Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1.I[C:20]1[C:28]2[C:23](=[N:24][CH:25]=[N:26][C:27]=2[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=[C:20]([C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([F:15])[CH:12]=3)[C:28]=12
Reactant: OB(O)c1cc(F)cc(OCc2ccccc2)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 77.6 %

Procedure:
A solution of (3-Benzyloxy-5-fluorophenyl)boronic acid (29 mg, 5.80 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA22 (15.6 mg, 60% yield). ESI-MS (M+H)+ m/z calcd 378.1, found 378.0.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[Si:19]([O:26][CH2:27][C@H:28]1[CH2:39][CH2:38][C:37]2[S:36][C:35]3[N:34]=[CH:33][N:32]=[C:31](Cl)[C:30]=3[C:29]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][C@H:28]1[CH2:39][CH2:38][C:37]2[S:36][C:35]3[N:34]=[CH:33][N:32]=[C:31]([O:3][CH:4]4[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:6][CH2:5]4)[C:30]=3[C:29]1=2)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 240 mg, 6.00 mmol, 3.00 equiv) was treated with tert-butyl N-(4-hydroxycyclohexyl)-N-methylcarbamate (642 mg, 2.80 mmol, 1.40 equiv) in freshly distilled tetrahydrofuran (14 mL) at 0° C. under nitrogen for 30 min. To this mixture was added a solution of (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (710 mg, 2.00 mmol, 1.00 equiv) in 5 mL of THF via syringe and the resulting solution was stirred overnight at room temperature. After completion, the reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (8:1) to give the desired tert-butyl N-(4-[[(3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (963 mg, 88%) as light yellow oil. MS: m/z 548 (M+H)+.
Reaction SMILES: C(#N)C.[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:16]([O:13][C:12]1[C:11]([O:14][CH3:15])=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[F:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(F)c1OCc1ccccc1
Yield: 67.2 %

Procedure:
To 40 ml of acetonitrile were added 7.3 g of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde, 8.8 g of benzyl bromide, 16.8 g of cesium carbonate and 10 ml of DMF, and the mixture obtained was heated under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. Hydrochloric acid was added to the residue and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.5 g of 4-benzyloxy-3-fluoro-5-methoxybenzaldehyde represented by the formula:
Reaction SMILES: [IH:1].CS[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>C(O)C>[IH:1].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1
Reactant: Cc1ccccc1CN
Reactant: CSC1=NCCc2ccccc21
Agent: I
Solvent: CCO
Product: Cc1ccccc1CNC1=NCCc2ccccc21
Yield: 73 %

Procedure:
1-Methylthio-3,4-dihydroisoquinoline hydroiodide (1.52 g, 0.005 mol) was dissolved in a solution of ethanol (50 ml) containing 2-methylbenzylamine (0.61 g, 0.005 mol). The colourless solution was heated at reflux temperature for six hours with effluent gases being passed through a CHLOROS trap. The solution was then cooled and stood in the refrigerator overnight to give white crystals (1.38 g). This material was crystallised from methanol/ ethanol to give the title compound (1.06 g) as its hydroiodide salt, m.p. 241°-243°.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH:11]2[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]2)[C:5]([F:18])=[C:4]([F:19])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]#[N:31]>CC#N>[F:8][C:7]1[C:2]([O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=2[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:30]#[N:31])=[N:3][C:4]([F:19])=[C:5]([F:18])[C:6]=1[O:9][CH2:10][CH:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]1
Reactant: CC1(C)OCC(COc2c(F)c(F)nc(F)c2F)O1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OCC(COc2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)O1
Reaction time: 24 h
Yield: 56.1 %

Procedure:
To 2,3,5,6-tetrafluoro-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridine (3.2 g, 11 mmol) in CH3CN (20 mL) was added Cs2CO3 (3.8 g, 12 mmol) and 3-hydroxy-4-(benzyloxy)benzonitrile (2.5 g, 11 mmol). After stirring for 24 hours the reaction was partitioned with water and ethyl acetate. The layers were separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. The residue was triturated with hexane/ethyl acetate (1/1) and the resulting solid was collected by filtration to give 3-[[3,5,6-trifluoro-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile (3.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1Cl.[OH-].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1

Procedure:
3-Hydroxybenzoic acid is an important intermediate product for the preparation of plant protection agents. Thus, in accordance with U.S. Pat. No. 4,031,131, 3-hydroxybenzoic acid can be reacted with 3,4-dichlorobenzotrifluoride in methanolic solution and in the presence of potassium hydroxide and dimethyl sulphoxide, to give 3-(2-chloro-4-trifluoromethylphenoxy)-benzoic acid. Nitrating this benzoic acid with potassium nitrate in concentrated sulphuric acid then gives 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid which, according to U.S. Pat. No. 3,798,276, is an important herbicide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([O:15][CH3:16])=[O:14])[N:3]=1.[CH3:17][Sn](C)(C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:17])=[N:3][C:4]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C)c2ccccc2c1O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
A mixture of methyl 1-chloro-4-hydroxyisoquinoline-3-carboxylate (1.00 g, 4.21 mmol, from Aldrich), tetramethylstannane (3.01 g, 16.8 mmol), and bis(triphenylphosphine)-palladium(II) chloride (0.295 g, 0.421 mmol) in N,N-dimethylformamide (30 mL) was stirred at 130° C. for 30 minutes. The mixture was cooled to room temperature, quenched with water and then filtered. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel chromatography, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (0.80 g, 88%). LCMS calculated for C12H12NO3 (M+H)+: m/z=218.1; Found: 218.1.
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH2:21]([NH2:23])[CH3:22]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:23][CH2:21][CH3:22])[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: CCN
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Solvent: CN(C)C=O
Product: CCNC(CC)C(=O)Nc1ncc(Cc2ccccc2Cl)s1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing ethylamine (2 M in tetrahydrofuran, 1.00 mL, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (19 mg, 0.056, 56%). ESI-MS m/z calc. 337.1, found 338.0 (M+1)+ Retention time 2.08 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[O-:9][CH2:10][CH3:11].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:9][CH2:10][CH3:11])[N:3]=1
Reactant: CC[O-]
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(Br)n1
Temperature: 25 °C

Procedure:
A mixture of 2,6-dibromopyridine (1.5 g) in ethanol (6 mL) was treated with sodium ethoxide (3.55 mL) solution dropwise and resulting mixture was refluxed for 18 hours. The mixture was allowed to cool to room temperature and poured into a beaker containing 5% sodium bicarbonate, extracted with diethyl ether. The combined organics were washed with brine, dried, evaporated in vacuo and purified by column chromatography on silica gel (1-3% methanol in dichloromethane) to obtain the title compound (0.840 g) having the following physical data.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31][CH2:32][CH3:33])=[CH2:30])CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:32]([O:31][C:29]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:30])[CH3:33]
Reactant: Fc1cc2ncccc2c(F)c1Cn1nnc2ncc(Br)nc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 54.3 %

Procedure:
To a degassed solution of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (10 mg, 0.03 mmol) in DMF (1 mL) was added Pd(Ph3P)4 (3.1 mg, 2.65 μmol). After stirring for 20 min, tributyl(1-ethoxyvinyl)stannane (14.4 mg, 0.04 mmol) was added. The reaction was heated at 100° C. until the LC-MS showed its completion. The reaction mixture was filtered through celite and washed with ether. The filtration was washed with water, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography with hexane:EtOAc to give 6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (6.0 mg, 61%). 1H-NMR (400 MHz, CDCl3) δ ppm 9.16 (s, 1H), 8.98 (d, 1H), 8.43 (d, 1H), 7.65 (d, 1H), 7.48 (m, 1H), 6.17 (s, 2H), 5.60 (s, 1H), 4.57 (s, 1H), 4.04 (q, 2H), 1.49 (t, 3H). LCMS (method B): [MH]+=369.0, tR=2.45 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:22])[CH:10]=2)[O:5]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:22][C:24](=[O:26])[CH3:25])[CH:10]=2)[O:5]1
Reactant: CC(=O)OC(C)=O
Reactant: COCC1(C)Oc2ccc(N)cc2C(n2ccccc2=O)C1O
Solvent: c1ccncc1
Product: COCC1(C)Oc2ccc(NC(C)=O)cc2C(n2ccccc2=O)C1O
Reaction time: 24 h

Procedure:
A mixture of 1 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-amino-3-chromanol, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20° C. for 24 hours. The mixture is evaporated, worked up in the customary manner and 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-acetamido-3-chromanol is obtained.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13](O)=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O:21][C:22]([C:24]1[N:25]([NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1)=O)C=C.ClCCl.[O-]CC.[Na+].Cl>CN(C)C=O.C(O)C>[OH:21][C:22]1[C:24]2[N:25]([CH:26]=[CH:27][CH:28]=2)[N:29]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:13](=[O:14])[C:12]=1[C:7]1[NH:6][C:5]2[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: C=CCOC(=O)c1cccn1NCCC(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (Example 4b, 0.2 g, 0.546 mmol) was dissolved in N,N-dimethylformamide (2.7 mL). 1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.129 g, 0.546 mmol) was added followed by a 1.0 M solution of N,N-dicyclohexylcarbodiimide in dichloromethane (0.574 mL, 0.574 mmol). The mixture was stirred at 25° C. for 2 h. N,N-Dicyclohexylurea precipitation was visible at this point. The mixture was diluted with dichloromethane (5 mL) and filtered under reduced pressure. The filtrate was washed with 1.0 M aqueous hydrochloric acid solution (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (2.7 mL). A 21% solution of sodium ethoxide in ethanol (0.448 mL) was added and the mixture was stirred at 80° C. for 4 h. Additional sodium ethoxide in ethanol (0.448 mL) was added and the mixture was stirred at 80° C. for 4 h. Upon cooling to 25° C., the pH was adjusted to approximately 6 by the addition of 3.0 M aqueous hydrochloric acid solution. Immediate precipitation was observed. Methanol (3 mL) was added and the mixture was shaken vigorously. The solid was collected by vacuum filtration, rinsed with methanol (3×2 mL) and dried in vacuo for 16 h to afford the desired product, 4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.196 g, 0.372 mmol, 68% yield) as a white powder. LC-MS (ESI) calcd for C19H19IN4O4S. found 526.02. found 527.15 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1(C2C3C(=C4C(=CC=3)C(C3C=CC=CC=3)=CC=N4)N=CC=2)C=CC=C[CH:17]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OC=C)CCC>[CH:16]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[CH2:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Agent: [Pd+2]
Agent: C=COCCCC
Agent: CC(=O)[O-]
Product: C=COCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9182.5 %

Procedure:
4.3 g of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate, 66 mg of 4,7-diphenyl-1,10-phenanthroline, and 45 mg of palladium acetate were added to 50 mL of butylvinyl ether, followed by stirring at room temperature for 15 minutes, and stirring at 75° C. for 2 days. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 4.4 g of tert-butyl 4-[(vinyloxy)methyl]piperidine-1-carboxylate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:29]([O:32][CH2:33][C:34]1[CH2:41][S:40][CH:39]2[N:36]([C:37](=[O:43])[CH:38]2[NH2:42])[C:35]=1[C:44]([OH:46])=[O:45])(=[O:31])[CH3:30]>C1COCC1>[C:29]([O:32][CH2:33][C:34]1[CH2:41][S:40][CH:39]2[N:36]([C:37](=[O:43])[CH:38]2[NH:42][C:11](=[O:13])[CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:35]=1[C:44]([OH:46])=[O:45])(=[O:31])[CH3:30]
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc4c(c3)CCO4)C2SC1
Temperature: 0 °C

Procedure:
A solution of 10 mmole of 2,3-dihydo-5-benzofuranyl acetic acid and 10 mmole of triethylamine in 100 ml of THF is cooled to about 0° C. While stirring, isobutylchloroformate (10 mmole) is added and the temperature maintained at 0° C. for 15 minutes. A cold solution of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (10 mmole) and 10 mmole of triethylamine in 80 ml of 50% aqueous THF is added to the previously prepared solution. The mixture is stirred at 5° C. for 1 hour and at room temperature for 1 hour. Then the THF is evaporated and the residue is dissolved in water and washed with ethyl acetate. The aqueous phase is covered with ethyl acetate and the pH is adjusted to 3 with 6N hydrochloric acid. The mixture is filtered and the layers separated. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]([CH3:12])=[CH2:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH3:16]OC(OC)N(C)C>>[CH3:14][N:6]1[C:5](=[O:15])[C:4]2=[CH:16][NH:2][N:1]=[C:3]2[N:8]([CH2:9][C:10]([CH3:12])=[CH2:11])[C:7]1=[O:13]
Reactant: C=C(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: COC(OC)N(C)C
Product: C=C(C)Cn1c(=O)n(C)c(=O)c2c[nH]nc21
Temperature: 90 °C

Procedure:
A mixture of 6-hydrazino-3-methyl-1-(2-methyl-2-propenyl)pyrimidine-2,4[1H,3H]-dione (0.575 g) and dimethylformamide dimethylacetal (0.73 ml) was heated at 90° C. for 20 minutes. The mixture was allowed to cool and was directly purified by column chromatography over silica eluting with ethyl acetate: hexane (2:1) and then recrystallisation from ethyl acetate/hexane to give the subtitle compound (0.063 g). Melting point: 232-233° C. MS (EI) 220 (M+) 1H NMR (CDCl3 /DMSO-d6) δ 1.80 (3H, s); 3.39 (3H, s); 4.60 (2H, s); 4.75 (1H, s), 4.89 (1H, s); 8.04 (1H, s); 13.04 (1H, s, br).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CCCCCC>[Cl:1][CH2:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: O=C1Cc2cc(CCCl)ccc2N1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
5-Chloroacetyl-2-oxindole (7.0 g) was added to 25 mL of trifluoroacetic acid and the mixture cooled in an ice bath with stirring. Triethylsilane (12.3 mL) was added dropwise over 2 minutes. The reaction was then stirred at room temperature for 4 hours and poured into ice water. Hexane was added, the mixture stirred vigorously, and the solid collected by vacuum siltation and washed with hexane to give 5.9 g (91% yield) of the product as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]([Cl:23])([C:19]([F:22])([F:21])[F:20])[CH:8](O)[CH2:9][C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].O>N1C=C(C)C=C(C)C=1>[Cl:6][C:7]([Cl:23])([C:19]([F:20])([F:21])[F:22])[CH:8]=[CH:9][C:10]([CH3:16])([CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC(C)(C)CC(O)C(Cl)(Cl)C(F)(F)F
Agent: Cc1cncc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)CC(C)(C)C=CC(Cl)(Cl)C(F)(F)F
Temperature: 0 °C
Yield: 55.3 %

Procedure:
Phosphorus oxychloride (10 cm3) was added dropwise to a stirred solution of methyl 6,6-dichloro-3,3-dimethyl-5-hydroxy-7,7,7-trifluoroheptanoate (5.49 g) in 3,5-lutidine (50 cm3) maintained at 0° C. The resultant mixture was heated at 100° C. for 30 minutes, and then cooled to the ambient temperature under a nitrogen atmosphere, and poured into a stirred mixture of ice and water (300 cm3). The mixture was extracted with ethyl acetate (2×150 cm3), diethyl ether (3×150 cm3) and finally with ethyl acetate (150 cm3). The volume of the combined extracts was reduced to about 400 cm3 by evaporation of some of the solvents under reduced pressure, and then washed with dilute (3.5M) hydrochloric acid. The aqueous washings were extracted with diethyl ether (3×50 cm3) and the extracts combined with the organic phase. After washing the combined organic phase with brine and drying over anhydrous magnesium sulphate, the solvents were removed by evapoation under reduced pressure and the residual oil purified by Kugelrohr distillation (128° C./1 mm Hg) to give methyl 6,6-dichloro-3,3-dimethyl-7,7,7-trifluorohept-4-enoate as a pale yellow oil (2.86 g, 52% yield), together with a quantity of the allylically rearranged isomer methyl 4,6-dichloro-3,3-dimethyl-7,7,7-trifluorohept-5-enoate.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:11]2[NH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:10]=2[CH2:9][CH2:8]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:11]2[NH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:10]=2[CH2:9][CH2:8]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cccc(OC)c1)CC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc2c([nH]1)C(Cc1cccc(O)c1)CC2
Temperature: 25 °C

Procedure:
Methyl 6-(3-methoxybenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (140 mg, 0.50 mmol) in dry CH2Cl2 (20 mL) was cooled to −78° C., then BBr3, (1.0 M in CH2Cl2) (0.80 mL, 0.80 mmol) was added. The mixture was allowed to warm slowly to room temperature overnight. The mixture was added to saturated sodium bicarbonate, (100 mL) extracted with CH2Cl2, (50 mL) (×3), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 50 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.07-2.19 (m, 1H), 2.48-2.74 (m, 4H), 2.90 (dd, J=13.42, 6.30 Hz, 1H), 3.26-3.44 (m, 1H), 3.79 (s, 3H), 6.62 (s, 1H), 6.70 (d, J=1.71 Hz, 1H), 6.72-6.80 (m, 2H), 7.21 (t, J=7.81 Hz, 1H), 8.29 (br. s, 1H).