Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[H][H].C>CO.C(O)(=O)C.[Pd]>[OH:11][C:8]1[CH:7]=[CH:6][C:3]([CH3:4])=[C:2]([OH:1])[C:9]=1[CH3:10]
Reactant: [H][H]
Reactant: Cc1c(O)ccc(C=O)c1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(O)c(C)c1O
Yield: 30.5 %

Procedure:
1 g (6.5 mmol) of 2,4-dihydroxy-3-methylbenzaldehyde is hydrogenated, at 3 bar hydrogen pressure for 24 h, with 100 mg of Pd on active charcoal (10%) in 100 ml of methanol and 1 ml of glacial acetic acid. A further 100 mg of Pd on active charcoal (20%) are added and the mixture is hydrogenated at 3 bar hydrogen pressure for 12 h. The catalyst is filtered off, the solvent is removed in vacuo and the residue is purified by chromatography (dichloromethane/acetone). 274 mg (30%) of 1,3-dihydroxy-2,4-dimethylbenzene are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CO>[CH3:12][N:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CNCCc1ccccn1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)Cc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
6.8 g of 3-nitrobenzyl chloride in 25 ml of methanol are slowly added dropwise to a solution of 5.4 g of 2-(2-methylaminoethyl)pyridine in 20 ml of methanol at 40° C. 15 ml of triethylamine in 15 ml of methanol are subsequently added, and the mixture is stirred for 15 hours at 40° C. After removal of the solvent by evaporation in vacuo, the residue is taken up in 300 ml of water and extracted three times with dichloromethane. After drying over sodium sulphate, the dichloromethane is evaporated in vacuo and the residue is chromatographed on silica gel (eluent:dichloromethane/methanol 100:5).
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:8]1[C:16]2[C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][C:9]=1[NH2:21].N1C=CC=CC=1>O1CCCC1>[C:1]([NH:5][C:6]([NH:21][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[C:16]=2[CH:8]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ccc2oc3c(c2c1)CCCC3
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.6 %

Procedure:
tert-Butylisocyanate (0.55 g, 5.5 mmol) was added to a cooled (0° C.) solution of 6,7,8,9-tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred for 10 minutes at 0° C. and then allowed to warm to ambient temperature for 5 hours. An additional portion of tert-butylisocyanate (0.65 mL) was added the reaction mixture was stirred overnight. The reaction was incomplete, so pyridine (10 mL) was added and the reaction mixture was heated to reflux for 4.5 hours and then concentrated under reduced pressure. The crude material was dissolved in ethyl acetate and washed with 1 N HCl, water, and brine, dried (Na2SO4) and concentrated. The crude material was recrystallized from acetonitrile to provide 1-tert-butyl-3-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-urea (0.71 g). Mp 310-312° C. (DEC); Anal. Calcd. for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78; Found: C, 71.18; H, 7.84; N, 9.79.
Reaction SMILES: Cl[C:2]([N:6](C)C)=C(C)C.[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([C:25]([OH:27])=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.C(N(CC)CC)C.Cl.CN.CN(C1C=CN=CC=1)C>[CH3:2][NH:6][C:25]([CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17]1)=[O:27]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)c2ccccc21
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.35 ml of 1-chloro-N,N,2-trimethylpropenylamine is added to a solution of 0.59 g of 1-(tert-butoxycarbonyl)indoline-3(R,S)carboxylic acid in methylene chloride at 0° C. After 30 min, 0.93 ml of triethylamine, 0.23 g of methylamine hydrochloride and 4-DMAP, as a catalyst, are added and the mixture is stirred at room temperature for 3 h. The reaction mixture is then chromatographed directly over 80 g of silica gel (mobile phase J). This gives the title compound: Rf (P)=0.65.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH:13]([C:15](O)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:15][OH:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1C(C(=O)O)c1ccccc1-2
Solvent: C1CCOC1
Product: Cc1cccc2c1C(CO)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 1-methyl-9-fluorenecarboxylic acid (4.0 g, 17.9 mmol) in 100 mL of THF was charged with IM THF solution of BH3 -THF complex (35 mL, 35 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature then quenched with water (20 mL). The organic layer was washed with 10% potassium carbonate solution, water, brine, dried and evaporated to afford 1-methyl-9-fluorenemethanol (3.2 g, 84.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.[CH2:15]([N:18]=[C:19]=[O:20])[CH2:16][CH3:17].[N-]=C=O>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH:13][C:19]([NH:18][CH2:15][CH2:16][CH3:17])=[O:20])[O:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)OC(CN)=CO2
Reactant: CCCN=C=O
Agent: [N-]=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCNC(=O)NCC1=COc2ccc(OC)cc2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The amine obtained in Step C of Example 24 is dissolved in 16 ml of anhydrous toluene; 0.78 g (9.17 mmol) of n-propyl isocyanate is then added to the medium. After 4 hours of stirring under an inert atmosphere and at ambient temperature, the excess of isocyanate is neutralised with a few drops of water. The solvent is then evaporated in vacuo. The residue obtained is purified on a silica column (eluant: MeOH/CH2Cl2: 10/90) to yield the title urea in the form of a white solid.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:17](=[O:29])[CH2:16]2)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=O)(C)C.C[O-].[Na+]>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:18]2[C:17](=[O:29])[C:16]3[N:15]([C:13](=[O:14])[C:12]4[CH:11]=[CH:10][CH:9]=[N:8][C:7]=4[C:5]=3[OH:4])[CH2:20][CH2:19]2)=[CH:23][CH:24]=1
Reactant: CC(C)OC(=O)c1ncccc1C(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2c(O)c3ncccc3c(=O)n2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.5 %

Procedure:
To a solution of 36 (0.900 g, 2.26 mmol) in 12 mL of dry MeOH under a N2 atmosphere was added 12.5 mL of a 0.5 M sodium methoxide (NaOMe). The solution was stirred at ambient temperature for 2.5 hours. The reaction was worked up by removing the solvent and dissolving the residue in CH2Cl2. The organic layer was washed with a saturated aqueous solution of NH4Cl and dried to provide 610 mg of the product 37 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 3.58 (t, 2H, J=6 Hz), 4.308 (t, 2H, J=5 Hz), 4.77 (s, 2H), 7.09 (t, 2H, J=8 Hz), 7.34 (t, 2H, J=8 Hz), 7.61 (dd, 1H, J=5.8 Hz), 8.73 (d, 1H, J=8 Hz), 9.12 (d, 1H, J=3 Hz), 13.00 (s, 1H); 13C NMR (75 M, CDCl3) δ 38.8, 43.9, 49.5, 111.9, 115.9, 116.2, 124.7, 130.0, 130.1, 131.0, 136.4, 146.8, 147.2, 154.7, 157.3, 163.0 (d, J=245 Hz), 163.7; 19F NMR (282.6 MHz, CDCl3) δ 63.2; EI MS (m/z) 340.5 [MH+], 362.3 [M+Na].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[O-:11][C:12]#[N:13].[Na+].C(O)(C(F)(F)F)=O>C1C=CC=CC=1.[OH-].[Na+]>[C:12](=[O:11])([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[NH2:13]
Reactant: OCCc1ccccc1Br
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of commercially available 2-(2-bromophenyl)ethanol (1 eq.) in Benzene (0.85M) at room temperature was added sodium cyanate (2.1 eq) then TFA (2.2 eq) dropwise. The mixture was stirred at room temperature for 6 h, poured in aqueous NaOH (1N) and extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Recrystallization in Et2O afforded the desired compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14](Cl)=[N:15][OH:16].[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])#[CH:20].N>>[F:8][C:9]1[CH:18]=[C:13]([C:14]2[CH:20]=[C:19]([C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[O:16][N:15]=2)[CH:12]=[N:11][CH:10]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cccc(N)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared as the trifluoroacetic acid salt according to Method CD using the product of Example 28B (88 mg, 0.5 mmol) and 3-ethynylaniline (Aldrich, 59 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 6.82-6.91 (m, 1H), 7.13-7.49 (m, 4H), 8.16 (dt, J=9.2, 2.2 Hz, 1H), 8.60 (d, J=2.7 Hz, 1 H), 8.96 (s, 1H) ppm; MS (DCI/NH3) m/z 256 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([NH:19][C:20]([O:22]C3C=CC=CC=3)=O)[S:18][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CN(C=O)C.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([NH:19][C:20]([NH:2][CH3:1])=[O:22])[S:18][C:12]=2[CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)Oc3ccccc3)sc2C1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.7 %

Procedure:
25 mg methylamine was added to 200 mg 2-phenoxycarbonylamino-6,7-dihydro-4H-thiazolo-[5,4-c]pyridine-5-carboxylic acid tert-butyl ester in 25 mL DMF. The reaction was stirred for 12 h at RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and concentrated. The residue was purified by column chromatographie (silica gel, eluent: 40% ethylacetate in hexane) to give 151 mg of desired product. (M+H)+: 313
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][CH2:21][CH2:22][CH3:23])(=[O:19])=[O:18].[H-].[Na+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([NH:20][CH2:21][CH2:22][CH3:23])(=[O:19])=[O:18])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCCNS(=O)(=O)c1ccccc1N
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (90 μL, 0.70 mmol) and 2-amino-N-propyl-benzenesulfonamide (100 mg, 0.47 mmol), sodium hydride (54.2 mg, 0.56 mmol) in DMSO (1.0 mL) is added and the resulting solution is stirred at 80° C. for 3.0 h. The mixture is poured into water and extracted with ethyl acetate three times. The organic layer is washed with water and then brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford the title compound as a slightly yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[CH:12](=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:3]1
Reactant: C(c1ccccc1)=[N+]1CCOCC1
Reactant: Cn1ccc2ccccc21
Agent: [Cl-]
Product: Cn1cc(C(c2ccccc2)N2CCOCC2)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and 4-benzylidene-morpholin-4-ium chloride.
Reaction SMILES: C(OCC)(=O)C.[C:7]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:15]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C:16]([C:26]([O:28]CC2C=CC=CC=2)=[O:27])=[C:17]([CH2:21][O:22][CH2:23][CH2:24][Cl:25])[NH:18][C:19]=1[CH3:20])=[O:13])#[N:8]>[H][H].[C].[Pd]>[C:7]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:15]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C:16]([C:26]([OH:28])=[O:27])=[C:17]([CH2:21][O:22][CH2:23][CH2:24][Cl:25])[NH:18][C:19]=1[CH3:20])=[O:13])#[N:8]
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCc2ccccc2)=C(COCCCl)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)O)=C(COCCCl)N1

Procedure:
5 ml of ethyl acetate and 10% palladium carbon were added to 340 mg (0.640 mmol) of 2-(2-chloroethoxy) methyl-4-(3-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-benzyl ester 5-(2-cyanoethyl) ester. The obtained solution was stirred at room temperature in hydrogen atmosphere under normal pressure for 8 hours. After filtering the reaction mixture, the filtrate was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C>C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: c1ccc2c(c1)CCN2
Reactant: BrCCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: BrCCN1CCc2ccccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 1,2-dibromoethane (58.0 ml) were added indoline (5.0 g) and triethylamine (28.7 ml), and the mixture was stirred at 90° C. for 2 hr. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with saturated brine (400 ml) and dried over Na2SO4. Ethyl acetate was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (4.09 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].C([Si](C)(C)[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:32][CH3:33])(C)(C)C.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: COc1cc(C=O)ccc1OCCO[Si](C)(C)C(C)(C)C
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(OC)c3)nc2c1
Temperature: 150 °C
Yield: 7.8 %

Procedure:
NaH (0.12 g, 0.0050 mol, 60% in mineral oil) was added to 4-hydroxy-3-methoxylbenzalde (0.636 g, 4.18 mmol) in anhydrous DMF (15 mL) and then (2-bromoethoxy)-tert-butyl-dimethylsilane (1.0 g, 4.18 mmol) was added and the reaction was kept at room temperature overnight. The reaction mixture was poured into water. The mixture was extracted with dichloromethane and the combined organic layers were passed through a column to yield 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (170 mg, 13%). 2-Amino-4,6-dimethoxy-benzamide (101 mg, 0.515 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (160 mg, 0.515 mmol), sodium hydrogen sulfite (100 mg, 58.5%) and p-toluenesulfonic acid monohydrate (10 mg) were mixed with N,N-dimethyl acetamide (15 mL) and heated to 150° C. for 16 h. N,N-dimethyl acetamide was removed under vacuum and the residue was poured into water (50 mL). The solid was filtered off and further purified by column chromatography to yield 2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (15 mg, 7.8%). Selected data: MS (ES) m/z: 373.1; MP 246-248° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[C:3]=1[Cl:13].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:12]1[C:2]([Br:1])=[C:3]([Cl:13])[C:4]2[O:8][C:7]([F:10])([F:9])[O:6][C:5]=2[CH:11]=1)([O-:16])=[O:15]
Reactant: FC1(F)Oc2ccc(Br)c(Cl)c2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(c(Cl)c1Br)OC(F)(F)O2
Temperature: -10 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
The solution of 5-bromo-4-chloro-2,2-diflouro-1,3-benzodioxole (1.5 g, 5.53 mmol) in 10 mL conc. sulfuric acid was cooled to −10° C. Then a solution of 1 mL fuming nitric acid and 2 mL of conc. sulfuric acid was added drop wise. The resulting solution was stirred at −10° C. for ˜2 h. Then the reaction mixture was poured into ice water and a yellow solid precipitated out. Filtered off the solid, rinsed with water and collected the solid. The crude solid was purified by flash chromatography (SiO2, 0-5% ethyl acetate in hexanes) to afford pure 6-nitro-5-bromo-4-chloro-2,2-diflouro-1,3-benzodioxole (1.0 g, 3.16 mmol, 57%). MS: (ES) m/z calculated for C7HBrClF2NO4 [M+H]+ 316.0. found 316.
Reaction SMILES: ClCCl.[N+:4]([O-:18])([O:6][CH2:7][C@H:8]([O:14][N+:15]([O-:17])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:5].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.O>[N+:4]([O-:18])([O:6][CH2:7][C@H:8]([O:14][N+:15]([O-:17])=[O:16])[CH2:9][CH2:10][CH2:11][CH:12]=[O:13])=[O:5]
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=CCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrapropylammonium perruthenate (16 mg, 0.05 mmol) was added to a dichloromethane (5 mL) solution of (2R)-6-hydroxyhexane-1,2-diyl dinitrate (intermediate 2, 105 mg, 0.49 mmol) and 4-methylmorpholine N-oxide (137 mg, 1.17 mmol). The solution was stirred at room temperature for 30 minutes. Water was added and the solution was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica eluting with ethyl acetate/hexanes afforded the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.79 (s, 1H), 5.25-5.32 (m, 1H), 4.76 (dd, J=13.0, 3.5 Hz, 1H), 4.49 (dd, J=13.0, 6.5 Hz, 1H), 2.59-2.54 (m, 2H), 1.83-1.73 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=S)[NH:11][NH2:12].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:21]([CH3:23])[NH:12][N:11]=1
Reactant: NNC(=S)Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(Cl)cccc2Cl)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A slurry of 9.4 g (0.04 mole) of 4-(2,6-dichlorophenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was stirred under nitrogen atmosphere while 6.8 g (0.04 mole) of ethyl 2-choroacetoacetate was added. The reaction mixture became yellow as it stirred for 1 hr at room temperature. Then 40 mL of 2N ethanolic hydrogen chloride was added and the reaction mixture heated at reflux for 3 hr. Insoluble sulfur was removed by filtration and the filtrate concentrated in vacuo to give an orange solid, which when triturated with hot acetone yielded 11.3 g of pale yellow crystals, mp: plastic 175°-191° C., degasses at 195° C., and forms a clear melt at 215° C. Recrystallization from acetonitrile gave 6.5 g of product, mp 180°-190° C. Additional material was obtained from the reaction mixture filtrate upon setting. The filtrate was then concentrated to a solid. All crude materials were combined and dissolved in 125 mL of benzene, treated with charcoal, filtered, and the volume reduced to 40 mL. The benzene solution was treated with 25 mL of ligroin and the product crystallized from the hot solution to give 9.7 g of crystalline product which had a pink color, mp 191°-192° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([O:22][C:18]2[CH:17]=[C:16]([N:8]3[C:9]4[CH:14]=[CH:13][N:12]=[CH:11][C:10]=4[N:15]=[C:7]3[C:3]3[C:2]([NH2:1])=[N:6][O:5][N:4]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:26][CH2:25]1
Reactant: Nc1nonc1-c1nc2cnccc2n1-c1cccc(O)c1
Reactant: CN1CCC(O)CC1
Product: CN1CCC(Oc2cccc(-n3c(-c4nonc4N)nc4cnccc43)c2)CC1

Procedure:
The title compound was prepared from the product of Example 39 using the general method of Example 50 using N-methyl-4-hydroxy-piperidine. MS (ES+) m/e 392 [M+H]+.
Reaction SMILES: [C:1]([OH:15])(=[O:14])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C=C[CH:19]=[CH:18][CH:17]=1.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:19]([O:14][C:1](=[O:15])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:18]=[CH2:17]
Reactant: c1ccncc1
Reactant: CCCCCCC=CC=C/C=C/C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: C=CCOC(=O)/C=C/C=CC=CCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.2 g of 3,7,11-trimethyl-2-cis/trans, 4-cis/trans, 10-cis/trans-tridecatrienoic acid are dissolved in 65 ml of absolute benzene and 3.5 ml of pyridine and then treated at a temperature between 5° C and 10° C with 3.4 ml of thionyl chloride (dropping time ca 15 minutes). The mixture is subsequently stirred for 1 hour at room temperature, then the liquid is decanted off and the residue is washed out with benzene. The solution is evaporated to dryness under anhydrous conditions. The residue is dissolved in 20 ml of absolute benzene and added dropwise at a temperature between 5° C and 10° C to a solution of 3.6 ml of allyl alcohol and 3.5 ml of pyridine in 50 ml of benzene (dropping time ca 30 minutes). After stirring overnight at room temperature, the solution is diluted with ether and washed with 1-N aqueous hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and finally with sodium chloride solution. After drying, the ether phase is evaporated. The crude product is chromatographed on the 30-fold amount of Kieselgel (eluant: hexane/ether 19:1 parts by volume). 3,7,11-Trimethyl-2-cis/trans, 4-cis/trans, 10-cis/trans-tridecatrienoic acid allyl ester is obtained as a colorless oil of boiling point 120° C/0.05 mmHg (bulb-tube); nD25 = 1.5026.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[S:22][CH:21]=[C:20]([CH3:23])[C:18]=2[N:19]=1>C1COCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[S:22][CH:21]=[C:20]([CH3:23])[C:18]=2[N:19]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(Oc2nc(Cl)nc3c(C)csc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A stirred suspension of NaH (16 mg, 0.4 mmol) in dry THF (2 mL) was added 2,4,6-trimethyl phenol and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (87 mg, 0.4 mmol) in dry THF (2 mL) at 0° C. and slowly warmed up to room temperature. After stirring the reaction for 2 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1) to give the product as a white solid (136 mg, 90%):