Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[C@@H:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)(=[O:3])[CH3:2].[CH2:41]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:42]#[CH:43].C(N(CC)CC)C>C(Cl)Cl.[Cu]I>[C:1]([O:4][C@H:5]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:43]#[C:42][CH2:41][NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:15][CH:14]=2)[C@@H:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)(=[O:3])[CH3:2]
Reactant: C#CCNS(C)(=O)=O
Reactant: CC(=O)O[C@@H](CC[C@H]1C(=O)N(c2ccc(I)cc2)[C@@H]1c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(F)cc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H](CC[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 0.5 g (0.742 mmol, 1 equiv) (1S)-3-[(2S,3R)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-(4-iodophenyl)-4-oxoazetidin-3-yl]-1-(4-fluorophenyl)propyl acetate (intermediate of step A), 0.198 g (1.48 mmol, 2 equiv.) N-prop-2-yn-1-ylmethanesulfonamide (i-5), 0.086 g (0.074 mmol, 0.1 equiv.) tetrakistriphenylphosphine palladium(0) and 7 mg (0.04 mmol, 0.05 equiv) copper(I) iodide in 8 mL methylene chloride was deoxygenated by a slow stream of anhydrous nitrogen delivered by a needle through a rubber septum. To the resulting solution was added by syringe 1 mL (7.42 mmol, 10 equiv.) triethylamine. The resulting solution was stirred at room temperature for 4.5 hr at which time the mixture was partitioned 5 mL of a 5% aq. solution of citric acid. The mixture was transferred to a spearatory funnel and extracted with EtOAc (3×5 mL) and methylene chloride (2×5 mL) The combined organic extracts were dried over anhydrous Na2SO4 filtered and the solvent removed under vacuum. The residue was purified by prep. Tlc eluting with EtOAc/hexanes (4/1) followed by further purification by prep. Tlc eluting with EtOAc/hexanes (1/1) to afford the title compound. m/z (ES) 619.0 (M−HOAc+).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)[CH2:7][CH2:6]1)=[O:4]>CCO.C1COCC1>[CH3:1][N:2]([CH3:34])[C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)[C@H]1CC[C@H](n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)C1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1

Procedure:
Trimethylaluminium (1.50 mL; 3.0 mmol; 5.4 eq.) was added dropwise over 1 min to a solution of dimethylamine (2.50 mL; 5.0 mmol; 9.1 eq.) in DCE (50 mL) at 0° C. After 10 min, 4-(4-{2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid ethyl ester (prepared as described in example 62, step; 300 mg; 0.55 mmol; 1.0 eq.) in DCE (50 mL) was added dropwise over 5 min. The reaction solution was stirred for 16 h then a further portion of trimethylaluminium (10 mL; 20 mmol; 36 eq.) was added and the reaction solution refluxed for 4 h. The reaction mixture was then poured into ice-cold MeOH and concentrated under reduced pressure. The residue was redissolved in DCM, washed with 1 N HCl solution, Rochelle's salt solution and brine. Organic phase was finally dried over magnesium sulfate, filtered and concentrated to give the title compounds as a 3:1 mixture of cis and trans 4-(4-{2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide (165 mg; 60%) in the form of a beige solid. HPLC (Chiralpak IC, EtOH:THF 90:10): Rt 6.61; 10.38 min (purity 76, 24%); MS (ESI+): 456.4.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1>CCCCO>[C:12]([NH:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[C:3]=2[N:25]2[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)[NH:8][CH:9]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 78.4 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.190 g, 0.698 mmol), DIEA (0.365 mL, 2.10 mmol), and (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.390 g, 2.10 mmol) were placed in n-BuOH (2 mL) and heated to 135° C. for 8 hours. The reaction was then cooled to room temperature and concentrated to dryness. The residue was purified by silica gel chromatography (500:18 DCM:MeOH) to give (S)-tert-butyl 1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.240 g, 78% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]2[CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=[C:18]2[CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Cc1ccnc(N)c1
Product: Cc1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Yield: 19 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-4-methylpyridine instead of 2-amino-3-methylpyridine, to the title compound (22 mg, 19%) which was obtained as a yellow solid. MS: m/e=290.0 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:12]=1[C:13]([NH:15][CH3:16])=[O:14]>O.CO.[Zn]>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13](=[O:14])[N:15]([CH3:16])[NH:21]2
Reactant: CNC(=O)c1c(-c2ccc(C)cc2C)cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cccc3[nH]n(C)c(=O)c23)c(C)c1
Yield: 12 %

Procedure:
A solution of sodium hydroxide (0.035 g, 0.88 mmol) in water (2 ml) was added to a solution containing 0.095 g (0.33 mmol) of 2-(2,4-dimethylphenyl)-N-methyl-6-nitrobenzamide in methanol (1.5 ml). Zinc powder (0.03 g, 0.44 mmol) was then added to the mixture, which was heated under reflux for 24 h. After cooling, the zinc residue was separated by filtration and the methanol was partially evaporated. The residual solution was then adjusted to pH 7 with aqueous hydrochloric acid. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 40% ethyl acetate/hexanes gave 0.01 g (22%) of product.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([OH:13])=[O:12])[N:5]2[C:4](=[O:14])[NH:3]1.Cl.[CH3:16]O>>[O:1]=[C:2]1[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:16])=[O:12])[N:5]2[C:4](=[O:14])[NH:3]1
Reactant: CO
Reactant: O=C(O)C1C=CCn2c(=O)[nH]c(=O)n21
Agent: Cl
Product: COC(=O)C1C=CCn2c(=O)[nH]c(=O)n21
Yield: 74 %

Procedure:
In a manner analogous to that described in the first paragraph of Example 17, from 2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid and methanolic hydrogen chloride there was obtained in 74% yield methyl 2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo-[1,2-a]pyridazine-5-carboxylate of melting point 210°-213° C. (from methanol).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:23])=[CH:5][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ccc(Sc2cnc(N)s2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(S(=O)c2cnc(N)s2)cc1
Yield: 87.5 %

Procedure:
To a solution of 2-amino-5-(4-aminophenylthio)thiazole (4.0 g) in a mixture of chloroform (140 ml) and N,N-dimethylformamide (20 ml) was dropwise added the solution of 3-chloroperbenzoic acid (4.65 g) in chloroform (50 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 4 hours. The precipitates were collected by filtration, washed with 10% aqueous sodium bicarbonate and water. The solid was dried in vacuo to give 2-amino-5-(4-aminophenylsulfinyl)thiazole (3.75 g, yield: 87.5%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:22][CH:21]([CH3:23])[CH:20]=[C:19]([C:42]1[CH:43]=[C:38]([C:35](=[O:37])[CH3:36])[CH:39]=[CH:40][CH:41]=1)[C:11]1[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Yield: 56.2 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.0 mmol), 3-acetylphenylboronic acid (2.5 g, 15 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.42 g, 0.6 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated in a microwave at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×50 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (40 g, 10% ethyl acetate/petroleum ether) afforded 1-(3-(3-methyl-1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)phenyl)ethanone (1.5 g, 56.3%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 7.90 (dd, 1H, J1=7.8 Hz, J2=1.5 Hz), 7.81 (dd, 1H, J1=8.1 Hz, J2=1.8 Hz), 7.68-764 (m, 3H), 7.45-7.16 (m, 6H), 6.58 (s, 1H), 6.18 (d, 1H, J=10.2 Hz), 2.67-2.65 (m, 1H), 2.44 (s, 3H), 1.17-1.12 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc(F)c1
Yield: 81.7 %

Procedure:
The title compound (D44) (239.7 mg) was prepared according to the experimental procedure described in Description 40 starting from (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (D43) (200 mg, 0.993 mmol) and 3-Fluorophenol (0.089 ml, 0.993 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([I:25])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH:31][CH3:30])=[O:19])=[CH:20][C:21]([I:25])=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:26]([F:27])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(I)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 3 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Example 1, Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (15 mL) was added dropwise methylamine (2.0 M solution in THF, 1.4 mL, 2.8 mmol) and the reaction mixture was stirred for 3 hours, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure and the residual solid was purified by chromatography on silica gel to afford 400 mg of the title compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[SH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>O>[S:21]1[C:2]2=[CH:3][N:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[C:22]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CS
Reactant: O=Cc1ccncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccncc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a 50-mL round-bottom flask was added 3-fluoro-4-pyridinecarboxaldehyde (0.8 mL, 8.02 mmol) and N,N-dimethylformamide (14 mL) and the solution was cooled to 0° C. To this solution was added potassium carbonate (1.22 g, 8.828 mmol) and methyl 2-mercaptoacetate (0.754 mL, 8.427 mmol). The solution turned to a clear yellow solution after stirring for 10 min. After 30 min at 0° C., the reaction was warmed to room temperature and stirred over the weekend by which time a solid precipitate was formed. Water was added provide a homogeneous solution, which was cooled to 0° C., the solid was collected via vacuum filtration, and washed with cold water until clear and colorless affording methyl thieno[2,3-c]pyridine-2-carboxylate (1.55 g, 82%) as a white solid. LCMS: (FA) ES+ 194; 1H NMR (d6-DMSO, 300 MHz) δ9.37 (s, 1 H), 8.56 (d, J=5.4 Hz, 1 H), 8.26 (d, J=0.6 Hz, 1 H), 7.97 (dd, J=5.4 Hz, 1.2 Hz, 1 H), 3.92 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[C:7]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:6]=2.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[C:7]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-methyl-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.20 g, 2.83 mmol), NBS (0.656 g, 3.68 mmol), and diphenylperoxyanhydride (0.069 g, 0.283 mmol) in carbon tetrachloride (20 mL) was heated to 100° C. and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to afford methyl 3-(bromomethyl)-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used directly in the next step without further purification. MS (m/z) 504.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc3ccccc3nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
First, 3.71 g of 4,4′-difluorobenzil and 1.71 g of o-phenylenediamine were stirred on heating in a solvent (200 mL of chloroform) for 6 hours. The reaction solution was cooled to room temperature, washed with HCl (1N) and a saturated aqueous solution of sodium chloride, and dried with magnesium sulfate. The solvent was removed to obtain a ligand HFdpq (2,3-bis(4-fluorophenyl)quinoxaline) (pale yellow powder, yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][O:17]C3CCCCO3)[N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]=[C:12]([CH2:14][CH2:15][CH2:16][OH:17])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cc(CCCOC3CCCCO3)ncn2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: OCCCc1cc(-c2ccc(Cl)cc2)ncn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
3.22 g (9.67 mmol) of 4-(4-chlorophenyl)-6-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]pyrimidine, prepared in stage 5.3., are dissolved in 32 ml of methanol, and 16 ml of a 4N solution of hydrochloric acid in dioxane are added. The mixture is stirred at ambient temperature for 1.5 hours and then 150 ml of a half-saturated aqueous sodium hydrogencarbonate solution are added portionwise. Extraction is carried out with 350 ml of ethyl acetate. The organic phase is washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to produce 2.33 g (9.36 mmol) of product in the form of a white solid.
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([N:11]([CH2:19][CH3:20])[C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)[CH3:10].[CH2:21]([O:23][C:24]([C:26]1[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([NH2:36])[S:28][C:27]=1[NH2:37])=[O:25])[CH3:22]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:21]([O:23][C:24]([C:26]1[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([N:36]=[CH:17][C:15]2[S:16][C:12]([N:11]([CH2:19][CH3:20])[CH2:9][CH3:10])=[CH:13][CH:14]=2)[S:28][C:27]=1[NH2:37])=[O:25])[CH3:22]
Reactant: CCN(CC)c1ccc(C=O)s1
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(N)sc(N=Cc2ccc(N(CC)CC)s2)c1C(=O)OCC
Yield: 67 %

Procedure:
In a 50 mL round bottom flask, 67 mg of 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester was dissolved in 20 mL of anhydrous toluene to which was subsequently added 1,4-diazabicyclo[2.2.2]octane (DABCO, 32 mg), 286 μL of titanium(IV) chloride, 1.0M solution in toluene at 0° C. and 5-diethylamino-thiophene-2-carbaldehyde (52 mg). The mixture was refluxed for two hours and the solvent removed. Purification by flash chromatography (SiO2) yielded the title product as a yellow-orange solid (67%). 1H-NMR (300 MHz, [D] acetone): δ=7.96 (s, 1H), 7.23 (s, 2H), 7.21 (d, 1H, 3J=4.4 Hz), 5.93 (d, 1H, 3J=4.2 Hz), 4.27 (q, 2H, 3J=7.2 Hz), 4.17 (q, 2H, 3J=7.1 Hz), 3.43 (q, 4H, 3J=7.1 Hz), 1.35 (t, 3H, 3J=7.1 Hz), 1.24 (t, 3H, 3J=7.1 Hz), 1.21 (t, 3H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=164.5, 162.3, 159.3, 146.9, 135.7, 125.5, 124.5, 102.2, 101.7, 60.7, 59.7, 47.3, 14.2, 14.1, 12.0.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:13][CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)=[O:18]
Reactant: NCCC#Cc1cccc(CF)n1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: O=C(NCCC#Cc1cccc(CF)n1)c1c(Cl)cccc1Cl
Yield: 27.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39 mg, 0.22 mmol) and 2,6-dichlorobenzoyl chloride (60 mg, 0.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 21 mg (0.06 mmol, 27%) of 2,6-dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([OH:26])[C:22]([N+:23]([O-:25])=[O:24])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:26][CH3:28])[C:22]([N+:23]([O-:25])=[O:24])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(O)cc(c23)C(=O)N1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc2c3c(cccc3c1[N+](=O)[O-])C(=O)N(OCc1ccccc1)C2=O
Yield: 75.5 %

Procedure:
Methylation of 2-benzyloxy-5-hydroxy-6-nitro-benzo[de]isoquinoline-1,3-dione (0.24 g, 0.7 mmol, from Example V) was accomplished following the procedure of Example J using potassium carbonate (0.3 g, 2.2 mmol), and dimethyl sulfate (0.3 g, 2.1 mmol) in acetone (40 mL) to give 0.2 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](C(OCC)=O)=[N:10]2)=[CH:5][CH:4]=1.[OH-].[K+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(OC)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Yield: 142.5 %

Procedure:
To a solution 1-[(4-methoxy)phenyl]-3-(ethoxycarbonyl)-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide (2.05 g, 4.43 mmol) in 10 mL of THF and 10 mL of water was added potassium hydroxide (0.32 g, 5.76 mmol). The resulting solution was stirred at ambient temperature for 18. The THF was removed in vacuo and the aqueous was extracted with ether to remove unreacted ester. The aqueous layer was acidified with HCl and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated to afford 1.1 g (57%) of the title compound, which was used without further purification. LRMS (ES-): 433.0 (M-H)-.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]12([NH2:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.O>N1C=CC=CC=1>[C:14]12([NH:24][C:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:12])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Reaction time: 0.5 h

Procedure:
2-Quinoxaloyl chloride (0.84 g, 4.4 mmol) was added to a solution of 1-adamantanamine (0.60 g, 4.0 mmol) in pyridine (10 mL). The reaction was then stirred for 30 min. To the stirring reaction mixture was added water (100 mL) which caused the product to precipitate. This precipitate was filtered, washed with water (3×25 mL), and dried under high vacuum for 16 h. This provided 1.00 g (82%) of (91):