Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](C)[C:5]2(O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.N[OH:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:23])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NO
Reactant: CN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 83 %

Procedure:
A stirred mixture of 86.6 g (0.3 mole) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone and 62.5 g (0.9 mole) of hydroxylamine hydrochloride in 1500 ml ethanol was refluxed for 187 hr, and then cooled. The solid portion of the reaction mixture was collected on a filter, washed with ethanol, and dried in air to give 67.9 g (83%) of 6-chloro-4-phenyl-2(1H)-quinazolinone 3-oxide as yellow crystals: mp 267°-269°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1.[CH3:29][NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([N:30]([CH2:31][CH:32]([OH:35])[CH2:33][OH:34])[CH3:29])=[O:26])=[CH:27][CH:28]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(C(=O)O)cc1
Reactant: CNCC(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(CC(O)CO)C(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)c(F)cc43)OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid (50 mg, 0.13 mmol), 3-methylamino-1,2-propanediol (40 mg, 0.38 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 61 mg, 0.16 mmol) and diisopropylethylamine (37 mg, 0.29 mmol) in 6 mL of anhydrous DMF was stirred at room temperature for 10 minutes. The mixture was poured into 100 mL of water. The precipitates were filtered, washed with water, and dried in vacuum to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-N-(2,3-dihydroxypropyl)-N-methylbenzamide as yellow solid. Yield: 47 mg, 81%.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([C:14]([Cl:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CC1C=CC=CC=1>[OH2:15].[ClH:16].[ClH:1].[C:2]1([C:8]2([C:14]([O:26][CH2:25][CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCN1CCCCC1
Reactant: O=C(Cl)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: Cc1ccccc1
Product: O
Product: O=C(OCCCN1CCCCC1)C1(c2ccccc2)CCNCC1
Reaction time: 8 h

Procedure:
To a stirred and refluxing mixture of 14 parts of 4-phenyl-4-piperidinecarbonyl chloride hydrochloride and 130 parts of methylbenzene are added dropwise 6.9 parts of 1-piperidinepropanol. Upon completion, stirring is continued overnight at reflux temperature. The methylbenzene-phase is decanted and the residual oil is boiled in a mixture of 2,2'-oxybispropane and ethanol. The precipitated product is filtered off and dried, yielding 14 parts of 3-(1-piperidinyl)-propyl 4-phenyl-4-piperidinecarboxylate dihydrochloride monohydrate; mp. 176.1° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.7 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 204 mg of 4-chloro-6-(3-fluorophenyl)pyrimidine and 82 mg of 2-butyn-1-ol, to which 47 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 151 mg of 4-(3-fluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (57)).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][C:4]([C:8]([F:11])([F:10])[F:9])=[N:3]1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:19]=[O:20].[OH-].[Na+]>O.CO>[OH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:5]=1[CH:19]=[O:20]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(C=O)c1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol (9.8 g, 0.059 mole) was added in portions to a mixture of phosphorus oxychloride (9.2 g, 0.060 mole) and N,N-dimethylformamide (10 mL, 0.12 mole) with cooling to control the reaction temperature near 40° C. The mixture was then heated and held at 90°-100° C. for one hour and poured while still warm (50° C.) into a mixture of methanol and water. The pH was adjusted to basic with 10% sodium hydroxide. The aqueous solution was washed with ether, then adjusted to acidic pH with 37% hydrochloric acid, and extracted with a mixture of ether and ethyl acetate. The extracts were dried with magnesium sulfate, filtered and concentrated in vacuo to give 5-hydroxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxaldehyde (9.4 g, 82% yield) which was recrystallized from ethyl acetate/cyclohexane to give a white solid, mp=116°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][OH:5].[CH2:12](Br)[CH:13]=[CH2:14].Cl[C:17]([N:19]1[C@H:24]([CH3:25])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C@@H:20]1[CH3:33])=[O:18]>>[CH3:25][C@H:24]1[CH2:23][NH:22][CH2:21][C@@H:20]([CH3:33])[N:19]1[C:17]([O:5][CH2:4][C:3]1[C:2]([F:1])=[CH:9][C:8]([O:10][CH2:14][CH:13]=[CH2:12])=[CH:7][C:6]=1[F:11])=[O:18]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: C=CCBr
Reactant: OCc1c(F)cc(O)cc1F
Product: C=CCOc1cc(F)c(COC(=O)N2[C@H](C)CNC[C@@H]2C)c(F)c1

Procedure:
2,6-Difluoro-4-(2-propenyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol, allyl bromide and cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 and 96: NMR δH (400 MHz, DMSO-d6) 1.25 (6H, d, J 6.9 Hz), 2.75–2.87 (4H, m), 4.04 (2H, m), 4.51 (2H, dt, J 5.3, 1.5 Hz), 5.14 (2H, s), 5.32 (1H, dq, J 10.5, 1.5 Hz), 5.41 (1H, dq, J 17.3, 1.5 Hz), 6.00 (1H, ddt, J 17.3, 10.5, 5.3 Hz) and 6.45 (2H, m), NH not observed; HPLC (XTERRA, 50/80, 220 nm) 97.3% (3.89 min).
Reaction SMILES: [I-].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N+:9]([CH3:14])=[C:10]2[CH3:13])=[CH:5][CH:4]=1.[CH3:15][Mg]Cl.O>C1COCC1>[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:14])[C:10]2([CH3:15])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC1=[N+](C)CCc2ccc(N)cc21
Reactant: C[Mg]Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2ccc(N)cc2C1(C)C
Temperature: -78 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
7-Amino-1,2-dimethyl-3,4-dihydroisoquinolinium iodide (1.44 g, 4.8 mmol) was suspended in THF (200 ml), cooled to −78° C. and treated with methyl magnesium chloride (10 ml of a 3M solution in THF) added as a single portion. The reaction was allowed to reach room temperature over 18 h and poured into water (200 ml). The organic solvent was removed in vacuo and the resultant oily residue extracted into dichloromethane (3×50 ml). Evaporation in vacuo and chromatography through silica gel eluting with (0.5% 0.88 NH3: 4.5% CH3OH: 95% CH2Cl2) yielded the title compound as a yellow oil (0.07 g, 8%). For ease of handling the product was converted into a monohydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14]C)(C)(C)[CH3:11]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:10](=[O:14])[CH3:11])[CH:7]=1
Reactant: COC(C)(C)C
Reactant: Nc1cc(Cl)ccc1O
Product: CC(=O)Nc1cc(Cl)ccc1O
Temperature: 22.5 °C
Reaction time: 0.67 h
Yield: 92 %

Procedure:
143.6 g (1 mole) of 2-amino-4-chlorphenol was suspended in 550 ml of methyl t-butyl ether under mild nitrogen purge. The mixture was heated to reflux until the material was dissolved. After 40 minutes, 112.3 g of acetic anhydride was added. After the addition the mixture was cooled to 20-25° C. in one hour. After stirring for an additional hour the mixture was cooled to 0-5° C. under stirring and kept on this temperature for an additional hour. The product was filtered off, washed with 200 ml of methyl t-butyl ether twice and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 92%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[S:14]([CH3:17])(=[O:16])=[O:15])(=[O:3])[CH3:2].[CH3:18][N:19]([CH:21](OC)OC)[CH3:20]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=[O:13])/[CH:12]=[CH:18]/[N:19]([CH3:21])[CH3:20])[CH:8]=[CH:7][C:6]=1[S:14]([CH3:17])(=[O:16])=[O:15])(=[O:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Oc1cc(C(C)=O)ccc1S(C)(=O)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(C(=O)/C=C/N(C)C)ccc1S(C)(=O)=O
Yield: 27.7 %

Procedure:
A solution of 5-acetyl-2-(methylsulfonyl)phenyl acetate (1.5 g, 5.8 mmol) and DMF-DMA (1.2 g, 10 mmol) in DMF (20 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (PE/EtOAc=4:1-2:1) to give the title compound (0.5 g, 30%). [M+H] Calc'd for C13H17NO4S, 284. Found, 284.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([NH2:17])[CH:11]=1>O1CCOCC1>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([NH:17][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])[CH:11]=1
Reactant: Nc1cc(Cl)cc(Cl)n1
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1cc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethoxycarbonyl isothiocyanate (2 g, 16 mmol) was added to a solution of 4,6-dichloropyridin-2-amine (2.2 g, 13 mmol) in 1,4-dioxane (100 mL) and stirred at rt for 18 h. LCMS showed desired product. The reaction mixture was concentrated in vacuo and the residue azeotroped with EtOAc (3×20 mL) to give a cream solid, which was triturated with EtOAc to give the desired product as a white solid (2.9 g, 76%). 1H NMR (DMSO) δ 12.31 (s, 1H), 11.77 (s, 1H), 8.86 (d, J=1.1 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H). m/z [M+H]+=293.88
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:8][CH2:9][CH:10]=[CH2:11])[CH:5]1[O:7][CH2:6]1>>[CH2:9]([O:8][CH2:4][CH:5]([OH:7])[CH2:6][N:2]([CH3:3])[CH3:1])[CH:10]=[CH2:11]
Reactant: CNC
Reactant: C=CCOCC1CO1
Agent: *O[SiH2]*
Product: C=CCOCC(O)CN(C)C
Reaction time: 3.5 h
Yield: 98 %

Procedure:
A charge of 112.7 g (1.00 mol, 40%) dimethylamine is made to a 500 ml three-necked, round-bottomed flask. The amine is heated to 40° C. with stirring while 114.1 g (1.00 mol) allyl glycidyl ether is added over 2.5 hours while keeping the temperature below 50° C. After 3.5 hours at 50° C., GC analysis on a 30 M×0.53 mm SPB-5 polysiloxane column shows a single peak as 98% of the desired product. A viscous oil is obtained in quantitative yield. Analysis by 1H NMR (500 MHz, CDCl3) gives the following results: δ=2.61 (6H, s, —N(CH3)2), 2.62 and 2.71 (2H, m, —CH(OH)CH2N(CH3)2), 3.40 and 3.51 (2H, dd, —OCH2CH(OH)—), 4.04 (1H, bm, —CH2CH(OH)CH2—), 4.36 (2H, m, CH2═CHCH2—), 5.13 (1H, dd, CH2═CH—, cis isomer), 5.22 (1H, dd, CH2═CH—, trans isomer), 5.80 (1H, m, CH2═CH—). This data supports the following structure:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)=[C:11]3[C:10]([CH3:25])=[N:9]2)=[CH:5][CH:4]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:40](=[O:41])[C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=[N:36]2)=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.C(N(C(C)C)C(C)C)C>O.CN(C=O)C>[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:40](=[O:41])[C:39]([C:42]([NH:24][C:21]3[CH:22]=[N:23][C:18]([O:17][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=6)[N:9]=[C:10]([CH3:25])[C:11]=45)=[CH:19][CH:20]=3)=[O:43])=[CH:38][CH:37]=[N:36]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cn4)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cn4)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 125.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyridin-3-amine (15 mg, 0.0415 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (24.3 mg, 0.104 mmol; prepared as in Example 19, Step C) HOBT-H2O (6.36 mg, 0.0415 mmol), EDCI (7.96 mg, 0.0415 mmol), N-ethyl-N-isopropylpropan-2-amine (5.36 mg, 0.0415 mmol) and DMF (3 mL). The reaction mixture was stirred at room temperature for 18 hours. Diluted with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to obtain product (30 mg, 90%) as a light brown solid. LRMS (esi+) 578 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]=1.CN1CCOCC1.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([NH:18][NH:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([Cl:10])=[N:12][CH:13]=1)=[O:8]
Reactant: COCCOCC(=O)Cl
Reactant: NNC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCCOCC(=O)NNC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
(2-Methoxy-ethoxy)-acetyl chloride (2.13 g, 13.99 mmol) was added to an ice-cold solution of 6-chloronicotinic acid hydrazide (2 g, 11.66 mmol) and N-methylmorpholine (1.92 mL, 17.49 mmol) in dichloromethane (60 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was then treated with sodium hydrogen carbonate solution and concentrated in vacuo. The aqueous residue was extracted with dichloromethane (×2) and the combined organic solutions were washed with brine and dried over sodium sulfate and concentrated in vacuo to give a pale yellow residue. The residue was then stirred in diethyl ether for 2 hours, filtered and dried to afford the title compound as a pale yellow solid in 51% yield, 1.7 g.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][CH2:6][C:5]=2[CH2:4]1.[Li].N.NC1C=CC=CC=1>C1COCC1>[CH3:2][N:3]1[CH2:12][CH2:11][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=32)[CH2:4]1
Reactant: CN1CCC2=C(CCc3ccccc32)C1
Agent: Cl
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CN1CC[C@H]2c3ccccc3CC[C@@H]2C1
Yield: 62.3 %

Procedure:
Following the procedure of Example 2, 0.64 g (2.71 mmol) of 1,2,3,4,5,6-hexahydro-3-methyl-benz[f]isoquinoline hydrochloride was reacted with 0.126 g of lithium wire in 100 ml of liquid ammonia, 25 ml of anhydrous THF and 0.25 ml of aniline. Chromatography on flash silica, eluting with 5-10% methanol/dichloromethane, then on alumina, eluting with 25% ethyl acetate/petroleum ether gave 0.340 g (62%) of the title product as a colourless oil. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent, the title product hydrochloride was obtained as a white solid, m.p. 277°-285° C. (dec). NMR δ(D2O) 1.52-1.92 (4H, m), 2.63-2.75 (2H, m), 2.86-2.98 (3H, m), 2.92 (3H, s), 3.19 (1H, t of d, J=13 and 3 Hz), 3.56 (1H, m), 7.22-7.28 (3H, m), 7.33-7.36 (1H, m). m/z (CI+, NH3) 202 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@@H:20]2[CH2:28][N:27]3[C@H:22]([CH2:23][O:24][CH2:25][CH2:26]3)[CH2:21]2)=[C:15]([N+:29]([O-])=O)[CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1.C1C=CC(O[C:58](OC2C=CC=CC=2)=[N:59][C:60]#[N:61])=CC=1>O1CCCC1.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@@H:20]3[CH2:28][N:27]4[C@H:22]([CH2:23][O:24][CH2:25][CH2:26]4)[CH2:21]3)/[C:58](=[N:59]/[C:60]#[N:61])/[NH:29][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(/C=C2/c3ccc(F)cc3OCc3c(F)cccc32)ccc1N[C@H]1C[C@H]2COCCN2C1
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#C/N=c1\[nH]c2cc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)ccc2n1[C@H]1C[C@H]2COCCN2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
Dissolve [4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-((7S,8aS)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (0.009 mol, 5.0 g) in tetrahydrofuran (40 mL). Add triethylamine (0.009 mol, 0.9 g) and 10% platinum on carbon (1.0 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 3 h. Filter off the catalyst through a plug of diatomaceous earth, add pyridine (40 mL) and diphenyl N-cyanocarbonimidate (0.009 mol, 2.35 g) to the filtrate. Stir at room temperature for 16 h, then heat at 60-70° C. for 8 h. Remove the solvent under reduced pressure. Dissolve the resulting residue in dichloromethane and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify on a silica gel column using 1% methanol in dichloromethane as eluent to give the title compound (1.9 g, 36%). LC-MS m/z 526.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH:11][C:12]2[N:17]=[C:16]([S:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[CH:5][C:4]=1[OH:26].[C:27](=O)([O-])[O:28]CC.[C:33](=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:26][CH3:33])=[CH:5][C:6]([NH:11][C:12]2[N:17]=[C:16]([S:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[CH:7][C:8]=1[O:9][CH2:10][CH2:27][OH:28]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[O-]
Reactant: COc1cc(Nc2nccc(Sc3ccc(F)cc3)n2)cc(O)c1OC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(Nc2nccc(Sc3ccc(F)cc3)n2)cc(OCCO)c1OC

Procedure:
N-[4,5-Dimethoxy-3-(2-hydroxyethoxy)phenyl]-4-(4-fluorophenylsulphanyl)pyrimidine-2-amine was prepared by treating a solution of N-(4,5-dimethoxy-3-hydroxyphenyl)-4-(4-fluorophenylsulphanyl)-2-pyrimidineamine (2.23 g, 60 mmol) and ethyl carbonate (0.79 g, 90 mmol) in dry DMF (25 ml) with potassium carbonate (1.66 h, 120 mmol) and heating the resulting mixture at 100° for 16 h. The reaction was concentrated under reduced pressure and the residue partitioned between ethly acetate and water. The aqueous layer was re-extracted with ethyl acetate, the combined organic layers dried (MgSO4) and evaporated to give a residue which was subjected to column chromatography [silica; 20% hexane-ethyl acetate] to give the desired compound (1.36 g) as a white foam. δH (d6DMSO) 9.48 (1H, s), 8.17 (1H, d, J 5.3 Hz), 7.69 (2H, m), 7.36 (2H, t, J 8.8 Hz), 7.08 (2H, m), 6.15 (1H, d, J 5.3 Hz), 4.81 (1H, t, J 5.2 Hz), 3.92 (2H, t, J 5.2 Hz), 3.73 (2H, m), 3.71 (3H, s) and 3.64 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11]C)=[O:10].Cl.O.C(OCC)(=O)C>O1CCOCC1>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCC(=O)O)c(Cl)cc2F)c1=O
Temperature: 0 °C
Yield: 64.8 %

Procedure:
0.4 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [Compound 3-11 of the present invention] was dissolved in 4 ml of 1,4-dioxane, to this was added a mixed solution of 1 ml of conc. hydrochloric acid and 1 ml of water while stirring, then, the mixture was heated for 12 hours while stirring under reflux condition. Thereafter, the solution was allowed to cool, and ice water was poured into the reaction solution, ethyl acetate and saturated saline were added to the solution which was separated subsequently, and aqueous sodium hydrogen carbonate was added to the organic layer before separation, aqueous hydrochloric acid was added to the aqueous layer to acidify it, then, ethyl acetate was added before separation, the organic layer was washed with saturated saline, and dried over magnesium sulfate, then, concentrated to obtain 0.252 g of [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetic acid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[F:42][C:39]([F:40])([F:41])[CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: Nc1cccc(S(=O)(=O)NCC(F)(F)F)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCC(F)(F)F)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2,2,2-trifluoroethyl)-benzenesulfonamide (example B.1) according to general procedure II. Yellow solid. MS (ISP) 610.0 [(M−H)−]; mp 259° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:12].[Br:13]Br.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[H][H]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: BrBr
Reactant: [H][H]
Reactant: Cc1ccc(C(C)(C)C)cc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(CBr)c(Br)c1
Yield: 89.2 %

Procedure:
To a mixture of 227 g (1.00 mol) of 2-bromo-4-tert-butyl-1-methylbenzene, 160 g (1.00 mol) of bromine and 1.4 liter of CCl4 1.0 g of benzoyl peroxide was added. This mixture was refluxed until evolution of hydrogen bomide was stopped, and red color of bromine disappeared. The resulting mixture was evaporated using rotary evaporated. Fractional rectification of the residue gave 273 g (89%) of the title product, b.p. 138° C.-141° C./4 mm Hg. Anal. calc. for C11H14Br2: C, 43.17; H, 4.61. Found: C, 43.30; H, 6.72. 1H NMR (CDCl3): δ 7.56 (d, J=1.8 Hz, 3-H), 7.37 (d, J=8.1 Hz, 1H, 5-H), 7.30 (dd, J=8.1 Hz, J=1.8 Hz, 1H, 6-H), 4.59 (s, 2H, CH2Br), 1.29 (s, 9H, tBu). 13C{1H} NMR (CDCl3): δ 153.9, 133.9, 130.9, 130.4, 125.1, 124.4, 34.7, 33.4, 31.06.