Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:5]1=[O:34])[CH:2]=[CH2:3].[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(C(C)C)CC)(C)C>ClCCCl.O>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:27][CH2:28][N:29]([S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])[CH2:30][CH2:31]2)[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCNCC2)C1=O
Reactant: O=S(=O)(Cl)C1CC1
Solvent: O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCN(S(=O)(=O)C3CC3)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one (Example 95, Step B) (60 mg, 0.117 mmol) in DCE (1.2 mL) was added cyclopropanesulfonyl chloride (23.76 μL, 0.233 mmol) followed by diisopropylethylamine (40.6 μL, 0.233 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with saturated NaCl solution (10 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[C@@H:9]([CH2:16][C:17]([NH:19][CH2:20][C:21]#[N:22])=[O:18])[O:8][C@H:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:6]=2[CH:30]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[C@@H:9]([CH2:16][C:17]([NH:19][CH2:20][C:21]3[NH:33][N:32]=[N:31][N:22]=3)=[O:18])[O:8][C@H:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:6]=2[CH:30]=1
Reactant: CC(C)N1C(=O)[C@@H](CC(=O)NCC#N)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)N1C(=O)[C@@H](CC(=O)NCc2nnn[nH]2)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
Trans-7-chloro-5-(2-chlorophenyl)-3-(cyanomethylaminocarbonylmethyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine and sodium azide were subjected to the same procedure as in Example 102 to yield a crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Yield: 47.3 %

Procedure:
A mixture of 7-chloro-2-(5-nitrobenzofuran-2-yl)-quinoline (1.7 g), 10% aqueous hydrochloride (20 ml) and tin(II) chloride bihydrate (4.0 g) in ethanol (10 ml) was stirred mechanically under reflux for 7 hours. After being cooled, the resulting mixture was made basic with aqueous sodium hydroxide and filtered. The precipitates were dissolved into tetrahydrofuran (100 ml) and filtered. The filtrate was concentrated under reduced pressure to give crude materials, which were purified by column chlomatography to give 7-chloro-2-(5-aminobenzofuran-2-yl)quinoline (0.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:36])[O:11][C:12]2[C:17]([C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[CH:16][CH:15]=[C:14]([OH:34])[C:13]=2I.[C:37]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:36])[O:11][C:12]2[C:17]([C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[CH:16][CH:15]=[C:14]([OH:34])[C:13]=2[CH3:37]
Reactant: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(O)ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(Cl)cc3Cl)c(=O)oc12
Temperature: 25 °C

Procedure:
A mixture of 3-(2,4-dichlorophenyl)-7-hydroxy-8-iodo-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-chromen-2-one (1.85 g, 2.91 mmol), K2CO3 (1.21 g, 8.75 mmol), trimethylboroxine (427 μL, 3.05 mmol) and Pd(Ph3P)4 (336 mg, 0.29 mmol) in anhydrous dioxane (22 mL) was stirred at reflux temperature for 2.5 h. After cooling the resultant green suspension to room temperature, the solvent was removed in vacuo. The resultant residue was dissolved in CH2Cl2, and the organic layer was washed with H2O and brine, dried (MgSO4) concentrated in vacuo. The resultant residue was purified using flash chromatography (125 g silica gel, 8:0.5:0.5→7:0.5:0.5 CH2Cl2:MeOH:AcOEt→9:1 CH2Cl2:MeOH) to afford a yellow solid that was further purified using reverse phase HPLC (followed by an extraction with CH2Cl2/NaHCO3). The title compound was isolated as a yellow solid (220.4 mg, 14%). 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=2.0 Hz, 1H), 7.24 (dd, J=2.0, 8.0 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 1H), 6.72 (d, J=8.8 Hz, 2H), 4.23 (t, J=5.0 Hz, 2H), 4.00 (d, J=15.5 Hz, 1H), 3.74 (d, J=15.5 Hz, 1H), 3.24 (t, J=5.0 Hz, 2H), 3.15–3.04 (m, 4H), 2.20 (s, 3H), 2.05–1.93 (m, 4H); MS (ESI) m/z 523.8 (M)+; HPLC tR 4.74 min.
Reaction SMILES: [CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17]C(NC(CCl)=O)=O)[C@H:10]1[O:25][CH3:26])[CH3:8].[N+]1([O-])C=CC=CC=1.[Na].COC1C=CC(C(C2C(=O)NC(=S)N(C3C=CC(Cl)=CC=3)C=2[O-])C2C(=O)NC(=S)N(C3C=CC(Cl)=CC=3)C=2O)=CC=1C[NH+]1C(C2C=CC=NC=2)CCCC1>>[CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:25][CH3:26])[CH3:8]
Reactant: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Agent: COc1ccc(C(c2c([O-])n(-c3ccc(Cl)cc3)c(=S)[nH]c2=O)c2c(O)n(-c3ccc(Cl)cc3)c(=S)[nH]c2=O)cc1C[NH+]1CCCCC1c1cccnc1
Agent: [Na]
Agent: [O-][n+]1ccccc1
Product: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 148.3 %

Procedure:
In the same manner as in Example 42, O-chloroacetylcarbamoylfumagillol (144 mg) was reacted with sodium pyridine-N-oxide-2-thiolate (60 mg) with stirring at room temperature for 10 minutes. Purification by silica gel column chromatography (eluent: chloroform-methanol=20:1) gave colorless, powdery O-C(pyridine-N-oxide-2-yl)thioacetylcarbamoyl]fumagillol (150 mg) (85% yield). 1H-NMR (CDCl3) δ: 1.07 (1H, m), 1.21 (3H, s), 1.65 (3H, s), 1.74 (3H, s), 1.8-2.4 (EH, m), 2.55 (1H, d, J=4.4 Hz), 2.57 (1H, t, J=6.4 Hz), 2.98 (1H, d, J=4.4 Hz), 3.46 (3H, s), 3.68 (1H, dd, J=11.4 Hz, J=2.6 Hz), 3.94 (1H, d, J=15.4 Hz), 4.13 (1H, d, J=15.4 Hz), 5.19 (1H, m), 5.60 (1H, m), 7.1-7.35 (2H, m), 7.50 (1H, d, J=7.2 Hz), 8.33 (1H, d, J=6.2 Hz), 9.29 (1H, br s).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[OH:12][CH2:13][C:14]([NH:16][CH2:17][CH:18]([OH:33])[CH2:19][O:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([C:28](=[NH:31])[NH:29]O)=[CH:23][C:22]=1[CH3:32])=[O:15]>>[CH:1]([C:3]1[S:7][C:6]([C:8]2[O:10][N:31]=[C:28]([C:24]3[CH:23]=[C:22]([CH3:32])[C:21]([O:20][CH2:19][CH:18]([OH:33])[CH2:17][NH:16][C:14](=[O:15])[CH2:13][OH:12])=[C:26]([CH3:27])[CH:25]=3)[N:29]=2)=[CH:5][C:4]=1[CH3:11])=[O:2]
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Reactant: Cc1cc(C(=O)O)sc1C=O
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)sc1C=O

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.90 min; [M+1]+=446.15; 1H NMR (D6-DMSO): δ 2.34 (s, 6H), 2.65 (s, 3H), 3.19-3.28 (m, 1H), 3.39-3.48 (m, 1H), 3.70-3.81 (m, 2H), 3.83 (d, J=5.8 Hz, 2H), 3.92-3.99 (m, 1H), 5.29 (d, J=5.5 Hz, 1H), 5.55 (t, J=6.0 Hz, 1H), 7.69 (m, 1H), 7.75 (s, 2H), 8.07 (s, 1H), 10.17 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:6]([CH:25]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=2[F:24])[CH2:11][CH2:10]1)=[O:8].C([Sn](CCCC)(CCCC)[C:37]([O:39]CC)=[CH2:38])CCC.Cl>C1(C)C=CC=CC=1.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>[C:37]([C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[C:6]([CH:25]=1)[C:7]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=2[F:24])[CH2:13][CH2:14]1)=[O:8])(=[O:39])[CH3:38]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(Br)ccc3N3CCOCC3)CC2)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(C)=O)ccc3N3CCOCC3)CC2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a suspension of 1-{4-[4-(5-Bromo-2-morpholin-4-yl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone (160 mg, 0.33 mmol) in toluene (2 ml) were added PdCl2(PPh3)2 (5 mg, 0.0065 mmol) and tributyl(1-ethoxyvinyl) tin (125 ul, 0.36 mmol). The mixture was heated to 100° C. for 6 hours. The mixture was cooled in an ice bath and 2N HCl (0.55 ml) was added. The mixture was stirred at room temperature overnight. The mixture was filtered. The organic layer was separated and 10% aqueous KF solution was added. The mixture was stirred at room temperature for 3 hours and filtered. The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude gum was chromatographed on silica gel, eluent: heptane/ethylacetate 0%-50% (10 minutes) to provide the title compound (15 mg, 10%) as a white solid MS (m/e): 454.2 (M+H, 100%).
Reaction SMILES: [C:1]1([S:7][CH2:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([O-:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CN(C)C=O>[O:16]([CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [O-]c1ccccc1
Reactant: ClCSc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OCSc2ccccc2)cc1
Yield: 77.1 %

Procedure:
A solution of 47.5 g (0.3 mol) of chloromethyl phenyl sulphide in 50 ml of dimethylformamide was added dropwise to a solution of 40 g (0.34 mol) of sodium phenolate in 200 ml of dimethylformamide at room temperature in the course of 30 minutes, while stirring. The temperature of the reaction mixture thereby rose from 24° C. to 35° C. The mixture was subsequently stirred at room temperature for 14 hours and then concentrated by stripping off the solvent under reduced pressure. The oil which remained was washed successively with water, 0.1N aqueous sodium hydroxide solution and water and, after drying sodium sulphate, subjected to fractional vacuum distillation. 50 g (77.2% of theory) of phenoxy-phenylthiomethane were obtained in this manner in the form of a colourless liquid of boiling point 112°-117° C./0.16 mm Hg.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[NH:10][C:9](=[O:18])[C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[OH-].[Li+]>O1CCCC1>[C:3]([CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[NH:10][C:9](=[O:18])[C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:4])=[O:2]
Reactant: COC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
A solution of 4-methoxycarbonylmethoxy-7-chloro-3-phenyl-2(1H)-quinolone (Example 14) (0.13 g) in 50 ml tetrahydrofuran was stirred at room temperature for 30 mins with lithium hydroxide (18.2ml, 0.5M solution). The solvent was removed in vacuo and the residue was dissolved in water and acidified to pH1 (1 N HCl). The precipitate was collected by filtration to give the title compound, 23 mg; mp 269°-272° C. (propan-2-ol then DMF-water); Found: C, 61.63; H, 3.61; N, 4.60.C17H12NO4Cl requires C, 61.92; H, 3.69; N, 4.25%. δ (360 MHz, DMSO-d6) 4.05 (2H, s, OCH2), 7.29 (1H, dd, J=2.7, 8.7 Hz, 6-H), 7.35-7.47 (6H, m, Ar +8-H), 8.07 (1H, d, J=8.7 Hz, 5-H), 11.68 (1H, s, NH). m/z (CI-) 328 (M-1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1>C(C#N)(C)=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:22]([CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[N:23]=[CH:24]3)[N:7]=1
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Reactant: Clc1ncnc(Cl)n1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccn3)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of the compound 2,4-dichloro-1,3,5-triazine (267 mg, 1.78 mmol) and solid K2CO3 (1.23 g, 8.42 mmol) was suspended in AcCN (20 mL) under nitrogen at 0° C. followed by addition of a solution of 1-pyridin-2-ylmethyl-1H-indazol-5-ylamine (Step 3) (400 mg, 1.78 mmol) in AcCN (3 mL) over 5 min. The mixture was stirred at 0° C. for 1 h. The reaction was quenched by pouring onto water. The organics were extracted into EtOAc (200 mL), washed with brine, dried over anh. Na2SO4, concentrated under reduced pressure then purified by column chromatography (elution with EtOAc followed by 9:1 CH2Cl2/MeOH) to give (4-chloro-[1,3,5]triazin-2-yl)-(1-pyridin-2-ylmethyl-1H-indazol-5-yl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]2[O:28][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cc(F)ccc3F)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21

Procedure:
Analogously to Method D, 1.09 g of tert-butyl 4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.720 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as slightly yellowish oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [N:1]([C:4]1[NH:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][C:22]3[CH:27]=[C:26]([C:28]#[N:29])[N:25]=[C:24]([Cl:30])[CH:23]=3)[C:15]=2[F:31])=[O:11])=[C:7]([Cl:9])[N:8]=1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCOC(C)=O>[NH2:1][C:4]1[NH:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][C:22]3[CH:27]=[C:26]([C:28]#[N:29])[N:25]=[C:24]([Cl:30])[CH:23]=3)[C:15]=2[F:31])=[O:11])=[C:7]([Cl:9])[N:8]=1
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N=[N+]=[N-])nc3Cl)c2F)cc(Cl)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Cl)c2F)cc(Cl)n1
Yield: 44.8 %

Procedure:
The title compound was prepared in a similar manner to that described herein using 2-azido-4-chloro-N-({4-chloro-3-[(2-chloro-6-cyano-4-pyridinyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (123 mg, 0.255 mmol), a catalytic amount of Lindlar catalyst in EtOAc (15 ml) under H2 (50 psi) to afford the title compound as a white powder (52 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (1H, s) 7.98 (1H, d) 7.78 (1H, t) 7.59 (1H, d) 7.53 (1H, d) 7.39 (1H, t) 5.83 (2H, s) 4.50 (2H, d). LCMS: m/z 455 (M+1).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[NH:17][CH:18]=[CH:19][N:20]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].CO>[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[NH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(-c3ncc[nH]3)o2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2ccc(-c3ncc[nH]3)o2)cc1

Procedure:
A mixture of 17 g (0.057 mole) of the compound of Example I, 200 ml of CH3OH and 1 teaspoon of 5% Pd/C (50% H2O) was shaken on a Parr apparatus with the theoretical amount of hydrogen being absorbed. The mixture was heated to reflux and CH3OH added to dissolution. The catalyst was removed by filtration and the filtrate cooled and diluted with ether. The resulting solid was recrystallized from anhydrous methanol and dried at 110° to yield 7 g (46%). An analytical sample was prepared by drying a sample in the vacuum pistol at the temperature of refluxing dimethylformamide, m.p. 242°-245°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=O)[C:9]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c2ccccc2[nH]c1=O
Product: CCOC(=O)c1c(Cl)nc2ccccc2c1-c1ccc(F)cc1

Procedure:
Ethyl 4-(4-fluorophenyl)-1,2-dihydro-2-oxo-3-quinolinecarboxylate (12.8 g) is dissolved in 40 ml of phosphorus oxychloride under an atmosphere of nitrogen. The resulting solution is refluxed one hour, cooled, concentrated, and the residue neutralized with cold 1N sodium hydroxide solution and extracted with ethyl acetate. The organic extracts are filtered through a bed of silica to give 13.2 g of ethyl 2-chloro-4-(4-fluorophenyl)-3-quinolinecarboxylate as a white solid; mp 113°-114° C.; 1H NMR (chloroform-d): δ 8.02 (d, 1H), 7.75-7.70 (m, 1H), 7.52-7.43 (m, 2H), 7.34-7.28 (m, 2H), 7.20-7.12 (m, H), 4.14-4.07 (q, 2H), 1.02 (t, 3H) ppm.
Reaction SMILES: [S:1]1[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:5]3[CH2:4][CH2:3][CH2:2][S:1][CH2:8][CH2:7][C:6]=3[C:15]=2[CH:14]=1
Reactant: O=C1CCCSCCC1
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)CCSCCC3
Reaction time: 5 h

Procedure:
A mixture of 14.42g (0.1 mole) of 1-thiacyclooctane-5-one, 17.46g (0.1 mole) of p-methoxyphenylhydrazine hydrochloride and 8.21g (0.1 mole) of anhydrous sodium acetate in 170 ml of acetic acid is refluxed with stirring for five hours under nitrogen. The mixture is cooled and poured into 1 liter of water. On standing there is deposited a solid which after washing with water and recrystallization from methanol, gives 18.1g (74%) of an analytical sample, m.p. 122.5°-123.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[O:5]1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>C1COCC1>[Si:18]([O:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[O:5]1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1OC(CCO)c2ccccc21
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC1OC(=O)c2ccccc21
Reaction time: 8 h

Procedure:
3-(2-hydroxyethyl)-3H-isobenzofuran-1-one (1.03 g, 5.781 mmol) dissolved in THF (10 mL) under N2 and TBDMSCl (958.4 mg, 6.359 mmol) then imidazole (472.3 mg, 6.937 mmol) added at RT. Reaction mixture stirred overnight then concentrated. Residue partitioned between EtOAc and water. Aqueous phase extracted with EtOAc and combined organics dried and concentrated. Residue purified by chromatography (silica, 0-100% EtOAc-petrol gradient elution). Title compound obtained as a colourless oil (1.47 g, 87%), 1H NMR (400 MHz, DMSO) 0.00 (3H, s), 0.01 (3H, s), 0.83 (9H, s), 1.76-1.85 (1H, m), 2.23-2.31 (1H, s), 3.71-3.80 (2H, m), 5.66 (1H, dd), 7.57 (1H, t), 7.68 (1H, d), 7.75 (1H, dt), 7.81 (1H, d); MS (ES+) 293.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH2:7].[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:17]=[N:18][CH:19]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1cc(CN)cc(OC)c1
Product: COc1cc(CNc2cncc(Cl)n2)cc(OC)c1
Yield: 91 %

Procedure:
In a procedure analogous to Example 21, reaction of 3,5-dimethoxybenzylamine and 2,6-dichloropyrazine furnished the product (91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[C:22]([O:26][C:27](=[O:28])[NH:29][C@@H:30]([C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 110.7 %

Procedure:
Preparation of example 118 from the title compound of Example 7 (hydrochloride) (43 mg, 0.138 mmol), (R)-tert-butoxycarbonylamino-3-phenyl-propionic acid (44 mg, 0.166 mmol), triethylamine (0.058 mL, 0.414 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.166 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (80 mg) as a yellow powder contaminated with an unknown impurity. The compound was carried on without further purification to Example 115.