Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Sn](CCCC)(CCCC)CCCC)[N:35]=2)[CH2:30][CH2:29]1>[Cu]I.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>[CH3:27][N:28]1[CH2:29][CH2:30][N:31]([C:34]2[N:35]=[C:36]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([C:11]5[S:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][N:15]=5)[CH:9]=4)[N:4]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH:3]=3)[CH:37]=[CH:38][CH:39]=2)[CH2:32][CH2:33]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCN(C)CC2)n1
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CN1CCN(c2cccc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5nnc(S(C)(=O)=O)s5)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
A solution of tert-butyl 3-iodo-5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (650 mg, 1.146 mmol) and 1-methyl-4-(6-(tributylstannyl)pyridin-2-yl)piperazine (596 mg, 1.146 mmol) DMF (10 mL) was purged the Argon gas for 5 min. To the solution was added CuI (327.5 mg, 1.71 mmol), Pd(PPh3)4 (159 mg, 0.137 mmol) and again the mixture was purged the Argon gas for 5 min. The mixture was stirred at RT for 2 h, then at 90° C. for 1 h. The mixture was poured into H2O and was extracted with EtOAc. The combined organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography to give tert-butyl 3-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (400 mg, 53.5%). MS (ESI, pos. ion) m/z: 555.1 (M+1); 1H-NMR (DMSO-d6, 300 MHz) δ: 9.245 (1H, s), 8.45 (1H, s), 8.35 (1H, d), 8.07 (1H, d), 7.65 (1H, m), 7.4 (1H, d), 6.85 (1H, d), 3.7-3.8 (3H, s), 3.7 (2H, brs), 2.3 (3H, s), 1.75 (9H, s), 1.2-1.3 (6H, m).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[NH2:2].N(C1NC=NC(=O)C=1)N.[CH3:19][CH2:20][C:21](=O)[CH2:22][CH3:23]>C(O)C>[CH3:19][CH2:20][C:21](=[N:2][NH:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[CH2:22][CH3:23]
Reactant: CCC(=O)CC
Reactant: NNc1cc(O)ncn1
Agent: NNc1cc(=O)nc[nH]1
Solvent: CCO
Product: CCC(CC)=NNc1cc(O)ncn1
Temperature: 3 °C
Yield: 75.7 %

Procedure:
A mixture comprising 5.0 g (39.6 mmol) 6-hydrazinopyrimidin-4-ol/6-hydrazinopyrimidin-4(1H)-one (CAS-No: 29939-37-5), 5.12 g pentan-3-one and 80.8 mL ethanol was heated under reflux for 2 hours. After cooling to 3° C., the precipitated solid was filtered off and washed with diethyl ether to give 5.82 g (72%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][C:6]([CH3:14])([CH3:13])[C:7]#[C:8][C:9]#[C:10][CH2:11]Br>C(O)C>[CH3:5][C:6]([CH3:14])([CH3:13])[C:7]#[C:8][C:9]#[C:10][CH2:11][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: CC(C)(C)C#CC#CCBr
Reactant: NCCN
Solvent: CCO
Product: CC(C)(C)C#CC#CCNCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
In 20 ml of ethanol was dissolved 1.5 g of ethylenediamine. Then 1.24 g of 6,6-dimethyl-2,4-heptadiynyl bromide was added to the solution followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure and the residue was extracted with ethyl ether and saturated sodium bicarbonate aqueous solution. After the organic layer was taken by fractionation, the aqueous layer was further extracted with ethyl ether. The procedure was repeated 5 times and the ethereal layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was then removed under reduced pressure to give 695 mg (yield: 63%) of N-(6,6-dimethyl-2,4-heptadiynyl)ethylenediamine as light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[C@H:3]1[C:13]([O:15]C(C)(C)C)=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[C@H:3]1[C:13]([OH:15])=[O:14]
Reactant: C#CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C#CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A mixture of 2.0 g of the product of Step A, 0.2 g of p-toluene sulfonic acid and 20 ml of anhydrous toluene was refluxed for 10 minutes and was cooled to 0° C. and stirred for 30 minutes. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 1.59 g of (1R,cis) 2,2-dimethyl-3-[Z-2-(propargyloxycarbonyl)-ethenyl]-cyclopropane-carboxylic acid which was used as is for the next step.
Reaction SMILES: CC(C)([O-:4])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][C@H:15]2[N+]([O-])=O)[CH:11]=[CH:12][CH:13]=1>ClCCl.CO>[Br:7][C:8]1[CH:9]=[C:10]([CH:14]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][C:15]2=[O:4])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2cccc(Br)c2)N1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C1CCC(=O)C(c2cccc(Br)c2)N1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Potassium t-butoxide (38.7 g) was added to a stirred solution of the trans-6-(3-bromo-phenyl)-5nitro-piperidin-2-one (96.3 g) in dichloromethane (500 ml) and methanol (500 ml). The mixture was cooled to -70° and ozone was vigorously bubbled through the stirred solution for 7 h. The mixture was purged with nitrogen and pH6.5 phosphate buffer (500 ml) added. Sodium thiosulphate (120 g) and water (500 ml) were added and the mixture stirred as it warmed to room temperature overnight. The mixture was tested for peroxides then extracted with dichloromethane (600 ml×3). The combined organic extracts were washed with water (500 ml) then saturated brine (500 ml), dried (MgSO4) and evaporated in vacuo. Trituration with ether and hexane gave the title compound as a white solid (70.0 g).
Reaction SMILES: [OH:1][C@@H:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].O.C(O)(=O)C>C(O)C.[Rh]>[CH:12]1([CH2:11][C@H:2]([OH:1])[C:3]([N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[O:4])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C([C@@H](O)Cc1ccccc1)N1CCOCC1
Agent: [Rh]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C([C@@H](O)CC1CCCCC1)N1CCOCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of 2 (20.5 g, 87.1 mmol) in a mixture of ethanol (80 mL), water (10 mL) and acetic acid (10 mL) is charged to a Parr bomb and treated with 2 g of 10% Rh/C. The bomb is sealed, evacuated and pressurized to 1000 psi with hydrogen. The reaction is then heated to 50° C. with stirring overnight. After cooling to room temperature and relieving the pressure, the bomb is evacuated and back filled with nitrogen twice. The reaction mixture is filtered through a pad of celite and the solvent is removed to afford 18.6 g (88.5%) of (S)-3-cyclohexyl-2-hydroxy-1-morpholin-4-yl-propan-1-one (3) as an oil; HPLC-MS calculated for C13H23NO3 (M+H+) 242.2, found 242.4.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C(O[C:18]([CH3:21])([CH3:20])C)(=O)CC(OC(C)(C)C)=O.[Br:22][C:23]1[N:24]=[C:25](Cl)[C:26]2[N:27](C(C)=[N:30][N:31]=2)[CH:28]=1.Cl>CN1C(=O)CCC1>[Br:22][C:23]1[N:24]=[C:18]([CH3:20])[C:21]2[N:27]([C:26]([CH3:25])=[N:31][N:30]=2)[CH:28]=1
Reactant: Cc1nnc2c(Cl)nc(Br)cn12
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1nc(Br)cn2c(C)nnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Caesiumcarbonate (7.25 g; 22.3 mmol) is suspended in 5 ml NMP. To this suspension di-tert-butyl malonate (4.80 g; 22.3 mmol) is added and the resulting mixture is stirred for 30 min at 25° C. Finally 6-bromo-8-chloro-3-methyl-[1,2,4]-triazolo[4,3-a]pyrazine J-1 (1.00 g; 4.04 mmol) is added and the reaction mixture is stirred for 18 h at 25° C. The reaction mixture is treated with aqueous 1 N HCl until the pH value is below 5 and then extracted with DCM. The organic layer is separated and dried over MgSO4 and is evaporated to dryness. The crude intermediate is purified using reverse phase chromatography (method prep. HPLC2). The intermediate is dissolved in 5 ml DCM and 5 ml TFA and stirred for 16 h at 40° C. The reaction mixture is evaporated and the crude product is purified using reverse phase chromatography (method prep. HPLC2).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N+:14]([C:17]1[S:21][C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:14]([C:17]1[S:21][C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:26][CH2:27]2)=[N:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cnc(N2CCNCC2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ncc([N+](=O)[O-])s3)CC2)cc1
Yield: 171.2 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (0.5 g), 1-(5-nitrothiazol-2-yl) piperazine (0.5 g) and potassium carbonate (0.5 g) in dimethylformamide (15 ml) was stirred at 80° C. for 3.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow solid (1.5 g). The obtained pale-yellow solid was crystallized from ethyl acetate to give the title compound (0.5 g) as yellow crystals, m.p.=151-152° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:29][CH:28]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (800 mg, 3.34 mM) and triethylamine (0.5 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-fluorophenyl isocyanate (570 mg/ml, 5.01 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was quenched with distilled water (1 mL) followed by the extraction with chloroform (3×15 mL). The combined fractions of chloroform was again washed with water and dried over sodium sulphate. Further concentration of chloroform fraction under vacuum afforded the crude product, which was cystallize with methanol-ether (1:5) to yield 8d as solid. Yield: 1.06 g, 84.23%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2cncn2C)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2cncn2C)ccc1-c1ccc(C(=O)O)cc1
Yield: 33.6 %

Procedure:
5-(4-Bromo-3-methylphenyl)-1-methylimidazole (D92, 1.52 g, 6.1 mmol) was dissolved in DME (50 ml) and water (50 ml), then treated with 4-boronobenzoic acid (1.0 g, 6.1 mmol), sodium carbonate (2.57 g, 24.2 mmol) and tetrakis(triphenylphosphine)palladium (O) (100 mg). The mixture was heated at reflux (48 hours), cooled and the DME removed in vacuo. The aqueous residue was treated with 10% Na2CO3 (approx 30 ml), then washed with ethyl acetate. The aqueous phase was acidified with 5N HCl and the solid that precipitated was collected by filtration. This solid was dried in vacuo to yield the title compound as a white solid (600 mg, 34%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: CCCN1CCN(c2ccc(N)c(OCC)c2)CC1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: CCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 120 °C
Yield: 48.9 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(ethyloxy)-4-(4-propyl-1-piperazinyl)aniline (Example 151, step B) (51 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.52 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (64 mg, 0.093 mmol, 47%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.35 (s, 1H), 8.34 (d, J=15.93 Hz, 2H), 8.21 (d, J=5.31 Hz, 1H), 8.03 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.69 Hz, 1H), 7.71 (d, J=8.97 Hz, 1H), 7.59 (t, J=7.78 Hz, 1H), 7.35-7.46 (m, 3H), 7.16-7.22 (m, 2H), 6.95 (t, J=6.78 Hz, 1H), 6.64 (d, J=2.20 Hz, 1H), 6.43-6.48 (m, 2H), 4.04 (q, J=6.96 Hz, 2H), 3.07-3.13 (m, 4H), 2.42-2.51 (m, 4H), 2.25 (t, J=7.33 Hz, 2H), 1.40-1.48 (m, 2H), 1.22 (t, J=6.96 Hz, 3H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 689 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1CCl
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: COc1ccccc1Cn1ccc2ccc(CC(=O)O)cc21

Procedure:
The titled compound (29 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-methoxybenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([O:32][CH3:37])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:33][CH:34]=1
Reactant: CI
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)C(CC(O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(CC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1)c1ccccc1
Yield: 84.1 %

Procedure:
To a solution of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-2-phenylethyl)piperazine (0.051 g, 0.11 mmol) in anhydrous ether (5 mL) was added sodium hydride (0.006 g, 0.15 mmol). The resultant mixture was stirred at ambient temperature for 30 minutes, then methyl iodide (0.016 g, 0.11 mmol) was added. Once thin layer chromatography analysis showed complete consumption of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-2-phenylethyl)piperazine had occurred, the mixture was poured into water and extracted with two portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford 0.046 g of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-methoxy-2-phenylethyl)piperazine as a yellow oil: NMR (CDCl3) 7.3 (m, 9), 7.0 (m, 2), 6.9 (m, 2), 4.8 (m, 3), 4.2 (m, 2), 3.9-3.2 (m, 5), 3.1 (d, 2), 3.0 (s, 1), 2.9(s, 1), 2.6 (m, 1), 2.4 (m, 1), 1.9 (m, 1) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=O.C(Cl)(=O)C(Cl)=O.C[N:19]1CCOCC1.N>C1(C)C=CC=CC=1.CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]#[N:19]
Reactant: CN1CCOCC1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C#N)cc1Br
Reaction time: 3 h

Procedure:
3-Bromo-4-methyl-benzoic acid (3 g) in toluene (75 ml) was treated with oxalyl chloride (10 ml) and DMF (4 drops). The mixture was then stirred at 20 C for 3 h. and then the solvent evaporated giving a yellow solid. This in turn was dissolved in THF (30 ml) containing N-methyl-morpholine (1.5 ml). Aqueous ammonia (0.880, 40 ml) was then added and the mixture stirred for 18 h. The THF was then evaporated and the resulting amide intermediate collected by filtration as a colourless solid (2.9 g). This material was then suspended in thionyl chloride (35 ml) and was heated to 85 C for 6 h. The excess reagent was then evaporated and the residue purified on silica gel. Elution with 5-50% ethyl acetate in hexane gave the title compound as a white solid (1.4 g)
Reaction SMILES: [CH2:1]([P:3]([OH:9])([CH2:5][C:6]([OH:8])=[O:7])=[O:4])[CH3:2].[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4:30]>C1(C)C=CC=CC=1>[Ti+4:30].[CH2:1]([P:3]([OH:9])([CH2:5][C:6]([O-:8])=[O:7])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][C:6]([O-:8])=[O:7])([OH:9])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][C:6]([O-:8])=[O:7])([OH:9])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][C:6]([O-:8])=[O:7])([OH:9])=[O:4])[CH3:2]
Reactant: CCP(=O)(O)CC(=O)O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Product: CCP(=O)(O)CC(=O)[O-]
Yield: 102.4 %

Procedure:
152 g (1 mol) of 2-(ethylhydroxyphosphinyl)acetic acid (produced as in Example 10) and 170 g of titanium tetrabutoxide are refluxed in 500 ml of toluene for 40 hours. The resulting butanol is distilled off from time to time with proportions of toluene. The solution formed is subsequently freed of solvent to leave 167 g (96% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid titanium salt.
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[CH:19][C:20]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:21]([CH:31]=1)[C:22]([NH:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:23]>COCCOC.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:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][O:32][C:20]2[CH:19]=[CH:18][C:17]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])=[CH:35][CH:36]=1
Reactant: Cn1nccc1B(O)O
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1nccc1-c1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Temperature: 120 °C

Procedure:
(1-Methyl-1H-pyrazol-5-yl)boronic acid (30.1 mg, 0.24 mmol), sodium carbonate (0.40 ml, 0.40 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.82 mg, 0.01 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in Example 59; 80 mg, 0.20 mmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated at 120° C. for 1 hour. The solvent was removed in vacuo and purified by MDAP to yield the title compound as a brown gum. 13 mg.
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][C:14]3[N:13](S(C4C=CC(C)=CC=4)(=O)=O)[N:12]=[C:11]([NH2:26])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCOCC1>O1CCCC1>[C:27]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([NH2:26])[C:10]=3[CH:9]=[CH:8]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(N)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Nc1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 50 °C
Yield: 41.9 %

Procedure:
A suspension of 0.22 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazol-3-ylamine and 1.5 cm3 of aqueous 1N sodium hydroxide solution in 5 cm3 of tetrahydrofuran is heated at a temperature in the region of 50° C. for about 24 hours. 5 cm3 of dioxane are added to the preceding mixture and the resulting mixture is heated at a temperature in the region of 100° C. for 2 hours. After concentrating the reaction mixture to dryness under reduced pressure (13 kPa), the residue is taken up in 30 cm3 of ethyl acetate and 30 cm3 of water. The aqueous phase is extracted with twice 30 cm3 of ethyl acetate and the combined organic phases are washed with 30 cm3 of saturated aqueous sodium bicarbonate solution, 30 cm3 of water and 30 cm3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated under reduced pressure (13 kPa). After purification by flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)], the residue is taken up in 5 cm3 of diisopropyl ether, drained by suction, washed with 2 cm3 of diisopropyl ether and dried under reduced pressure (13 kPa) at a temperature in the region of 30° C. 0.06 g of 6,6-diphenyl-6,7-dihydro-1H-indazol-3-ylamine is thus obtained in the form of a solid, the characteristics of which are as follows: