Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:3]=1.B.C1COCC1>CC(=O)OCC>[I:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:3]=1
Reactant: O=C(O)c1cn(C2CCCCO2)nc1I
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cn(C2CCCCO2)nc1I
Yield: 83.5 %

Procedure:
A solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylic acid (34 g, 105 mmol) in BH3-THF (340 mL, 340 mmol, 1M in THF) was stirred at rt overnight. Solvent was evaporated under vacuum and the residue dissolved in DCM (340 mL), washed with water (340 mL×3), dried and concentrated. The residue was purified by SGC using Hex: EA (0%-70%) as eluent to afford (3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methanol (27 g, yield: 83%). LCMS (method C): RT=1.74 min, m/z=309.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]2[C:36](=[C:37]([O:46][CH3:47])[CH:38]=[CH:39][CH:40]=2)[CH:35]=1>>[CH3:45][O:44][C:42]1[C:41]2[C:36](=[C:37]([O:46][CH3:47])[CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH2:33][O:1][CH:2]2[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]2)[CH:43]=1
Reactant: COc1cc(CCl)cc2c(OC)cccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3cccs3)cc2)C(O)C1
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3cccs3)cc2)cc2c(OC)cccc12

Procedure:
In an analogous manner to that described in Example 1 g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate [Example 123 b)] with 2-chloromethyl-4,8-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(4,8-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a beige solid; MS: 648 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[CH3:16])=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=2[CH3:16])=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CCl
Reactant: Nc1ccccc1
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CNc1ccccc1
Yield: 44 %

Procedure:
2-Chloro-N-(2-methyl-4-sulphamoylphenyl)-acetamide (13.1g) and aniline (9.5 g) were heated together 21/2 hr on a water bath at 90°. The mixture was worked up as in Example 1(b) to yield 7 g beige crystals, m.p. 195°-196°
Reaction SMILES: CO[CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.B(Br)(Br)[Br:18]>C(Cl)Cl>[Br:18][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1
Reactant: COCc1ccc2oc(S(N)(=O)=O)cc2c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1cc2cc(CBr)ccc2o1
Temperature: -30 °C

Procedure:
A suspension of 5-methoxymethyl-2-sulfamoylbenzo[b]furan in dry methylene chloride cooled to -30° C. is treated with boron tribromide to provide the title compound.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16]1
Reactant: O=C(NC1CCN(c2ccncc2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC1CCN(c2ccncc2)CC1
Yield: 99.9 %

Procedure:
1-(Pyridin-4-yl)piperidine-4-carbamic acid benzyl ester (9.46 g) was hydrogenated using 7.5% palladium carbon (3.57 g) in ethanol (95 ml) solution at 3 atm over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated and the residue was dried under reduced pressure to give the title compound (5.38 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH:29]1[C:33](B(O)O)=[CH:32][CH:31]=[N:30]1.C(=O)(O)[O-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:31]5[NH:30][N:29]=[CH:33][CH:32]=5)[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: OB(O)c1ccn[nH]1
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)cc(Cl)nn23)ccc1C(=O)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cnc3c(NCC(C)C)cc(-c4ccn[nH]4)nn23)ccc1C(=O)NC1CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a mixture of 125 mg (314 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, 111 mg (942 μmol) 1H-pyrazol-5-yl boronic acid, 44 mg Tetrakis(triphenylphosphin)palladium in 2 mL of ethanol and 2 mL of toluene was added 0.63 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then the mixture was filtered and concentrated and purified by chromatography to give 41 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=CC=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.Br.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:47])[C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([C:38]([N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[O:39])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:47])[C:31]=2[N:32]2[CH2:33][CH2:34][CH:35]([C:38]([N:40]3[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]3)=[O:39])[CH2:36][CH2:37]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CN1CCN(C(=O)C2CCN(c3c(N)cncc3F)CC2)CC1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccccc21
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CN1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)c3c(N)nn4cc(F)cnc34)CC2)CC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 56.5 %

Procedure:
A suspension of benzotriazol-1-yl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (6.271 g, 20.02 mmol), [1-(3-amino-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanone hydrobromide 17a (6.98 g, 16.68 mmol) and DIPEA (2.802 g, 3.776 mL, 21.68 mmol) in pyridine (63 mL) were placed in a sealed tube and heated at 100° C. for 24 h. The mixture cooled to room temperature then concentrated in vacuo. The resulting solid was loaded onto silica and purified by chromatography (330 g SiO2, 0.5-7.5% MeOH (containing 10% ammonium hydroxide)/DCM). The residue was stirred in ethanol for 5 mins and the solid that formed was collected by filtration, washed with minimal ethanol, dried by suction for 2 h, affording desired product as a pale yellow solid (4.71 g, 56.5%). MS (ES+) 500.2; 1H NMR (DMSO-d6) δ 10.63 (s, 1H), 9.67 (s, 1H), 9.47 (dd, J=4.8, 2.5 Hz, 1H), 9.25 (dd, J=2.6, 0.7 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 6.79 (s, 2H), 3.60 (t, J=5.0 Hz, 2H), 3.55 (t, J=4.9 Hz, 2H), 3.19 (m, 2H), 3.03 (m, 2H), 2.95 (tt, J=11.7, 3.6 Hz, 1H), 2.34 (t, J=5.0 Hz, 2H), 2.29 (t, J=5.1 Hz, 2H), 2.20 (s, 3H), 2.13 (qd, J=12.4, 3.9 Hz, 2H), 1.75-1.72 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5](CC)[CH2:6][CH2:7][N:8]1[C:27](=[S:28])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:29])C.O>FC(F)(F)C(O)=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:15][C:16]3[CH:17]=[C:10]4[C:9](=[O:29])[N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:32])=[O:3])[C:27](=[S:28])[N:11]4[C:12]=3[CH:13]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Temperature: 70 °C
Yield: 92.5 %

Procedure:
Compound 1 (10 mg, 0.023 mmol) was dissolved in trifluoroacetic acid (TFA, 2 ml), to give a clear red solution. Water (0.5 ml) was added and the mixture was heated at 70° C. overnight. Additional water (2 ml) was then added and the solvents of the reaction mixture were evaporated to give Compound 2 as a yellow-brown solid (8.5 mg, 88% yield).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:3])[CH3:2].[N+:10]([C:13]1C=[CH:20][CH:19]=[CH:18][C:14]=1C(Cl)=O)([O-:12])=[O:11].O>C1(C)C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:18][CH:19]=[CH:20][C:2]=1[C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])=[O:3])([O-:12])=[O:11]
Reactant: CC(=O)C1CCOC1=O
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCCC1C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 372 %

Procedure:
A mixture of Mg(OEt)2 (63 g, 0.55 mole) in toluene, under N2, is treated with dihydro-3-acetyl-(3H)-furanone (141 g, 1.10 mole) at 7°-10° C. over a 15 minute period and stirred at 25°-30° C. for 2 hours. The resultant reaction mixture is treated with a solution of o-nitrobenzoyl chloride (185.7 g, 1.0 mole) in toluene at 25°-35° C. over a 45 minute period, stirred at ambient temperatures for 1.75 hours, treated with 400 mL H2O and heated at 60°-75° until reaction is complete by LC analysis. The resultant reaction mixture is cooled to room temperature and the phases are separated to give the title product as a toluene solution, 875 g, 18% desired product by LC analysis (67% yield). The product solution is used as is in Example 6.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>ClCCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A suspension of 0.765 g of the product of Example 1 in 20 ml of 1,2-dichloroethane is sonicated under argon for 18 hours with 0.517 g of manganese dioxide. An additional 2 g of manganese dioxide is added and sonication continued for 2 hours. The reaction reaction mixture is filtered through diatomaceous earth which is washed with 500 ml of methylene chloride. The filtrate is concentrated in vacuo to give 0.696 g of the desired product as a solid. FAB MASS SPEC 685(M+Na).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][Mg]Br>>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([CH:11]([OH:12])[CH3:15])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Product: CC(O)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43b (210 mg, 1.15 mmol) and methylmagnesium bromide (2.29 mL, 2.29 mmol, 1 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. Light yellow solid. Yield: 201 mg, 88%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.51 (d, J=6.6 Hz, 3H), 3.05 (br, s, 1H), 4.92 (q, J=6.6 Hz, 1H), 7.38-7.50 (m, 3H), 7.65 (d, J=7.9 Hz, 1H), 7.74 (dd, J=8.2, 2.2 Hz, 1H), 7.91-7.97 (m, 2H), 8.58 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=25.0, 67.8, 120.4, 126.9, 128.7, 128.9, 134.0, 139.0, 139.5, 147.2, 156.6; MS (ESI): m/z=200.32 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:23]=3)[CH:20]=2)=[C:11]([C:31](O)=[O:32])[CH:10]=[N:9]1>>[N:24]1([C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:13]([C:12]4[N:8]([CH3:7])[N:9]=[CH:10][C:11]=4[C:31]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:32])=[O:30])=[CH:20][N:19]3[N:21]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Reactant: C1COCCN1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1

Procedure:
Using morpholine and 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (130 mg, 65%). MS: m/z=441 (M+H+).
Reaction SMILES: [OH:1][C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([CH3:32])[CH:23]=1)=[O:20].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH2:8]([C:2]1([OH:1])[CH2:7][CH2:6][N:5]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[O:20])[CH2:4][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)c2ccccc2n1
Temperature: 45 °C
Reaction time: 144 h

Procedure:
To a solution of 4-hydroxy-4-benzyl-piperidine (380.6 mg, 2 mmol) in dry THF (10 mL) is added 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (263.7 mg, 1 mmol) and solid NaHCO3 (672 mg, 8 mmol). The reaction mixture is stirred at 45° C. for 6 days. The reaction mixture is diluted with CH2Cl2 (100 mL) and washed with sat. Na2CO3 (2×30 mL). The aqueous phase is re-extracted with CH2Cl2 (2×25 mL), the combined organic phases are washed with brine (20 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.[C:27]([CH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]2[C:42]([F:43])=[CH:41][N:40]=[C:39](Cl)[N:38]=2)[CH2:32][CH2:31]1)([OH:29])=[O:28].C1COC2C=CC(N)=CC=2O1>>[C:27]([CH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]2[C:42]([F:43])=[CH:41][N:40]=[C:39]([NH:11][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:10][CH2:1][O:2][C:3]=4[CH:4]=3)[N:38]=2)[CH2:32][CH2:31]1)([OH:29])=[O:28]
Reactant: O=C(O)C1CCC(Nc2nc(Cl)ncc2F)CC1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2c(c1)OCCO2
Product: O=C(O)C1CCC(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)CC1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, N4-(4-carboxycyclohexyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-(4-carboxycyclohexyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.62 (d, 1H, J=4.2 Hz), 7.31 (d, 1H, J=2.4 Hz), 6.84 (dd, 1H, J=2.4 and 8.7 Hz), 6.70 (d, 1H, J=8.7 Hz), 4.23-4.18 (m, 4H), 3.99-4.08 (m, 1H), 2.59 (t, 1H, J=3.9 Hz), 2.16-2.09 (m, 2H), 1.91-1.84 (m, 2H), 1.78-1.57 (m, 4H); 19F NMR (CD3OD): −48152; LCMS: ret. time: 19.31 min., purity: 96%; MS (m/e): 389 (MH+).
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C([O:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29])(=O)C.CCOCC>ClCCl.C(OCC)(=O)C.C(O)C.N>[Cl:35][C:33]1[CH:32]=[CH:31][C:27]([C:28]([N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[OH:1])=[O:29])=[C:26]([OH:25])[CH:34]=1
Reactant: CC(=O)Oc1cc(Cl)ccc1C(=O)Cl
Reactant: O=P(O)(O)CCCNO
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: N
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1O)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g), bis(trimethylsilyl)acetamide (10.0 g) and dichloromethane (32 ml) was stirred for 3 hours at ambient temperature. To this mixture was added dropwise a solution of 2-acetoxy-4-chlorobenzoyl chloride (2.3 g) in dichloromethane (10 ml) with stirring under ice-cooling. The reaction mixture was stirred at the same temperature for 30 minutes and at ambient temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give a residue, which was dissolved in ethyl acetate (80ml). The solution was washed with cold 5% hydrochloride acid (30 ml). The washings was extracted three times with ethyl acetate (30 ml). The combined ethyl acetate layer was washed with saturated aqueous sodium chloride solution (10 ml), dried over magnesium sulfate and evaporated to dryness to give a crude powder (4.35 g) of 3-[N-(2-acetoxy-4-chloro benzoyl)-N-hydroxyamino]propylphosphonic acid. This crude powder (1 g) was dissolved in a mixture of ethanol (30 ml) and conc. aqueous ammonia (8 ml). The solution was stirred at ambient temperature for 4 hours and then concentrated under reduced pressure to give a residue, which was dissolved in a small volume of ethanol. To the solution was added ether to give precipitates, which were separated by filtration and dried to give powdery monoammonium salt of 3-[N-(4-chloro-2-hydroxy benzoyl)-N-hydroxyamino]propylphosphonic acid (430 mg).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]([O:17]CC)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[S:3][C:4]([C:15]([OH:17])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1
Reactant: CCOC(=O)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Ethyl 2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole-5-carboxylate (4.05 g, 10.6 mmol) in THF (50 mL) and water (20 mL) was added solution of sodium hydroxide in water (1.0M, 31.9 mL, 31.9 mmol). The solution was stirred at room temperature for 16 hours. The reaction was quenched by the addition of aqueous HCl solution (1N, 38 mL), and then extracted five times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give white solid which was dried overnight and then used directly in the next step (3.74 g, 99%). LCMS: (AA) ES+, 354. 1H NMR (400 MHz, d4-Methanol) δ: 7.57-7.55 (m, 1H), 7.41-7.39 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Yield: 102.6 %

Procedure:
A degassed mixture of methyl 4-bromo-3-(trifluoromethyl)benzoate (6.00 g, 21.2 mmol), o-tolylboronic acid (3.17 g, 23.3 mmol), potassium carbonate (14.65 g, 106 mmol), Pd(PPh3)4 (2.45 g, 2.12 mmol) was prepared in toluene (30 mL) and water (30 mL), and then heated at reflux for 3 hours. The reaction mixture was filtered through a pad of Celite and diluted with EtOAc (200 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 (50 mL), water (50 mL) and brine (50 mL), and then dried (MgSO4). The solvents were removed under reduced pressure affording the title compound as a brown oil (6.4 g, quantitative) used without further purification in the next step. HPLC (Method A), Rt 5.3 min (Purity: 60.0%).