Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][CH2:16][C:17]1[N:18]([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:19]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([NH2:27])[C:20]=2[N:28]=1)[CH3:14]>>[CH2:13]([O:15][CH2:16][C:17]1[N:18]([CH2:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:35][CH2:36]2)[C:19]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([NH2:27])[C:20]=2[N:28]=1)[CH3:14]
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
Using the method of Examples 61-75, trans-2-phenyl-1-cyclopropanecarbonyl chloride was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 476.3039.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[H-].[Na+].[CH3:14]N(C=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:14])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CN(C)C=O
Reactant: CCc1cc(Br)ccc1CO
Agent: [H-]
Agent: [Na+]
Product: CCc1cc(Br)ccc1COC
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of (4-bromo-2-ethyl-phenyl)-methanol (0.700 g, 3.25 mmol) in DMF (30 mL) was added NaH (0.156 g, 60% dispersion in mineral oil, 3.90 mmol) followed by Mel (0.22 mL, 3.58 mmol). The mixture was stirred for 16 hours and then partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to a yellow oil. Purification by flash column chromatography (0% to 4% EtOAc in hexanes) gave the product as a clear oil (0.51 g, 69%). 1H NMR (300 MHz, CDCl3): δ 1.15 (t, J=7.6 Hz, 3 H), 2.58 (q, J=7.5 Hz, 2 H), 3.32 (s, 3 H), 4.35 (s, 2 H), 7.12 (m, 1 H), 7.24 (m, 1 H), 7.27 (d, J=2.1 Hz, 1 H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:35])[C:19]([C:32]([OH:34])=[O:33])=[CH:20][N:21]3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:16][C:15]=2[F:36])[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:35])[C:19]([C:32]([OH:34])=[O:33])=[CH:20][N:21]3[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[CH:16][C:15]=2[F:36])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1

Procedure:
A solution of 1.02 g (2 mmol) of 7-[3-t-butoxycarbonylamino-1-pyrrolidinyl]-6,8-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 25 ml of trifluoroacetic acid is stirred at room temperature until gas evolution ceases. The solvent is evaporated and the residue treated with 1N sodium hydroxide and diluted with water. The pH is adjusted to 5.5 with 6N hydrochloric acid. The precipitate is filtered washed with water and ether to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH2:15](Cl)[O:16]CCl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[C:11]([CH:15]=[O:16])=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: ClCOCCl
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C=O)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3.84 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester are dissolved in 20 ml of dichloromethane, the whole is cooled to 0° and there are added dropwise thereto at from 0° to 5° firstly 3.16 g of titanium tetrachloride over a period of 3 minutes and then 3.83 g of dichlorodimethyl ether (Cl2CHOCH3) over a period of 20 minutes. The whole is then stirred for 5 minutes at from 0° to 5°, gradually heated to room temperature and then stirred for 15 minutes at 35°. The mixture is then left to cool to room temperature and poured onto 25 g of ice; the organic phase is separated off, the aqueous phase is then shaken three times with 10 ml of dichloromethane each time and the organic phases are combined, washed three times with 15 ml of ice-water each time, dried over magnesium sulphate, concentrated to dryness by evaporation and chromatographed over silica gel using dichloromethane as eluant. 4-formyl-5-methoxybenzocyclobutene-1-carboxylic acid methyl ester is obtained in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:7](=[O:18])[NH:6][CH2:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[NH:6][CH2:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1NCc2cc(Br)ccc2N1C1CCOCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(c1)CNC(=O)N2C1CCOCC1

Procedure:
The title compound was prepared as pale yellow solid, using 6-Bromo-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-2(1H)one and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, by a method analogous to that described in Example 3 above. MS m/e 406 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.C(OCC)C>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:2]4[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: Cc1nccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nccc(N2CCC(C(=O)N3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)n1
Yield: 30 %

Procedure:
4-Chloro-2-methylpyrimidine (135 mg) was added to a solution of 1-(4-bromophenylsulphonyl)-4-(4-piperidylcarbonyl)piperazine (415 mg) in THF (15 ml) containing triethylamine (0.2 ml). The mixture was heated under reflux for 16 hours. After cooling, the THF was evaporated. The residue was treated with H2O(20 ml) and the aqueous extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with saturated brine (1×20 ml) dried and evaporated to give an oil which was purified by chromatography on silica gel. Elution with dichloromethane/methanol/0.88 NH3 (96:3:1) gave an oil. Trituration with diethyl ether (10 ml) gave, as a colourless solid, l-(4-bromophenylsulphonyl)-4-[1-(2-methylpyrimidyl)-4-piperidylcarbonyl]piperazine (152 mg), mp 200-202° C.; NMR: 1.39-1.48 (m, 2H), 1.55-1.69 (m, 2H), 2.30 (s, 3H), 2.80-3.00 (m, 7H), 3.45-3.67 (m, 4H), 4.32 (m, 2H), 6.57 (d, 1H), 7.65 (d, 2H), 7.83 (d, 2H), 8.03 (d, 1H); EI-MS m/z 508 (M+H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10]P(=O)(OCC)OCC)=[CH:8][CH:7]=1)([O-:5])=[O:4].[Br:21][C:22]1[CH:23]=[C:24]([C:32]2([CH3:35])[CH2:34][CH2:33]2)[C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[CH:27]=O.O>C1COCC1.C1OCCOCCOCCOCCOC1>[Br:21][C:22]1[CH:29]=[C:26](/[CH:27]=[CH:10]/[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:20][CH:19]=2)[C:25]([O:30][CH3:31])=[C:24]([C:32]2([CH3:35])[CH2:33][CH2:34]2)[CH:23]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: COc1c(C=O)cc(Br)cc1C1(C)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(/C=C/c2ccc([N+](=O)[O-])cc2)cc(Br)cc1C1(C)CC1
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
Sodium hydride (60% dispersion, 0.10 g, 2.6 mmol) and 15-crown-5 (0.038 g, 0.17 mmol) were added to THF (5 mL) at 0° C. and stirred for 5 min. To the reaction mixture was then added dropwise over 5 min a solution of diethyl (4-nitrobenzyl)phosphonate (0.52 g, 1.9 mmol) in THF (5 mL), and stirring was continued at 0° C. for 5 min. To this reaction mixture was then added dropwise over 10 min a solution of 74b (0.47 g, 1.7 mmol) in THF (10 mL). The reaction mixture was stirred for 30 min at 0° C. then for 90 min at RT. Water was carefully added, and the mixture was partitioned between water and EtOAc. The EtOAc layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.67 g (94%) of 5-bromo-2-methoxy-1-(1-methylcyclopropyl)-3-[(E)-2-(4-nitrophenyl)vinyl]benzene (75) as a yellow solid (0.67 g, 94%).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]([Br:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22].CN[C@H]1CCCC[C@@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Cu]I>[Br:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])[C:11]=1[CH3:12]
Reactant: Cc1c(Br)nc2cc(F)cc(F)c2c1Br
Reactant: O=C1CCCCN1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Br
Reaction time: 3.5 h

Procedure:
The 2,4-dibromo-5,7-difluoro-3-methylquinoline (2.000 g, 5.90 mmol), piperidin-2-one (590 mg, 5.90 mmol), copper (I) iodide (57.0 mg, 0.300 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.094 mL, 0.59 mmol) and potassium phosphate tribasic (2.50 g, 11.9 mmol) were combined in 1,4-dioxane (10 mL) and stirred in the microwave reactor for 3.5 h. The reaction was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and dried over magnesium sulfate. The crude product was then purified by medium pressure chromatography (silica, 0 to 100% EtOAc:hexanes) to give 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one. Mass Spectrum (ESI) m/e=355.1 (M+1).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
Trityl chloride (13.1 g, 47.0 mmol) was added to a stirred suspension of 3-piperidone hydrochloride (5.79 g, 42.7 mmol) and triethylamine (14.9 ml, 107 mmol) in CH2Cl2 (100 ml) and the reaction was stirred for 16 h under N2 at room temperature. The resulting mixture was filtered and the filtrate washed sequentially with H2O and 5% aqueous citric acid, dried over MgSO4 and evaporated under reduced pressure. Trituration with pentane afforded the subtitle compound as a colourless solid (4.8 g, 33%). Rf 0.23 (CH2Cl2/pentane 2/3, v/v). 1H NMR (CDCl3) δ: 2.05 (2H, m), 2.35 (2H, m), 2.45 (2H, m), 2.85 (2H,s), 706-755 (15H, m).
Reaction SMILES: [CH2:1]1[O:7][CH2:6][C@@H:4](O)[C@H:2]1O.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[NH:11][C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.[BH3-]C#N.[Na+].O(CC=O)CC=O>O.CC#N.C(O)(=O)C.O>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([N:8]3[CH2:2][CH2:1][O:7][CH2:6][CH2:4]3)=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[NH:11][C:12]2=[O:21])=[CH:17][CH:16]=1
Reactant: O[C@@H]1COC[C@@H]1O
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2N)cc1
Agent: O=CCOCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2N2CCOCC2)cc1
Reaction time: 18 h
Yield: 8.3 %

Procedure:
NaIO4 (66 mg, 0.33 mmol) is added to a flask containing 1,4-anhydroerythritol (34 mg, 0.33 mmol) dissolved in a water/CH3CN mixture (1:1; 4 mL) and the mixture is maintained under stirring for 18 hours. 4-amino-7-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (compound 1) (100 mg, 0.33 mmol) and NaBH3CN (63 mg, 1 mmol) are then added to the solution of 2,2′-oxybis(acetaldehyde) prepared previously. Then, 3 drops of acetic acid are added and the medium is stirred for 3 hours at ambient temperature. The reaction is stopped by the addition of 10 mL of water. The medium is extracted with 3×10 mL of dichloromethane. The organic phases are washed with 3×10 mL of water, dried over MgSO4 and concentrated under vacuum. The residue is purified by silica gel column chromatography with dichloromethane-ethanol (100/0 to 98/2) as eluent in order to produce successively i) the compound 7-methoxy-3-(4-methoxyphenyl)-4-morpholinoisoquinolin-1(2H)-one 49 (10 mg, 8%) in the form of a white solid, mp>270° C.; 1H NMR (CDCl3): 8.18 (1H, br s), 7.99 (1H, d), 7.83 (1H, dd), 7.37 (3H, m), 7.03 (2H, d), 3.97 (3H, s), 3.91 (3H, s), 3.72 (4H, m), 2.90 (2H, m), 2.75 (2H, m); MS 367 (M+H); and ii) the compound 4-(2-(2-hydroxyethoxy)ethylamino)-7-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one 50 (15 mg, 12%) in the form of a white solid, mp 139° C.; 1H NMR (CDCl3): 8.71 (1H, br s), 7.89 (1H, d), 7.82 (1H, s), 7.45 (2H, d), 7.34 (1H, dd), 7.01 (2H, d), 3.94 (3H, s), 3.87 (3H, s), 3.60 (2H, t), 3.49 (2H, t), 3.38 (2H, t), 3.03 (2H, t), 1.75 (1H, br s), MS 385 (M+H).
Reaction SMILES: [CH3:1][CH:2]([NH:9][C:10](=[O:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]#[C:22][CH2:23][OH:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:33]([C:36]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[CH:38][C:37]=1F)([O-:35])=[O:34].C(=O)(O)[O-].[K+]>CS(C)=O.O>[CH3:1][CH:2]([NH:9][C:10](=[O:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]#[C:22][CH2:23][O:24][C:37]1[CH:38]=[CH:39][C:40]([N+:42]([O-:44])=[O:43])=[CH:41][C:36]=1[N+:33]([O-:35])=[O:34])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(NC(=O)CCCCCCCCC#CC#CCO)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(NC(=O)CCCCCCCCC#CC#CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 220 mg (0.65 mmol) of N-(α-methylbenzyl)-14-hydroxy-10,12-tetradecadiynamide in 10 ml DMSO was added 506 mg (5.00 mmol) of triethylamine. To the solution was then added 130 mg (0.70 mmol) of 2,4-dinitrofluorobenzene. The resulting red solution was stirred 16 hours at ambient temperature, and 25 ml of saturated aqueous potassium bicarbonate solution was then added. After stirring 15 minutes, the mixture was poured into 100 ml of water and the resulting solution was extracted with 100 ml portions of ethyl acetate. The combined organic extracts were washed with three 50 ml portions of water and three 50 ml portions of saturated aqueous sodium bicarbonate solution and dried over (MgSO4). Evaporation gave 312 mg of a red oil. NMR indicated no starting alcohol was present. The product was purified by passing it through silica gel (ether as eluent); crystallization from ether petroleum ether gave white crystals, m.p. 59°-60° C. NMR (CDC13): 9.42-7.30, m, 8H aryl H's; 6.00, br s, 1H, N--H; 5.10, br s 2H, O--CH3C=C and m, 1H, CHCH3 ; 2.30, m, 4H, C=CH2CH2 and --CH2CO--; 1.55, d, J=7 Hz, 3H, CH3 and 170--1.20, m, 12 H, other CH2.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:33])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:34][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:33])([CH3:6])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O
Reaction time: 4 h

Procedure:
0.221 g (0.453 mmol) of the above prepared 2-methyl-2-{2-methyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was dissolved in 2.7 ml of THF/EtOH=1/1, treated with 1.35 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 4 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt, the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane afforded finally 0.194 g of the title compound as white solid of mp. 164–165° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([C:12]([O:14]CC)=[CH2:13])=[CH:8][N:7]=2)[CH2:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O>C1COCC1.O.C(OCC)(=O)C>[Br:17][CH2:14][C:12]([C:9]1[CH:8]=[N:7][C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:11][CH:10]=1)=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1cnc(OCC2CC2)nc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1cnc(OCC2CC2)nc1
Temperature: 0 °C
Yield: 71.7 %

Procedure:
A solution of 480 mg (2.18 mmol) of 2-cyclopropylmethoxy-5-(1-ethoxyvinyl)pyrimidine in 8 mL of a THF/H2O mixture: (6/2: v/v) is cooled to 0° C. under argon. After addition of 380.02 mg (2.11 mmol) of N-bromosuccinimide, the reaction mixture is maintained at 0° C. for 1 hour. The solution obtained is taken up in ethyl acetate and washed with aqueous NaHCO3 solution and then with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 80/20 DCM/MeOH) to give 410 mg of 2-bromo-1-(2-cyclopropylmethoxypyrimidin-5-yl)ethanone, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[C:15]([F:19])=[CH:16][CH:17]=3)[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.CC(OC([N:39]1[CH2:44][CH2:43][O:42][CH2:41][C@H:40]1[C:45](O)=[O:46])=O)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:45]([C@@H:40]4[CH2:41][O:42][CH2:43][CH2:44][NH:39]4)=[O:46])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)[C@@H]2COCCN2)c1
Reaction time: 0.08 h

Procedure:
N-[1-{[3-(Aminomethyl)phenyl]methyl}-5-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 61) (100 mg, 0.208 mmol) was suspended in DCM (1 mL), (3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-morpholinecarboxylic acid (52.9 mg, 0.229 mmol) and HATU (87 mg, 0.229 mmol) were added to the reaction mixture and stirred for 5 min. DIPEA (0.109 mL, 0.624 mmol) was added to the reaction mixture and stirred over the weekend. LCMS showed the coupling had gone to completion. Trifluoroacetic acid (0.25 mL, 3.24 mmol) was added to the reaction and left to stir for 1 h and 50 min. LCMS showed the reaction had gone to completion so the mixture was concentrated under a stream of nitrogen. The sample was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the required product (as TFA salts). The residue was dissolved in methanol and loaded onto a methanol pre-conditioned SCX-2 ion-exchange cartridge cartridge (10 g). The cartridge was washed well with methanol, followed by 2M ammonia in methanol. Evaporation of the solvent from the ammoniacal fractions gave the title compound as a colourless glassy solid (71 mg, 57%). LCMS (System A) RT=0.82 min, ES+ve m/z 594/596 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([Sn](C)(C)C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(OC([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[S:37][C:36]3[C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[N:34][C:33](SC)=[N:32][C:31]=3[CH:30]=2)[CH2:24][CH2:23]1)=O)(C)(C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:3]([C:33]2[N:34]=[C:35]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[C:36]3[S:37][C:29]([CH2:28][N:25]4[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]4)=[CH:30][C:31]=3[N:32]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2n1
Reactant: C[Sn](C)(C)c1c(F)ccc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Temperature: 90 °C
Yield: 9.6 %

Procedure:
A solution of 5-fluoro-4-(trimethylstannyl)-1H-indole (100 mg, 0.33 mmol), 4-(2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (71 mg, 0.15 mmol) and copper(I) bromide-dimethyl sulfide complex (70 mg, 0.33 mmol) in THF (3 mL) was degassed with argon, treated with tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.008 mmol) and heated at 90° C. overnight. The reaction mixture was purified by column chromatography. The foregoing compound was treated with TFA-DCM (1:1, 2 mL), evaporated in vacuo and purified by ion-exchange chromatography (Isolute® SCX-2 cartridge, eluting with NH3 in methanol) and preparative TLC to give the title compound (6.5 mg, 10%).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH2:22]([Li])[CH2:23][CH2:24][CH3:25].O>O1CCCC1.CCCCCC>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])=[CH:10][C:3]=1[C:4](=[O:5])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCC(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (4.97 g, 16.0 mmol) in tetrahydrofuran (50 ml) was added dropwise slowly 1.6 M solution (20 ml) of n-butyllithium in n-hexane at −78° C., and after the completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 1-(2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pentan-1-one (3.45 g, yield 70%) as a pale-yellow oil.