Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:48][CH2:47]1.Cl>O>[C:57]([C:56]1[CH:55]=[CH:54][C:53]([CH2:52][N:49]2[CH2:48][CH2:47][CH:46]([NH:45][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[CH2:51][CH2:50]2)=[CH:60][CH:59]=1)#[N:58]
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NC2CCN(Cc3ccc(C#N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred mixture of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55 mmol) in anhydrous N,N-dimethylormamide (5 mL) was added triethylamine (2.6 ml, 18.32 mmol), HATU (2.32 g, 6.11 mmol), and 4-((4-aminopiperidin-1-yl)methyl)benzonitrile as its HCl salt (1.6 g, 5.55 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration, purified by column chromatography to yield 0.91 g (44%) of methyl 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoate as a white solid. LCMS (m/z): 379 (MH+).
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14](/[CH:19]=[N:20]/[OH:21])[CH:15]=[C:16]([Br:18])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:22]=[C:23]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.C(OCC)(=O)C.O>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:19]2[CH2:22][C:23]([CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[O:21][N:20]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=C(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O/N=C/c1cc(Br)cc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(Br)cc(OCc3ccccc3)c2)=NO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.2 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 7.92 g) was added dropwise to a solution of (E)-1-(3-(benzyloxy)-5-bromophenyl)-N-hydroxymethanimine (1.48 g) and di-tert-butyl 2-methylenesuccinate (1.171 g) in THF (15 mL) at 0 C, and the obtained mixture was stirred at 0 C for 2 hours and subsequently at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and water was added thereto. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.67 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]1[CH2:48][O:49][CH3:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:3]=3[C:2]([F:33])([F:34])[F:1])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44][C@H:43]1[CH2:48][O:49][CH3:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: COC[C@@H]1CNCCN1C(=O)OC(C)(C)C
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(S)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[CH2:27][CH2:28][N:20]([C:21]=34)[C:19]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:18]=3[N:17]=2)[CH2:12][CH2:11]1.ClCCl>CN(C)C=O>[Br:1][C:30]1[C:31]([CH3:33])=[CH:32][C:18]2[N:17]=[C:16]([N:13]3[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]3)[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[CH2:27][CH2:28][N:20]([C:21]=34)[C:19]=2[CH:29]=1
Reactant: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cccc3c1N2CC3
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1Br)N1CCc3cccc(c31)C(N1CCN(C)CC1)=N2
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
A solution of N-bromosuccinimide (0.91 g, 5.1 mmoles) in dimethylformamide (3 ml) was added dropwise to a solution of 6-(4-methyl-1-piperazinyl)-9-methyl-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (1.6 g, 4.8 mmoles) in dimethylformamide (30 ml) at 0°-3° C. The reaction mixture was stirred for 30 minutes. The solution was poured into dichloromethane (250 ml), and was washed with brine (4 times, 150 ml), and dried over anhydrous magnesium sulfate. The solvent was removed at reduced pressure and the residue was dried. Purification was accomplished by flash chromatography on an aluminium oxide column (grade III, 60 g), eluted with dichloromethane (500 ml) and 2% methanol in dichloromethane (250 ml) The fractions containing the product were pooled and concentrated. Recrystallization from 2-propanol:water (1:1, 20 ml) yielded 230 mg (11.6%) of product, mp 177°-177° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]#[N:13])=[CH:4][N:3]=1.[N:14]1([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.CCOCC>CC(O)CC>[N:14]1([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:2]3[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]#[N:13])=[CH:4][N:3]=3)=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc(S(=O)(=O)NCCN2CCCCC2)cc1
Reactant: CC(C)Oc1nc(Cl)ncc1C#N
Agent: Cl
Solvent: CCC(C)O
Solvent: CCOCC
Product: CC(C)Oc1nc(Nc2ccc(S(=O)(=O)NCCN3CCCCC3)cc2)ncc1C#N
Temperature: 70 °C
Reaction time: 18 h
Yield: 2.6 %

Procedure:
To a stirred suspension of 2-chloro-4-isopropoxy-5-cyanopyrimidine (Method 26; 505 mg, 2.56 mmol) and 4-[N-(2-piperidinoethyl)sulphamoyl]aniline (Method 43; 362 mg, 1.28 mmol) in 2-butanol (10 ml) was added 1M HCl in ether (3.6 ml, 3.6 mmol). The reaction was warmed to 70° C. and stirred for 18 hours. The reaction was filtered and the solvent removed under reduced pressure to yield a yellow solid. This solid was partitioned between DCM (40 ml) and 2M sodium hydroxide (40 ml). The phases were separated and the aqueous layer was extracted with DCM (30 ml). The organic phases were combined and washed with water (30 ml) and brine (30 ml). Solvent was removed under reduced pressure and the resulting solid was recrystallized from methanol to give the title compound (15 mg). NMR: 1.35 (m, 2H), 1.45 (m, 10H), 2.25 (m, 6H), 2.85 (m, 2H), 5.45 (m, 1H), 7.30 (br s, 1H), 7.80 (d, 2H), 7.90 (d, 2H),8.75 (s, 1H), 10.60 (br s, 1H); m/z 444.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH3:31].C1CCCCC=1.C(O)C>[OH-].[OH-].[Pd+2].O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:21][CH:22]=2)=[CH:11][C:10]=1[CH3:31]
Reactant: Cc1cc(/C=C/c2ccc(OCCCCCCO)cc2)ccc1OCCCCCCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1=CCCCC1
Product: Cc1cc(CCc2ccc(OCCCCCCO)cc2)ccc1OCCCCCCO
Yield: 84 %

Procedure:
A mixture of 2.1 g (5.0 mmol) of (E)-4,4′-di-(6-hydroxyhexyloxy)-3-methylstilbene (3), synthesized in accordance with the method described in the European patent application having application number 01204081.2 filed by Applicant (Applicant's reference PHNL010757), 0.25 g of Pd(OH)2 on carbon, 35 ml of cyclohexene and 50 ml of ethanol is refluxed for one night. The hot solution is passed through Celite and added dropwise to 400 ml of water. The precipitated product is washed with water. 1.8 g of the product (86%) was obtained after drying.
Reaction SMILES: COC1C=CC(C(C2SC=NN=2)[N:10]2[C:18]3[C:13](=[N:14][CH2:15][NH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=C(C(F)(F)F)C=1.FC1C=CC=CC=1C1NC2C=NC=NC=2C=1.[F:51][C:52]([F:72])([F:71])[C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[CH:55][C:54]=1[C:63]1[N:64]=[N:65][C:66]([CH2:69]Cl)=[CH:67][CH:68]=1>>[F:72][C:52]([F:51])([F:71])[C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:60])[F:61])[CH:56]=[CH:55][C:54]=1[C:63]1[N:64]=[N:65][C:66]([CH2:69][N:16]2[CH:17]=[C:18]3[N:10]=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH:12]=[C:13]3[N:14]=[CH:15]2)=[CH:67][CH:68]=1
Reactant: COc1ccc(C(c2nncs2)n2c(-c3ccccc3F)cc3c2=CNCN=3)c(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)nn2)c(C(F)(F)F)c1
Agent: Fc1ccccc1-c1cc2ncncc2[nH]1
Product: Fc1ccccc1-c1cc2ncn(Cc3ccc(-c4ccc(C(F)(F)F)cc4C(F)(F)F)nn3)cc-2n1
Yield: 5 %

Procedure:
Prepared analogously to the method described for 3-[5[(4-methoxy-2-trifluoromethyl-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-6-(2-fluorophenyl)-3H-pyrrolo[3,2-d]pyrimidine beginning with 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (200 mg, 0.93 mmol) and 3-(2,4-Bis-trifluoromethylphenyl)-6-chloromethylpyridazine (383 mg, 1.12 mmol) to obtained desired product (9 mg, 5%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14](/[N:16]=[C:17]2\[S:18][CH:19]=[CH:20][N:21]\2[CH2:22][O:23][CH3:24])[CH:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl.CO>[CH3:24][O:23][CH2:22][N:21]1[CH:20]=[CH:19][S:18]/[C:17]/1=[N:16]\[C:14]1[N:15]=[C:10]([CH2:9][OH:8])[CH:11]=[CH:12][CH:13]=1
Reactant: COCn1ccs/c1=N\c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCn1ccs/c1=N\c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 14.28 g of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ylidene)pyridin-2-amine in 30 ml of chloroform and 30 ml of methanol was added 30 ml of trifluoroacetic acid under cooling with ice, followed by stirring the reaction mixture at room temperature overnight. The reaction mixture was evaporated in vacuo. The resulting residue was neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The resulting ethyl acetate solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate =1/1) to give the title compound as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1.N#N.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.O>[Cl:8][C:9]1[CH:22]=[CH:21][C:20]2[N:19]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1
Reactant: Ic1ccccc1
Reactant: CC1(C)c2ccccc2Nc2ccc(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2ccccc2N(c2ccccc2)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A degassed solution of 16.6 ml (147 mmol) of 4-iodobenzene and 30 g (123 mmol) of 2-chloro-9,9-dimethyl-9,10-dihydroacridine in 600 ml of toluene is saturated with N2 for 1 h. Then, firstly 2.09 ml (8.6 mmol) of P(tBu)3, then 1.38 g (6.1 mmol) of palladium(II) acetate are added, and subsequently 17.7 g (185 mmol) of NaOtBu in the solid state are added to the solution. the reaction mixture is heated under reflux for 1 h. After the mixture has been cooled to room temperature, 500 ml of water are carefully added. The aqueous phase is washed with 3×50 ml of toluene and dried over MgSO4, and the solvent is removed in vacuo. Filtration of the crude product through silica gel with heptane/ethyl acetate (20:1) gives 32.2 g (81%) of 2-chloro-9,9-dimethyl-10-phenyl-9,10-dihydroacridine as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([CH2:24]Cl)=[CH:18][C:19](=[O:23])[O:20]2)=[CH:15][CH:14]=1.BrC1C(C)=CC([O:31]CCC(C)(O)C)=CC=1C.[OH-].[Na+].Cl>CCO.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH2:18][C:19]([OH:31])=[O:23])=[CH:24][O:20][C:21]=2[CH:22]=1
Reactant: O=c1cc(CCl)c2ccc(O[C@@H]3CCc4c(Br)ccc(F)c43)cc2o1
Reactant: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1coc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc12
Temperature: 25 °C

Procedure:
To 15.0 g (35.4 mmol) 7-((R)-4-bromo-7-fluoroindan-1-yloxy)-4-chloromethyl-chromen-2-one (product from step 2) in 45 ml EtOH, 9.29 ml (177 mmol) aq. NaOH (50%) is added. The funnel is rinsed with 50 ml water and the mixture is heated to reflux for approx. 0.5 h. Then, over a time period of 30 min a mixture of 30 ml water and 14.7 ml (177 mmol) conc. HCl (37%) is added. The suspension is cooled to r.t., the product is filtered off, washed with EtOH/water (1:1, 2×30 ml) and dried. Yield: 14.0 g; Rf=0.38 (silica gel, PE/EtOAc/AcOH=6/4/0.1); Mass spectrum (ESI): m/z=405 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9](=O)[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH:6]=1.O.Cl.[CH2:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23]>CS(C)=O.CN(C)C=O>[CH2:22]([O:24][C:25](=[O:27])[CH:26]=[C:9]1[C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:5]([O:4][CH3:3])=[CH:6][C:7]2[CH:19]=[CH:18][CH:17]=[CH:16][C:8]1=2)[CH3:23]
Reactant: CCOC(C)=O
Reactant: COc1cc2ccccc2c(=O)c2ccsc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCOC(=O)C=C1c2ccccc2C=C(OC)c2sccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
21.6 g pre-dried NaH are suspended in 0.9 l dimethylsulfoxide and 200 g ethoxycarbonylmethylen-diethylphosphonate [(C2H5O)2POCH2COOC2H5 ] are added drop-wise over ca. 1 hour, the temperature being maintained at ca. 25°-30° C. by light cooling. The obtained mixture is then stirred for 30 minutes at room temperature and 121 g 10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one dissolved with warming in 0.9 l dimethylformamide are then added in a single portion. The obtained reaction mixture is stirred for ca. 17 hours at ca. 95° C. under argon, and then stirred into a mixture of 7 l H2O/3 kg ice and 50 ml conc. HCl covered with a layer of 2 l ethylacetate. The organic phase is separated off and the aqueous phase extracted 3× with 2 l and 3× with 1 l ethyl acetate. The combined organic phases are washed 3× with 2 l H2O and 3× with 2 l saline, dried with MgSO4, filtered under suction and concentrated on a rotary evaporator to yield the title compound as a (Z,E)-isomer mixture: m.p.=91°-93° C.
Reaction SMILES: C([O:4][C:5]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C@H:9]1[CH2:11][O:10]1)C=C.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:15]1[C:5]2[O:4][CH:9]([CH2:11][OH:10])[CH2:8][O:7][C:6]=2[CH:12]=[CH:13][C:14]=1[N+:16]([O-:18])=[O:17])[CH:19]=[CH2:20]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1OC[C@H]1CO1
Product: C=CCc1c([N+](=O)[O-])ccc2c1OC(CO)CO2

Procedure:
(R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmoles) prepared as above was heated at 155° C. in mesitylene for 24 hours under nitrogen. Filtration of the black solid which formed gave 1.5 g of very polar material. Evaporation of the solvent in vacuum followed by column chromatography on silica gel with methylene chloride as eluant gave 10 g of recovered starting material and 7.5 g of the desired rearranged (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol, which slowly crystallized on standing in vacuum (m.p 67° C.). The yield based on recovered starting material is 75%.
Reaction SMILES: [CH3:1][C:2](=C)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.I([O-])(=O)(=O)=[O:16].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[O:16]=[C:2]([CH3:1])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: C=C(C)Cc1ccc2c(c1)COC2=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Cc1ccc2c(c1)COC2=O
Reaction time: 0.17 h

Procedure:
To a solution of 5-(2-methylprop-2-en-1-yl)-2-benzofuran-1(3H)-one (175 mg, 0.930 mmol) in THF was added osmium tetroxide (295 mg, 0.0460 mmol) and the mixture was stirred for 10 minutes. Then a solution of sodium periodate (497 mg, 2.32 mmol) in water was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with DCM, and washed with Na2S2O3 solution. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (30% ether/hexanes) to afford the title compound. LC-MS (IE, m/z): 191.3 [M+1]+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:22]1[CH:26]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[N:24]=[CH:23]1.CO>N1C=CC=CC=1.C(OCC)C>[C:1]([N:22]1[CH:26]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[N:24]=[CH:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CO
Product: O=C(O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trityl chloride (51 g, 0.18 mol) is added to a suspension of (1H-imidazol-4-yl)acetic acid hydrochloride (25 g, 0.15 mol) in pyridine (500 mL). This is stirred at room temperature for 16 h, at the end of which MeOH (150 mL) is added. This solution is stirred at room temperature for 1 h. Solvents are evaporated and the residue is taken up in CH2Cl2 and washed with 1 M aqueous citric acid solution (2×) and brine. The organic phase is dried over anhydrous Na2SO4 and evaporated to give a sticky residue which when taken up in diethyl ether and evaporated gave the product as a white solid that is used without further purification. MS (ESI) m/z 368.9 (M+H) (Procedure adapted from J. Org. Chem. 1993, 58, 4606, also prepared in WO2003013526)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[Cl:31][CH2:32][CH2:33][CH2:34][NH2:35].C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:35][CH2:34][CH2:33][CH2:32][Cl:31])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCCl)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
A mixture of 4-benzyloxy benzoic acid (5.0 g, 21.9 mmol), 1,1,-carbonyl-diimidazole (3.6 g, 1.05 eq.) and DMF (50 ml) was stirred at 50° C. for 1 h. After cooling to r.t., 3-chloropropylamine hydrochloride (3.4 g, 26.1 mmol) and sodium carbonate (3.5 g, 32.0 mmol) were added and stirring continued for 45 min. After the addition of water, the mixture was extracted with ether. The organic layer was dried (Na2SO4), filtered and evaporated to give 4-benzyloxy-N-(3-chloro-propyl)-benzamide (5.44 g, 85%) as a white solid. MS: me/e=304 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH3:2].C=O.[C:16](=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[C:5]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[CH2:16])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Product: C=C(C(=O)OCC)c1ccc(Br)cc1

Procedure:
is prepared by treating a toluene solution of (4-bromo-phenyl)-acetic acid ethyl ester with paraformaldehyde, potassium carbonate, tetrabutylammonium iodide according to the following literature: H. Stalder, M. Boes Chimia 2000, 54, 669-671.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][CH2:25][CH:26]([CH2:44][F:45])[O:27][C:28]1[C:29]([CH3:43])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([CH3:43])=[C:28]([O:27][CH:26]([CH2:25][F:24])[CH2:44][F:45])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1OC(CF)CF
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC(CF)CF

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-fluoro-1-fluoromethyl-ethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 189.1.1) to give the title compound as a white foam. (HPLC: tR 2.26 min (Method A); M+H=479 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.17 (m, 1H), 8.14-8.10 (m, 2H), 8.00-7.95 (m, 1H), 7.58-7.52 (m, 2H), 5.16-5.01 (m, 1H), 4.92-4.66 (m, 4H), 3.89 (s, 3H), 3.58 (s, 3H), 2.41 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.CO.C(N(CC)CC)C.Cl.[NH2:26][C@H:27]([CH3:31])[C:28]([NH2:30])=[O:29]>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:26]([C@H:27]([CH3:31])[C:28]([NH2:30])=[O:29])[CH:6]=[CH:5]2
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 55 °C

Procedure:
A round bottom flask was charged with 6-chloro-5-nitro-1H-isochromen-1-one (950 mg, 0.0042 mol), methanol (30 mL, 0.7 mol), triethylamine (0.64 mL, 0.0046 mol) and (R)-2-aminopropanamide hydrochloride (0.58 g, 0.0046 mol) and the reaction heated to 55° C. overnight. The reaction went to 90% completion. The solvent was removed and the residue purified by flash chromatography (40 g silica gel, 0-10% MeOH/DCM) to obtain the pure product as a light yellow solid. MS m/z=296.4 (M+H).