Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:31][C:32](=[O:35])[CH2:33][CH3:34])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24]C(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:31][C:32](=[O:35])[CH2:33][CH3:34])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([OH:24])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)OC(C)(C)C)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)O)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
tert-Butyl (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoate (0.07 g) was dissolved in DCM (2 ml), and trifluoroacetic acid (2 ml) was added. The mixture was stirred at room temperature for 1.5 h and then partitioned between water and DCM. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.063 g) as an orange gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:20][C:14]=3[CH:15]=[N+:16]([O-])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:40]=C=O)=O.C[O-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:20][C:14]=3[C:15]([NH2:40])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Product: CCCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Reaction time: 2 h
Yield: 64.3 %

Procedure:
A modification of the general method described in Part C of Example 3 was used to treat 7-benzyloxy-2-butyl-5-oxido-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline (1.0 g, 2.1 mmol). An analysis by TLC indicated that the reaction with trichloroacetyl isocyanate (1.35 mL, 11.3 mmol) was incomplete after two hours, and additional trichloroacetyl isocyanate (1 mL) was added and stirred for one hour. Following the reaction with sodium methoxide, a tan precipitate formed, and the mixture was stirred over two days. The precipitate was isolated by filtration, recrystallized from ethanol, isolated by filtration, washed with hexanes, and dried overnight in a vacuum oven to provide 0.63 g of 7-benzyloxy-2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 188.0-189.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:15]O)=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.O=S(Cl)[Cl:19]>C(Cl)Cl>[Cl:19][CH2:15][C:4]1[C:3]([O:2][CH3:1])=[N:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: COc1nc(-c2ccccc2)cnc1CO
Solvent: ClCCl
Product: COc1nc(-c2ccccc2)cnc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-methoxy-5-phenyl-pyrazin-2-yl)-methanol (60 mg, 0.28 mmol) in DCM (5 mL) is added SOCl2 (5 eq) at room temperature. The mixture is stirred at room temperature for an additional one hour. Solvent and volatile materials are removed in vacuo to dryness to give 65 mg of 2-chloromethyl-3-methoxy-5-phenyl-pyrazine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:30][N:31]([CH3:36])[CH2:32][C:33]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1)=[O:34]
Reactant: CN(C)CC(=O)O
Reactant: NC(=O)c1cccc2oc(-c3cccc(N)c3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1cccc(-c2nc3c(C(N)=O)cccc3o2)c1
Temperature: 30 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
To a solution of 2-(3-aminophenyl)benzo[d]oxazole-4-carboxamide (60 mg, 0.23 mmol) in DMF (3 mL) was added HOBT (35 mg, 0.26 mmol), dimethylglycine (24 mg, 0.23 mmol), DIPEA (91 mg, 0.7 mmol) and EDCI (54 mg, 0.29 mmol). The mixture was stirred at 30° C. for 18 hr. The reaction mixture was purified by pre-HPLC to obtain 2-(3-(2-(dimethylamino)acetamido)phenyl)benzo[d]oxazole-4-carboxamide (30 mg, yield 37%). 1H-NMR (400 MHz, DMSO-d6) δ 2.29 (s, 6H), 3.12 (s, 2H), 7.54-7.58 (m, 2H), 7.95-8.06 (m, 5H), 8.46 (s, 1H), 8.69 (s, 1H), 10.11 (s, 1H); LC-MS (ESI) m/z 339 [M+1]−.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:21])([CH2:19][CH3:20])[C:14]2=[O:22])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>CC(C)=O>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:21])([CH2:19][CH3:20])[C:14]2=[O:22])[CH:10]=[CH:11][CH:12]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCC1(C)CC(=O)N(c2cccc(N)c2)C1=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cccc(N2C(=O)CC(C)(CC)C2=O)c1

Procedure:
Two and eight-tenths g. of propionylchloride was added dropwise to a well-stirred solution of 7 g. of N-m-aminophenyl-2-methyl-2-ethylsuccinimide and 3.5 g. of triethylamine in 50 ml. of acetone in a water bath. When the reaction was complete (after approximately 30 minutes), the mixture was poured into approximately 500 ml. of water and the product extracted with approximately 50 ml. of methylene chloride, dried and the solvent stripped under vacuum. The yield was 7.7 g. of a thick oil having a nD30 of 1.5510. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[O:31][CH:30]=[CH:29][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16](C)=[N:17][N:18]4C4CCCCO4)=[C:14](F)[CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1.Cl.O1CCOC[CH2:34]1>>[CH:1]1([NH:4][C:5]2[C:6]3[O:31][CH:30]=[CH:29][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[N:17][NH:18]4)=[C:14]([CH3:34])[CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1
Reactant: Cc1nn(C2CCCCO2)c2cc(Nc3nc(NC4CC4)c4occc4n3)cc(F)c12
Reactant: C1COCCO1
Agent: Cl
Product: Cc1cc(Nc2nc(NC3CC3)c3occc3n2)cc2[nH]ncc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A flask was charged with N4-cyclopropyl-N2-(4-fluoro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (0.19 g, 0.45 mmol, prepared using B from Preparation #A.1 with Preparation #AN.1) and 4 M HCl in 1,4-dioxane (2 mL). The mixture was stirred at about 50° C. for about 2 h, cooled to rt, concentrated under reduced pressure and purified by reverse phase HPLC (Table 2, Method o) to give N4-cyclopropyl-N2-(4-methyl-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (0.030, 20%): LC/MS (Table 2, Method h) Rt=1.85 min; MS m/z: 321 (M+H)+. Syk IC50=A
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:28]([C:29]2[N:33](C3CCCCO3)[N:32]=[CH:31][CH:30]=2)=[CH:27][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([Cl:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[CH:11][N:10]=1>C(Cl)Cl>[Cl:8][C:9]1[C:28]([C:29]2[NH:33][N:32]=[CH:31][CH:30]=2)=[CH:27][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([Cl:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[CH:11][N:10]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Temperature: 25 °C

Procedure:
TFA (7.3 mL) was added to a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 1.285 g, 2.366 mmol) in DCM (20 mL) and the RM was stirred at RT. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc (150 mL), washed with aq. sat. NaHCO3 solution (2×50 mL) and water (2×50 mL) dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue was crystallized from iPr2O/EtOAc to give the title product as a white solid. HPLC (Condition 7) tR=6.797 min, UPLC-MS (Condition 3) tR=1.05-min, m/z=398.9/401.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([S:8](Cl)(=[O:10])=[O:9])[C:4]([CH3:12])=[N:3]1.[C:13]1([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][C:30]4[S:31][C:32]([CH2:35][NH2:36])=[CH:33][N:34]=4)[CH:25]=3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[C:13]1([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][C:30]4[S:31][C:32]([CH2:35][NH:36][S:8]([C:5]5[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=5[CH3:7])(=[O:10])=[O:9])=[CH:33][N:34]=4)[CH:25]=3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1cnc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)s1
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1S(=O)(=O)NCc1cnc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)s1
Temperature: 40 °C

Procedure:
33 mg of 1,3,5-trimethyl-1H-pyrazole-4-sulfonic acid chloride (0.16 mmol, 1.2 eq) were weighted into a reaction tube and dissolved in dry tetrahydrofuran (1 ml). 44 mg of [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (0.13 mmol) in dry tetrahydrofuran (3 ml) and 30 mg triethylamine (0.3 mmol, 2.3 eq) were added, the tube was flushed with argon, closed with a screw cap, and shaken over night at 40° C. 0.008 ml of tris-(2-aminoethyl)amine in 0.5 ml tetrahydrofuran were added, the mixture was shaken for 2 h at room temperature and then evaporated. The residue was dissolved in 2 ml of a mixture of dimethylformamide/trifluoroacetic acid (19:1), filtered, and submitted to preparative reversed phase HPLC purification (water/acetonitrile gradient (+0.1% trifluoroacetic acid)). 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide was obtained as a white solid (42 mg, 63%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[Cl-].[CH2:45]([C:47]1[S:48][CH:49]=[C:50]([CH2:52][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:51]=1)[CH3:46].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:45]([C:47]1[S:48][CH:49]=[C:50](/[CH:52]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:28]5[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:33]=5)[O:25][C:26]=4[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=2)[N:51]=1)[CH3:46]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4csc(CC)n4)cc3OC)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
A mixture of ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (2.00 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (2.19 g), anhydrous potassium carbonate (713 mg) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:4 to 1:1, v/v) to give ethyl {4-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as colorless crystals (0.71 g, yield 31%). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 136-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([CH:17]4[CH2:19][CH2:18]4)[CH2:15][C:14](=[O:20])[CH2:13][CH:12]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:28]O.Cl.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CCO.O.ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@H:16]([CH:17]4[CH2:19][CH2:18]4)[CH2:15][C:14](=[O:20])[NH:28][CH2:13][C@@H:12]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(C2CC2)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: O=C1C[C@@H](C2CC2)[C@]2(C(=O)Nc3cc(Cl)ccc32)[C@@H](c2cccc(Cl)c2)CN1
Temperature: 90 °C
Yield: 14.6 %

Procedure:
In a manner similar to the method described in example 2 (method B), rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-cyclopropylspiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (148.1 mg, 0.37 mmole) was reacted with NH2OH—HCl (128.6 mg, 1.85 mmol), NaOH (74.0 mg, 1.85 mmole) in EtOH-water (3/2, 10 mL) at refluxing for 2 hrs, followed by reacting with p-toluenesulfonyl chloride (141.1 mg, 0.74 mmol) in dichloromethane (1 mL) at room temperature for 30 min, and heating under microwave irradiation at 90° C. for 20 min. After diluted with AcOEt the mixture was washed with water, dried over Na2SO4 and concentrated. The residue was purified by chiral column chromatography to give (3R,4S,5S)-6′-chloro-3-(3-chlorophenyl)-5-cyclopropyl-1,1′,2,2′,3,5,6,7-octahydrospiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (22.5 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, Found: 415.0974; (3R,4S,5S)-6′-chloro-5-(3-chlorophenyl)-3-cyclopropyl-1,1′,2,2′,3,5,6,7-octahydrospiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (25.8 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, Found: 415.0974; (3S,4R,5R)-6′-chloro-3-(3-chlorophenyl)-5-cyclopropyl-1,1′,2,2′,3,5,6,7-octahydrospiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (14.1 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, Found: 415.0975; and (3S,4R,5R)-6′-chloro-5-(3-chlorophenyl)-3-cyclopropyl-1,1′,2,2′,3,5,6,7-octahydrospiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (15.2 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, Found: 415.0975.
Reaction SMILES: C(F)(F)=C(Cl)F.[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=[C:14]([C:23](O)=[O:24])[C:13]=2[CH:26]=1>C(OCC)(=O)C.CCCCCC>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=[C:14]([CH2:23][OH:24])[C:13]=2[CH:26]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)=Cc1ccccc1O2
Agent: FC(F)=C(F)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(CO)=Cc1ccccc1O2
Yield: 96 %

Procedure:
Preparation analogous to Example 12 f) from 8-methoxy-dibenz[b,f]oxepine-10-carboxylic acid. Yield: 96% in the form of a brown oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.31; 1H-NMR (CDCl3, 300 MHz): 1.80 (sbr, 1H); 3.78 (s, 3H); 4.69 (s, 2H); 6.82-7.33 (m, 8H); MS: 254 (M+), 211, 182, 181 168, 165. 153, 152.
Reaction SMILES: [O:1]1[CH:6]([CH2:7][OH:8])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12.[H-].[Na+:13].[CH2:14]1[S:19](=[O:21])(=[O:20])[O:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[Na+:13].[O:1]1[CH:6]([CH2:7][O:8][CH2:17][CH2:16][CH2:15][CH2:14][S:19]([O-:21])(=[O:20])=[O:18])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12
Reactant: O=S1(=O)CCCCO1
Reactant: OCC1COc2cscc2O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])CCCCOCC1COc2cscc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (6.9 g, 40 mmol) was dissolved into tetrahydrofuran (100 mL) and blanketed by nitrogen. Sodium hydride (1.76 g) was added and stirring was continued for 30 min. Then butanesultone (6.0 g) was added dropwise after which the reaction mixture was brought to reflux for 3 h. Then it was cooled to 25° C. again, the solvent was removed, methanol was added, the mixture was stirred, filtered and the filtrate was concentrated. The remaining oil was solidified by addition of hexanes and ethanol, followed by stirring. Final filtration and drying resulted in pure 4-(2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-butane-1-sulfonic acid sodium salt as was demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][O:4]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=1[CH3:22]>CS(C)=O>[CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][O:10][C:14]2[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=2[CH3:22])[CH2:5][O:4]1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: COC1OCC(CO)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC1OCC(COc2cc[n+]([O-])c(C)c2C)CO1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 49.5 %

Procedure:
To a dimethylsulfoxide (10 ml) solution of the (2-methoxy-1,3-dioxan-5-yl)methanol (2.0 g, 13.5 mmol) obtained in the same manner of step (6a), sodium hydride, in oil (770 mg, 14.9 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (2.13 g, 13.5 mmol) was added and the mixture was stirred at 60° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, it was concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (1.8 g, 49.5% yield), which was a cis and trans (1:1) mixture, as a yellow oil.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C(CCC(O)=O)=O.N1CCC[C@H]1C(O)=O.[F:26][C:27]([F:49])([F:48])[C:28]1[CH:29]=[C:30]([CH:45]=[CH:46][CH:47]=1)[C:31]([CH2:33][CH2:34][C:35]([N:37]1[CH2:44][CH2:43][CH2:42][C@H:38]1[C:39]([OH:41])=[O:40])=[O:36])=[O:32].[Br:50]Br>C(O)(=O)C>[Br:50][CH:33]([C:31](=[O:32])[C:30]1[CH:45]=[CH:46][CH:47]=[C:28]([C:27]([F:26])([F:48])[F:49])[CH:29]=1)[CH2:34][C:35]([N:37]1[CH2:44][CH2:43][CH2:42][C@H:38]1[C:39]([OH:41])=[O:40])=[O:36]
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1cccc(C(F)(F)F)c1
Reactant: BrBr
Agent: O=C(O)CCC(=O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(=O)O
Product: O=C(c1cccc(C(F)(F)F)c1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O

Procedure:
As described in Example 15, 3-(3-trifluoromethylbenzoyl)propionic acid, hydroxysuccinimide ester is prepared and coupled to L-proline as in Example 16. The 1-[3-(3-trifluoromethylbenzoyl)propionyl]-L-proline in acetic acid is reacted with bromine as in Example 20 to give 1-[3-bromo-3-(3-trifluoromethylbenzoyl)propionyl]-L-proline. The preceding compound is reacted with potassium thioacetate in ethanol-water (1:1) as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: O=Cc1ccco1
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C1CCC(N2Cc3c(NCc4ccco4)cccc3C2=O)C(=O)N1
Reaction time: 24 h
Yield: 29.5 %

Procedure:
To a stirred suspension of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.52 g, 2.0 mmol) in methanol (50 ml) was added furan-2-carbaldehyde (0.200 g, 2.05 mmol). The mixture was heated to reflux for 4 hours. The solvent was evaporated in vacuo and the residue was dissolved in acetic acid (20 ml). Sodium triacetoxyborohydride (0.450 g, 2.05 mmol) was added to the reaction mixture. The reaction mixture was stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml), washed with H2O (3×100 ml), saturated aqueous NaHCO3 (2×100 ml), brine (1×100 ml), and dried over MgSO4. The solvent was evaporated in vacuo and the residue was partially purified by chromatography (100% ethyl acetate) to give an off-white solid which was recrystallized from ethanol to give 0.20 g of product as a white solid: mp 248–250° C.; 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 7.57 (s, 1H), 7.27 (t, J=7.6 Hz, 1H), 6.96 (d, J=7.3 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.36 (d, J=1.2 Hz, 2H), 6.22 (t, J=5.4 Hz, 1H), 5.12 (dd, J=4.9 and 13.1 Hz, 1H), 4.37 (d, J=5.5 Hz, 2H), 4.27 (d, J=17.2 Hz, 1H), 4.14 (d, J=17.2 Hz, 1H) 3.00–2.86 (m, 1H), 2.65–2.59 (m, 1H), 2.37–2.23 (m, 1H), 2.08–1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.83, 171.16, 168.70, 152.82, 143.06, 142.00, 132.09, 129.02, 126.76, 112.35, 110.63, 110.33, 107.08, 51.50, 45.73, 31.20, 22.75; Anal. Calcd. For C18H17N3O4: C, 63.71; H, 5.05; N, 12.38. Found: C, 63.41; H, 5.03; N, 11.98.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:20])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Cc1noc(N)c1Br
Product: COc1ccc(S(=O)(=O)Nc2onc(C)c2Br)cc1OC
Yield: 64 %

Procedure:
3,4-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3,4-dimethoxybenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 136°-138° C., yield 64 %.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a5) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].Cl[CH2:21][CH2:22][NH:23][C:24](=[O:28])[O:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:19][CH2:21][CH2:22][NH:23][C:24](=[O:28])[O:25][CH2:26][CH3:27]
Reactant: CCOC(=O)NCCCl
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1Cl
Temperature: 0 °C

Procedure:
To a solution of 0.65 g (2.25 mmol) of 2-chloro-4-(4-trifluoromethylphenoxy)-phenol in 20 ml of N,N-dimethylformamide, there are added 0.38 g (2.47 mmol) of ethyl 2-chloroethylcarbamate and 0.69 g (4.95 mmol) of potassium carbonate with stirring, and the resultant mixture is stirred at 50° C. for 8 hours. The reaction mixture is poured into 100 g of ice-water and extracted twice with 100 ml of ethyl acetate. The extracts are combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give ethyl 2-[2-chloro-4-(4-trifluoromethylphenoxy)phenoxy]ethylcarbamate.