Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18]Br.[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18][NH:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCBr)c2n1
Reactant: NCCCN1CCOCC1
Solvent: CC#N
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCN3CCOCC3)c2n1

Procedure:
The product of step (vii) (4 g) was suspended in acetonitrile (40 ml) and 4-(3-aminopropyl)morpholine (15 ml) was added. The mixture was stirred under reflux for 14 h. then the mixture evaporated under reduced pressure. The residue was purified by RPHPLC. Yield 3.59 g.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[CH:24]=[CH:23][C:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[N:19][C:20]=3[CH2:21][CH2:22][C:13]=2[CH:12]=1.[NH4+].[Cl-]>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>[CH2:2]([C:11]1[CH:24]=[CH:23][C:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[N:19][C:20]=3[CH2:21][CH2:22][C:13]=2[CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccc2c(c1)CCc1ncccc1-2
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Product: c1ccc(Cc2ccc3c(c2)CCc2ncccc2-3)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Benzylzinc bromide (0.5 mol/L in tetrahydrofuran, 7.7 mL) is added to a flask charged with a stir bar, tetrakis(triphenylphosphine)palladium(0) (53 mg), and 8-bromo-5,6-dihydro-benzo[f]quinoline (0.20 g) and kept under argon atmosphere at room temperature. The resulting solution is heated to reflux temperature and stirred at this temperature for 6 h. After cooling the solution to room temperature, aqueous NH4Cl solution is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to afford the title compound as an oil. Yield: 0.17 g (81% of theory); LC (method 1): tR=3.08 min; Mass spectrum (ESI+): m/z=272 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][NH:6]2.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][C:28]([F:32])=[CH:29]2)[CH2:25][CH2:24][CH:23]([CH3:33])[N:22]3[CH:21]=1)=O>>[CH3:33][CH:23]1[CH2:24][CH2:25][C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:4]4[C:3]5[C:7](=[CH:8][CH:9]=[CH:10][C:2]=5[F:1])[NH:6][CH:5]=4)=[CH:21][N:22]13)[CH:29]=[C:28]([F:32])[CH:27]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)CCC2C
Reactant: NC(=O)Cc1c[nH]c2cccc(F)c12
Product: CC1CCc2cc(F)cc3c(C4=C(c5c[nH]c6cccc(F)c56)C(=O)NC4=O)cn1c23

Procedure:
Beginning with (4-fluoroindol-3-yl)acetamide and (4-methyl-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2ncoc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2ncoc2c1
Yield: 77.9 %

Procedure:
A mixture of 6-methylbenzoxazole (5.0 g; J. T. Gupton, K. F. Correia and B. S. Foster, Synthetic Communications, 1986, 16, 365), N-bromosuccinimide (7.0 g) and azobisisobutyronitrile (0.55 g) in dry chloroform (100 ml) was heated at reflux for 1 hour. The cooled reaction mixture was washed three times with water (40 ml), dried over magnesium sulphate and evaporated. The residual orange coloured viscous solid was triturated twice with pentane (50 ml) affording the title compound (6.20 g) as a buff coloured solid, m.p. 52-56° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH3:30])=[CH:13][CH:12]=2)[C:5]([O:8]C)=[N:6][CH:7]=1>O1CCOCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:30])=[CH:15][N:16]=2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CNCCN1c1ccc(Nc2cc(Cl)c[nH]c2=O)nc1
Yield: 201.2 %

Procedure:
A solution of 138a (1.0 g, 2.3 mmol) in dioxane/HCl (30 mL) was stirred at 100° C. for 2 h. It was then evaporated under reduced pressure to afford 138b (1.48 g, crude) as a yellow solid. MS-ESI: [M+H]+ 320.3
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[C:8](B(O)O)([CH3:10])=[CH2:9].COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[Br:7][C:5]1[N:6]=[C:2]([C:8]([CH3:10])=[CH2:9])[S:3][CH:4]=1
Reactant: C=C(C)B(O)O
Reactant: Brc1csc(Br)n1
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: CCO
Solvent: COCCOC
Product: C=C(C)c1nc(Br)cs1
Temperature: 100 °C

Procedure:
In a tube were placed 2,4-dibromothiazole (100 mg, 0.411 mmol), isopropenylboronic acid (39 mg, 0.452 mmol), DME (1.625 mL), EtOH (563 μL), and 1M aqueous Na2CO3 (1.03 mL, 1.03 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (24 mg, 0.0206 mmol) was added and the mixture was degassed again with N2. The tube was sealed and heated at 100° C. for 2 hours. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 15% EtOAc/hexanes) afforded 4-bromo-2-isopropenyl-1,3-thiazole; NMR showed an impurity present that was not removed. Rf=0.53 (15% EtOAc/hexanes). LCMS=206.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.13 (s, 1H), 5.87 (s, 1H), 5.33 (d, J=1.3 Hz, 1H), 2.21 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][OH:25].C(OCC)(=O)C>C(#N)C.O>[OH:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(OCCO)cc([N+](=O)[O-])c1C
Temperature: 80 °C
Yield: 74.5 %

Procedure:
To a stirred solution of methyl 5-hydroxy-2-methyl-3-nitrobenzoate (1.5 g, 7.1 mmol) in ACN (15 mL), were added cesium carbonate (4.6 g, 14 mmol) and 2-bromoethanol (2.5 mL, 35 mmol). The resulting reaction mixture was heated at 80° C. overnight. On completion, the reaction mixture was diluted with water and extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to afford the title compound (1.35 g, 74%).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][C:11]#[N:12])=[C:5]([CH3:13])[CH:4]=1>ClCCl>[OH:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][C:11]#[N:12])=[C:5]([CH3:13])[CH:4]=1
Reactant: COc1cc(C)c(CC#N)cc1C
Solvent: ClCCl
Product: Cc1cc(CC#N)c(C)cc1O
Temperature: -80 °C
Reaction time: 0.5 h

Procedure:
A solution of (4-methoxy-2,5-dimethylphenyl)acetonitrile (0.5 g, 2.9 mmol) in dichloromethane (10 mL) was cooled to −80° C. and treated with borontribromide (1M in dichloromethane, 14.3 mL, 14.3 mmol). The reaction mixture was stirred at −80° C. for a further 30 minutes and then was allowed to warm to room temperature over a period of 2 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate solution (20 mL) and the organic layer was separated. The organic solution was washed with brine (20 mL), dried over sodium sulfate and the concentrated in vacuo to afford a pale brown solid. Purification by column chromatography on silica gel, eluting with ethyl acetate:pentane 20:80 to 33:67, afforded the title compound as a colourless solid in 60% dispersion in mineral oil yield, 0.28 g. 1H NMR (400 MHz, CD3OD) δ: 2.13 (3H, s), 2.23 (3H, s), 3.66 (2H, s), 6.60 (1H, s), 6.98 (1H, s); LRMS ESI m/z 160 [M−H]−
Reaction SMILES: ClC([N:6](C)C)=C(C)C.[NH2:9][C:10]1[C:11]([Cl:20])=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13](O)=[O:14].N>C1COCC1>[NH2:9][C:10]1[C:11]([Cl:20])=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([NH2:6])=[O:14]
Reactant: Nc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: CC(C)=C(Cl)N(C)C
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethyl-amine (16.1 mL, 116 mmol) is added to 3-amino-2,4-dichloro-benzoic acid (20.0 g, 97.1 mmol) in THF (320 mL). After 4 h at rt the mixture is added dropwise to conc. NH3 (320 mL) and stirred at rt overnight. The reaction mixture is concentrated, cooled and filtered. The filtercake is dried to give the sub-title compound.
Reaction SMILES: [O:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C@H:2]1[O:10][C@H:9]([C:11]([O-:13])=[O:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[Na+]>O>[O:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C@H:2]1[O:10][C@H:9]([C:11]([OH:13])=[O:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCCCCCCCO[C@H]1O[C@H](C(=O)[O-])[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O
Product: CCCCCCCCO[C@H]1O[C@H](C(=O)O)[C@H](O)[C@H](O)[C@H]1O

Procedure:
50 g (0.15 mole) of sodium octyl α-D-galactopyranoside uronate prepared according to Example 12 are solubilized in water (30% solution). After passing through 400 ml of a cationic resin of the IR 120 H+ type and concentrating under vacuum, α-D-galactopyranoside uronic acid, whose physicochemical characteristics are indicated below, is quantitatively recovered in the form of a gum:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH2:36]1[CH:38]([CH:39]([OH:42])C#N)[CH2:37]1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:39]([CH:38]2[CH2:36][CH2:37]2)[OH:42])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: N#CC(O)C1CC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)C3CC3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and cylopropyl carboxaldehyde.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[C:4]([CH3:9])=[N:3]1.[C:10]([O-])(=[O:12])[CH3:11].[K+].C(OC(=O)C)(=O)C>CCOC(C)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:10](=[O:12])[CH3:11])[C:4]([CH3:9])=[N:3]1
Reactant: Cc1nn(C)c(C)c1N
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C)nn(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A suspension of 1,3,5-trimethylpyrazol-4-amine (1 g, 7.99 mmol), potassium acetate (0.862 g, 8.79 mmol) and acetic anhydride (0.889 mL, 7.99 mmol) in EtOAc (25 mL) was stirred at 25° C. overnight. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford N-(1,3,5-trimethylpyrazol-4-yl)acetamide (1.390 g, 104%) as a off-white solid. Mass spectrum: MH+ 168
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH:8]1([C:11]2[N:16]=[C:15]([N:17]([CH3:19])[CH3:18])[C:14](/[CH:20]=[CH:21]/[N+:22]([O-])=O)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>C1COCC1>[NH2:22][CH2:21][CH2:20][C:14]1[C:15]([N:17]([CH3:18])[CH3:19])=[N:16][C:11]([CH:8]2[CH2:9][CH2:10]2)=[CH:12][CH:13]=1
Reactant: CN(C)c1nc(C2CC2)ccc1/C=C/[N+](=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)c1nc(C2CC2)ccc1CCN
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
To a stirred solution of lithium borohydride (1055 μL, 2.11 mmol) (in 2 mL of THF) was added chlorotrimethylsilane (535 μL, 4.22 mmol) dropwise. After stirring for 15 minutes, Argon was bubbled through the reaction mixture for 2 minutes to eliminate any trimethylsilane in the reaction mixture. (E)-6-Cyclopropyl-N,N-dimethyl-3-(2-nitrovinyl)pyridin-2-amine (123 mg, 0.527 mmol) was added (in 1 mL of THF). The reaction was heated to reflux for 2 hours, cooled to 0° C. and carefully quenched with methanol (1 mL). The reaction mixture was concentrated, diluted with dichloromethane and 20% aqueous KOH. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated to yield 3-(2-aminoethyl)-6-cyclopropyl-N,N-dimethylpyridin-2-amine (107 mg, 0.521 mmol, 98.8% yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:15][CH2:16][C:17](O)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[OH-].[K+]>CCOCC>[CH2:7]([O:15][CH2:16][CH2:17][OH:18])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)COCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: OCCOCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (0.93 g, 24.63 mmol) in dry Et2O (60 mL), 2-phenethyloxyacetic acid (1.1 g, 6.15 mmol) in dry Et2O (6 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0° C. H2O (0.93 mL), 3.0 M KOH solution (0.93 mL) and H2O (3.12 mL) were very slowly added. The mixture was stirred at 0° C. for 1 h, filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness. The crude mixture was purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (from 100:0 to 60:40) affording the title compound (0.69 g, 68%) as a colorless oil. 1H NMR (DMSO-d6): δ 2.81 (t, J=7.1 Hz, 2H), 3.40-3.44 (m, 2H), 3.45-3.51 (m, 2H), 3.60 (t, J=7.1 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 7.15-7.30 (m, 5H).
Reaction SMILES: Cl.NO.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[C:12](=[CH:18][N:19](C)C)[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[C:7]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:12]2[CH:18]=[N:19][O:14][C:13]=2[CH:15]2[CH2:17][CH2:16]2)=[O:22])=[C:7]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[CH:6]=1
Reactant: CC(=O)N(C)c1cc(Cl)ccc1C(=O)C(=CN(C)C)C(=O)C1CC1
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC(=O)N(C)c1cc(Cl)ccc1C(=O)c1cnoc1C1CC1
Reaction time: 0.75 h
Yield: 41 %

Procedure:
Hydroxylamine hydrochloride (0.1 g) was added to a stirred solution of 1-[4-chloro-2-(N-methylacetamido)phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropane-1,3-dione (0.32 g) in ethanol. The mixture was stirred for 0.75 hours and evaporated to dryness. Water was added to the residue, which was extracted (dichloromethane). The extract was dried (magnesium sulphate) and evaporated to give an oil. This was purified by chromatography eluting with ethyl acetate/dichloromethane (1:8) to give 4-[4-chloro-2-(N-methylacetamido)benzoyl]-5-cyclopropylisoxazole, (compound number 1, 0.12 g), m.p. 106.5°-107.5° C., as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[O:26])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[BH4-].[Na+].O.C(OCC)(=[O:41])C>C1COCC1.[Cu]Cl>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=2[Cl:33])=[O:26])=[CH:22][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][OH:41])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: CCOC(C)=O
Reactant: C=CCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Agent: Cl[Cu]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCCCO)CCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 62 %

Procedure:
To a suspension of 4-[[(2,6-dichlorophenyl)carbonyl]arnino]-N-[[1-(3-butenyl)cyclopentyl]-carbonyl]-L-phenylalanine methyl ester (3.13 mmol, 1.62 g) and anhydrous copper (I) chloride (5.0 mmol, 500 mg) in THF (30 mL) was added solid sodium borohydride (5.0 mmol, 200 mg) at −5° C. over 5 min. After the addition, the reaction mixture was allowed to warm to room temperature and the brown reaction mixture was stirred for 36 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the excess hydride was quenched by the addition of water (5 mL) and the reaction mixture was cooled to 0° C. To this, a solution of sodium acetate (20 mL, 3.0N) was added dropwise maintaining the temperature below 10° C. this was followed by H2O2 (25 mL, 30%). After addition of hydrogen peroxide, the reaction mixture was allowed to warm to room temperature and was stirred for 3 h and followed by 1 h at 40-45° C. to complete the hydrolysis. Then, it was poured into a mixture of water (50 mL) and ethyl acetate (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The comined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent gave a crude product which was purified by silica gel column chromatography to afford 1.04 g (62%) of a white amorphous solid. HR MS (C27H32Cl2N2O5): Obs. mass, 535.1758. Calcd. mass, 535.1766, M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[C:40]4[C:35](=[CH:36][C:37]([O:41][CH3:42])=[CH:38][N:39]=4)[N:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[N:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:42][O:41][C:37]1[CH:36]=[C:35]2[C:40]([C:31]([O:30][C:27]3[CH:28]=[CH:29][C:24]([NH:23][C:16]4[C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:13]([C:7]5[CH:8]=[C:3]([CH:4]=[CH:5][CH:6]=5)[C:1]#[N:2])=[N:14][N:15]=4)=[CH:25][CH:26]=3)=[CH:32][CH:33]=[N:34]2)=[N:39][CH:38]=1
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5cccc(C#N)c5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C

Procedure:
In a nitrogen purged sealed tube, 1,4-dioxane (1.4 mL) was added and the tube was purged with nitrogen for 5 min and sealed. 3-Cyanophenylboronic acid (0.056 g, 0.384 mmol), 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (0.150 g, 0.349 mmol), and 2.0 M sodium carbonate (0.349 mL, 0.698 mmol) were added to the tube, followed by 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.013 g, 0.017 mmol). The tube was purged with nitrogen, sealed, and the mixture was heated to 100° C. for 17 h. The mixture was allowed to cool to RT and was concentrated in vacuo. The crude material was purified by silica gel chromatography using 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2. The remaining impurities were removed by diluting the crude with methanol causing a light yellow solid to precipitate, which were filtered and air dried to yield 3-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)benzonitrile. MS [M+H]=497.0; Calc'd 496.5 for C30H20N6O2.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>C1OC2C(=C[C-]=CC=2)OC1.[Mg+2].[Br-]>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:15]3[CH:14]=[CH:27][C:28]4[O:29][CH2:30][CH2:26][O:5][C:4]=4[CH:6]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: C1CCOC1
Agent: [Br-]
Agent: [Mg+2]
Agent: [c-]1ccc2c(c1)OCCO2
Product: O=C(c1ccc2c(c1)OCCO2)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 3,4-(ethylenedioxy)phenylmagnesium bromide. Yield: 77 mg of a white solid. LC-MSD, m/z for C24H17BrN2O4 [M+H]+=477.0, 479.0; HPLC retention time: 2.4 min.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18]([C:30]2[CH:29]=[N:28][CH:27]=[N:32][CH:31]=2)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(-c2cncnc2)c1
Yield: 120.6 %

Procedure:
To the solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromo-6-chloropyridine (500 mg, 1.1 mmol) in toluene (10 mL) was added tetrekis(triphenylphosphine)palladium (50 mg, 1%) and tributyl(pyrimidinyl)tin (0.64 g, 1.72 mmol). The mixture was stirred and heated under reflux for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 2:3) to afford an oil (500 mg, 100%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.26-2.42 (m, 2H), 3.84-3.92 (m, 2H), 4.20 (m, 1H), 4.40 (m, 1H), 4.54 (m, 1H), 7.31 (d, 1H, J=3.0 Hz), 8.22 (d, 1H, J=3.0 Hz), 8.88 (s, 2H), 9.28 (s, 1H); MS (CI/NH3) m/z 377 (M+H)+.