Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[OH:13].[Cl:14][CH2:15][CH:16]=O.Cl.O>CC(O)=O>[Cl:14][CH2:15][CH:16]1[O:13][C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: OCc1ccc(C(F)(F)F)cc1O
Reactant: O=CCCl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2c(c1)OC(CCl)OC2
Reaction time: 24 h
Yield: 6.1 %

Procedure:
2-(hydroxymethyl)-5-(trifluoromethyl)phenol (1.0 g, 5.2 mmol) was dissolved in AcOH (4 ml) and cooled on ice-bath. Chloroacetaldehyde (0.93 ml, 7.3 mmol) and concentrated HCl (1.0 ml) were consecutively added drop wise. After 24 h, further addition of chloroacetaldehyde (0.50 ml, 3.9 mmol) and concentrated HCl (1.0 ml) were done and the reaction mixture was allowed to stir another 24 h. Water was added and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated under reduced pressure to give an oil. Twice purification by flash column chromatography (isooctane/EtOAc 4:1) gave the pure title compound (0.08 g, 6%). MS m/z (rel. intensity, 70 eV) 252 (M+, 10), 174 (76), 146 (bp), 145 (47), 127 (44).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1>C(O)CCC>[O:24]=[S:21]1(=[O:25])[CH2:22][CH2:23][N:18]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:19][CH2:20]1
Reactant: O=S1(=O)CCNCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1cc(N2CCS(=O)(=O)CC2)ncn1
Temperature: 200 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.4 g, 3.09 mmol) and diisopropylethylamine (0.4 g, 3.09 mmol) were suspended in n-butanol and thiomorpholine 1,1-dioxide (0.417 g, 3.09 mmol) was added. The reaction was stirred at 200° C. for 18 hours, the butanol was evaporated off and the product was purified on a silica column eluted with DCM:MeOH:NH4OH (95:5:0.5). Yield=2.45 mmol (79%). 1H-NMR (CD3OD): 8.03 ppm (s, 1H); 5.87 ppm (s, 1H); 4.10 ppm (t, 4H); 3.09 ppm (t, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]([CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[N:42]=[CH:41][C:40]3[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=3)[C:34]2=[O:48])=[N:26][CH:27]=[CH:28][C:29]=1B(O)O)(=[O:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[N:42]=[CH:41][C:40]3[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:45])([CH3:44])[CH3:46])[CH:39]=3)[C:34]2=[O:48])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]([CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CCc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)nn1C
Temperature: 100 °C
Yield: 25 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 122b (310 mg, 1.0 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (1.24 g, 3.0 mmol), K3PO4 (424 mg, 2.0 mmol), sodium acetate (164 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (73 mg, 0.10 mmol), acetonitrile (10 mL), and water (0.5 mL). The system was subject to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 2.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified with silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 122c (150 mg, 25%) as a yellow oil. MS-ESI: [M+H]+ 600.0
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].CC([O-])(C)C.[K+].[I:19]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:19][C:11]1[CH:12]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: II
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: [Ag+2]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
To a stirred suspension of 4-(methylsulfonyl)aniline hydrochloride (2.0 g, 9.7 mmol) in EtOH (40 mL) was added KOtBu (1.3 g, 11.4 mmol). The reaction mixture was stirred for 15 minutes, then a slurry of silver sulfate (3.3 g, 10.6 mmol) and iodine (2.4 g, 9.6 mmol) in EtOH (100 mL) was added. The reaction mixture was stirred at 50° C. for 3 h, then cooled to r.t., filtered through Celite®, and the filtrate concentrated in vacuo. Recrystallisation from EtOH gave the title compound (1.9 g, 66%) as an off-white solid. LCMS (ES+) 319.8 (M+Na)+, RT 2.77 minutes (Method 5).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C1(C)C=CC=CC=1>CN(C)C=O.O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([O:16][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=C1c2ccccc2-c2c(Cl)cc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-Chloro-2-hydroxy-9H-fluoren-9-one (48.6 g) was dissolved in N,N-dimethylformamide (150 ml), potassium carbonate (58.3 g) and ethyl 4-bromobutyrate (33.5 ml) were added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was cooled to 40° C., and toluene (300 ml) and water (300 ml) were added to allow for layer separation. The obtained aqueous layer was extracted again with toluene (100 ml). The obtained organic layers were combined, washed twice with water (100 ml), anhydrous sodium sulfate and activated carbon (2.5 g) were added, and the mixture was stirred at room temperature for 5 min. The insoluble material was filtered off through celite, and the solvent in the filtrate was evaporated. To the obtained residue was added hexane (220 ml), and the mixture was stirred at 50° C. for 10 min and at room temperature for 1 hr. The precipitated solid was collected by filtration, and washed with hexane. The obtained solid was dried under reduced pressure to give the title compound (66.9 g). In addition, the solvent in the obtained filtrate was evaporated, to the residue were added ethyl acetate (5 ml) and hexane (20 ml), and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration, and washed with hexane. The obtained solid was dried under reduced pressure to further give the title compound (2.5 g).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CC([O:24][CH2:25][C@H:26]1[O:31][C@H:30]([O:32][C@:33]2([CH2:51][O:52]C(C)=O)[O:37][C@H:36]([CH2:38]OC(C)=O)[C@@H:35]([O:43]C(C)=O)[C@@H:34]2[O:47]C(C)=O)[C@H:29]([O:56]C(C)=O)[C@@H:28]([O:60]C(C)=O)[C@@H:27]1[O:64]C(C)=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+].C>C(O)(C)C>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][CH2:38][C@H:36]1[O:37][C@:33]([O:32][C@H:30]2[O:31][C@H:26]([CH2:25][OH:24])[C@@H:27]([OH:64])[C@H:28]([OH:60])[C@H:29]2[OH:56])([CH2:51][OH:52])[C@@H:34]([OH:47])[C@@H:35]1[OH:43])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CC(=O)OC[C@H]1O[C@@](COC(C)=O)(O[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reaction time: 4.5 h
Yield: 70 %

Procedure:
0.06 mol (16.93 g) of oleic acid (Fluka Chemika, Switzerland) was weighed into a three-necked, round-bottom flask equipped with a magnetic stirrer, stopcocks, a vacuum take-off line leading to a liquid nitrogen cold-trap and a vacuum pump. 0.01 mol (6.79 g) of sucrose octaacetate, SOA, (Fluka Chemika, Switzerland) was added and the mixture was heated to 80-95 degree C. in an oil bath with continuous stirring until a homogenous solution was formed. 0.01% w/w tosylic acid (or alkyl sulfonic acid polysiloxane, or BF3.OEt2) was then added. Reaction temperature was then reduced to between 60-75 degree C. and 5-10 Torr pressure was applied. The reaction was continued for 3 to 6 hours. The product was taken up in 250 ml of iso-propanol, neutralized with aqueous 1M NaHCO3, decolourised with 2.0 g activated charcoal, and filtered. Iso-propanol was then removed by vacuum distillation. Unreacted oleic acid was extracted with 50×4 ml hexane and kept for reuse. The sucrose fatty ester was redissolved in warm iso-propanol to form 30-40% w/v solution, cool to −4 to 0 degree C. and filtered to give unreacted SOA as precipitate. The filtrate iso-propanol was then distilled off to give 70-85% pure acetylated sucrose oleate. Repeated hexane extraction and SOA precipitation gave 90-95% pure product (87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[C@@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].[CH2:31]([Si](C)(C)C)[CH:32]=[CH2:33]>O1CCCC1.ClCCCl.[I-].[Zn+2].[I-].O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:33][CH:32]=[CH2:31])[C@@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CC[Si](C)(C)C
Reactant: COc1ccc([C@]2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: C=CC[C@H]1c2ccc(OC)cc2SC[C@@]1(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.1 %

Procedure:
A solution of the (3S)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one prepared in Example 1 (15 g, 0.048 mol) in anhydrous tetrahydrofuran (250 ml) was cooled to −78° C. To this solution, lithium aluminum hydride (905 mg, 0.024 mol) was added dropwise and the resulting mixture was stirred for 12 hours at room temperature. After the reaction was completed, saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, zinc iodide (18.0 g, 0.053 mol) and allyltrimethylsilane (15 ml, 0.088 mol) were added dropwise to a solution of the residue in 1,2-dichloroethane (300 ml) while cooling at 0° C., followed by stirring overnight at room temperature. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give (3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman (10.8 g, Yield 67%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=O)[S:4][N:3]=1.[F:11][C:12]1[C:13]([NH2:27])=[N:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:16][CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.ClN1C(Cl)=C(C(Cl)=O)SC1>C(Cl)(=O)C(Cl)=O.CN(C)C=O.C1COCC1.O>[F:11][C:12]1[C:13]([NH:27][C:8]([C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[Cl:7])=[O:10])=[N:14][C:15]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:16][CH:17]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: O=C(O)c1snc(Cl)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C1=C(Cl)N(Cl)CS1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc(OCc2ccc(F)cc2)ncc1F)c1snc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
To a suspension of 3,4-dichloroisothiazole-5-carboxylic acid (0.15 g, 0.76 mmol) in oxalyl chloride (2 mL) was added a catalytic amount of dimethylformamide (2 drops) and the mixture was heated to 80° C. and stirred for 2 h. The excess oxalyl chloride was removed on the rotary evaporator. Meanwhile, 5-fluoro-2-(4-fluorobenzyloxy)-pyrimidin-4-ylamine (0.17 g, 0.68 mmol) was dissolved in THF (1 mL), treated with LiHMDS (1M in THF, 0.76 mL, 0.76 mmol) and stirred for 10 min. The freshly prepared 3,4-dichlorothiazole-5-carbonyl chloride*, dissolved in THF (1 mL), was added and the reaction was capped and stirred for 12 h. The reaction was diluted with water and the target compound was extracted with CH2Cl2 (3×5 mL). The combined extracts were dried over MgSO4 and then evaporated under reduced pressure. The mixture was eluted with CH2Cl2 through an anionic-exchange solid phase extraction column and then further purified by reverse-phase chromatography to give 3,4-dichloroisothiazole-5-carboxylic acid [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]amide (0.035 g, 12%) as a tan solid: mp 87-90° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.67 (s, 1H), 7.51-7.48 (m, 2H), 7.24-7.19 (m, 2H), 5.25 (s, 2H); MS (ESI) m/z 417 (M+H)+, 415 (M−H)−. *Nagata, T.; Kogure, A.; Yonekura, N.; Hanai, R.; Kaneko, I.; Nakano, Y. JP 2007211002 A
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)[C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=O.O.NN.C([N:27](CC)CC)C>C(O)C.O>[Cl:12][C:9]1[S:8][C:7]([C:5]2[C:4]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=3)=[CH:3][NH:2][N:27]=2)=[CH:11][CH:10]=1
Reactant: CSc1nccc(C(=CN(C)C)C(=O)c2ccc(Cl)s2)n1
Reactant: CCN(CC)CC
Agent: NN
Solvent: CCO
Solvent: O
Product: CSc1nccc(-c2c[nH]nc2-c2ccc(Cl)s2)n1
Yield: 81 %

Procedure:
To a mixture of 3-(dimethylamino)-1-(5-chloro-2-thienyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one (1 eq, 96 mmol) in 300 mL ethanol was added dropwise hydrazine hydrate (1.5 eq, 144 mmol) and then triethylamine (1.5 eq, 144 mmol). The mixture was heated under reflux for 2 h and then overnight at room temperature. The solvent was then slowly poured in 1 L of water. The resulting precipitate was filtered and dried to afford 24 g of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]-2-(methylsulfanyl)pyrimidine (80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH:20]=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1cc(N)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 4-chloro-3-methoxyaniline (1.57 g, 10.0 mmol) in methanol (27 ml) were added acetic acid (3 ml), N-(tert-butoxycarbonyl)-L-prolinal (2.40 g, 12.05 mmol) and sodium cyanoborohydride (1.56 g, 24.1 mmol). The resulting suspension was stirred for 2 hours at room temperature. Aqueous sodium bicarbonate solution (30 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=70:30) to yield a light yellow oil (2.31 g, 68%); MS (ISP): 341.0, 342.9 ((M+H)+.).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([CH:7]=O)[CH:3]=1.Cl.[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:7][C:4]2[CH:3]=[C:2]([Br:1])[S:6][CH:5]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1csc(Br)c1
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Agent: Cl
Product: CC(C)(C)NC(=O)C1CCN(Cc2csc(Br)c2)CC1

Procedure:
The title compound is prepared according to the reaction 3.01c described above using 5-bromo-thiophene-3-carbaldehyde and piperidine-4-carboxylic acid tert-butylamide hydrochloride as in 3.01c: LC-MS A: tR=0.64 min; [M+H]+=360.95.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=O)[CH2:11][C:12]2[NH:13][C:14](=[O:24])[CH:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)=[C:4]([OH:26])[CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl.C(Cl)Cl.CO>C1(C)C(C)=CC=CC=1.C(OCC)C>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]2[O:26][C:10]([CH2:11][C:12]3[NH:13][C:14](=[O:24])[CH:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=3)=[N:9][C:5]=2[CH:6]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)c(F)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1C
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(F)c(F)cc3o2)[nH]1
Yield: 14.2 %

Procedure:
The product can be prepared as described in stage 2 of Example 12, but using 465 mg of N-(4,5-difluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in 30 ml of xylene and 77 mg of 4-methylbenzenesulphonique acid hydrate. After refluxing for six hours, addition of 100 mg of 4-methylbenzenesulphonic acid hydrate and purification by silica column chromatography, eluent: gradient of pure CH2Cl2 to CH2Cl2/MeOH: 96/04, the product obtained is taken up with 20 ml of diethyl ether and then spin-filter-dried and dried under vacuum. 63 mg of 2-[(5,6-difluoro-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:7]CC)=O)(=O)[CH3:2].[C:17](=[NH:23])([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21].C[O-].[Na+].CO.C(OCC)(=O)C>CO.O>[CH2:18]([C:17]1[NH:23][C:5](=[O:7])[C:4]([CH2:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15])=[C:1]([CH3:2])[N:22]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCCCc1nc(C)c(CC(=O)C(C)(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-acetyl-5,5-dimethyl-4-oxohexanoate (1.04 g) and pentanimidamide (0.89 g) in methanol (10 mL) was added 28% sodium methoxide-methanol solution (3.7 mL), and the mixture was stirred at room temperature for 24 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.34 g, 36%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a cold solution (ice water bath) of the compound (346 g, 1.48 mol) prepared in Example 134 in 4.2 L CH2Cl2, was added AlCl3 (984.6 g, 7.38 mol) portionwise under Ar such that the reaction temperature was maintained below 10° C. The light brown suspension was stirred 10 minutes, then EtSH (546 mL, 7.38 mol) was added dropwise at such a rate that the reaction temperature was maintained below 5° C. After 2.5 hours of stirring below 10° C., the reaction mixture was slowly poured into 6 L ice water with strong agitation. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3×1 L). The combined CH2Cl2 layers were washed with water (2×1 L), then dried over Na2SO4. The solvent was removed under reduced pressure, giving a brown oil, which was filtered through a pad of silica gel (eluted with 0–10% EtOAc/Hexanes). Fractions were collected and the title compound (314 g, 96%) was obtained as a thick yellow oil after solvent removal and vacuum drying. 1H NMR (CDCl3) δ 6.92(d, 1H), 6.62(d, 1H), 6.55(dd, 1H), 4.10(q, 2H), 3.43(q, 1H), 2.75(m, 2H), 2.64(dd, 1H), 2.31(dd, 1H), 2.29(m, 1H), 1.67(m, 1H), 1.20 (t, 3H). MS (Cl) m/z 221 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(OCC)(=O)C.CCCCCCC>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCC(=O)NS(=O)(=O)c1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(=O)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 120.2 %

Procedure:
At 80° C., N-bromosuccinimide (1.43 g, 8.06 mmol) and dibenzoylperoxide (62 mg, 0.25 mmol) were added successively to a solution of N-dodecanoyl-4-methylbenzenesulfonamide (3 g, 8.48 mmol) in tetrachloromethane (75 ml). The reaction mixture was heated for 1 h to 80° C. Another portion of dibenzoylperoxide (100 mg, 0.41 mmol) was added. The reaction mixture was heated another 2 h to 80° C. It was cooled to room temperature and left for 16 h. Ethyl acetate (100 ml) and heptane (100 ml) were added. The solid was removed by filtration. The solvent was removed from the filtrate to give 4.19 g of crude 4-bromomethyl-N-(dodecanoyl)benzenesulfonamide, which was used for the next step, without further purification.