoromethoxy-benzoyl chloride instead of 4-trifluoromethoxy-benzoyl chloride in step 7B) with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless amorphous solid. MS: 463.3 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:21]I>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:21])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(Nc2nc(C)nc3ccccc23)cc1
Reactant: CI
Product: CCc1ccc(N(C)c2nc(C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (4-ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-amine (122 mg, 0.46 mmol) and methyl iodide (0.2 ml, 3.25 mmol) by a procedure similar to example 7. 1H NMR (CDCl3): 7.74 (d, J=8.1 Hz, 1H), 7.54-7.49 (m, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.09-6.92 (m, 4H), 3.61 (s, 3H), 2.73-2.63 (m, 5H), 1.26 (d, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([C:16]1([NH2:39])[C:22](=[O:23])[N:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]1=[O:38])=O)C>>[CH:1]1([CH2:6][C:7]([NH:39][C@H:16]([C:22]([NH:39][CH:16]2[C:17](=[O:38])[N:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:19]3[CH:32]=[CH:31][CH:30]=[CH:29][C:20]=3[N:21]([CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:22]2=[O:23])=[O:23])[CH3:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)NC1C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white amorphous solid. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (2:1 gradient to 3:2). Rf=0.29 (CH2Cl2/EtOAc, 2:1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(O)C.[ClH:47]>O1CCCC1>[ClH:47].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH2:24][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:26]=1)([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN2CCCCC2)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and piperidine (0.13 mL, 1.3 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. Additional piperidine (013 mL, 1.3 mmol) and sodium triacetoxyborohydride (0.30 g, 1.4 mmol) were added and the reaction was stirred under nitrogen for 4 hours. The reaction was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a yellow syrup which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and the solid was filtered off to afford 4-(tert-butyl)-2-(piperidin-1-ylmethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (0.29 g, 62% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH:11]=[CH2:12]>[C].[Pd].CCOC(C)=O.CO>[CH2:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:2]=1[F:1])[CH3:12]
Reactant: C=Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cnccc1Oc1ccc(N)cc1F
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A solution of 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridine (80 mg, 0.30 mmol) in 1:1 EtOAc/MeOH (2 mL) was hydrogenated over 10% palladium-carbon (30 mg) for 1 h using H2 from a latex balloon. Pt2O (10 mg) was added to the mixture and the reaction continued for 1 h. The mixture was filtered through Celite® and concentrated in vacuo to give the title compound (50 mg, 63%) as a yellow oil. 1H NMR (DMSO-d6) δ 8.33 (s, 1H), 8.22 (d, 1H, J=5.6 Hz), 6.96 (dd, 1H, J=8.7, 9.1 Hz), 6.50 (dd, 1H, J=2.0, 13.7 Hz), 6.56 (d, 1H, J=5.6 Hz), 6.41 (dd, 1H, J=2.5, 6.1 Hz), 2.69 (q, 2H, J=7.6 Hz), 1.21 (t, 3H, J=7.6 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][C:8](=[O:9])[N:7]([CH3:13])[C:5]1=[O:6].Br[CH2:15][C:16](=[CH2:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(#N)C>[CH2:20]([O:19][C:17]([C:16](=[CH2:22])[CH2:15][C:10]1([CH2:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH2:15])[C:11](=[O:12])[N:4]([CH3:3])[C:5](=[O:6])[N:7]([CH3:13])[C:8]1=[O:9])=[O:18])[CH3:21]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: C=C(CBr)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: C=C(CC1(CC(=C)C(=O)OCC)C(=O)N(C)C(=O)N(C)C1=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a suspension of sodium hydride (0.75 g, 80% dispersion in oil) and 1,3-dimethylbarbituric acid (1.56 g, 0.01 mol) in acetonitrile (10 mL) was added a solution of ethyl 2-(bromomethyl)propenoate (3.86 g, 0.02 mol) in acetonitrile (5 mL). The resulting mixture was allowed to stir at room temperature under nitrogen overnight. Thin layer chromatography (ethyl acetate/petroleum spirit: 1/4) indicated all the starting materials had been consumed. Water (30 mL) was added and the slightly pink solution was extracted three times with ethyl acetate (3×30 mL). The combined organic layer was washed with water, brine and then dried over anhydrous magnesium sulfate. After removal of solvent, purification by column chromatography (silica-gel 100 g, ethyl acetate:pet. spirit 40°-60° C. 1:4) gave pure product (11) (3.20 g, 84%) as a colourless liquid which solidified when stored in the freezer. 1 H-NMR (CDCl3) δ(ppm): 1.22 (t, 6H); 3.00 (s, 4H); 3.20 (s, 6H); 4.08 (q, 4H); 5.50 (s, 2H) and 6.15 (s, 2H). 13C-NMR (CDCl3) δ(ppm): 13.9, 28.2, 39.9, 55.4, 61.0, 128.2, 135.2, 151.0, 166.2 and 169.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]([CH2:19][CH2:20][CH2:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:14]([O:16]CC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(OCC)(=O)C>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:12][CH:13]([CH2:19][CH2:20][CH2:21][S:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[C:14]([OH:16])=[O:15])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(CCCS(=O)(=O)c1ccc(OC)cc1)CS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)CCCC(CS(=O)(=O)c2ccc(OC)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-[(4-methoxybenzenesulfonyl)methyl]-5-(4-methoxybenzenesulfonyl)pentanoic acid, ethyl ester (0.70 g, 1.4 mmol) in 6N hydrochloric acid (20 ml) is refluxed overnight. The mixture is transferred to ethyl acetate which is extracted with aqueous sodium bicarbonate. The combined aqueous extract is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. This organic extract is concentrated in vacuo to yield the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:7])=[O:6].[CH3:26]I>CN(C)C=O>[CH3:3][N:4]([CH3:26])[S:5]([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:6])=[O:7]
Reactant: CI
Reactant: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(c2c[nH]c3ccc(CCS(=O)(=O)N(C)C)cc23)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (60% w/w with paraffin; 124 mg) was added cautiously to a stirred solution the product of Example 1 in dry dimethylformamide (20 ml). The resultant mixture was stirred at room temperature under nitrogen for 0.25 h then a solution of methyl iodide (440 mg) in dry dimethylformamide (1 ml) was added in a stream. The mixture was stirred at room temperature for 2.5 h. The reaction mixture was quenched with water (3 ml), evaporated in vacuo and the residue was chromatographed on silica (150 g), eluting with dichloromethane, ethanol and ammonia (80:10:1) to give a gum. The gum was briefly triturated in diethyl ether and the title compound crystallised out as a powder (238 mg), m.p. 170°-172°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].O>C(#N)C>[CH3:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCNCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A suspension of piperazine (3.0 mmol), N,N-diisopropylethylamine (6.0 mmol), and 2-fluoro-5-nitrotoluene (7.5 mmol) in acetonitrile are stirred at 50° C. for 3 h and then 100° C. for 9.5 h, and poured into water. The mixture is extracted with AcOEt. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give the product in 85% yield.
Reaction SMILES: Cl[Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21].CCN(CC)CC.C[SiH]([N:34](C1C2C(=C(C)C=C(C)C=2)C(C)=C1C)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)C>CCCCCC>[CH:35]1([NH:34][Si:2]([CH3:23])([CH3:22])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[CH3:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Reactant: CC1=C(C)C(N(C2CCCCC2)[SiH](C)C)c2cc(C)cc(C)c21
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-3-phenyl-s-indacen-1-yl) silane (9c)) (5.6340 g, 0.01633 moles) was stirred in hexane (100 mL) as NEt3 (2.9673 g, 0.02932 moles) and cyclohexylamine (1.6373 g, 0.01651 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.8969 g, 89.9 percent).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.O1CCOCC1.[OH-].[K+]>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: CCOC(=O)CCN[C@H]1CC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](NCCC(=O)O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 80 °C

Procedure:
A mixture of cis-ethyl 3-({4-[4-amino-3-(4-{[2-fluoro-4trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoate (0.23 g, 0.36 mmol), p-dioxane (15 mL), potassium hydroxide (0.10 g, 1.81 mmol) and water (1.5 mL) were heated at 80° C. for 3 hours. The solvents were evaporated and the residue was purified by preparative HPLC to yield cis-3-({4-[4-amino-3-(4-{[2-fluoro-4-trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoic acid (0.11 g, 0.18 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.91 (dd, 1H), 8.31 (d, 1H), 8.25 (s, 1H), 8.00 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 6.89 (br, 2H), 4.79 (m, 1H), 3.95 (s, 3H), 2.46-3.00 (m, 7H), 2.29 (m, 2H), 1.91 (m, 2H), 1.80 (m, 2H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 6.06 min. MS: MH+ 616.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=1[C:10]#N)([O-:3])=[O:2].[CH3:13][N:14]([CH:16]=O)[CH3:15].C[NH:19]C.CN(C)C=O>O>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:10][C:9]1[CH:8]=[CH:7][C:6]([C:12]#[N:19])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CNC
Reactant: Cc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Solvent: O
Product: CN(C)C=Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 74 %

Procedure:
A mixture of 3-nitro-p-tolunitrile (30.0 g, 185 mmol), DMF (100 mL), and dimethylformamide dimethylamine (24.3 g, 204 mmol) was heated to 110° C. for 16 h. The deep red solution was poured into H2O (1L) and extracted with EtOAc (4×250 mL). The organic layers were washed with H2O, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The solid residue was triturated with hexanes to give 4-(2-dimethylamino-vinyl)-3-nitro-benzonitrile (28.5 g, 74%) after filtration. 1H NMR (400 MHz, DMSO-d6) 8.22 (1H, s), 7.83 (2H, m), 7.65 (1H, m), 5.67 (1H, d, J=13 Hz), 2.98 (6H, s); MS m/e 219 (M+H)+. Anal calcd. for C11H11N3O2: C, 60.82; H, 5.10; N, 19.34. Found: C, 60.54; H, 4.99; N, 19.40.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[CH3:13][O-:14].[Na+].[Na]>CO>[CH3:13][O:14][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(CBr)nc1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COCc1ccc(C(=O)OC)cn1
Yield: 85 %

Procedure:
5.1 g (0.022 mol) of methyl 6-(bromomethyl)nicotinate [described in J. Med. Chem.; (2002), 45(23), 5005-5022], dissolved in 60 mL of methanol are added at room temperature to a solution of sodium methoxide obtained by adding 1 g (0.044 atom/g) of sodium to 40 mL of methanol. The reaction medium is then heated under reflux for 2 hours. The reaction medium is concentrated under vacuum and the residue is taken up in an aqueous solution of potassium hydrogen sulfate and dichloromethane. The organic phase is separated by decantation, dried over sodium sulfate and evaporated to dryness. 3.4 g of a yellow solid are obtained.
Reaction SMILES: [ClH:1].Cl.C([O:6][CH:7]([CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]4[O:27][CH2:28][O:29][C:22]=34)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31])(=O)C.N.Cl.C(OCC)C>C(Cl)Cl.C(O)(C)C>[ClH:1].[ClH:1].[OH:6][CH:7]([CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]4[O:27][CH2:28][O:29][C:22]=34)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31]
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCC(CN1CCOCC1)OC(C)=O
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCC(O)CN1CCOCC1

Procedure:
A mixture of 7-(2-acetoxy-3-morpholinopropoxy)-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline dihydrochloride (0.104 g) and a saturated methanolic ammonia solution (3 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography on silica (Isolute ammonia-treated silica from International Sorbent Technology Limited, catalogue reference 9470-0100) using a 19:1 mixture of methylene chloride and methanol as eluent. The material so obtained was dissolved in methylene chloride (3 ml) and a 6M solution of hydrogen chloride in isopropanol (0.3 ml) was added with stirring. Diethyl ether (10 ml) was added and the resultant precipitate was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.095 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 3.15–3.45 (m, 4H), 3.54 (d, 2H), 3.743.91 (d, 2H), 3.97 (d, 2H), 4.02 (s, 3H), 4.24 (d, 2H), 4.49–4.58 (m, 1H), 6.08 (s, 2H), 6.96–7.04 (m, 3H), 7.47 (s, 1H), 8.23 (s, 1H), 8.88 (s, 1H); Mass Spectrum: M+H+ 455.