Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].CO.[OH:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CS(C)=O>[CH2:22]([O:21][C:19]([CH:18]([O:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=1)[CH3:24])=[O:20])[CH3:23]
Reactant: Cc1ccc(-n2cnc(O)n2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(C)cc2)n1
Yield: 28.7 %

Procedure:
The process was carried out as described in Example 8, starting with 1.1 g of sodium, 20 ml of methanol, 150 ml of dimethylsulfoxide, 8.5 g of 3-hydroxy-1-(4-methylphenyl)-1,2,4-1H-triazole and 8.7 g of ethyl 2-bromopropionate. A yield of 3.8 g of the desired product, m.p. 69°-71°, was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[H-].[Na+].C([O:16][C:17]1[C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][C:20]([CH2:27][CH2:28][CH2:29]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:19][C:18]=1[C:41]([CH3:44])([CH3:43])[CH3:42])(=O)C>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:41]([C:18]1[CH:19]=[C:20]([CH2:27][CH2:28][CH2:29][O:10][CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:21]=[C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[OH:16])([CH3:43])([CH3:44])[CH3:42]
Reactant: OCCCc1cccnc1
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)c1cc(CCCOCCCc2cccnc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 3.66 g (26.68 mmol) of 3-(3-pyridyl)propanol in 30 ml anhydrous THF and 3.5 ml dry HMPA is added via syringe to a stirred suspension of 2.56 g (60% oil dispersion, 53.33 mmol) of NaH in 35 ml of anhydrous THF under an inert atmosphere at O° C., followed by a 2 h period at reflux. The sodium alcoholate solution is then recooled to 0° C. and 10.68 g (23.19 mmol) of 3-(4-acetoxy-3,5-di-tert-butylphenyl)-1-(tosyloxy)propane, dissolved in 35 ml of anhydrous THF, is added, fo-Wowed by refluxing for 2 h and stirring overnight at room temperature. After usual workup, the crude product (9.88 g; brown oil) is purified by flash-chromatography over silica gel, eluting with n-hexane/ethyl acetate 3:1, yielding 2.88 g (62% of 2,6-ditert-butyl-4-[7-(3-pyridyl)-4-oxaheptyl]phenol as amber oil. (C25H37NO2 ; F.W. 383.6).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:26])[C:9]=2[N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)[NH:4][CH:3]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29].[Li+].[OH-].O>CN1C(=O)CCC1.N1C=CC=CC=1.CC#N.O.C(Cl)Cl>[Cl:26][C:8]1[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:12]2)=[C:10]2[C:2]([NH:1][C:27](=[O:30])[CH2:28][CH3:29])=[CH:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N(C)C(=O)OC(C)(C)C)C3)c12
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
(R)-tert-Butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.300 g, 0.790 mmol; Example 112, Step A) in NMP (2 mL), pyridine (1 mL) and propionyl chloride (0.365 g, 3.95 mmol) were stirred at room temperature for 1 hour. 3M aqueous LiOH (3 mL) was then added, and the reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the organic fraction was separated, dried, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-95% CH3CN/water) to give (R)-tert-butyl 1-(5-chloro-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.160 g, 46% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:2]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH:2]=1
Reactant: O=C(c1cccnc1)c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OC(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with di(pyridin-3-yl)methanone (500 mg, 2.72 mmol), MeOH (30 mL), and CH2Cl2 (15 mL) and cooled to 0° C. NaBH4 (51 mg, 1.35 mmol) was added in one portion. The solution was stirred for 1 h at 0° C. and quenched with 1N NaOH and the reaction was extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. Crude di(pyridin-3-yl)methanol (505 mg, 100%) was used in the next step without further purification. 1H NMR 400 MHz (CDCl3) δ 8.32 (s, 2H), 8.24 (d, J=4.8 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 7.09-7.01 (m, 2H), 5.67 (s, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[CH:9][C:10]([F:14])=[C:11]([OH:13])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1>CN(C=O)C>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[CH:9][C:10]([F:14])=[C:11]([O:13][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 8 h

Procedure:
A solution of 53.0 g 5-(tert-butyl-dimethyl-silanyloxy)-2-fluoro-phenol (M. Kawase, A. K. Sinhababu, R. T. Borchardt, Chem. Pharm. Bull. (1990),38, 2939) in 120 ml DMF was cooled to 0° C. Within 15 min 61.6 ml tert-butyldiphenylsilyl chloride were added. Then 16.4 g imidazole were added portionwise. The suspension was stirred overnight, then quenched with 150 ml H2O at 0° C. The crude product was isolated by extraction with hexanes and purified by chromatography on silica gel (hexanes) to yield 88.9 g of 4-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-diphenyl-silanyloxy)-fluorobenzene as colorless liquid.
Reaction SMILES: [C:1]1([CH2:9]Br)[C:2]([CH2:7]Br)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:11][N:12]([NH2:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(CC)CC)C>CN(C)C=O.O>[C:16]([O:15][C:13]([N:12]([CH3:11])[N:20]1[CH2:7][C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: BrCc1ccccc1CBr
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A vigorously stirred solution 13.15 g (0.05 mole) of o-xylylene dibromide and 7.3 g (0.05 mole) of t-butyl 2-methylcarbazate in 25 ml of dimethylformamide was warmed to 50° and 14 ml of triethylamine was added during 5-8 minutes while maintaining the temperature at 50°-60°. After complete addition the reaction mixture was stirred at room temperature for 3 hrs. and diluted with 100 ml of water. After stirring for 1 hr the mixture was extracted with ethyl acetate. The organic phase was separated and dried. Filtration and evaporation gave a gummy solid which was used without further purification. The IR and NMR of the material were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[N:10]=[C:11]([CH2:13][CH3:14])[N:12]=[C:4]2[CH:3]=1.[OH-:15].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([OH:15])[N:5]2[N:10]=[C:11]([CH2:13][CH3:14])[N:12]=[C:4]2[CH:3]=1
Reactant: [OH-]
Reactant: CCc1nc2cc(Cl)nc(SC)n2n1
Agent: [K+]
Product: CCc1nc2cc(Cl)nc(O)n2n1

Procedure:
In analogy to Example 33A, 242 mg (99% of theory) of the product are obtained from 280 mg (1.22 mmol) of 7-chloro-2-ethyl-5-(methylsulphanyl) [1,2,4]triazolo[1,5-c]pyrimidine (Example 101A) by heating in methanolic potassium hydroxide solution.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[CH:4][C:3]=1[O:15][CH3:16].Br.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:22][NH2:23].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>>[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:22][NH:23][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:15][CH3:16])[CH:4]=1
Reactant: NCc1ccc(O)c(O)c1
Reactant: COc1cc(/C=C/C=C/C(=O)O)ccc1O
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C=C/C(=O)NCc2ccc(O)c(O)c2)ccc1O

Procedure:
The compound was prepared as described in Example 5 using 11 mg (0.05 mmol) of 5-(4-hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid [Example 3], 22 mg (0.10 mmol) of 3,4 dihydroxybenzylamine hydrobromide, 50 g (0.50 mmol) of triethylamine, and 33 mg (0.075 mmol) of BOP reagent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[N:10][OH:11])[NH2:9])=[N:6][CH:7]=1.[C:12](OC(=O)C)(=O)[CH3:13]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:12]([CH3:13])[O:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(=NO)c1ccc(Br)cn1
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc(Br)cn2)no1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
To a solution of 5-bromo-N′-hydroxypicolinimidamide II (0.75 g, 3.50 mmol) in acetic acid (50.0 mL) was added acetic anhydride (0.75 mL, 7.0 mmol) and the resulting reaction mixture was heated to 100° C. for 2 h. After the completion of reaction (TLC monitoring), acetic acid was distilled off, added water (25.0 mL) and extracted with EtOAc (2×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.27 g, 45%). MS: 240.01 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]([CH2:35][CH2:36][CH2:37]Cl)[C:32]([NH2:34])=[O:33])[CH2:25][CH2:24]1>CN(C)C=O>[CH3:19][O:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]([C:32]([NH:34][CH2:5][CH2:6][CH2:7][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[O:33])[CH2:35][CH:36]2[CH2:37][CH2:9][CH2:10][CH2:11][CH2:2][CH2:3][CH2:4]2)[CH2:25][CH2:24]1
Reactant: COCOC1CCN(CCN(CCCCl)C(N)=O)CC1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOC1CCN(CCN(CC2CCCCCCC2)C(=O)NCCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 0 °C

Procedure:
A solution of 1.6 g of 6-hydroxycarbostyril, 1.4 g of potasium carbonate and 4.2 g of N-cyclo-octylmethyl-N-[2-(4-methoxymethoxy-1-piperidinyl)-ethyl-N-(3-chloropropyl)urea in 20 ml of dimethylformamide was stirred at 80° C. for 1 day. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 5% methanol/dichloromethane) to obtain 0.76 g of 6-[3-{N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]-N-cyclooctylmethylamino}carbonylaminopropoxy]carbostyril.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:12]1[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=1
Reactant: Brc1nccs1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a solution of 2-bromothiazole (0.26 g, 1.6 mmol) and 4-formylphenylboronic acid (0.48 g, 3.2 mmol) in toluene (16 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.08 mmol) and K2CO3 (0.33 g, 2.4 mmol) and the solution stirred at reflux for 16 h. The reaction was cooled to room temperature, diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine (30 mL), dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (2% MeOH/CH2Cl2) to give 4-(2-thiazolyl)-benzaldehyde (45 mg, 15%). 1H NMR (CDCl3) δ 7.45 (d, 1H, J=3.0 Hz), 7.90 (d, 1H, J=3.0 Hz), 7.97 (d, 2H, J=7.8 Hz), 8.15 (d, 2H, J=7.2 Hz), 10.07 (s, 1H (CHO)).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[C:19](=[O:30])[CH2:18][S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[C:19](=[O:30])[CH2:18][S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C2SCC(=O)N2c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C2SCC(=O)N2c2ccc(N)cc2)cc(C(C)(C)C)c1O
Temperature: 70 °C
Yield: 69 %

Procedure:
1.3 g of 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone (3 mmol) and 3.4 g (15 mmol) of dihydrated tin chloride are dissolved in 25 ml of ethyl acetate. The reaction is maintained for 2 hours at 70° C. After the mixture has returned to ambient temperature, it is poured into a saturated solution of sodium hydrogen carbonate. The expected product is then extracted from the organic phase then it is washed 3 times with 10 ml of water. The 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinone is purified on silica gel in an ethyl acetatelheptane mixture (1/1) and is obtained in the form of a beige oil with a yield of 69% (0.82 g).
Reaction SMILES: [O-2].[Al+3].[O-2].[O-2].[Al+3].C([O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][C-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)C.[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25]>C(Cl)Cl>[C-:14]1([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25]
Reactant: CCOC(=O)CCCC[c-]1cccc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Product: OCCCCC[c-]1cccc1

Procedure:
Yield: 378 mg (89% of the theoretical) TLC: Rf (aluminum oxide, CH2Cl2)=0.2 Column chromatography: aluminum oxide, neutr. (act. III), CH2Cl2
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([OH:27])=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:38][CH3:39])(=O)=O.O>CN(C)C=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([O:27][CH2:38][CH3:39])=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccccc1C(=O)O)c1ccccc1Oc1ccccc1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1

Procedure:
In 10 ml of N,N-dimethylformamide were stirred 0.50 g of N-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline, 0.20 g of anhydrous potassium carbonate and 0.22 ml of diethyl sulfate at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:7) to give 0.50 g of N-acetyl-N-(2-ethoxycarbonylbenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [OH:1][C:2]#[C:3][CH3:4].I[C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[OH-].[Na+].[NH4+].[Cl-]>C1C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][CH2:2][C:3]#[C:4][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: Ic1ccc(-c2cccs2)s1
Reactant: CC#CO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: c1ccccc1
Product: OCC#Cc1ccc(-c2cccs2)s1
Yield: 74.3 %

Procedure:
Hydroxy-1-propyne (48 mg) was dissolved in benzene (1 ml). 5-Iodo-2,2'-bithiophene (0.1 g) was added immediately and stirred. A mixture of CuI (0.05 g), benzyltriethylammonium chloride (0.05 g), catalyst Pd(PPh3)4 (0.1 g) and 3 ml of NaOH solution (2.5N) were mixed together at room temperature and stirred for 2 hours. NH4Cl solution (4 ml) was then added. The reaction solution was extracted with ethyl acetate. The extract was washed with 10 ml of HCl (10%) for 3 times, 50 ml of water twice and dried over anhydrous magnesium sulfate. The residual solid was purified by silica gel column chromatography, eluted with ethyl acetate/n-hexane (3/1) to yield 56 mg of the product (74%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[CH2:12]([C:14]1([CH2:32][CH3:33])[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:17]2[CH:27]=[CH:28][C:29]([NH2:31])=[CH:30][C:16]=2[O:15]1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:32]([C:14]1([CH2:12][CH3:13])[N:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:17]2[CH:27]=[CH:28][C:29]([NH:31][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:30][C:16]=2[O:15]1)[CH3:33]
Reactant: CCC1(CC)N=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCC1(CC)N=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (63 μL) and pyridine (131 μL) were added dropwise to a solution of 2,2-diethyl-4-(4-fluorophenyl)-2H-1,3-benzoxazin-7-amine (a compound of Reference Example 4, 81 mg) in chloroform (5 mL), and the mixture was stirred at 40° C. overnight. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10), and the resultant powder was suspended in diisopropyl ether. The resultant precipitates were collected by filtration and washed with hexane-diisopropyl ether to give the titled compound (69 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:4]O)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[CH:11]12[CH2:21][CH:17](C(=O)C1)[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1>C(O)(=O)C.ClCCl>[CH:11]12[CH2:21][CH:17]([O:4][C:1](=[O:3])[CH2:2]1)[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1
Reactant: CC(=O)OO
Reactant: O=C1CC2CC1C1CCCC21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CC2CC(O1)C1CCCC21
Reaction time: 48 h

Procedure:
18 g of a 50 % peracetic acid solution in acetic acid containing 1 g of sodium acetate were added to a stirred mixture of 15 g of tricyclo[5.2.1.02,6 ]decane-8-one (which can be purchased from Ruhrchemie, Bruchstrasse, D-42 Oberhausen Holten, West Germany) and 9 g of anhydrous sodium acetate in 60 g of dichloromethane. The temperature of the reaction mixture was kept at 20°-25° by external cooling by means of a ice-water bath during the whole addition, then it was kept at this value during 48 hours while stirring.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:28]=[C:27]([CH3:29])[C:18]([O:19][CH2:20][CH2:21]OS(C)(=O)=O)=[C:17]([CH2:30][CH3:31])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:32])[N:5]=1)[CH3:2].[CH3:35][NH2:36]>CO>[CH2:1]([N:3]([CH2:33][CH3:34])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:28]=[C:27]([CH3:29])[C:18]([O:19][CH2:20][CH2:21][NH:36][CH3:35])=[C:17]([CH2:30][CH3:31])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:32])[N:5]=1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCOS(C)(=O)=O
Reactant: CN
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCNC

Procedure:
A solution of crude methanesulfonic acid 2-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethyl ester (110 mg, 0.225 mmol, Example 55 step a)) in 8 M methylamine in methanol (4 mL) is stirred in a sealed glass vial at 70° C. for 15 h. The solvent is evaporated and the crude product is purified on prep. TLC plates using DCM containing 10% of 7 N NH3 in methanol to give the title compound (93 mg) as a pale yellow oil; LC-MS: tR=0.71 min; [M+1]+=424.19.
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10](OCC)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-]>C1COCC1.Cl>[N:1]1([C:6]2[CH:16]=[CH:15][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1ccc(-n2cccn2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: OCc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of ethyl 4-(1H-pyrazol-1-yl)benzoate (73.7 g) in THF (500 mL) were added sodium borohydride (19.5 g) and calcium chloride (56.8 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hr, and then heated with reflux for 2 days. The reaction mixture was diluted with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (×4). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with tert-butyl methyl ether to give the title compound (49.6 g).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2C(=[CH:12][CH:13]=1)N[C:9](=O)[NH:8][C:7]2=[O:15].IC.[Cl-].[NH4+].[CH3:20][N:21]([CH:23]=[O:24])[CH3:22]>>[CH3:20][N:21]1[C:22]2[C:6](=[CH:5][C:4]([I:3])=[CH:13][CH:12]=2)[C:7](=[O:15])[N:8]([CH3:9])[C:23]1=[O:24]
Reactant: O=c1[nH]c(=O)c2cc(I)ccc2[nH]1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CI
Product: Cn1c(=O)c2cc(I)ccc2n(C)c1=O
Reaction time: 1 h

Procedure:
Sodium hydride (0.24 g of a 60% dispersion in oil) was added portionwise to a stirred solution of 6-iodoquinazolinedione (0.58 g) (Method 53) and iodomethane (0.63 ml) in DMF (10 ml). The mixture was stirred for 1 hour then added cautiously to saturated aqueous ammonium chloride solution (200 ml). Extraction with ethyl acetate followed by recrystallization from ethanol plus a little chloroform gave the title compound (0.48 g) as a solid. MS (CI+): 317 (M+H)+.