Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21].[OH-].[Na+]>O>[Cl:20][C:19]1[C:14]([Cl:13])=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=1[N:1]=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1cccc(Cl)c1Cl
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc(N=Nc2ccccc2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 119.1 %

Procedure:
At 0 to 5° C., a solution of 7.6 g (0.11 mol) of NaNO2 in 12 ml of H2O is added dropwise to 50 ml of aqueous HCl (15%) and 9.8 g (0.105 mol) of aniline in a 100 ml two-neck flask fitted with internal thermometer and magnetic stirrer. After 10 minutes, this diazonium salt solution is added at 5 to 10° C. to a solution of 16.3 g (0.1 mol) of 2,3-dichlorophenol and 20 g (0.5 mol) of NaOH in 200 ml of H2O. The mixture is allowed to warm to room temperature, stirred for an additional 4 hours, neutralized with aqueous HCl and extracted 3× with 100 ml of ethyl acetate each. The combined organic phases are washed with NaCl solution and dried with Na2SO4, and the solvent is distilled off using a rotary evaporator. 31.8 g of (2,3-dichloro-4-hydroxyphenyl)phenyldiazene are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH2:7]Cl.[CH2:10]([O:12][C:13](=[O:16])[CH2:14][NH2:15])[CH3:11].C(N(C(C)C)CC)(C)C.C1C[O:29]CC1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]([NH:15][CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:16])=[O:29]
Reactant: ClCc1cncc(Br)c1
Reactant: C1CCOC1
Reactant: CCOC(=O)CN
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A solution of 5-bromonicotinic acid (4 g, 0.02 mol) in thionyl chloride (25 mL) was heated under reflux for 4 h. The excess thionyl chloride was removed under reduced pressure to provide 5-bromonicotinyl chloride which was used without further purification. To 5-bromonicotinyl chloride (3.5 g, 13.6 mmol) was added glycine ethylester (2.1 g, 20.3 mmol) and diisopropyl ethyl amine (2.6 g, 20.1 mmol) in THF (70 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was diluted with EtOAc and washed with brine solution. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography using 25% EtOAc in hexane to provide ethyl 2-(5-bromonicotinamido)acetate 1.2 g (33%) as a brown solid. LCMS Method T: retention time 1.28 min; [M+1]=288.2
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].[CH3:13][C:14](C)=[CH:15]CN.C(O)(=O)C(O)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:37]=[CH:36][C:30]([O:31]C2CNC2)=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:13][C:14]([CH3:15])=[CH:11][CH2:12][NH:8][C:1]([N:3]1[CH2:4][CH:6]([O:31][C:30]2[CH:36]=[CH:37][C:27]([C:26]([F:25])([F:38])[F:39])=[CH:28][CH:29]=2)[CH2:7]1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)=CCN
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CCNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 16 h
Yield: 83.8 %

Procedure:
A solution of 3.6 g. (0.022 mole) of 1,1'-carbonyldiimidazole in 100 ml of methylene chloride was cooled in a tap water bath and while stirring under nitrogen, 1.87 g (0.022 mole) of 3-methyl-2-butenylamine was added dropwise. After stirring for 1 hr, 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 0.5 hr with 5 ml of triethylamine and stirring continued for an additional 16 hr. The reaction mixture was washed with 2×50 ml of water, dried over magnesium sulfate and concentrated on a rotary evaporator to yield a semi-solid residue. Trituration with isopropyl ether and filtration yielded 7 g of crude product which was recrystallized from ethanol-water to give 5.5 g (83.8%) of white crystals, m.p. 156.5°-158° C.
Reaction SMILES: [OH:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[CH:3]=1.O>C(O)CCC.C1C=CC=CC=1>[CH2:5]([O:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[CH:3]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=c1cc(O)c1=O
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCO
Product: CCCCOc1cc(=O)c1=O
Yield: 162.8 %

Procedure:
A suspension of 1.25 g of 1-hydroxycyclobutene-3,4-dione (A) in 10 ml of absolute n-butanol and 15 ml of benzene is heated to reflux in a Soxhlet apparatus. A passes slowly into solution. The water of reaction is bound to the molecular sieve 4A which is present in the apparatus. The reaction mixture is concentrated after 2 hours. The distillation of the residue at 105°-115° C/0.01 Torr yielded 1.6 g (=82% of theory) of 1-n-butoxycyclobutene-3,4-dione as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:34])C(=O)C1>ClCCCl>[Cl:34][C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH2:17])[C:16]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Cl)cc1)cn2-c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Product: Nc1ncnc2c1c(-c1ccc(Cl)cc1)c(Cl)n2-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A suspension of 5-(4-chlorophenyl)-7-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (26) (527 mg, 1.4 mmol) and NCS (289 mg, 2.2 mmol) in DCE (95.0 mL) was heated to reflux for 2 hr. The reaction was then cooled down to r.t., before it was quenched with H2O (10.0 mL). The layers were separated. Aqueous phase was extracted with DCM (15.0 mL×2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to afford 6-chloro-5-(4-chlorophenyl)-7-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (27) (550 mg, 95% yield) as a red solid. LC-MS (ESI): m/z (M/M+2) 399.9/401.9.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[N:25][CH:26]=2)[CH2:2][CH2:3]1
Reactant: CCCc1noc(N2CCC(NC3CC3)CC2)n1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Product: CCCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.09 min; Mass spectrum (ESI+): m/z=423 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]1[CH:8]=[C:9]([N:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]#N)[C:15]2=[O:23])[CH:10]=[CH:11][C:12]=1[F:13].[OH-:24].[Na+]>O>[F:6][C:7]1[CH:8]=[C:9]([N:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([OH:2])=[O:24])[C:15]2=[O:23])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C#N)c(=O)n1-c1ccc(F)c(F)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)c(F)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
Water (7.2 mL) and conc. sulfuric acid (7.2 mL) were added to 1-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (3.6 g, 14.6 mmol), and the mixture was stirred at 100° C. for 20 hr. The mixture was basified (pH 10) with 8N aqueous sodium hydroxide solution at 0° C. and washed with ethyl acetate. The aqueous layer was acidified (pH 3) with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate/hexane (=1/1) and collected by filtration to give the title compound (2.49 g, 64%) as a thin-yellow powder.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C(O)C.[OH-].[Na+]>ClCCl>[C:2]([C:3](=[O:5])[CH:4]=[CH:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: O=Cc1ccncc1
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)C=Cc1ccncc1
Reaction time: 12 h

Procedure:
A mixture of 3,3-dimethyl-2-butanone (2.5 ml, 20.0 mmol), 4-pyridinecarboxaldehyde (2.15 ml, 22.3 mmol), ethanol (7.6 ml), and 4.5% aqueous sodium hydroxide (4.6 ml) was kept at room temperature for 12 h. It was diluted with dichloromethane, washed with aqueous hydrochloric acid and water, dried and evaporated. Subsequent column chromatography (hexane-ethyl acetate=3:1) provided the title compound. MS (m/z): 190.4 (M+H)+; C12H15NO requir.189.3.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=O.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=[C:10]2[C:9]([OH:14])=[O:13]
Reactant: Cc1ccccc1N
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: Cc1cccc2c(C(=O)O)cc(-c3ccccc3)nc12
Yield: 19.5 %

Procedure:
A solution of 2 -methylaniline (28 g) in EtOH (50 mL) was added to a solution of pyruvic acid (33 g) and benzaldehyde (28 g) in EtOH (100 mL), and the mixture was heated under reflux for 3 h and then allowed to cool overnight. The resulting solid was collected by filtration, washed well with cold EtOH and benzene and dried to give a product (13.4 g) of acceptable purity. A sample crystallized from EtOH had mp 245°-246° C. (lit. mp 245° C. Doebner and Giesecke, Ann. 1887, 242, 290).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:20]([O:22]C)=[O:21])[C:18](=[O:19])[N:8]2[C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][CH2:11][C@@H:7]2[CH2:6]1.O[Li].O>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:20]([OH:22])=[O:21])[C:18](=[O:19])[N:8]2[C@@H:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:10][CH2:11][C@@H:7]2[CH2:6]1
Reactant: COC(=O)C1(CCCCl)C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(CCCCl)C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Temperature: 0 °C

Procedure:
The (3R,7aS)-methyl 6-(3-chloropropyl)-5-oxo-3-phenyl-hexahydropyrrolo[1,2-c]oxazole-6-carboxylate (36.90 g) was dissolved in 300 mL of THF and the mixture cooled to 0° C. A solution of LiOH.H2O (22.97 g, 0.548 mol, 5.0 equiv) in water (273 mL, 2.0 M) was cooled to ˜5° C. and added to the THF solution. The mixture was stirred at 10° C. and the progress of the hydrolysis monitored by LC/MS. After 3 h the methyl ester was completely consumed. EtOAc (100 mL) was added and concentrated HCL added till the pH<2. The mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with 100 mL EtOAc, the combined organic layers washed with brine, dried over Na2SO4, filtered and evaporated. The (3R,7aS)-6-(3-chloropropyl)-5-oxo-3-phenyl-hexahydropyrrolo[1,2-c]oxazole-6-carboxylic acid was isolated as a tan solid (32.65 g, 92% yield) after removal of residual solvent in vacuo.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14](Cl)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:22]2[CH2:24][CH2:23]2)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C.Cl>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:22]2[CH2:24][CH2:23]2)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Temperature: 70 °C

Procedure:
A solution of 3-benzyloxy-7-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione (Example E-3, 0.15 g, 0.42 mmol) in DMF (4.0 mL) was reacted with pyrrolidine (1.0 mL) and heated to 70° C. overnight. The mixture was then cooled, diluted with 0.25 M HCl, and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated. The residue was then purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide 0.15 g of the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH3:16])[CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.O>[CH:24]([C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH3:16])[CH:3]=1)=[O:25]
Reactant: Cc1cc(Br)ccc1C(=O)NCC(F)(F)F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)NCC(F)(F)F

Procedure:
In a solution of 1.00 g of 4-bromo-2-methyl-N-(2,2,2-trifluoroethyl)benzoic acid amide in 15 ml of tetrahydrofuran under nitrogen atmosphere, 4.7 ml of n-butyl lithium (1.58M hexane solution) was added dropwise at −70° C. with stirring, and then 0.4 ml of N,N-dimethylformamide were added dropwise. After stirring at the same temperature for 30 minutes, 10 ml of 1 N hydrochloric acid and then 30 ml of water were added, and extracted with ethyl acetate (30 ml×2). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.80 g of the aimed product as pale yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[C:13]([I:16])=[N:14][NH:15][C:7]=2[CH:6]=1.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>O1CCCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[C:26]([O:25][C:23]([N:15]1[C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=3[F:1])[C:10](=[O:11])[N:9]([CH3:12])[C:8]=2[C:13]([I:16])=[N:14]1)=[O:22])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2[nH]nc(I)c21
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1c(I)nn2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 120 %

Procedure:
To a solution of 6-(2,4-difluorophenoxy)-3-iodo-4-methyl-1,4-dihydro-pyrazolo[4,3-b]pyridin-5-one (12 mg, 0.0298 mmol) in tetrahydrofuran (5 mL) was added BOC2O (16 mg, 2.5 eq) and DMAP (catalytic). The resulting mixture was heated under reflux for 30 minutes, cooled to room temperature, and diluted with ethyl acetate (35 mL) and water (25 mL). The organic layer was separated, washed successively with water (2×25 mL), 0.5 N HCl (2×20 mL) and brine (1×25 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound as a white powder (18 mg, (M+H)+=504).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:24])[N:19]([CH3:23])[N:20]=[C:21](Cl)[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:24])[N:19]([CH3:23])[N:20]=[C:21]([O:30][CH3:29])[C:16]=4[N:15]=[CH:14]3)=[CH:25][CH:26]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1nc(Cl)c2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nn(C)c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 70 %

Procedure:
In methanol (5 ml) was dissolved 1-[4-(4-chloro-benzoyl)benzyl]-4-chloro-6-methylimidazo[4,5-d]pyridazin-7(6H)-one (72 mg) followed by addition of 28% sodium methoxide/methanol (1.0 ml), and the mixture was refluxed for 5 hours. To this reaction mixture was added a large quantity of water and the resulting crystals were rinsed with water and dried under reduced pressure to provide 50 mg (yield 70%) of the title compound. 1H-NMR (CD3OD) δ: 3.7.1(3H,s), 4.00(3H,s), 5.85(2H,s), 7.50(2H,d,J=8.6Hz), 7.52(2H,d,J=8.8Hz), 7.74(2H,d,J=8.8Hz), 7.75(2H,d,J=8.6Hz), 8.42(1H,s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([CH3:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c[nH]c2nc(Cl)nc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
503 mg 2,4-dichloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (5) (2.5 mmol) and 523 mg TsCl (2.75 mmol) were dissolved in 20 mL of DMF. After cooling to 0° C., 200 mg NaH (2.75 mmol) was slowly added under N2. The reaction mixture was stirred at 0° C. for 30 minutes and quenched by adding 10 mL of 10% aqueous NH4Cl at this temperature, then extracted with EtOAc (3×50 mL). Combined organic layers were washed with brine, dried over Na2SO4 and purified by flash column chromatography to give the title compound as light yellow solid.
Reaction SMILES: CC(CC(C)(C)C)C[CH2:4][CH:5](C(C)CC(C)(C)C)[CH2:6][OH:7].[CH2:20]([CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:28][OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:4]([O:29][CH2:28][CH:27]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:5]1[O:7][CH2:6]1
Reactant: CC(CCC(CO)C(C)CC(C)(C)C)CC(C)(C)C
Reactant: CCCCCCCCCC(CO)CCCCCCC
Product: CCCCCCCCCC(CCCCCCC)COCC1CO1
Yield: 80 %

Procedure:
The same reaction as in Reference Example 1 was carried out under the same conditions except that the 5,7,7-trimethyl-2-(1,3,3-trimethylbutyl) octanol in Reference Example 1 was replaced by 2-heptylundecanol, whereupon 65 g (yield: 80%) of 2-heptylundecyl glycidyl ether was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCCC1.[Cl:41]N1C(=O)CCC1=O>CO.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:41])=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][CH:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 29 h
Yield: 69.3 %

Procedure:
Di-tert-butyl {[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (150 mg) prepared in a similar manner according to Step 5 of Production Example 18 was dissolved in methanol (1.5 ml) and tetrahydrofuran (3 ml) under nitrogen atmosphere. Then N-chlorosuccinimide (59.7 mg) was added to the solution at 0° C. The reaction mixture was stirred at room temperature for 29 hours, and diluted in ethyl acetate. The organic solution was washed with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with ethyl ether to give di-tert-butyl {[(4-{2-[2-(acetylamino)-5-chloro-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (111 mg) as an off-white solid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([O:33][CH3:34])=[N:16][N:17]2[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([O:33][CH3:34])=[N:16][N:17]3[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])=[CH:13][CH:12]=2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(Cn2nc(OC)c3ccc(N)cc32)c(OC)c1
Reactant: O=C(Cl)OC1CCCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(OC)c3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
Cyclopentyl chloroformate (0.17 ml.) was added to a cooled (-20° C.) solution of methyl 4-[6-amino-3-methoxyindazol-1-ylmethyl]-3-methoxybenzoate (S) (0.381 g.) and pyridine (0.11 ml.) in dichloromethane (3.0 ml.). After warming to ambient temperature, the mixture was diluted with ethyl acetate, and washed with hydrochloric acid (1N), water, brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (56 g.), eluting with 5:95 v/v ethyl acetate:dichloromethane, to give the title compound (0.365 g., 75%) as an oil, with satisfactory NMR spectral data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([N-:11][CH2:12][CH3:13])C.[Li+].[CH2:15](OCC)[CH3:16]>>[CH2:4]([C:3]1([OH:8])[CH:2]=[CH:7][CH:6]=[C:13]([CH2:15][CH3:16])[CH:12]1[NH2:11])[CH3:5]
Reactant: CCOCC
Reactant: Oc1ccccc1Br
Reactant: CC[N-]CC
Agent: [Li+]
Product: CCC1=CC=CC(O)(CC)C1N
Yield: 15 %

Procedure:
Amer. Chem. Soc., 74 (1952), 3027-29, discloses that the treatment of o-bromophenol with twice the molar amount of lithium diethylamide in boiling diethyl ether gives rise to m-diethyl-aminophenol. However, the process described there is completely unsuitable for an industrial synthesis, since m-diethylaminophenol is formed only in a yield of 15%.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=C.B(F)(F)F.[CH3:10]COCC.[C:15]([N:20]1[C@H:24]([CH:25]([CH3:27])[CH3:26])[C:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:22][C:21]1=[O:40])(=[O:19])/[CH:16]=[CH:17]/[CH3:18]>C1COCC1.[Cu]I>[CH:25]([C@@H:24]1[C:23]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:22][C:21](=[O:40])[N:20]1[C:15](=[O:19])[CH2:16][C@H:17]([CH3:10])[CH2:18][CH:1]=[CH2:2])([CH3:27])[CH3:26]
Reactant: C/C=C/C(=O)N1C(=O)OC(c2ccccc2)(c2ccccc2)[C@H]1C(C)C
Reactant: C=CC[Mg]Cl
Reactant: CCOCC
Agent: [Cu]I
Agent: FB(F)F
Solvent: C1CCOC1
Product: C=CC[C@@H](C)CC(=O)N1C(=O)OC(c2ccccc2)(c2ccccc2)[C@H]1C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 22.35 g (117 mmol) CuI in 400 ml THF at −40° C. are added dropwise 70 ml (140 mmol) of a 2M THF solution of allylmagnesium chloride. After 1 h the mixture is cooled to −78° C. and 17.7 ml (140 mmol) BF3.OEt2 are added in 15 minutes. Then a solution of 41 g (117 mmol) (R)-3-((E)-but-2-enoyl)-4-isopropyl-5,5-diphenyl-oxazolidin-2-one in 100 ml THF is added as quickly as possible. The temperature rises to −40° C. Stirring is continued for 1 h and then the mixture is quenched with 500 ml 10% aqueous NH4Cl. The mixture is stirred for 1 h at 25° C. and filtered over celite and washed with 150 ml TBME. The organic phase is washed successively with water, 10% aqueous NaHCO3, water, 5% citric acid and water. Chromatography (silica gel, EE/hexane 1:10) of the crude product yields the (R)-4isopropyl-3-((R)-3-methyl-hex-5-enoyl)-5,5-diphenyl-oxazolidin-2-one.