Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][CH2:12][B-](F)(F)F)([CH3:10])([CH3:9])[CH3:8].[K+].[Br:18][C:19]1[CH:20]=[C:21]2[C@@:33]3([CH2:37][O:36][C:35]([NH2:38])=[N:34]3)[C:32]3[C:27](=[N:28][CH:29]=[C:30](I)[CH:31]=3)[O:26][C:22]2=[CH:23][C:24]=1[F:25].O1CCOCC1>CCOC(C)=O.C([Pd-2](Cl)=C1N(C2C(CCC)=CC=CC=2CCC)CCN1C1C(CCC)=CC=CC=1CCC)C=C.O>[Br:18][C:19]1[CH:20]=[C:21]2[C@@:33]3([CH2:37][O:36][C:35]([NH2:38])=[N:34]3)[C:32]3[C:27](=[N:28][CH:29]=[C:30]([CH2:12][O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:31]=3)[O:26][C:22]2=[CH:23][C:24]=1[F:25]
Reactant: CC(C)(C)OC[B-](F)(F)F
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)c(F)cc1Oc1ncc(I)cc12
Agent: C=CC[Pd-2](Cl)=C1N(c2c(CCC)cccc2CCC)CCN1c1c(CCC)cccc1CCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OCc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)c(F)cc1O2
Temperature: 130 °C
Yield: 19.9 %

Procedure:
A vial charged with allylchloro[1,3-bis(2,6-di-1-propylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(ii) (0.072 g, 0.126 mmol), cesium carbonate (1.10 g, 3.36 mmol), potassium tert-butoxymethyltrifluoroborate (0.49 g, 2.52 mmol), and (S)-7-bromo-8-fluoro-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.40 g, 0.84 mmol, prepared as described in Method BB24) was treated with 3 mL dioxane and 0.3 mL water, was capped under argon, and was heated to 130° C. overnight. The reaction mixture was diluted with EtOAc, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-7-bromo-3-(tert-butoxymethyl)-8-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.073 g, 0.167 mmol, 19.91% yield) with impurities.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH3:14]>C1COCC1.C(OCC)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:14])=[O:12]
Reactant: N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of Naphthalene-2-carbonyl chloride obtained from Step A was dissolved in THF (30 mL) and this was cooled down to 0° C. Ammonia gas was passed for approximately 1.5 hrs through the solution and the reaction was stirred at room temperature under a closed system for 4 hrs. A white solid precipitate was observed in the reaction mixture. The reaction mixture was dissolved in ethyl acetate and washed using water followed by brine solution. The organic layer was separated and dried over sodium sulphate and the volatiles were evaporated off in vacuo to afford the crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[CH:7]2
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cccc2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2cccc(Br)c21
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
To a solution of 7-bromo-1H-indazole (1 g, 5.1 mmol) in dry tetrahydrofuran (20 mL) was added NaH (305 mg, 60%, 7.65 mmol) at −20° C. under N2 atmosphere. After 20 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (1 g, 6.1 mmol) was added and the mixture was warmed to 20° C. and stirred for 1 hour. Water (2 mL) was added and product extracted with dichloromethane (100 mL), organic phase washed with water (2×10 mL) and brine (2×10 mL) then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with ethyl acetate:petroleum ether=1:20) to afford 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.27 g, 77%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.03 (s, 1H), 7.69 (d, 1H, J=8.7 Hz), 7.60 (d, 1H, J=8.1 Hz), 7.06-7.01 (m, 1H), 6.08 (s, 2H), 3.60 (t, 2H, J=7.8 Hz), 0.90 (d, 2H, J=8.1 Hz), 0.01 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:21]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]CC2C=CC=CC=2)[CH:6]=1)[OH:4]>C(O)C.[Pd]>[NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30])[CH:21]=1)[CH:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[OH:4]
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(O)c1
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-[3-(benzyloxy)-phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (5.50 g, 12.23 mmol) in ethanol (100 ml) was added 10% palladium/carbon (containing water by 50%, 500 mg), and the mixture was stirred under a hydrogen stream overnight. The catalyst was removed from the reaction solution using celite, and the filtrate was concentrated to give the objective substance (4.04 g, 92%, crude). To obtain data, a portion was purified by alumina column chromatography (ethanol) and recrystallized from diisopropyl, ether-hexane.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7](Cl)=[O:8].Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:37]=[CH:36][C:23]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:36][CH:37]=1)=[O:8]
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)Cl
Reactant: COC(=O)c1ccccc1COc1ccc(CCN)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CCNC(=O)c2cc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-5-phenylfuran-3-carbonyl chloride (36.4 mg, 0.165 mmol) and methyl 2-{[4-(2-aminoethyl)phenoxy]methyl}benzoate hydrochloride (53 mg, 0.165 mmol) were mixed in DCM (4 ml). PS-DIBA (3.66 mmol/g, 135 mg, 0.494 mmol) was added. The mixture was shaken at room temperature overnight. LC-MS showed there was only a trace amount of desired product and a big peak of 2-methyl-5-phenyl-3-furoic acid. TBTU (55 mg, 0.17 mmol) was added. The mixture was shaken for 2 hours and filtered. The filtrate was evaporated to dryness. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM and then MeOH/DCM (0.5:99.5) as eluant gave 34 mg the desired product, yield 44%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>>[C:31]([C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:17]=2)=[O:14])=[CH:36][CH:35]=1)(=[O:33])[CH3:32]
Reactant: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: COc1ccc(NC(=O)Cc2cccc3c(-c4ccc(C(C)=O)cc4)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylacetamide (E20) and 4-acetylphenylboronic acid using a similar procedure to Example 4 (20%).
Reaction SMILES: [CH2:1](/[C:3](=[CH:7]\[CH:8]([OH:10])[CH3:9])/[C:4]([NH2:6])=[O:5])[CH3:2].N1C=CC=CC=1.C1COCC1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.Cl>[CH2:1](/[C:3](=[CH:7]\[CH:8]([O:10][C:24](=[O:25])[CH2:23][Cl:22])[CH3:9])/[C:4]([NH2:6])=[O:5])[CH3:2]
Reactant: CC/C(=C\C(C)O)C(N)=O
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC/C(=C\C(C)OC(=O)CCl)C(N)=O
Reaction time: 0.25 h
Yield: 95 %

Procedure:
25 (rac-Ethyl (2E)-4-hydroxypent-2-enamide) (886 mg, 6.0 mmol), pyridine (969 μl, 12 mmol) and DMAP (147 mg, 1.2 mmol) are dissolved in toluene (30 ml) and THF (10 mL) and cooled to 0° C. Chloroacetylchloride (954 μl, 12 mol) in toluene (4 ml) is added dropwise under stirring at ≦2° C. over 15 min. The reaction mixture is stirred for 2.5 hours at 0° C. The resulting suspension is then poured in 2 M HCl (25 ml) and extracted with tBuOMe (250 and 150 ml). The organic phases are washed with 2 M HCl (25 ml), saturated NaHCO3 (15 ml) and brine (25 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. yielding 33 (rac-Ethyl (2E)-4-(chloroacetoxy)pent-2-enamide) (1.26 g, 95%) as a beige solid.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]2[CH:11]=[CH:12][N:13]=[C:5]2[CH:4]=1.[O:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][S:9][C:7]1[N:6]2[CH:11]=[CH:12][N:13]=[C:5]2[CH:4]=[C:3]([C:23]2[CH:22]=[CH:21][C:20]([N:17]3[CH2:16][CH2:15][O:14][CH2:19][CH2:18]3)=[CH:25][CH:24]=2)[N:8]=1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CSc1nc(Cl)cc2nccn12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: CC(C)O
Product: CSc1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Temperature: 90 °C
Yield: 25.9 %

Procedure:
A suspension of 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride (1.85 g, 7.83 mmol; Preparation H, Step A), 4-morpholinophenylboronic acid (1.78 g, 8.62 mmol) and potassium phosphate (3.33 g, 15.7 mmol) in isopropanol (25 mL) was purged with argon for 5 minutes, and then Pd2dba3 (0.717 g, 0.783 mmol) and XPHOS (1.49 g, 3.13 mmol) were added. The reaction was again purged for 5 minutes with argon before being sealed and heated to 90° C. for 18 hours. The reaction mixture was diluted with EtOAc (75 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography, eluting with 10-15-20% acetone in DCM to afford 4-(4-(5-(methylthio)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.663 g, 25.9% yield) as a yellow solid. MS (apci) m/z=327.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:10](=[O:11])[N:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH:17](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>CO.C(#N)C>[CH3:17][O:1][C:2]1[C:10](=[O:11])[N:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(O)C(=O)N2CCCCC12
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)C1=C(OC)C(=O)N2CCCCC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
At 0° C. to a solution of Intermediate 22C (30 mg, 0.13 mmol) and N,N-diisopropylethylamine (35 μL, 0.20 mmol) in methanol (0.15 mL) and acetonitrile (1.35 mL) was added (trimethylsilyl)diazomethane (0.10 mL, 2.0 M in diethyl ether, 0.20 mmol). The reaction mixture was stirred at rt for 2 h, concentrated and the residue was purified by ISCO chromatography (ethyl acetate/hexane 0-100%, column, 4 g) to afford Intermediate 22D (20 mg, 63%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25-1.41 (5H, m), 1.50-1.61 (1H, m), 1.76-1.98 (2H, m), 2.44-2.52 (1H, m), 2.79-2.90 (1H, m), 3.95 (1H, dd, J=11.4, 3.6 Hz), 4.23-4.38 (6H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1>CCO.[Pt]>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 60 °C

Procedure:
Follow modified procedure from WO 99/35146. 1-(3-Fluoro-benzyl)-5-nitro-1H-indazole (2.49 g, 9.2 mmol) is suspended in 40 ml absolute EtOH and Pt/C (5%, wet, 150 mg) is added. The reaction mixture is stirred and heated at 60° C. under a hydrogen atmosphere (balloon). Roughly 4 hours into the reaction LC/MS reveals the formation of substantial amounts of product. The mixture is filtered through Celite and concentrated under reduced pressure. Yield: 2.01 g (90.8%) of a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]3[N:7]=2)[CH2:5][CH2:4]1.[H-].[Na+].[N:27]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:17]([C:16]1[CH:15]=[C:14]([C:13]2[N:8]3[N:7]=[C:6]([C:3]4([CH2:2][O:1][C:32]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:33])[CH2:5][CH2:4]4)[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=2)[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: O=C(Cl)N1CCCC1
Reactant: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(CO)CC3)nc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(COC(=O)N4CCCC4)CC3)nc12
Reaction time: 1 h

Procedure:
Under an argon atmosphere 3-[2-(1-Hydroxymethyl-cyclopropyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzonitrile (compound 150) (0.03 g, 0.08 mmol) was dissolved in DMF (0.5 mL). NaH (0.02 g, 0.48 mmol) was added and the suspension was heated at 65° C. for 1 h after which 1-pyrrolidine carbonylchloride (0.088 mL, 0.8 mmol) was added. Stirring was performed at 65° C. for 1 h. The reaction mixture was cooled and aq. NaHCO3 and H2O was added. The aqueous phase was extracted with EtOAc (×2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using DCM:MeOH 99:1 as eluent to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH:9]([C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)CC(=O)CNC(=O)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)CC(C)C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
4.0 g of N-(4-fluorobenzoyl)isovalerylmethylamine are dissolved in 20 ml of dimethylsulfoxide and 1.3 g of potassium hydroxide are added thereto at 5° C. to 10° C. under vigorous stirring. The mixture is further stirred for 10 minutes. 3.1 g of ethyl bromoacetate are added dropwise to the mixture at the same temperature, and said mixture is further stirred for 2 hours. After the reaction, the mixture is treated in the same manner as described in Preparation 1-(5). 3.5 g of ethyl 3-(4-fluorobenzoylamino)-3-isovalerylpropionate are thereby obtained as oil. Yield: 64.8%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.Br[C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CS(C)=O.[Cu]>[F:18][C:12]([F:19])([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 50 %

Procedure:
To a solution of 1-iodo-3-nitrobenzene (1.450 g, 5.82 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.3 g, 6.40 mmol) in anhydrous DMSO (10 ml) was added Copper powder (0.740 g, 11.64 mmol). The mixture was purged with N2 and heated at 70° C. in a sealed vial for 17 h. After being cooled to room temperature, the reaction mixture was poured into 20% aqueous NH4Cl solution (100 mL) and was extracted with EtOAc (2×100 mL). The organic extract was washed with brine (2×30 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to obtain ethyl 2,2-difluoro-2-(3-nitrophenyl)acetate (0.714 g).
Reaction SMILES: [F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=O)([F:4])[F:3].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[N:17][OH:18])([F:4])[F:3]
Reactant: NO
Reactant: O=C(c1ccc2c(c1)OCO2)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C(c1ccc2c(c1)OCO2)C(F)(F)F
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Trifluoromethyl(3,4-methylenedioxyphenyl) methanone (1.46 g, 0.0067 mole), hydroxylamine hydrochloride (1.06 g), 0.015 mole) and sodium acetate (0.86 g, 0.010 mole) were dissolved in a mixture of methanol (4 ml) and water (4 ml) and heated to reflux for 4.5 hours. After cooling to room temperature, water (10 ml) was added and the mixture extracted with ether (3×15 ml). The combined extracts were washed with water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. After filtration and removal of the solvent in vacuo the residue was recrystallized from a mixture of dichloromethane and petroleum spirit (40°-60° C.) to give trifluoromethyl(3,4-methylenedioxyphenyl)methanone-oxime (1.2 g), (76.9%) m.p. 96.0° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:26][OH:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:44][O:45][CH2:46][C:47](O)=[O:48]>O1CCCC1>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:26][O:27][C:47](=[O:48])[CH2:46][O:45][CH3:44])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CO)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Reactant: COCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COCC(=O)OCc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)nncc12
Yield: 60 %

Procedure:
0.1 g (0.25 mmol) of 1-benzyl-7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo [2,3-d]pyridazine, 0.164 g (0.8 mmol) of dicyclohexylcarbodiimide and 0.061 ml (0.8 mmol) of methoxyacetic acid are reacted in 5 ml of anhydrous tetrahydrofuran as described for Example 7a. Yield: 60%, m.p.: 119°-121° C.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15].Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:15][CH:14]([CH3:16])[C:13]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 48370 %

Procedure:
With ice-cooling, a solution of 73.0 g (0.985 mol) of tert-butanol, 190 g (1.877 mol) of triethylamine and 0.573 g (0.0047 mol) of DMAP in 750 ml of dichloromethane is treated with a solution of 100 g (0.939 mmol) of isobutyryl chloride in 150 ml of dichloromethane, and the mixture is then stirred overnight. 500 ml of 2 M hydrochloric acid are then added, the aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water, sat. NaHCO3 solution and sat. NaCl solution, dried over sodium sulphate and concentrated. Distillative purification of the crude product gives 65.5 g (48%) of tert-butyl 2-methylpropionate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O.N1(O[C:46](N(C)C)=[N+:47](C)[CH3:48])C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CNC.O1CCCC1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:11])[N:47]([CH3:48])[CH3:46])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CNC
Agent: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled solution of (S)-2-tert-butoxycarbonylamino-3-phenylpropionic acid (available from Aldrich; 5.3 g, 20 mmol) in dimethylformamide (50 mL) at 0° C. were added 1-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 2.97 g, 22 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluororophosphate (available from Aldrich; 8.30 g, 22 mmol). Diisopropylethylamine (10.7 mL, 61.4 mmol) and dimethylamine in tetrahydrofuran (2M, 15 mL, 30 mmol) were added dropwise. The mixture was stirred for 1 h at 0° C. and ethyl acetate was added. The mixture was washed with water and brine, and dried over sodium sulfate. Evaporation of the solvents gave ((S)-1-dimethylcarbamoyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester as a yellow oil (5.52 g) which was used in the next step without further purification.
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[Br:6][C:7]1[C:8]([C:12]2[C:13]([F:31])=[C:14]([NH:19][S:20]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])(=[O:22])=[O:21])[CH:15]=[CH:16][C:17]=2[F:18])=[N:9][NH:10][CH:11]=1>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Br:6][C:7]1[CH:11]=[N:10][N:9]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:8]=1[C:12]1[C:13]([F:31])=[C:14]([NH:19][S:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])(=[O:22])=[O:21])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=S(=O)(Nc1ccc(F)c(-c2n[nH]cc2Br)c1F)c1cc(F)ccc1F
Reactant: CC(C)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Cn1ncc(Br)c1-c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the residue, dissolved in dichloromethane (10 mL), isobutyl bromide (1 mL, 9 mmol) and tetrabutylammonium bromide (0.16 g, 0.5 mmol) in 7 N sodium hydroxide (10 mL) were added and the mixture was vigorously stirred at room temperature. After 2 h, only N-[3-(4-bromo-1H-pyrazol-3-yl)-2,4-difluorophenyl]-2,5-difluorobenzene-sulfonamide was present. Upon addition of more isobutyl bromide (3 mL, 27 mmol) and tetrabutylammonium bromide (0.45 g, 1.4 mmol) and after 18 h additional stirring the reaction was completed. The phases were separated and the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by flash chromatography (eluant: dichloromethane). First the regioisomer N-{3-[4-bromo-1-(2-methyl propyl)-1H-pyrazol-5-yl]-2,4-difluorophenyl}-2,5-difluoro-benzenesulfonamide (0.065 g, 0.13 mmol) was isolated, then the title product was obtained as a white solid (0.12 g, 0.2 mmol, 15% four steps).