Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=3[F:24])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2([C:39](O)=[O:40])[CH2:38][CH2:37]2)=[O:35])=[CH:29][CH:28]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:39]([C:36]4([C:34](=[O:35])[NH:33][C:30]5[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=5)[CH2:37][CH2:38]4)=[O:40])=[CH:19][C:18]=3[F:24])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2cc(NC(=O)Oc3ccccc3)ncn2)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)Oc1ccccc1
Reaction time: 5 h
Yield: 20.7 %

Procedure:
A crude product of [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]carbamic acid phenyl ester (303 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (497 mg), triethylamine (0.310 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (984 mg) were added in this order under a nitrogen atmosphere at room temperature, followed by stirring for 5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture. The resultant organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give residue, which was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:1). Fractions containing the target compound were concentrated under reduced pressure, the resultant residue was purified again by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:1). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as white powder (100.4 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH:11]=1)[NH2:10].[O-:20][C:21]#[N:22].[Na+]>C(O)(=O)C.O.Cl>[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([NH:10][C:21]([NH2:22])=[O:20])[CH:11]=1
Reactant: NCCc1ccc(OCc2ccccc2)c(N)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NCCc1ccc(OCc2ccccc2)c(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
2.4 g of 5-(2-aminoethyl)-2-benzyloxyaniline, hydrochloride, is dissolved in a mixture of 20 ml of acetic acid, 5 ml of water and 0.5 ml of 2N hydrochloric acid. A solution of 0.72 g of sodium cyanate in 5 ml of water is added and the mixture is stirred for one hour at room temperature. Thereafter, the mixture is diluted with 100 ml of water, the product is extracted by shaking with methylene chloride and recrystallized from isopropanol, thus obtaining 0.56 g of N-[5-(2-aminoethyl)-2-benzyloxyphenyl]urea, mp 176°-180° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][N:15]([CH3:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>C(O)(C)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([N:15]([CH3:24])[CH3:14])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: CN(C)c1cccc(CN)c1
Solvent: CC(C)O
Product: CN(C)c1cccc(CNc2ncnc3cc(N)ncc23)c1
Yield: 40 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (236 mg, 1.23 mmol) (described in a previous experimental) and 3-dimethylamino-benzylamine (1.36 g, 9.07 mmol) in isopropanol (5 mL) is stirred under N2 at reflux for 1 h, and the resulting product is chromatographed on silica gel (10-15% EtOH/EtOAc), then on alumina (1% EtOH/CHCl3) to give 7-amino-4-(3-dimethylaminobenzylamino)pyrido[4,3-d]pyrimidine (145 mg, 40%) as a white solid. 1H NMR (DMSO) δ 9.11 (1H, s), 8.79 (1H, t, J=5.9 Hz), 8.26 (1H, s), 7.11 (1H, dd, J=8.0, 7.7 Hz), 6.73 (1H, brs), 6.63 (1H, d, J=7.6 Hz), 6.60 (1H, dd, J=8.1, 2.2 Hz), 6.44 (2H, brs), 6.35 (1H, s), 4.67 (2H, d, J=5.8 Hz), 2.86 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22]([NH:24][C:25]3[N:29]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=3)=[O:23])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:50][O:51][CH2:52][C:53](Cl)=[O:54]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:53](=[O:54])[CH2:52][O:51][CH3:50])[CH:7]=3)=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(N)c3)c3ccccc23)cc1
Reactant: COCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cc(CCOc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Yield: 12.7 %

Procedure:
To a suspension of 1-(4-(2-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate D) (35 mg, 0.065 mmol) in DCM (0.5 mL) was added DIPEA (23 μl, 0.131 mmol) and methoxyacetyl chloride (7 μl, 0.072 mmol). The mixture was stirred at RT, until judged to be complete by LC-MS; diluted with saturated aq NaHCO3 (1.5 mL) and the layers were separated through a phase separator cartridge. The organics were collected, evaporated under reduced pressure and the residue subjected to SCX capture and release. The resulting residue was purified further by preparative RP HPLC to give N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-2-yl)-2-methoxyacetamide (Example 18) as a white solid (5 mg, 13%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.37 (3H, s), 3.20 (2H, t), 3.37 (3H, s), 4.06 (2H, s), 4.38 (2H, t), 6.33 (1 H, s), 6.95 (1H, d), 7.19 (1H, dd), 7.33 (2H, m), 7.42-7.47 (3H, m), 7.54 (1H, m), 7.59 (1H, d), 7.87 (1H, d), 8.12 (1H, d), 8.18 (1H, bs), 8.23 (1H, d), 8.67 (1H, s), 8.84 (1H, s), 9.89 (1 H, s).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].Cl>CS(C)=O>[CH2:12]([O:19][C:3]1[C:2]([Br:1])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCc2ccccc2)c(Br)c1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
A suspension of 5-bromo-6-chloro-nicotinic acid (CAS [29241-62-1], 1 g), benzylalcohol (0.686 g) and KOH (1.104 g) in DMSO (4 ml) was stirred at 140° C. for 15 min. DMSO (2 ml) was added and the mixture was stirred at 140° C. for 30 min. The mixture was cooled to room temperature. Ice was added and the mixture was acidified using 1 M HCl. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried, filtered and concentrated. The product was purified by flash chromatography (SiO2, CH2Cl2=>CH2Cl2/MeOH 4:1) to give 6-benzyloxy-5-bromo-nicotinic acid (0.308 g) as a white solid.
Reaction SMILES: [Si]([O:8][CH:9]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH3:11])(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[CH3:11][CH2:10][CH:9]([OH:8])[CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCC=CC(CC)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC=CC(O)CC
Reaction time: 0.5 h
Yield: 228 %

Procedure:
Compound 18E (23 mg, 0.0245 mmol) was dissolved in 2 ml of THF and 60 μl (0.060 mmol) of a 1M solution of nBu4NF in THF was added thereto at room temperature. After stirring for 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over Glauber's salt and concentrated under reduced pressure. Then the resulting residue was dissolved in 2.3 ml of THF and 100 μl of 12M hydrochloric acid was added thereto. The reaction mixture was stirred at room temperature for 1 hour and then neutralized with sodium hydrogencarbonate. After concentration, the residue was dissolved in ethanol-chloroform (1:5) and the salt was filtered off. The resulting product was purified by silica gel column chromatography (2 g of K-60 manufactured by Katayama Kagaku, eluent; methanol:chloroform=1:5). Thus 15 mg of compound 19E was obtained (yield: 99%). The properties of compound 19E were as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[CH:17]1([C:20](=O)[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:19][CH2:18]1.S(=O)(=O)(O)O>CO>[CH:17]1([C:20]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:1]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the solution of 2-amino-4′-fluorobenzophenone (100 g) in methanol (500 ml) added Methyl 3-cyclopropyl-3-oxopropanoate (132 g), sulfuric acid (5 ml) and stirred for 15 minutes at 25° C. Heated the reaction mixture to 65° C. for 22 hrs. Distilled off the methanol completely under reduced pressure. Cooled the reaction mixture to 25° C., added water (500 ml) and stirred for 30 minutes. Cooled the reaction mixture to 0° C. and pH adjusted to 6.0 with sodium carbonate solution. Stirred the reaction mixture for 45 minutes at 25° C. Filtered the cake and washed with water. Spin dry the compound for 60 minutes. To this compound added methanol (150 ml) and stirred for 1 hr at 25° C. Filtered the solid and washed with methanol (50 ml). Dried the obtained solid to get the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[S:8]1(=[O:10])(=[O:9])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:12][NH:11]1
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=S1(=O)NCNc2cccnc21

Procedure:
A mixture of 1 g of 3-aminopyridine-2-sulfonamide (Preparation 1) and 0.23 g of paraformaldehyde (1.3 eq.) in 10 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 1 to 2 hours. After cooling, the crystalline precipitate of the title compound is collected on a filter and washed with isopropanol. The product is recrystallized from hot water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[BH3-]C#N.[Na+]>CO.CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)C=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of [2-(3-fluoro-4-nitro-phenyl)-vinyl]-dimethyl-amine (1.7 g, 8 mmol) in MeOH, was added NaBH3CN (770 g, 12 mmol) and one drop of AcOH. The reaction mixture was stirred at room temperature for 2 hours and quenched with water. After removal of all volatiles in vacuo, the residue was extracted with 10% methanol in DCM twice. The combined extracts were washed with brine, dried over anhydrous sodium sulfate. Concentration under vacuum gave a crude product, which was purified by reverse phase column to afford the title compound (1.08 g, yield: 63%). MS (ESI): 213 [M+H]+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39]>CN(C=O)C.C(Cl)Cl>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[N:1]([CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:2]=[CH:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6[nH]ccc6c5)sc4n3)CC2)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCCn1ccc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(1H-Indol-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (80 mg, 0.218 mmol) was dissolved in DMF (1.1 mL) before cesium carbonate (156 mg, 0.479 mmol) was added and stirred at ambient temperature for 1 h; to the reaction mixture was added methyl 4-bromobutanoate (43 mg, 239 μmol) before it was stirred for 20 h at 80° C. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with water, washed 1 times with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give methyl 4-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)butanoate after flash chromatography. MS (ESI) m/z: Calculated: 467.2; Observed: 468.4 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:12])([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:19]([C:18]3[CH:21]=[CH:22][C:15]([N:14]([CH3:23])[CH3:13])=[CH:16][CH:17]=3)[O:20][C:9]([CH3:11])([CH3:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC1(C)N=C1c1cccc(Cl)c1
Solvent: C1COCCO1
Product: CN(C)c1ccc(C2OC(C)(C)N=C2c2cccc(Cl)c2)cc1

Procedure:
3 g of 3-(m-chlorophenyl)-2,2-dimethyl-2H-azirine and 2.4 g of p-(dimethylamino)benzaldehyde were exposed to light for 2 hours in 350 ml of 1,4-dioxane (with the light source described in Example 2). After removing the solvent in a water-jet vacuum, the residue was chromatographed twice on aluminum oxide (neutral, activity 1), the elution was carried out in both cases with n-hexane/ether (9:1). Crystallization from n-hexane gave 4-(m-chlorophenyl)-5-[p-(dimethylamino)phenyl]-2,2-dimethyl-3-oxazoline which melted at 96°-97° C. after drying for 5 hours at 60° C. and 13 Torr.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[NH2:15][OH:16]>CCO>[OH:16][N:15]=[C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[NH2:2]
Reactant: NO
Reactant: COC(=O)c1cc(C#N)c(C)cc1C
Solvent: CCO
Product: COC(=O)c1cc(C(N)=NO)c(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 6 g, 28.54 mmol, 1.00 equiv, 90%) and NH2OH (10 mL, 5.00 equiv, 50% in water) in EtOH (20 mL) was stirred at 100° C. in an oil bath. After 2 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate, washed with 2×20 mL of brine, dried (Na2SO4), and concentrated under reduced pressure to yield 4.66 g (66%) of the title compound as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)=[N:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:20][C:16]1([C:14]2[S:15][C:11]([C:9]3[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[C:7]([NH:21][C:22]4[N:27]=[C:26]([O:28][CH:29]5[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]5)[CH:25]=[CH:24][N:23]=4)[CH:8]=3)=[CH:12][N:13]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)Nc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(Nc2nccc(OC3CCNCC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91176.5 %

Procedure:
To the product of Step 4 (20 mg, 0.034 mmol) in DCM (1 mL) was added TFA (133 μL, 1.722 mmol). The mixture was stirred at ambient temperature for 1 hr. LCMS indicated complete reaction. To the reaction was added saturated aqueous NaHCO3 to adjust pH>8 and the product was extracted with ethyl acetate, The combined organic layer was dried, filtered and solvent removed in vacuo to afford 15 mg (0.031 mol, 91%) of N-(3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-{[4-(piperidin-4-yloxy)pyrimidin-2-yl]amino}phenyl)acetamide as pale yellow oil. MS ESI: [M+H]+ m/z 481.2. 1H NMR (600 MHz, CD3OD): δ 8.16 (m, 2H); 7.90 (s, 1H); 7.55 (s, 1H); 7.30 (s, 1H); 6.26 (d, J=5.4 Hz, 1H); 5.58 (m, 1H); 3.34 (m, 2H); 3.21 (m, 2H); 2.65 (m, 2H); 2.40 (m, 2H); 2.22 (m, 2H); 2.14 (s, 3H); 2.01 (m, 4H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][CH2:7][CH2:8]Cl.[OH:14][C:15]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][CH2:7][CH2:8][N:18]1[CH2:19][CH2:20][C:15]([OH:14])([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:16][CH2:17]1
Reactant: OC1(c2ccc(Cl)c(Cl)c2)CCNCC1
Reactant: ClCCCOc1ccc(Cl)c(Cl)c1
Product: OC1(c2ccc(Cl)c(Cl)c2)CCN(CCCOc2ccc(Cl)c(Cl)c2)CC1
Yield: 97.4 %

Procedure:
3-(3,4-dichlorophenoxy)propylchloride 1.38 g and 4-hydroxy-4-(3,4-dichlorophenyl)piperidine 1.35 g are reacted in the same manner as Example 109 (1) to prepare 2.40 g (Yield: 97.5%) of 1-{3-(3,4-dichlorophenoxy)propyl}-4-hydroxy-4-(3,4-dichlorophenyl) piperidine (III-66). mp. 118.0°-118.5° C.
Reaction SMILES: BrBr.[CH3:3][N:4]1[C:8]([CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)=[CH:7][C:6]([CH3:18])=[N:5]1.[S-:19][C:20]#[N:21].[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[CH3:3][N:4]1[C:8]([CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]3[N:15]=[C:20]([NH2:21])[S:19][C:13]=3[CH:12]=2)=[CH:7][C:6]([CH3:18])=[N:5]1
Reactant: N#C[S-]
Reactant: Cc1cc(COc2ccc(N)cc2)n(C)n1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(COc2ccc3nc(N)sc3c2)n(C)n1
Yield: 80.6 %

Procedure:
add, dropwise, a solution of 0.103 cm3 of dibromine in 3 cm3 of glacial acetic acid at around 20° C. to a solution of 0.44 g of 4-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]aniline and 0.787 g of potassium thiocyanate in 6 cm3 of glacial acetic acid. After stirring for about twenty hours, the reaction mixture is poured into 50 cm3 of water. The pH of the solution obtained is adjusted to 8-9 by adding solid potassium carbonate. A gum forms. After stirring for about an hour, the beige solid that formed is drained, washed three times with 20 cm3 of water, then dried in a desiccator under reduced pressure (0.2 kPa) in the presence of phosphoric anhydride. We obtain 0.448 g of 6-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]-1,3-benzothiazol-2-amine in the form of a beige powder, which has the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[O:11][C:10](=[O:14])[NH:9]2)=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CN1CCOCC1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12](=[O:13])[O:11][C:10](=[O:14])[N:9]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NC(c2ccc(F)cc2)C(=O)O1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1OC(=O)N(C(=O)OCc2ccccc2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of 4-(4-fluorophenyl)oxazolidine-2,5-dione (2.5 g, 12.8 mmol) in THF (30 mL) cooled to −25° C. was added benzyl chloroformate (2.3 mL, 16.6 mmol), followed by the slow addition (˜10 min) of N-methylmorpholine (2.11 mL, 19.2 mmol) as a solution in THF (5 mL). The solution was stirred at this temperature for 1 h. and then allowed to warm to rt overnight. The resulting solution was filtered through Celite, and the filtrate was concentrated. The resulting crude material was recrystallized from 2:2:1 t-butyl methyl ether:hexanes:THF to give benzyl 4-(4-fluorophenyl)-2,5-dioxooxazolidine-3-carboxylate (2.7 g, 64%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:14][CH2:13][CH2:12][NH2:15])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NCCCc1nc(Cl)nc2ccsc12
Yield: 91.9 %

Procedure:
3.95 g (19.26 mmol) of 2,4-dichlorothieno[3,2-d]pyrimidine (III), 1.90 mL (23.11 mmol) of propylamine, and 6.71 mL (38.52 mmol) of diisopropylethylamine are stirred for 16 hours in 40 mL of tetrahydrofuran at ambient temperature. Then the reaction mixture is concentrated by evaporation, the residue is combined with water. The precipitate formed is suction filtered and dried. 4.03 g of product IV (92%) is obtained as a powder.
Reaction SMILES: NCC1C2C(=CC(S(O)(=O)=[O:14])=CC=2)C=CC=1.[CH:17]([C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18].C1N2CN3CN(C2)CN1C3.[Mn]([O-])(=O)(=O)=O>>[C:17]([C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)([OH:14])=[O:18]
Reactant: NCc1cccc2cc(S(=O)(=O)O)ccc12
Reactant: O=Cc1cccc2cc(S(=O)(=O)O)ccc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: C1N2CN3CN1CN(C2)C3
Product: O=C(O)c1cccc2cc(S(=O)(=O)O)ccc12

Procedure:
The 1-aminomethylnaphthalene-6-sulphonic acid can be converted into 1-formylnaphthalene-6-sulphonic acid in a manner which is known per se by a Sommelet reaction (see, for example, Houben Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), 4th edition, volume 7/1 page 198 or Organic Reactions 8, 197 (1954)), that is to say by reaction with hexamethylenetetramine. The 1-formylnaphthalene-6-sulphonic acid is in turn oxidized by processes known for the oxidation of aldehydes to carboxylic acids (see, for example, Houben Weyl loc. cit. volume 8, pages 407-413), for example by oxidation with permanganate (see, for example, Houben Weyl, volume 4 I/b, pages 615-621), to give 1-carboxynaphthalene-6-sulphonic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23]O)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[NH:37]([CH3:39])[CH3:38]>>[CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23][N:37]([CH3:39])[CH3:38])[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: CNC
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2
Solvent: O=S(Cl)Cl
Product: CN(C)Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(3-hydroxymethyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 46) (53 mg, 0.12 mmol) by treatment with SOCl2 (3 eq.) and 40% aqueous Me2NH-sol. (10 eq.) as described in Example 45. Obtained as a light yellow solid (21 mg).