Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].C(O)C.[F:13][C:14]([F:23])([F:22])[C:15](=O)[C:16](OCC)=[O:17]>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:9]=[C:16]([OH:17])[C:15]([C:14]([F:23])([F:22])[F:13])=[N:8]2
Reactant: Nc1cccc(F)c1N
Reactant: CCOC(=O)C(=O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Oc1nc2c(F)cccc2nc1C(F)(F)F
Temperature: 90 °C
Reaction time: 3 h
Yield: 196.5 %

Procedure:
To an ACE sealable tube was added 3-fluorobenzene-1,2-diamine (475.99 mg, 3.77 mmol), ethanol (5 ml) and ethyl trifluoropyruvate (0.500 ml, 3.77 mmol) at rt. The tube was sealed and placed in an oil bath at 90° C. The mixture was stirred at 90° C. for 3 hr, cooled to rt and the LC/MS showed starting diamines and three new peaks. More ethyl trifluoropyruvaate (0.2 ml) was added and the mixture was stirred at 90° C. overnight. The reaction mixture was cooled to rt and LC/MS showed no diamines, and two of the three new peaks remained. The reaction mixture was concentrated to give a dark solid, diluted with dichloromethane/dimethylformamide (3/1, 60 ml) and washed with HCl (1 N, 2×20 ml) and an aquious solution of sodium thiosulfate (0.1 M, 2×20 ml). The combined aq. layers were back-extracted with dichloromethane/dimethylformamide (3/1, 2×20 ml). The combined organic layers were washed with water and concentrated to give a dark solid (1.72 g). The solid was dissolved in acetone and silica gel (46 g) was added. The mixture was dried in vacuo, loaded on a silica gel column and purified by flash chromatography (CH3CN/CHCl3=1/8, 1/6 then 1/4) to give the title compound 112a (474.9 mg, 2.046 mmol, 54.2% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.CN(C)CCCN=C=NCC.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.O>C1COCC1.C(OCC)(=O)C>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:21](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([C:16]#[C:15][Se:14][C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:1])([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)=[CH:25][CH:24]=2)=[CH:40][CH:41]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)Nc4ccc(O)cc4)cc3)ccc21
Yield: 63.2 %

Procedure:
A solution of 250 mg (0.63 mmol) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid obtained in Example 5, 169 mg (1.25 mmol) of 1-hydroxybenzoctriazole, 240 mg (1.25 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 82 mg (0.75 mmol) of 4-aminophenol in 20 ml of THF is stirred at room temperature for 15 h. Water and ethyl acetate are then added. After stirring and separation of the phases by settling, the aqueous phase is extracted with ethyl acetate. The organic phases are then combined and washed with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified on a column of silica (ethyl acetate 20/heptane 80). 200 mg (65%) of a white solid are obtained. m.p.=202° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([OH:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[CH2:32](Br)[CH:33]=[CH2:34]>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([O:30][CH2:34][CH:33]=[CH2:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: C=CCBr
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Product: C=CCOC(Cc1ccc(CCN(CCCCCCC)C(=O)OC(C)(C)C)cc1)C(=O)OCC
Yield: 41 %

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 47 and substituting allyl bromide as the electrophile to give 2-allyloxy-3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-propionic acid ethyl ester as a clear oil (187 mg, 41%)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[S:14])[NH:12][NH2:13])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[OH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[CH:26]=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[S:14])[NH:12][N:13]=[CH:26][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[OH:15])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: NNC(=S)Nc1cccc(C(=O)O)c1
Reactant: O=Cc1c(O)ccc2ccccc12
Product: O=C(O)c1cccc(NC(=S)NN=Cc2c(O)ccc3ccccc23)c1
Yield: 49 %

Procedure:
The procedure described in example 7 was followed here, using 4-(3-carboxyphenyl)-3-thiosemicarbazide in place of 4-(4-carboxyphenyl)-3-thiosemicarbazide and 2-hydroxy-1-naphthaldehyde in place of 3,5-dichloro-2-hydroxybenzaldehyde to give the title compound (49%) as a solid. MS (ES−) m/e 364 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[CH:56]=[CH:55][N:54]=[C:53]([C:57]3[NH:61][CH:60]=[C:59]([C:62]([O:64][CH3:65])=[O:63])[CH:58]=3)[CH:52]=2)[CH:47]=[CH:48][CH:49]=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[CH:56]=[CH:55][N:54]=[C:53]([C:57]3[NH:61][CH:60]=[C:59]([C:62]([O:64][CH3:65])=[O:63])[CH:58]=3)[CH:52]=2)[CH:47]=[CH:48][CH:49]=1)=[O:9]
Reactant: Cc1ccoc1C(=O)O
Reactant: COC(=O)c1c[nH]c(-c2cc(Nc3cccc(N)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c[nH]c(-c2cc(Nc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methyl-2-furoic acid (22 mg, 0.18 mmol), HATU (73 mg, 0.19 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of methyl 5-(4-((3-aminophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (50 mg, 0.16 mmol). The mixture was stirred at room temperature for 3 hours and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give methyl 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate as off-white solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=1.CN([CH:22]=[O:23])C.O>C1COCC1>[Br:9][C:10]1[C:11]([CH:22]=[O:23])=[C:12]([F:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c(C=O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of LDA (62 mmol) in THF (100 mL) was added 4-bromo-2-fluoro-1-methoxybenzene (12 g, 59 mmol) in THF (20 mL) slowly at −78° C. The reaction mixture was left to stir at −78 C for 2 h, treated with DMF (15 g, 210 mmol) in THF (20 mL) slowly, left to stir at −78 C for 1 h, and allowed to warm to room temperature as the bath did. The reaction mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.34 (s, 1H); 7.39 (dd, 1H); 7.04 (t, 1H); 3.92 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:23]=1[CH3:24])=O)(=O)OC.O.[NH2:32][NH2:33]>>[CH3:1][C:2]1([CH3:9])[CH2:6][C:5]2[N:32]=[N:33][C:17]([C:19]3[CH:20]=[N:21][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:23]=3[CH3:24])=[CH:16][C:4]=2[CH2:3]1
Reactant: COP(=O)(CC(=O)c1cnn(-c2ccccc2)c1C)OC
Reactant: CC1(C)CC(=O)C(=O)C1
Reactant: NN
Solvent: O
Product: Cc1c(-c2cc3c(nn2)CC(C)(C)C3)cnn1-c1ccccc1

Procedure:
light yellow crystalline solid. MS (ESI): 305.2 (MH+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione (synthesis described in: J. Chem. Soc., 121, 1922, p523), [2-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[NH:14][C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].O>ClCCl>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c(OCc3ccccc3)cc(Br)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
18.6 g (58.6 mmol) 4-Benzyloxy-6-bromo-2-methyl-1H-benzimidazole and 9 ml (70.3 mmol) triethyl-amine were suspended in 370 ml dichloromethane and 13.9 ml (70.3 mmol) (2-chloromethoxy-ethyl)-trimethylsilane were added dropwise. The reaction was stirred at room temperature for 3 h, poured into water (400 ml) and extracted with dichloromethane (3×100 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=9:1) to afford 5.9 g (23%) of the title compound as a beige solid. m.p. 94°-95° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][OH:16].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(OCC)(=O)C>ClCCl>[CH3:26][S:27]([O:16][CH2:15][CH2:14][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[S:6][C:2]=1[CH3:1])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2nc(CCO)c(C)s2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nc(CCOS(C)(=O)=O)c(C)s2)cc1
Reaction time: 4 h
Yield: 104.9 %

Procedure:
To a yellow solution of 2-(5-methyl-2-p-tolylthiazol-4-yl)ethanol (200 mg, 857 μmol) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (166 mg, 225 μL, 1.29 mmol) at RT. Methanesulfonyl chloride (113 mg, 76.8 μL, 986 μmol) was added at 0-5° C. and stirring was continued for 4 h at 0° C. The reaction mixture was poured into ethyl acetate (25 mL) and extracted with KHSO4 (10% aqueous solution, 15 mL). The organic phase was washed with water (2×15 mL) and brine (1×20 mL). The aqueous layers were back-extracted with ethyl acetate (1×25 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo to give 280 mg (99%) of yellow oil which was used without further purification for the next step.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4]Cl.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>COCCOC>[Cl:1][CH2:2][C:3]1[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]2[CH:4]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccccn1
Solvent: COCCOC
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The method of Vanelle et al. Tetrahedron 1991, 47, 5173-5184 was used. To a solution of 1,3-dichloro-2-propanone (2.69 g, 21.2 mmol) in 1,2-dimethoxyethane (5 mL) was added 2-aminopyridine and the mixture was stirred at room temperature for 2 hours. During this time a thick precipitate formed, and this was collected by filtration. The precipitate was refluxed in absolute ethanol for 2 hours after which volatiles were removed by evaporation. The residue was dissolved in water (30 mL) and solid NaHCO3 was added to neutralize the mixture. A white precipitate formed, and this was collected by filtration, washed with water and vacuum dried to yield the title compound pure as a cream white solid (1.43 g, 42%). 1H NMR (500 MHz, CDCl3): δ8.08 (d, J=6.7 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.17-7.22 (m, 1H), 6.80 (t, J=6.8 Hz, 1H), 4.78 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C1N=CN([C:32]([N:34]2C=N[CH:36]=[CH:35]2)=[O:33])C=1.[CH3:39][O:40][C:41]1[CH:42]=C(N)C=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1.Cl.C(O)(C(F)(F)F)=O>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:39][O:40][C:41]1[CH:42]=[C:35]([NH:34][C:32]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][C:14]4[C:15]5[CH2:16][NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)=[O:33])[CH:36]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4[nH]ccc4c3)c2C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CNC5)ccc32)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (158 mg, 0.44 mmol) in DMF (4 mL), CDI (145 mg, 0.89 mmol) is added in one portion, followed by TEA (0.37 mL, 2.7 mmol). After 3 h at rt, 3-methoxy-5-trifluoromethyl-phenylamine (514 mg, 2.7 mmol) and DMAP (5.5 mg, 0.04 mmol) are added and the reaction is left stirring for 40 h. Ethyl acetate (2 mL) is added followed by the addition of 1 N HCl solution (3 mL). The organics are extracted with EtOAc (×3) and concentrated. The crude mixture is dissolved in CH2Cl2 (10 mL) and cooled to 0° C. and TFA (10 mL, 130 mmol) is added. The reaction is allowed to reach it over 2 h. The reaction mixture is evaporated, redissolved in EtOAc and few drops of NH4OH are added to freebase the amine. The solvent is removed and the residue separated by FCC (DCM/MeOH/NH4OH (100:0:0 to 93:6:1)) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-methoxy-5 trifluoromethyl-phenyl)-amide. MS (ESI) m/z 471.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50-8.56 (m, 1H) 7.93 (d, J=3.54 Hz, 1H) 7.59 (d, J=19.71 Hz, 2H) 7.42 (d, J=2.27 Hz, 1H) 7.12 (dd, J=8.97, 2.40 Hz, 1H) 6.96 (s, 1H) 6.73 (d, J=3.79 Hz, 1H) 6.52 (s, 1H) 4.19 (d, J=8.34 Hz, 4H) 3.76 (s, 3H)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:10][C:11]1[O:12][C:13]2[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[C:16]([O:25][C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[C:14]=2[CH:15]=1.O>CN(C=O)C>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C:16]2[C:14]3[CH:15]=[C:11]([CH2:10][N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])[O:12][C:13]=3[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=2)=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CBr)oc2c1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CN3CCCC3=O)oc2c1
Yield: 24.8 %

Procedure:
To a solution of 2-ketopyrrolidine (75.1 mg, 0.882 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 44 mg, 1.1 mmol) at room temperature. After stirring the reaction for 30 min, ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (285a) (200 mg, 0.441 mmol) was added. The mixture was stirred at room temperature for another 2 h. Water was added to the reaction, and the product was extracted with CHCl3. The combined organic layer was dried and concentrated. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (100/0 to 95/5) to give the title compound (50 mg, 25%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 1.98-2.14 (m, 2 H) 2.42 (t, J=8.10 Hz, 2 H) 3.06 (s, 3 H) 3.44 (t, J=7.06 Hz, 2 H) 4.38 (q, J=7.16 Hz, 2 H) 4.58 (s, 2 H) 6.49 (d, J=0.75 Hz, 1 H) 7.04-7.12 (m, 2 H) 7.61 (d, J=1.13 Hz, 1 H) 7.83-7.94 (m, 2H) 8.05 (t, J=1.13 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][O:4][CH2:3]1.[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1.C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][S:29](=[O:31])(=[O:30])[NH2:32])[CH2:3][O:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)COC3)s2)c1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(N)(=O)=O)COC3)s2)c1
Temperature: 100 °C
Yield: 55.7 %

Procedure:
To a solution of N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 59, 25 mg, 0.061 mmol) in dioxane (600 uL), sulfamide (70 mg, 0.725 mmol) was added. The reaction mixture was stirred at 100° C. The resulting mixture was stirred at 100° C. for 4 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10-100% ethyl acetate in hexanes) and lyophilized to afford N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}sulfuric diamide (16.3 mg, 0.034 mmol, 54.6% yield) as a pale yellow solid. MS ESI: [M+H]+ m/z 487.0. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 2H), 8.85 (m, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.51 (s, 1H), 7.28 (m, 1H), 7.17 (s, 1H), 6.98 (s, 2H), 5.02 (m, 2H), 4.84 (m, 2H), 2.32 (s, 3H). rhSYK activity=+++
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22]>CCCCCC.C1COCC1>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC1CCN(C(=O)CCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)CC1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
The title compound was prepared by following general procedure 7. Sodium hydride (34 mg, 0.43 mmol) washed with hexane for removal of oil and dried under vacuum and taken in THF. To this solution 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.43 mmol) in THF was added dropwise at 0° C. Then the reaction mixture was stirred for 0.5 h. The solution of 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (89 mg, 0.51 mmol) in THF was added dropwise in reaction mixture. Then the reaction mixture was stirred at RT for 2 h. The reaction monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water. THF was evaporated and aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to gives 95 mg of desired compound, which was stirred with ethanolic HCl to give the HCl salt of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[OH:9][C:10]1[C:15]([C:16]2[C:20]3[CH:21]=[C:22]([N:25]4[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]4=[O:37])[CH:23]=[CH:24][C:19]=3[S:18][N:17]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:38]>CC(C)=O>[OH:9][CH:10]1[C:15]([C:16]2[C:20]3[CH:21]=[C:22]([N:25]4[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]4=[O:37])[CH:23]=[CH:24][C:19]=3[S:18][N:17]=2)([I:1])[CH:14]=[CH:13][CH:12]=[C:11]1[CH3:38]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1O
Solvent: CC(C)=O
Product: CC1=CC=CC(I)(c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
A solution of N-iodosuccinimide (0.240 g, 0.00107 mol) in acetone is added dropwise to a solution of 3-[3-(2-hydroxy-m-tolyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.430 g, 0.000992 mol) in acetone and the resultant mixture is stirred overnight at room temperature. Additional N-iodosuccinimide (0.120 g, 0.000635 mol) is added and the mixture is stirred three hours at room temperature. The mixture is concentrated in vacuo to afford a red gum which is chromatographed on silica gel with ether:methylene chloride. The fractions containing the title compound are washed with 1M sodium thiosulfate and brine, dried over anyhdrous magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow solid (0.280 g, 46.8%, mp 241-242° C.).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C:21](=[O:25])[O:22]CC)=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C:21]([OH:25])=[O:22])=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)NCC(=O)OCC)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCSc2ccc(C(=O)NCC(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound of Example 1 (500 mg, 1.06 mmoles) was taken up in a mixture of THF (10 ml), 1N NaOH (2.2 ml) and water (7.8 ml). The reaction mixture was stirred at room temperature for three hours, then concentrated in vacuo. The residue was taken up in water, filtered, acidified with dilute HCl and extracted with chloroform. The combined chloroform extracts were dried and concentrated in vacuo to afford the title compound which was recrystallized from ethyl acetate/hexane, m.p. 133°-135° (dec.).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=O)[CH:2]=[CH2:3].[C:13]([O-])(=[O:15])[CH3:14].[Na+].[C:18]([NH:21][CH2:22][C:23]([OH:25])=[O:24])(=O)[CH3:19].C(OC(=O)C)(=O)C>>[CH3:19][C:18]1[O:25][C:23](=[O:24])[C:22](=[CH:7][C:6]2[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:15])[CH3:14])=[C:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=2)[N:21]=1
Reactant: C=CCc1cc(C=O)ccc1O
Reactant: CC(=O)[O-]
Reactant: CC(=O)NCC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: C=CCc1cc(C=C2N=C(C)OC2=O)ccc1OC(C)=O
Temperature: 0 °C

Procedure:
40.5 g (0.25 mol) of 3-allyl-4-hydroxy-benzaldehyde, 10.3 g of sodium acetate, 19.9 g of N-acetylglycine and 63.5 g of acetic anhydride are together heated for 30 minutes to 100°C and then for 21/2 hours to the reflux temperature. The resulting solution is cooled to 0°C and the crystals which have separated out are filtered off, washed with water, dried in a vacuum desiccator and finally recrystallised from carbon tetrachloride. 2-Methyl-4-(4-acetoxy-3-allyl-benzylidene)-5(4H)-oxazolone of melting point 108°-109°C is obtained.