Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: OCCO
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)nc1

Procedure:
To a solution of 5-bromopyridine-2-aldehyde (3.72 g, 20 mmol) in toluene (60 mL) was added TsOH monohydrate (190 mg, 1 mmol) and ethane-1,2-diol (2.48 g, 40 mmol). The mixture was heated to reflux for 6 hours. The solvent was removed, and the residue was dissolved in ethyl acetate and washed with sodium bicarbonate and brine. The organic layer was dried with sodium sulfate and concentrated to give the crude product. MS: calc'd 230 (MH+), exp 230 (MH+).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[O:26][CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:20]2[CH:21]=[C:22]([F:25])[C:23]([F:24])=[C:18]([F:17])[C:19]=2[O:26][CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1ccc(F)c(F)c1F
Product: CCSc1ncc(C(=O)c2cc(F)c(F)c(F)c2OC)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2,3,4-trifluoroanisole (Matrix) in an analogous manner as described in Example 169.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[OH:16][CH2:17][C:18]#[C:19][C:20]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)=[O:21].Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([O:16][CH2:17][C:18]#[C:19][C:20](=[O:21])[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)=[O:7]
Reactant: COc1cc(C(=O)C#CCO)cc(OC)c1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)C#CCOC(=O)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC

Procedure:
2.21 g (9.59 mmol) of 3,4,5-trimethoxybenzoyl chloride in 10 ml of methylene chloride and 1 ml of pyridine were o added simultaneously at 0° to a solution of 2.0 g (7.99 mmol) of 4-hydroxy-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one in 25 ml of methylene chloride. The reaction mixture was stirred at 0° for 30 minutes and at room temperature for 1.5 hours, Whereupon 30 ml of 0.5M hydrochloric acid and 100 ml of methylene chloride were added and the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated, and the residue was chromatographed on silica gel with ether. After recrystallization from ethyl acetate/hexane there was obtained 3-(3,4,5-trimethoxybenzoyl)-2-propynyl 3,4,5-trimethoxybenzoate of melting point 106°-108°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28].N1C=CN=C1.CN(C)C=O>O>[CH3:26][O:25][C:5]1[CH:4]=[C:3]([CH2:2][O:1][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[O:12][C:13]=1[CH3:14]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc(CO)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
A mixture of 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (0.40 g), triisopropylsilyl chloride (0.75 g), imidazole (0.27 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 3-{4-[(2-methoxy-4-{[(triisopropylsilyl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile as a colorless oil (0.53 g, yield 95%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [C:1]([C:4]1(O)[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.C(OCC)(=O)C.O>N1C=CC=CC=1>[C:1]([C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[CH2:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1CCC(O)(C(C)=O)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC=C(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
To a solution of 4-acetyl-1-allyloxycarbonyl-4-hydroxypiperidine (0.2 g) in pyridine (4.0 ml) was added dropwise thionyl chloride (0.12 ml) at -20° C. The resultant mixture was allowed to warm to ambient temperature for 1 hour and stirred for another period of 2 hours. Evaporation of the mixture in vacuo gave a residue which was taken up into a mixture of ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (10 g) eluting with a mixture of n-hexane and ethyl acetate (9:1-1:1 V/V) to give 4-acetyl-1-allyloxycarbonyl-1,2,3,6-tetrahydropyridine (69 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH2:22].C1(C)C=CC=CC=1>C(OCC)C>[O:19]1[CH2:18][CH2:24][O:23][CH:20]1[CH2:21][NH:22][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1cc([N+](=O)[O-])c(NCC2OCCO2)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 285.4 %

Procedure:
4-t-Butyl-2,6-dinitrochlorobenzene (1.8 grams; 0.007 mole), aminoacetaldehyde dimethyl acetal (1.5 grams; 0.0014 mole) and toluene (50 ml) were placed in a glass reaction vessel equipped with a stirrer, heating mantle, reflux condenser and thermometer and stirred overnight. Diethyl ether (50 ml) was added to the reaction mixture which was filtered and the filtrate then was evaporated. Toluene (50 ml), ethylene glycol (0.49 grams) and P-toluenesulfonic acid were added and the solution was refluxed for 2 hours. Then one-half the toluene was removed by distillation. The residue was chromatographed on silica to remove unreacted starting materials. The product (1.3 grams) was obtained as a yellow solid (melting point 81°-82° C.).
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[NH:15][C:14]2=[O:24])=[C:11]([N+:25]([O-:27])=[O:26])[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc2N1
Solvent: CC(=O)O
Product: O=C1COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[7-Fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (7.0 g) was added by portion to a mixture of acetic acid (30 ml) and fuming nitric acid (90 ml) at 0° C. After stirring for 1 hr at room temperature, the solution was mixed with ice-water (200 ml) and then extracted with ethyl acetate (60 ml×3). The organic layers were combined and washed with water (20 ml×2) and brine (20 ml), dried over sodium sulfate. After filtration and evaporation, the residue was recrystallized from methylene chloride (8.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17](OCC)=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)[C@H]1CC[C@@H](Nc2ncnc(CC)c2Cl)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncnc(N[C@H]2CC[C@@H](CO)CC2)c1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 12.47 g (0.040 mol) of ethyl cis-4-(5-chloro-6-ethylpyrimidin-4-ylamino)-cyclohexanecarboxylate (preparation: DE-A-44 17 163) in 25 ml of dry tetrahydrofuran was added dropwise at from 20° to 30° C. to a suspension of 1.52 g (0.04 mol) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran. The mixture was subsequently stirred at 50° C. for 1 hour and cooled to room temperature, and 10 ml of water were carefully added dropwise. After removal of inorganic material by filtration with suction, the organic phase was dried and concentrated. For purification, the crude product was chromatographed on silica gel (using ethyl acetate as eluent). 5.2 g (48.2% of theory) were obtained of a yellow oil which solidified on standing. m.p.: 71° to 72° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.CC1(C)C(C)(C)OB([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Cc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
A 50-mL flask, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (870 mg, 3.44 mol, 1 eq.), methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (1.00 g, 3.44 mmol, 1 eq.), Pd(dppf)Cl2 (280 mg, 0.34 mmol, 0.10 eq.), and powdered Na2CO3 (1.09 g, 10.3 mmol, 3.0 eq.). Dioxane (16 mL) and water (8 mL) were added. The resulting mixture was stirred under Ar at 90° C. for 2 hr. until the starting chloride was consumed. After cooling to room temperature, the reaction mixture was filtered through celite washing with ethyl acetate until the filtrate was colorless. The filtrate was washed with sat. sodium chloride (3×25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue (1.8 g) was purified by chromatography on silica gel using hexane/dichloromethane (10:0 to 0:10) as eluent, followed by chromatography on silica gel using hexane/ethyl acetate (10:0 to 3:1) as eluent, to afford methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate (0.65 g, 50% yield) as a colorless oil. MW=380.87. 1H NMR (CDCl3, 500 MHz) δ 8.49-8.47 (m, 1H), 8.37 (dt, J=7.5, 1.5 Hz, 1H), 7.44-7.38 (m, 2H), 7.31-7.27 (m, 2H), 7.27-7.23 (m, 2H, overlaps with CDCl3), 6.85 (s, 1H), 4.10 (s, 2H), 3.69 (s, 3H), 3.61 (s, 2H), 2.76 (q, J=7:5 Hz, 2H), 1.31 (t, J=7.5 Hz, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(O[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[OH:31][C:25]1[CH:30]=[CH:29][C:28]([CH:8]2[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[S:9]2)=[CH:27][CH:26]=1
Reactant: Oc1ccccc1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Solvent: CC#N
Product: CC1=C(c2ccncc2)SC(c2ccc(O)cc2)C(=O)N1
Temperature: 50 °C
Reaction time: 35 h
Yield: 23.4 %

Procedure:
Silica gel (Wakogel C-200, 40 mg) was added as catalyst to a solution of 2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.98 g) and phenol (0.51 g) in acetonitrile (20 ml) and the mixture was stirred at 50° C. for 35 hours. The mixture was chromatographed on silica gel (Wakogel C-200) column, using chloroform-acetonitrile (=5:1) as an eluant. The residue was recrystallized from ethanol to give the titled compound (0.19 g, yield 23.4%) as pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].O.O.O.O.O.O.O.O.O.[S-2:20].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[SH:20])[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(S)c(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
3-Bromo-4-fluorobenzonitrile (100 g) was dissolved in dimethylformamide (DMF) (500 ml), and sodium sulfide nonahydrate (132 g) was added thereto at 0° C. and then stirred overnight at room temperature. The reaction mixture was poured to ice water (1 L) and the insoluble material was filtered off. The filtrate was added to a 1N aqueous hydrochloric acid solution (700 ml) under ice-cooling and the precipitate was collected by filtration. The crystals thus obtained were washed with hexane/diisopropyl ether and water and then dried to obtain 3-bromo-4-mercaptobenzonitrile (95.0 g) as a light-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([NH:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:14])[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccccc3)cc2C(=O)N2CCCCC2)cn1
Reactant: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccccc3)cc2C(=O)N2CCCCC2)cn1
Reaction time: 3 h

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-2-[(phenylmethyl)oxy]-4-(1-piperidinylcarbonyl)benzoic acid (may be prepared as described in Description 38; 80 mg, 0.19 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.13 ml, 0.76 mmol), 3-aminopyridine (32.3 mg, 0.34 mmol), 1-hydroxy-7-azabenzotriazole (46.7 mg, 0.34 mmol) and EDC (91 mg, 0.48 mmol). The solution was stirred for 3 hours. The solvent was removed in vacuo and the residue purified by MDAP to give the title compound as a white solid. 33 mg.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20]([NH:22][C:23](=[N:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])SC)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>O1CCOCC1.CCOCC>[CH2:30]([O:29][C:27]([NH:26][C:23](=[N:22][C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: O=C(N=C(NC(=O)OCc1ccccc1)N1CCCC(C(=O)O)C1)OCc1ccccc1
Reaction time: 48 h
Yield: 71.1 %

Procedure:
To a solution of nipecotic acid (1.66 g, 12.8 mmol) in 2 N NaOH (12.8 mL, 25.6 mmol) and dioxane (30 mL) was added 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (4.6 g, 12.8 mmol). After 48 h, the reaction mixture was added to H2O (200 mL) and Et2O (200 mL). The aqueous layer was separated and extracted with Et2O (2×200 mL). The aqueous layer was acidified to pH 2.0 with 3 N HCl and extracted with EtOAc (500 mL). The organic layer was MgSO4 dried and concentrated to give the title compound (4.0 g, 71%): TLC Rf=0.65 (1:15: 135 Acetic Acid:Methanol:Chloroform); NMR (CDCl3) δ1.55-1.92 (m, 6H), 2.00-2.15 (m, 1H), 2.70-2.80 (m, 1H), 3.20-3.35 (q, 1H), 3.38-3.45 (m, 1H), 3.75-4.10 (m, 1H), 5.10 (s, 2H), 5.22 (s, 2H), 7.30-7.40 (m, 10H); FD-MS 440 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6]2.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([F:15])([F:13])[F:14])=[CH:6]2
Reactant: COc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
A solution of 5-methoxy-2-trifluoromethylindole (800 mg, 3.7 mmol) in methylene chloride (6 ml) was cooled to −15° C. and a solution of 1M boron tribromide in methylene chloride (7.44 ml, 7.4 mmol) was added in portions. The mixture was allowed to warm to ambient temperature and was stirred for 45 minutes. After cooling to 0° C., saturated aqueous sodium hydrogen carbonate (25 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether. After removal of the volatiles by evaporation, the solid was triturated with pentane, collected by filtration and dried under vacuum to give 5-hydroxy-2-trifluoromethylindole (290 mg, 39%).
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.[Cu][C:28]#[N:29].CN(C)C=O.Cl>O>[C:28]([C:2]1[C:7]2[O:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1)#[N:29]
Reactant: N#C[Cu]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c3c2OC(C)(C)O3)c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(C#N)c3c2OC(C)(C)O3)c1=O
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
In a flask are placed 2.20 g (0.005 mole) of 3-(7-bromo-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)- 1 -methyl-6-trifluoromethyluracil, 0.62 g (0.0069 mole) of copper(I) cyanide and 60 mL of N,N-dimethylformamide. The resulting mixture is heated at reflux for 5 hours. This mixture is then cooled and poured into a solution of 2.5 g of hydrated ferric chloride, 0.62 mL of concentrated hydrochloric acid, and 3.8 mL of water. The resulting mixture is maintained at 60-70 ° C at which it is stirred for 20 minutes. After being cooled the mixture is extracted with methylene chloride, and the extract is washed with dilute hydrochloric acid. The extract is then dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated under reduced pressure, leaving a residue. This residue is passed through a column of silica gel, eluting with ethyl acetate/heptane (1:1 ). The product-containing fractions are combined, and the solvent is evaporated under reduced pressure, leaving 3-(7-cyano-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl)-1-methyl-6-trifluoromethyluracil (Compound 15) as a residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[CH:30]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=[CH:33][N:32]=2)[CH:3]=1)[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=1
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC)ccn1
Product: COc1ccnc(-c2cccc(C3(c4ccnc(OC)c4)N=C(N)c4c(F)cccc43)c2)c1
Yield: 13 %

Procedure:
The title compound was synthesized as described in Example 29 in 13% yield starting from 1-(3-bromophenyl)-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (0.150 g, 0.36 mmol) and 4-methoxy-2-(tributylstannyl)pyridine (0.188 g, 0.47 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7]1=[O:18].ClCCCCN1C(=O)C2C(=CC=CC=2)N(C)C1=O.[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7]1=[O:18]
Reactant: Cn1c(=O)n(CCCCBr)c(=O)c2ccccc21
Reactant: [I-]
Agent: Cn1c(=O)n(CCCCCl)c(=O)c2ccccc21
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cn1c(=O)n(CCCCI)c(=O)c2ccccc21
Yield: 100 %

Procedure:
A solution of the title A compounds, 3-(4-bromobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline and 3-(4-chlorobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (1:1mixture; 2.35 g, 8.13 mmol) in 30 mL of methyl ethyl ketone is treated with sodium iodide (2.64 g, 17.62 mmol) at RT. The reaction is heated at reflux for 16 h, then cooled and the solvent is evaporated under reduced pressure. The residue is partitioned between 200 mL of ethyl acetate and 5 mL of water. The organic solution is washed with 10 mL of 1% aqueous sodium sulfite and 10 mL of brine, dried over anhydrous MgSO4, and concentrated to give 3.10 g (100%) of 3-(4-iodobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline as a white solid: m.p. 105-107° C.; NMR (CDCl3) 1.75-1.95 (m, 4H), 3.22 (t, 2H, J=6.8), 3.59 (s, 3H), 4.11 (t, 2H, J=7.1), 7.17-7.28 (m, 2H), 7.67 (dt, 1H, J=1.6, 7.9), 8.21 (dd, 1H, J=1.5, 7.9); IR 1702, 1658; ESI-MS 359 (M++1).
Reaction SMILES: Cl[CH:2]([C:10]([CH3:31])=[CH:11][CH:12]([C:22]1[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=1[CH3:30])S(C1C=CC=CC=1)(=O)=O)[CH2:3][CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8].[OH-].[K+].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C.C1(C)C=CC=CC=1>[CH3:30][C:23]1[CH2:24][CH2:25][CH2:26][C:27]([CH3:28])([CH3:29])[C:22]=1/[CH:12]=[CH:11]/[C:10](/[CH3:31])=[CH:2]/[CH:3]=[CH:4]/[C:5](/[CH3:9])=[CH:6]/[CH2:7][O:8][C:34]([CH3:35])=[O:36]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=CCO)CCC(Cl)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Reaction time: 3 h

Procedure:
A 200 ml flask purged with nitrogen was charged with 9.29 g (20 mmols) of 6-chloro-1-hydroxy-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadiene and 40 ml of toluene, followed by agitation for a while, further addition of 5.89 g (100 mmols) of powdery potassium hydroxide (purity of 95%) and 66.3 mg (0.4 mmols) of tetraethylammonium chloride and further agitation at 10° C. for 12 hours. 50 ml of a 5% saline solution was added to the reaction solution for phase separation of the solution. To the resultant organic phase was added 10 ml (105.4 mmols) of acetic anhydride and 0.9 g of sodium carbonate, followed by agitation at 40° C. for 3 hours. After addition of 100 ml of a 10% sodium hydroxide aqueous solution to the reaction solution, the resulting organic phase was separated and washed twice with 100 ml of a 5% saline solution, followed by removal of the solvent by distillation to obtain 12.8 g of a red cily substance. This oily substance was subjected to quantitative determination by high performance liquid chromatography with the result that the yield of vitamin A acetate was 80.9% and the content of the all-trans isomer in the vitamin A acetate was 94.5%. The liquid chromatographic analysis conditions were as follows.