Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[CH:12]1([C:18]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
15.6 g (0.1 mol) of 4-fluoro-3-nitro-aniline and 17.9 g (0.11 mol) of cyclohexylcarboxylic acid chloride are dissolved in 250 ml tetrahydrofuran and after the addition of 12.1 g (0.12 mol) of triethylamine the mixture is stirred for 3 hours at ambient temperature. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:19]([O:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: OCc1cccnc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 23 h
Yield: 85.5 %

Procedure:
To a solution of 2-chloro-3-pyridylmethanol (2.07 g) in 100 mL CH2Cl2 was added imidazole (1.96 g). TBDMSCl (2.39 g) was added in one portion, and the reaction was stirred at room temperature for 23 h, then filtered through a fritted funnel The liquid filtrate was concentrated and purified via flash chromatography to give 3.18 g of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloropyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl.O>C1COCC1>[Cl:17][C:10]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=[CH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1nccc1Cl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
N,N-dimethyl-1H-pyrazole-1-sulfonamide (8.89 g, 50.8 mmol) was dissolved in anhydrous THF (250 mL). The solution was cooled at −78° C., a solution of n-butyl lithium (32.6 mL, 81.4 mmol, 2.5 M in hexane) was added dropwise, and then the mixture was stirred for 45 minutes. A solution of hexachloroethane (18.0 g, 76.3 mmol) in anhydrous THF (20 mL) was added dropwise at −78° C., and the reaction stirred for 1.5 hours. Water was added, and the mixture was extracted 5 times with dichloromethane. The combined organic phases were washed with brine and then dried over magnesium sulfate. After evaporation of the solvent, 5-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide was obtained and used in the next step without further purification.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH:13]([C:26]([OH:28])=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[OH-:29].[Na+].[SH-].[Na+].Cl>O>[C:1]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]3[C:18]([NH:23][C:26](=[O:28])[CH:13]2[CH2:12]1)=[CH:19][CH:20]=[CH:21][CH:22]=3)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:29]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1ccccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Agent: [SH-]
Solvent: O
Product: O=C1Nc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC12
Reaction time: 2.5 h

Procedure:
To a solution of 13 g. of 4-carbobenzoxy-1-(o-nitrophenyl)piperazine-2-carboxylic acid and 11.0 g. of sodium hydroxide in 200 ml. of water is added a solution of 20 g. of sodium hydrosulfide in 200 ml. of H2O. The orange solution gradually turns colorless over a period of 2-3 hours. Dilute hydrochloric acid is added to bring the pH of the solution to about 3. A white precipitate forms. Stirring is continued for about 3-5 minutes, and the pH is raised to about 7 by the addition of 40% sodium hydroxide. Filtration gives 8.6 g. of product, m.p. 125°-140°. The analytical sample on recrystallization from ethyl acetate hexane gave a m.p. 167°-170°.
Reaction SMILES: CNC(C/C=C/C1C=NC=C(Br)C=1)C.[Br:15][C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[CH2:24][CH:25]([OH:27])[CH3:26])[CH:19]=[N:20][CH:21]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([O:27][CH:25]([CH2:24]/[CH:23]=[CH:22]/[C:18]2[CH:19]=[N:20][CH:21]=[C:16]([Br:15])[CH:17]=2)[CH3:26])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)C/C=C/c1cncc(Br)c1
Agent: CNC(C)C/C=C/c1cncc(Br)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)C/C=C/c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3,5-dibromopyridine (23.60 g, 100.0 mmol), 4-penten-2-ol (10.8 g, 125.0 mmol), palladium(II) acetate (230 mg, 1.02 mmol), tri-o-tolylphosphine (1.20 g, 3.94 mmol), triethylamine (29.7 mL, 213.45 mmol), and acetonitrile (40 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation, followed by column chromatography over silica gel eluting with acetone-chloroform (1:9, v/v) furnished 8.10 g (34.0%) of a pale-yellow oil. (4E)-N-Methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine To a stirring solution of (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol (3.14 g, 13.0 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride (3.71 g, 19.5 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol p-toluenesulfonate. The resulting tosylate was treated with excess methylamine (40% solution in water), ethyl alcohol (10 mL), and stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation followed by column chromatography over silica gel eluting with chloroform-methanol (95:5, v/v) produced 1.50 g (45.0%) of a pale-yellow oil.
Reaction SMILES: [C:1]([N:8]([CH2:37][CH3:38])[C:9]([NH:11][C:12]1[NH:16][C:15]2[C:17]([C@H:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[C:18]([F:31])[C:19]([C:21]3[CH:22]=[N:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=3)=[CH:20][C:14]=2[N:13]=1)=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=NN=N1.CC(N([P:51]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[O:52]CC1C=CC=CC=1)C(C)C)C.C1C=C(Cl)C=C(C(OO)=[O:76])C=1>C(Cl)Cl>[CH2:61]([O:60][P:51]([OH:52])([O:33][CH2:32][C:17]1[CH:15]=[CH:14][CH:20]=[CH:19][CH:18]=1)=[O:76])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1.[C:1]([N:8]([CH2:37][CH3:38])[C:9]([NH:11][C:12]1[NH:16][C:15]2[C:17]([C@H:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[C:18]([F:31])[C:19]([C:21]3[CH:22]=[N:23][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:25][CH:26]=3)=[CH:20][C:14]=2[N:13]=1)=[O:10])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCN(C(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c([C@H]3CCCO3)c2[nH]1)C(=O)OC(C)(C)C
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: O=P(O)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To Boc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea (25) (12.69 g, 23.58 mmol) and tetrazole (3.304 g, 47.16 mmol) under N2 at 23° C. was added DCM (240 mL) followed by N-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (9.775 g, 9.509 mL, 28.30 mmol). After 3 hours at 23° C., the reaction was cooled to 0° C. then mCPBA (6.977 g, 28.30 mmol) was added. The resulting solution was stirred for 45 min at 0° C. then for 20 min at 23° C. The reaction mixture was then partitioned between DCM (50 mL) and saturated aqueous sodium bicarbonate (400 mL). The organic layer was separated, then washed successively with aqueous sodium bisulfate (63 g in 350 mL water) and saturated aqueous sodium bicarbonate (400 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by MPLC using an ISCO COMBIFLASH brand flash chromatography purification system (330 g silica column) eluting with a 0-100% EtOAc in hexanes linear gradient over 16 column volumes at 200 mL/min. Product containing fractions were evaporated in vacuo to give Boc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea dibenzyl phosphate (26) (11.92 g, 15.11 mmol, 64.09%). ESMS (M+1)=789.2; 1H NMR (300.0 MHz, CDCl3) δ 9.51 (s, 1H), 9.03 (t, J=5.4 Hz, 1H), 8.91 (d, J=1.6 Hz, 2H), 7.73 (d, J=6.5 Hz, 1H), 7.37-7.28 (m, 10H), 5.58 (t, J=7.8 Hz, 1H), 5.17-5.05 (m, 4H), 4.23 (t, J=7.5 Hz, 1H), 4.05 (td, J=7.8, 4.3 Hz, 1H), 3.53-3.44 (m, 2H), 2.39 (dd, J=7.9, 14.5 Hz, 2H), 2.28-2.15 (m, 2H), 1.98 (s, 6H), 1.72 (m, 9H) and 1.31 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A mixture of 5-bromo-2-fluoro-benzonitrile (25.0 g, 125 mmol), 4-methylimidazole (12.5 g, 152 mmol), potassium carbonate (34.55 g, 250 mmol) in DMSO (500 mL) was stirred at 90° C. for 16 h. Water (1.5 L) was added and the resulting suspension was stirred with ice-bath cooling for 1 h. The precipitate was filtered, washed with water (0.5 L) and dried at 50° C. over KOH. The resulting raw material (25.6 g) was dissolved in boiling Ethyl acetate (300 ml). After addition of diisopropylether (300 ml) the solution was allowed to cool to room temperature. Filtration and drying afforded the title compound (19.35 g, 59%) as a white solid. Mp 166° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.[CH3:23][O:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[C:27]([Cl:32])[N:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.CCO>[Cl:32][C:27]1[N:26]=[C:25]([O:24][CH3:23])[N:30]=[C:29]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:28]=1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1nc(Cl)cc(-c2ccc3nc(NC(C)=O)sc3c2)n1
Yield: 13.6 %

Procedure:
Argon is bubbled through a mixture of N-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazol-2-yl]-acetamide (1.12 g, 3.52 mmol), 2-methoxy-4,6-dichloropyrimidine (700 mg, 3.91 mmol), Na2CO3 (625 mg, 5.9 mmol), and bis(triphenylphosphine)palladium(II)chloride (280 mg, 0.4 mmol), in dimethoxyethane (8 mL), water (3.4 mL) and EtOH (2.2 mL) for 10 minutes. The mixture is irradiated by microwave at 160° C. for 10 minutes added water (20 mL) and extracted with EtOAc (40 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford N-[6-(6-chloro-2-methoxy-pyrimidin-4-yl)-benzothiazol-2-yl]-acetamide (160 mg) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[Cl-].[NH4+].[OH-].[NH4+].[CH3:19][N:20](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[C:8]([C:5]1[C:4]([C:11]([F:14])([F:13])[F:12])=[CH:3][C:2]([C:19]#[N:20])=[CH:7][N:6]=1)(=[O:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(=O)c1ncc(Br)cc1C(F)(F)F
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(=O)c1ncc(C#N)cc1C(F)(F)F
Reaction time: 1 h

Procedure:
Heat a solution of 1-(5-bromo-3-trifluoromethyl-pyridin-2-yl)-ethanone (268 mg, 1.0 mmol), zinc cyanide (75 mg, 0.63 mmol), pd2(dba)3 (30 mg), and DPPF (35 mg) in DMF (3 mL) and water (0.03 mL), under a nitrogen atmosphere, at 120° C. for 1 hour. Cool the reaction to 0° C. and add a solution of saturated ammonium chloride solution (2 mL), water (2 mL) and concentrated ammonium hydroxide (0.5 mL) and stir for 1 hour. Extract the mixture with ethyl acetate (3×20 mL) and wash the combined organics with brine (50 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with a 9:1 mixture of hexane:ether to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11])([O-:3])=[O:2].Br[CH:13](Br)[CH3:14].C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[N+:1]([C:4]1[C:5]2[O:11][CH2:14][CH2:13][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1O
Reactant: CC(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2c1OCCO2
Yield: 92.4 %

Procedure:
3-Nitro-1,2-benzenediol (5 g; 32.26 mmol), dibromoethane (12.13 ml; 64.52 mmol), tetra(n-butyl)ammonium bromide (1.1 g; 32.26 mmol) and K2CO3 (13.35 g; 96.78 mmol) were stirred at reflux in toluene overnight. The reaction was then poured onto water (150 ml) and twice extracted with diethyl ether (2×150 ml). The combined organics were washed with water (100 ml) and brine (100 ml) then dried with MgSO4 and the solvents removed to afford the desired product (5.4 g; 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CC#N
Product: Nc1ncc(Br)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
3-(Benzyloxy)pyridin-2-amine (25.0 g, 124.9 mmol) was added to acetonitrile (300 mL) and cooled to 0° C. 1-Bromopyrrolidine-2,5-dione (22.22 g, 124.9 mmol) was added portionwise and the reaction mixture was stirred for 15 minutes, then concentrated to dryness. The residue was dissolved in EtOAc and partitioned with water. The organic layer was washed twice with saturated sodium bicarbonate and once with brine. Activated charcoal was added to the organic layer, and the organic layer was warmed to reflux, then cooled, filtered through a plug of celite, and concentrated to give 9.4 g of the title compound. The celite and charcoal were resuspended in EtOAc and filtered through a celite plug to give an additional 3.6 g of the title compound, to provide a total of 12.0 g (34.3% yield). 1H NMR (CDCl3) δ 7.74 (d, 1H), 7.41 (m, 5H), 7.08 (d, 1H), 5.04 (s, 2H), 4.74 (bs, 2H). Mass spectrum (apci) m/z=279.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].Cl[CH2:19][C:20]1[N:29]=[C:28]([CH3:30])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[CH3:30][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH2:19][N:4]2[C:5](=[O:16])[C:6]3[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:17])[N:29]=1
Reactant: Cc1nc(CCl)nc2ccccc12
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A mixture of 28.91 g of 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine, 20.00 g of 2-chloromethyl-4-methylquinazoline and 27.74 g of potassium carbonate in 235 ml of N-methylpyrrolidone is warmed to 75° C. and stirred at this temperature for six hours. Subsequently, the reaction mixture is slowly treated with 235 ml of water, a pale precipitate depositing. The suspension is cooled in an ice bath. The precipitate is filtered off with suction, washed with water and a little petroleum ether and dried at 50° C. in a circulating air drying oven.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1O

Procedure:
82.2 g of 7A was dissolved in 300 ml of ethanol. 0.5 g of platinum oxide catalyst was added and the mixture was hydrogenated at 50 p.s.i.g. Fresh portions of catalyst were added periodically. The resulting mixture was filtered, and the solvent was evaporated from the filtrate. The residue was crystallized from water to give 2-amino-4-trifluoromethyl-phenol (7B).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH3:15])[CH:5]=[CH:6][CH:7]=[C:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(Cl)Cl.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[CH3:14][C:8](=[CH:7][CH:6]=[CH:5][C:4]([CH3:15])=[CH:3][CH:2]=[O:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C)=CC=CC(C)=CCO
Agent: [Ni+3]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)C(C)=CC=CC(C)=CC=O
Temperature: 50 °C
Yield: 79.3 %

Procedure:
21 g of ethyl 8-hydroxy-2,6-dimethyl-octa-2,4,6-trien-1-oate in 500 ml of methylene chloride are stirred at -25° C. for 2 hours with 50 g of nickel peroxide (prepared in Example 1 and containing 6.1% of active oxygen). The mixture is then filtered, the solution evaporated to 100 ml, treated with 250 ml of n-hexane and again evaporated to 100 ml. The residual solution is cooled to 50° C., seeded with crystals of ethyl 2,6-dimethyl-8-oxo-octa-2,4,6-trien-1 -oate and left to crystallise for 30 minutes at 0° C. After filtration under suction and drying of the crystals, there are obtained 16.5 g (79.5%) of pure ethyl 2,6-dimethyl-8-oxo-octa-2,4,6-trien-1-oate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11]I)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:15][C:13](=[O:16])[CH3:14])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CC([O-])=S
Reactant: COC(=O)C1(CI)CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CSC(C)=O)CCOCC1
Reaction time: 18 h
Yield: 97 %

Procedure:
4-Iodomethyl-tetrahydro-pyran-4-carboxylic acid methyl ester (3.05 g) was dissolved in N,N-dimethylformamide (20 ml) at room temperature and potassium thioacetate (1.47 g) added. The mixture was stirred for 18 hours then diluted with water (50 ml) and extracted with diethyl ether (4×25 ml). The combined organics were washed with saturated sodium bicarbonate solution (3×20 ml) and brine (20 ml), then dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound as a yellow solid (2.42 g, 97%).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[C:3](=[O:14])[O:2]1)[CH:7]=[CH:8][CH:9]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[OH:2][CH2:1][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[C:4]([CH2:3][OH:14])=[CH:13][CH:12]=[CH:11]2
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2cccc(CO)c12
Reaction time: 8 h

Procedure:
Benzo[de]isochromene-1,3-dione (30 g, 0.15 mol) in anhydrous THF (300 mL) was added dropwise to a solution of LAH (10 g, 0.38 mol) in anhydrous THF (200 mL). The result reaction mixture was refluxed for 3 h, then allowed to cool and stand overnight at room temperature. Water and 10% aq. NaOH was added dropwise, filtered. The filtrate was concentrated in vacuum to give the crude product, which was used directly without purification (1.15 g, crude). 1H-NMR (CDCl3): 5.06 (m, 4H), 5.23 (m, 2H), 7.42 (m, 2H), 7.60 (m, 2H), 7.82 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH:18]=[C:17]([C:19](OCC)=[O:20])[CH:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cnn(Cc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnn(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of lithium aluminum hydride (LAH) (68 mg, 1.79 mmol) in THF (8 mL) at 0° C. was added dropwise over 5 min a solution of ethyl 1-benzyl-1H-pyrazole-4-carboxylate (250 mg, 1.1 mmol) in THF (5 mL). After stirring for 1 h at 0° C., it was warmed to rt for 30 min and then quenched with 1N HCl until a clear solution was obtained. Extraction with EtOAc (3×50 mL) and washing of the combined organic layers with water, and then brine, provided the crude (1-benzyl-1H-pyrazol-4-yl)methanol after drying and evaporation of the solvent. Crude 1H NMR was clean enough to be used as is without further purification: crude yield 192 mg (94%). 1H NMR (400 MHz, CDCl3) δ ppm 4.58 (s, 2H), 5.29 (s, 2H), 7.21-7.26 (m, 2H), 7.29-7.38 (m, 3H), 7.39 (s, 1H), 7.55 (s, 1H); LCMS-MS (ESI+) 188.90 (M+H).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](Cl)=[O:16])[O:7][CH2:6]1)[CH2:2][CH3:3].[CH2:21](N(CCC)C1CC2C(=CC=CC=2C(OC)=O)OC1)CC.[Li]C.O>O1CCCC1.[Cu]I>[CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](=[O:16])[CH3:21])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2cccc(C(=O)Cl)c2C1
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Agent: [Cu]I
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Dipropylamino-5-chloroformylchroman*HCl (4.42 g, 13.4 mmol), prepared from 3-dipropylamino-5-methyloxycarbonylchroman (Example 2) analogous to the procedure used in Example 3,in dry tetrahydrofuran (20 ml), was added to a pre-formed solution of lithium dimethylcuprate; prepared from MeLi and CuI, in 200 mL tetrahydrofuran at -78° C. The solution was stirred for 15 minutes at -78° C. and was then allowed to reach room temperature during 10 minutes. Then, 30 mL H2O was slowly added. The organic phase was decanted, dried with Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8. The title compound was crystallized as salt from ethyl acetate. Mp 106°-108° C. (oxalate).