Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.CO[N:5](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]1[NH:7][C:8](=[O:22])[C:9]2[N:10]=[CH:11][N:12]([CH2:15][CH2:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19])[C:13]=2[N:14]=1.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>N1C=CC=CC=1>[C:42]([O:21][CH2:20][CH:17]([CH2:18][O:19][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:16][CH2:15][N:12]1[CH:11]=[N:10][C:9]2[C:8](=[O:22])[NH:7][C:6]([NH2:5])=[N:14][C:13]1=2)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CON(c1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCC(CCn1cnc2c(=O)[nH]c(N)nc21)COC(=O)C(C)(C)C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
To a solution of N2 -monomethoxytrityl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (0.47 g, 0.9 mmol) in pyridine (4.5 ml) was added pivalyl chloride (0.55 ml, 4.5 mmol) and the solution was stirred for 45 minutes. The mixture was precipitated in water (45 ml) and the resulting precipitate was stirred in 80% acetic acid (10 ml) at 80° for 20 minutes. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with chloroformmethanol (10:1) to afford 9-(4-pivalyloxy-3-pivalyloxymethylbut-1-yl)guanine (0.22 g, 58%), m.p. 225°-237° C.; νmax (KBr) 3430, 2980, 1730, 1690, and 1620 cm-1 ; δH [(CD3)2SO] 1.11 (18 H, s, 2×C(CH3)3), 1.81 (2 H, q, J 6.8 Hz, 2'-H), 1.93 (1 H, m, 3'-H), 4.0-4.1 (6 H, m, 1'-H and 2×4'-H), 6.38 (2 H, s, 2-NH2), 7.69 (1 H, s, 8-H), and 10.58 (1 H, br.s, 1-H); (Found: C, 56.58; H, 7.26; N, 16.14%; C20H31N5O5 requires: C, 56.99; H, 7.41; N, 16.62%).
Reaction SMILES: Cl.CO.C=O.[C:6]([BH3-])#N.[Na+].[CH:10]1([NH:14][CH2:15][CH2:16][CH:17]([C:24]2[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12][CH2:11]1>CO>[CH:10]1([N:14]([CH3:6])[CH2:15][CH2:16][CH:17]([C:24]2[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:12][CH2:13]1
Reactant: [BH3-]C#N
Reactant: Brc1ccc(OCc2ccccc2)c(C(CCNC2CCC2)c2ccccc2)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 M HCl-methanol (0.46 mL, 2.32 mmol), formaldehyde (0.870 g, 28.97 mmol) and sodium cyanoborohydride (0.255 g, 4.056 mmol) were added to a solution of N-cyclobutyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (2.61 g, 5.79 mmol) in methanol (8 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica (hexane-triethylamine, 9:1). Yield 1.59 g (59%); 1H NMR (CDCl3) δ1.59 (m, 2H), 1.73 (m, 2H), 1.91 (m, 2H), 2.06 (s, 3H), 2.16 (m, 4H), 2.68 (m, 1H), 4.38 (t, 1H), 5.00 (s, 2H), 6.72 (d, IH), 7.12-7.58 (m, 12H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:33][CH2:34][CH3:35])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:33][CH2:34][CH3:35])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 77.8 %

Procedure:
To a solution of ethyl [2-methyl-4-({propyl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)phenoxy]acetate (88 mg, 0.18 mmol) in MeOH (2 ml) and THF (2 mL) at room temperature was added 2M NaOH (1 mL, 2 mmol). The resultant solution was stirred for 1 h, then the solvents were removed in vacuo. The residue was diluted with HCl (10 mL) and extracted with CH2Cl2 (2×10 mL), followed by EtOAc (2×10 mL). The organic solutions were dried (MgSO4) and the solvents were removed in vacuo affording the title compound as a white crystalline solid (64.1 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>CN(C)C=O.[Cl-].[Li+]>[NH2:1][C:2]1[C:10]2[O:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C)Cc2cccc(N)c2O1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)Cc2c(Br)ccc(N)c2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.6 %

Procedure:
A stirred solution of 1.2 grams (0.005 mole) of 7-amino-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran in 50 mL of N,N-dimethylformamide was cooled in an ice-water bath, and 1.0 gram (0.005 mole) of N-bromosuccinimide was added. Upon completion of the addition, the reaction mixture was stirred at the ice-water bath temperature for about one hour and then allowed to warm to ambient temperature, where it stirred for about 18 hours. The reaction mixture was diluted with an aqueous 10% lithium chloride solution, and extracted with two portions of ethyl acetate. The combined extracts were washed with 50 mL of an aqueous 10% lithium chloride solution and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of 7-amino-4-bromo-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[N:14]=[C:13]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[NH4+].[Cl-]>CO.O.[Fe]>[F:30][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[C:13]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3cnccn3)nc(Nc3cccc(OC(F)F)c3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc2nc(-c3cnccn3)nc(Nc3cccc(OC(F)F)c3)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a mixture of N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl) quinazolin-4-amine (1.40 g, 3.4 mmol, 1.0 eq.) in MeOH-H2O (v/v, 3:1, 110 mL) was added NH4Cl (1.80 g, 34 mmol, 10.0 eq.) and Fe (1.91 g, 34 mmol, 10.0 eq.). The resulting mixture was stirred at 60° C. for 3 h. After the reaction was completed, the mixture was cooled to room temperature, and the iron was filtered off. The filtrate was concentrated to 15 ml, and a precipitate formed and was collected and dried in vacuo to give 1.13 g of N4-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamine as a pale yellow solid (87.5%). LCMS m/z=381.1 (M+1) (Method B) (retention time=1.60 min), 1H-NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 9.52 (d, J=1.2 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.30 (s, 1H), 7.87 (dd, J=8.4, 0.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.49-7.42 (m, 2H), 7.33-7.32 (m, 1H), 7.31 (t, J=7.4 Hz, 1H), 5.85 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](O)[CH:7]=C[C:9]=1[NH2:10])([O-])=O.[CH3:12][OH:13]>[Pd]>[OH:13][C:12]1[C:9]([NH2:10])=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1cccc(O)c1N
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-nitro-4-aminophenol (4.6 g, 30 mmol) in methanol is added 500 mg of Pd/C. A hydrogenation reaction is performed at room temperature for 2 hours and then terminated. The Pd/C is removed by filtration to obtain 4.1 g of 3-hydroxy-o-phenylenediamine, with a yield of 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[N:14]=[CH:13][O:12][N:11]=1.CCCCCC.C(O[CH:24](OCC)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)C>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH:24]=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[N:14]=[CH:13][O:12][N:11]=1
Reactant: Nc1ccccc1SCc1ncon1
Reactant: CCOC(OCC)c1ccc(OC)c(OC)c1
Solvent: CCCCCC
Product: COc1ccc(C=Nc2ccccc2SCc2ncon2)cc1OC

Procedure:
A solution of 3-(2-aminophenylthiomethyl)1,2,4-oxadiazole (4.2 g) in 3,4-dimethoxybenzaldehyde diethyl acetal (9.6 g) was heated under reflux for 30 minutes. On cooling and the addition of hexane yellow crystals precipitated. These were removed by filtration and re-crystallised from ethanol to give 3-[2-(3,4-dimethoxybenzylideneamino)phenylthiomethyl]-1,2,4-oxadiazole, m.p. 146°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([O-])(=O)C.[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35](OS(C(F)(F)F)(=O)=O)=[CH:34][CH:33]1[CH3:46])=[O:31])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(P([Pd-4](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)C=CC=CC=1.C(OCC)C.C1(C)C=CC=CC=1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)=[CH:34][CH:33]1[CH3:46])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Fc1cc(Br)c2occc2c1
Reactant: CC1C=C(OS(=O)(=O)C(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1C=C(c2cc(F)cc3ccoc23)CCN1C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 69.5 %

Procedure:
A flask purged of oxygen and under a nitrogen atmosphere was charged with 0.104 gm (0.482 mMol) 5-fluoro-7-bromobenzofuran, 0.184 gm (0.723 mMol) bis(pinacolato)di-boron, 0.0043 gm (0.0024 mMol) palladium(II) chloride, 0.016 gm (0.0029 mMol) 1,1′-bis(diphenylphosphino)ferrocene, 0.142 gm (1.45 mMol) potassium acetate, and 3 mL toluene. This mixture was heated at 90° C. for 5 hours and was then poured into 150 mL diethyl ether and filtered through a bed of celite. The filtrate was concentrated under reduced pressure to provide a dark residue. This material was dissolved in 3 mL tetrahydrofuran and the resulting solution purged of oxygen and placed under a nitrogen atmosphere. To this solution were added 0.028 gm (0.0024 mMol) tetrakis(triphenylphosphino)palladium(0), 0.153 gm (0.723 mMol) potassium phosphate, and 0.15 gm (0.434 mMol) 1-(tert-butoxycarbonyl)-2-methyl-4-trifluoromethylsulfonyloxy-1,2,5,6-tetrahydropyridine. The resulting mixture was stirred at reflux for 3.5 hours and was then charged with an additional 0.5 equivalents of 1-(tert-butoxycarbonyl)-2-methyl-4-trifluoromethylsulfonyloxy-1,2,5,6-tetrahydropyridine. The mixture was stirred at reflux for an additional 1.5 hours and was then poured into 150 mL diethyl ether. The mixture was filtered through a bed of celite and the filtrate concentrated under reduced pressure. The residue was dissolved in 2 mL dichloromethane and the solution was subjected to silica gel chromatography, eluting with a gradient of hexane containing 0-5% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.10 gm (62%) of the desired compound.
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:10]=[C:9]([O:11][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[F:1][CH:2]([F:20])[C:3]1[CH:10]=[C:9]([O:11][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[CH:8]=[CH:7][C:4]=1[C:5]1[NH:31][C:30]2[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=2[N:21]=1
Reactant: CC1(C)OC[C@H](COc2ccc(C=O)c(C(F)F)c2)O1
Reactant: Nc1cccc(C(=O)O)c1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc(-c3nc4c(C(=O)O)cccc4[nH]3)c(C(F)F)c2)O1
Temperature: 110 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a solution of (S)-2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzaldehyde (66; 1.83 g, 6.40 mmol) in DMF (150 ml) was added 2,3-diaminobenzoic acid (1; 0.97 g, 6.40 mmol), and Na2S2O5 (1.82 g, 9.60 mmol). The reaction mixture was stirred at 110° C. for 18 h. It was then cooled to room temperature and diluted with water. The resulting solids were collected by filtration and dried to afford (S)-2-(2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 67 as dark yellow solid (0.84 g, 51%). MS (ESI) calcd for C21H20F2N5O5: 418.13; found: 419 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1Br.[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: OB(O)C1=CCCCC1
Reactant: NC(=O)c1ccc(N)c(Br)c1
Product: NC(=O)c1ccc(N)c(C2=CCCCC2)c1
Yield: 76 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 11, step (e) using 4-amino-3-bromo-benzamide (as prepared in the previous step, 500 mg, 2.32 mmol), and cyclohexane-1-enyl boronic acid (322 mg, 2.56 mmol). The mixture was purified by trituration with DCM to afford the title compound (382 mg, 76%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C13H16N2O, 217.1 (M+H), found 217.2.
Reaction SMILES: C([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][C@H:24]3[C@:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)([CH2:23]3)[CH2:21]2)[C:10]1=[O:36])(=O)C1C=CC=CC=1>N.CO>[I:16][C:13]1[C:14](=[O:15])[NH:9][C:10](=[O:36])[N:11]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][C@H:24]3[C@:22]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=4)([CH2:23]3)[CH2:21]2)[CH:12]=1
Reactant: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c1=O
Agent: N
Solvent: CO
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
3-Benzoyl-5-iodo-1-{3-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-propyl}-1H-pyrimidine-2,4-dione (Prep 9, 840 mg, 1.38 mmol) was dissolved in 10% NH3 in MeOH solution (5 mL). The mixture was stirred at room temperature for 1 hour, the solvent was then evaporated under vacuum and the crude purified by flash chromatography with DCM-MeOH—NH4OH (98-2-1) to give the title compound as a white solid (515 mg).
Reaction SMILES: Br[C:2]1[CH:3]([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>C1C=CC=CC=1.CCO.O.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>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][CH:6]=1
Reactant: OCCC1CCC=C1Br
Reactant: OB(O)c1ccccc1F
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: O
Solvent: c1ccccc1
Solvent: CCO
Product: OCCC1CCC=C1c1ccccc1F
Temperature: 80 °C

Procedure:
2-(2-Bromo-cyclopent-2-enyl)-ethanol Intermediate FIVE1 (1.21 g, 6.33 mmol) in benzene (40 mL), and Na2CO3 (7 mL, 2M) was treated with a solution of 2-fluorophenylboronic acid (1.08 g, 7.72 mmol) in EtOH (28 mL). Tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4 (0.38 g, 5 mol %) was added and the mixture was heated to 80° C. for 1.5 h. The mixture was diluted with water and extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The oil was purified by column chromatography on silica gel with 30% EtOAc:hexane to give 2-[2-(2-fluoro-phenyl)-cyclopent-2-enyl]-ethanol Intermediate FIVE2 (1.21 g).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[S:16][CH:15]=1.[CH3:23][S:24]SC>C1COCC1>[Br:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[S:16][C:15]=1[S:24][CH3:23]
Reactant: CSSC
Reactant: Brc1csc2ncccc12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1sc2ncccc2c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (3.25 mL, 1.7M in hexanes, 5.2 mmol) was added to a cooled solution of diisopropylamine (0.74 mL, 5.2 mmol) in THF (15 mL) at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction was cooled to 0° C. and 3-bromothieno[2,3-b]pyridine (prepared by the method of Klemm L. H. et al., Journal of Heterocyclic Chemistry, 1974, 11(2), 205-209) (1 g, 4.7 mmol) added. After stirring for a further 20 minutes dimethyl disulphide (443 mg, 0.42 mL, 4.7 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with water, extracted into DCM, dried (sodium sulphate), filtered and concentrated in vacuo. Chromatography (silica; DCM) yielded the title compound as a pale yellow solid (850 mg). δH (DMSO-d6) 8.57 (1H, dd, J 4.7, 1.5 Hz), 8.00 (1H, m), 7.54 (1H, dd, J 8.1, 4.5 Hz), 2.70 (3H, m). LCMS (pH 3) RT 2.64 minutes, (ES+) 259/261 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:12]Br>CO>[Br:12][C:5]1[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[C:2]([OH:1])=[N:3][CH:4]=1
Reactant: BrBr
Reactant: Oc1ncccc1C(F)(F)F
Solvent: CO
Product: Oc1ncc(Br)cc1C(F)(F)F
Yield: 94.2 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine (10.0 g) and bromine (3.08 ml, 9.60 g) in methanol (50 ml) was stirred at 20° C. for 22 h. The solution was concentrated and the residue partitioned between ethyl acetate (400 ml) and water (100 ml). The layers were separated and the organic layer was washed with 5% Na2S2O3aq. (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated. Purified by Biotage SNAP cartridge KP-Sil column twice (100 g, heptane:ethyl acetate=1:0, 3:1 to 2:1) to give 13.69 g light yellow solid as 5-bromo-2-hydroxy-3-(trifluoromethyl)pyridine (95%).
Reaction SMILES: Cl[C:2]1[N:3]2[C:8]([CH:9]=[CH:10][CH:11]=1)=[C:7]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])[C:6](=[O:20])[CH:5]=[CH:4]2.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[N:3]2[C:8]([CH:9]=[CH:10][CH:11]=1)=[C:7]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])[C:6](=[O:20])[CH:5]=[CH:4]2
Reactant: OB(O)c1ccccc1Cl
Reactant: O=c1ccn2c(Cl)cccc2c1-c1c(Cl)cccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=c1ccn2c(-c3ccccc3Cl)cccc2c1-c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 42 %

Procedure:
To a solution of 6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (Example 1, 54 mg) in DME was added 2-chlorophenylboronic acid (31 mg), palladium acetate (3.5 mg), triphenylphosphine (8 mg) and 2N sodium carbonate (0.32 mL). The mixture was heated to 80° C. for 12 hrs, then cooled to room temperature, and diluted with ethyl acetate/saturated aqueous sodium bicarbonate. The organic layers were dried over magnesium sulfate and concentrated. The residue was purified by silica gel (methylene chloride/acetone=2/1) and recrystallized from methylene chloride/acetone/hexanes to give title compound as a yellowish solid (28 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([OH:19])=[N:12][CH:13]=[N:14]2
Reactant: COCCO
Reactant: O=c1[nH]cnc2cccc(F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCCOc1cccc2ncnc(O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxyethanol (0.528 ml, 6.70 mmol) in DMA (6 mL) was slowly added 514 mg of a 60% dispersion of NaH (0.308 g, 12.8 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. 5-Fluoroquinazolin-4(3H)-one (1.0 g, 6.09 mmol) was added and the reaction mixture was heated at 80° C. for 2 hours. The reaction was concentrated and the residue was suspended in EtOH (75 mL) and then filtered through GF/F paper. The filtrate was concentrated to afford the desired product as a yellow solid.
Reaction SMILES: CO.[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].C1(C(C2C=CC=CC=2)[N:16]2[CH2:19][C@@H:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C@@H:17]2[CH3:31])C=CC=CC=1.[OH-].[NH4+]>O>[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].[CH3:31][C@H:17]1[C@H:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=2)[CH2:19][NH:16]1
Reactant: C[C@H]1[C@H](Oc2cccc(C(F)(F)F)c2)CN1C(c1ccccc1)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Reaction time: 12 h
Yield: 122.4 %

Procedure:
A methanol-warm water solution of 33 g (0.068 mole) of trans-1-diphenylmethyl-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was treated with ammonium hydroxide until basic, then extracted with 4×150 ml of methylene chloride. The combined methylene chloride extracts were washed with water, dried over magnesium sulfate, and concentrated in vacuo to a pale yellow oil. This oil was dissolved in 200 ml of 190 ethanol plus 5 ml of triethylamine and hydrogenated on a Parr apparatus with 3.3 g of 5% palladium-on-charcoal catalyst with a 40 psi atmosphere of hydrogen at 70° C. for 12 hr. After the calculated amount of hydrogen had been absorbed, the catalyst was removed by filtration and the filtrate concentrated in vacuo to yield 26.73 g of crude product. An 8 g portion was converted to the oxalate salt in isopropyl alcohol yielding 6.1 g of fine white powder; m.p. 155°-156° C. Total yield extrapolated from the aliquot converted to the oxalate salt was 84% of theory.
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].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][N:28]=1.C([Mg]Cl)(C)C>C1COCC1>[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:30]3[CH:29]=[N:28][C:27]([Cl:26])=[CH:32][CH:31]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ccc(I)cn1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 275 mg (0.68 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 3 mL THF and 360 mg (1.51 mmol) of 2-chloro-5-iodo-pyridine in 2 mL THF with 0.79 mL 2M isopropylmagnesium chloride. Yield: 187 mg of a white powder. LC-MSD, m/z for C21H13BrClN3O2 [M+H]+=454.0, 456.0; HPLC retention time: 2.2 min.