Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=O)[CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:7](=O)[CH2:6]1)=[O:4].[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl>CO>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:7]2[CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:11]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=3)[CH2:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(Nc2ccc(F)cc2)CC(C(=O)OC)=C(Nc2ccc(F)cc2)C1
Yield: 181.6 %

Procedure:
Dimethyl 1,4-cyclohexanedione-2,5-dicarboxylate (9.12 gm; 40 mmol) and methanol (200 ml) were heated to boiling, then 4-fluoroaniline (8.35 ml (9.78 gm); 42 mmol) was added followed by conc. hydrochloric acid (400 μl). The mixture was refluxed for 3 hours under a nitrogen atmosphere. On cooling a yellow solid precipitated out which was collected by filtration, washed with methanol and dried under vacuum to give 15.8 gm (96%) of dimethyl 2,5-bis{(4-fluorophenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.B(Br)(Br)Br.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: COc1cccc(Cl)c1CSc1nc(C)cc(O)n1
Agent: BrB(Br)Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)nc(SCc2c(O)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
In a 250 mL round bottom flask, 2-{[(2-chloro-6-methoxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (200 mg, 0.67 mmol) was dissolved in DCM (10 mL). BBr3 (1.42 mL, 1.42 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. Water (5 mL) was added, followed by Na2SO4 (20 g) and DCM (100 mL) after 5 minutes. The solution was filtered and evaporated. The crude product was purified by column chromatography to provide the title compound as a white solid (180 mg, 95% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.06 (s, 3H), 4.48 (s, 2H), 6.02 (br, 1H), 6.83 (d, 1H), 6.93 (d, 1H), 7.15 (t, 1H), 10.44 (br, 1H); M+ 283.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([O:9][CH2:7][C:6]1[CH:10]=[CH:2][CH:3]=[CH:4][CH:5]=1)=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1cc(F)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 10.5 g (67.3 mmol) 5-fluoro-2-hydroxybenzoic acid and 37.1 g (269 mmol) fine mesh K2CO3 in 250 mL of acetone was added 18.0 μL (151.2 mmol) benzyl bromide and the resulting mixture was refluxed for 5 h. After cooling to room temperature, the solids were filtered off, the filtrate was concentrated, loaded onto a silica gel column, and eluted with EtOAc/hexanes to provide 3-1 as a white solid. Data for 3-1: 1HNMR (500 MHz, CDCl3) δ 7.55 (m, 1H), 7.4-7.3 (m, 10H), 7.1 (m, 1H), 6.95 (m, 1H), 5.35 (s, 2H), 5.1 (s, 2H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:11]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 97.1 %

Procedure:
3-Nitro-phenol (1.00 g, 7.189 mmol) was treated with benzyl bromide (1.352 g, 7.91 mmol), and K2CO3 (1.242 g, 8.986 mmol) in DMF. The reaction mixture was heated to 100° C. for 1 hr at which time the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (1.6 g, 97%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([F:26])[CH:17]=2)=[CH:9][C:8]=1[CH3:27])[CH2:2][CH3:3].C=O.[C:31]([BH3-])#N.[Na+].O>CO>[CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[C:18]([F:26])[CH:17]=2)[CH3:31])=[CH:9][C:8]=1[CH3:27])[CH2:2][CH3:3]
Reactant: CCCOC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)c(F)c2)cc1C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOC(=O)Nc1c(C)cc(N(C)Cc2ccc(C(F)(F)F)c(F)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
[4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl ester (4f, 22 mg) and formaldehyde (0.1 mL) were refluxed in methanol (1 mL) for 3 hours. Sodium cyanoborohydride (35 mg) was added and the reaction mixture was stirred for 16 hours at 25° C., followed by addition of water (3 mL). The product was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with brine (5 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was subjected to preparative LC-MS purification to furnish 9.7 mg (43% yield) of the title compound as a solid. LC-MS (m/z) 413 (MH+); tR=3.68, (UV, ELSD) 88%, 96%.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([N:24]([CH3:23])[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CNS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C1CN(C(c2ccccc2)c2ccccc2)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (WO 96/05193) (1.4 g) in dioxane (25 mL) were added N-methyl benzenesulphonamide (1.2 g) and caesium carbonate (2.6 g). The reaction mixture was heated to reflux for 3 h, then cooled to room temperature. Water (20 mL) was added to the resulting slurry, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organics were washed with brine, dried over magnesium sulphate, filtered and dried in vacuo to yield crude product. Chromatography on silica gel eluting with ethyl acetate:hexanes (2:3 by volume) yielded the title compound as a white foam (1.31 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:19][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: Cc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: BrCc1ccc2nccnc2c1
Yield: 77.5 %

Procedure:
To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCL4 (80 mL) was added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling, the mixture was evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (50 mL×5). The extracts were concentrated under vacuum. The organics were combined and concentrated to give crude 6-bromomethylquinoxaline (12.0 g), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.85-8.87 (m, 2H), 8.10-8.13 (m, 2H), 7.82 (dd, J=2.1, 8.7 Hz, 1H), 4.70 (s, 2H).
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH2:20])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>O1CCOCC1>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH:20][S:37]([CH3:36])(=[O:39])=[O:38])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8]
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)N1c2cc(NS(C)(=O)=O)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Pyridine (4.07 μL, 0.050 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.010 g, 0.025 mmol) in 1,4-dioxane (200 μL). Methanesulfonyl chloride (1.96 μL, 0.025 mmol) was added, and the mixture stirred at rt for 18 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with 1 N aqueous HCl, and the organic phase was separated and concentrated to afford isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-(methylsulfonamido)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.0087 g, 73% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.16 (m, 6 H), 1.18-1.36 (m, 8H), 2.30 (s, 3 H), 2.99 (s, 3 H), 3.58-3.80 (m, 2 H), 3.84-3.99 (m, 1 H), 4.99-5.08 (m, 1 H), 6.85 (br s, 1 H), 7.49-7.50 (m, 1 H), 7.71 (d, J=4.40 Hz, 2 H), 7.97 (br s, 1 H). MS (ESI, pos. ion) m/z 476 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: OB(O)c1ccco1
Reactant: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(-c3ccco3)cc2C1=CNc1ccc(CN2CCCC2)cc1
Temperature: 150 °C

Procedure:
To a suspension of 6-bromo-4-[(4-pyrrolidin-1-ylmethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (40 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) is added 2-furanboronic acid (11.2 mg, 0.1 mmol), followed by 60 μL of 2M aqueous cesium carbonate and tetrakis triphenylphosphine palladium (6 mg, 0.005 mmol). The reaction mixture is subjected to microwave heating at 150° C. for 100 seconds. The reaction mixture is then diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield Example 169.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]1[CH2:14][N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=2[NH:10][C:9]1=[O:29])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]1[C:9](=[O:29])[N:10]([CH2:37][C:38]([F:41])([F:40])[F:39])[C:11]2[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=2[N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Yield: 86 %

Procedure:
In an analogous manner to that described in Example 2a), the alkylation of the [(S)-1-(2-benzyloxy-ethyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester with 2,2,2-trifluoroethyl trifluoromethanesulphonate using lithium bis(trimethylsilyl)amide (1M solution in tetrahydrofurane) as the base yielded title compound as a white foam (yield 86% of theory); MS (m/e): 494 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.[CH3:14][C:15](OC(C)=O)=[O:16]>>[CH3:12][C:8]1([CH3:13])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:15](=[O:16])[CH3:14])[S:3][C:4]=2[C:10](=[O:11])[CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Product: CC(=O)Nc1nc2c(s1)C(=O)CC(C)(C)C2
Temperature: 25 °C
Yield: 75 %

Procedure:
2-Amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one (40.5 g, 0.206 mol) and Ac2O (400 mL) are heated at 100° C. for 4 h. After cooling to RT, the reaction mixture is concentrated in vacuo. The precipitated solid is collected by filtration and affords N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (36.5 g, 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[O:16][CH3:17].[N+:19]([O-])([OH:21])=[O:20].O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COC(=O)CCCOc1ccc(C=O)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of the aldehyde 11 (50 g, 0.197 mol) in acetic anhydride (150 mL) was slowly added to a mixture of 70% nitric acid (900 mL) and acetic anhydride (200 mL) at 0° C. and was then left to stir for 2.5 hours at 0° C. The solution was then poured onto ice in a 5 L flask and the volume adjusted to 5 L with ice and water. The resulting light sensitive pale yellow precipitate was immediately filtered (the ester is slowly hydrolysed at room temperature in those conditions) and washed with cold water. The product 12 was used directly in the next step. TLC analysis (50/50 EtOAc/Pet Et) proved the product pure. 1H NMR (CDCl3) δ 10.4 (2H, s), 7.61 (1H, s), 7.4 (1H, s), 4.21 (2H, t, J=6.2 Hz), 4.00 (3H, s), 3.71 (2H, s), 2.58 (2H, t, J=7.1 Hz), 2.23 (2H, p, J=6.3 Hz); 13C NMR (CDCl3) δ 188.5, 172.8, 152.7, 151.0, 143.5, 124.7, 110.1, 108.2, 68.4, 56.4, 51.3, 29.7, 23.8; MS (ES+) m/z (relative intensity) 298 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=1)[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC.N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>ClCCl>[Br:17][C:13]1[N:12]=[C:11]([NH:10][C@H:8]([C:4]2[CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[C:19]([CH3:18])[CH:20]=[N:21][CH:22]=3)[CH:7]=[CH:6][CH:5]=2)[CH3:9])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: C[C@H](Nc1cccc(Br)n1)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cncc(C(=O)Nc2cccc([C@H](C)Nc3cccc(Br)n3)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.8 %

Procedure:
A mixture of N-[(1S)-1-(3-aminophenyl)ethyl]-6-bromopyridin-2-amine (70 mg, 0.24 mmol), 5-methylnicotinic acid (39 mg, 0.29 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol), 4-pyrrolidinopyridine (7 mg, 0.05 mmol) and triethylamine (0.08 mL, 0.58 mmol) in dichloromethane (3 mL) was stirred at room temperature for 17 hours. After this time the mixture was diluted with dichloromethane (20 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×15 mL) and brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark yellow oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give N-(3-{(1S)-1-[(6-bromopyridin-2-yl)amino]ethyl}phenyl)-5-methylnicotinamide (62 mg, 63%) as a pale yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH2:18]O)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:5])[CH3:2].[Cl:33]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>O1CCCC1>[Cl:33][CH2:18][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)CN(c1cc(CO)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CN(c1cc(CCl)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1

Procedure:
The product of step (v) (0.5 g) in tetrahydrofuran (20 ml) was treated with triphosgene (0.114 g) then pyridine (0.183 g). After 16 hours the reaction was evaporated and purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 0.4 g.
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16]([OH:18])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[OH:32])[CH2:27][NH2:28]>>[C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][C:31]([OH:32])=[C:24]([OH:23])[CH:25]=3)=[O:18])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COc1cc(O)c(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: NCc1ccc(O)c(O)c1
Product: COc1cc(O)c(C(=O)NCc2ccc(O)c(O)c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.17 g of the target compound is obtained as white solid in substantially the same manner as in (2) of Example 1, except for using 5-adamantan-1-yl-2-hydroxy-4-methoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using 3,4-dihydroxybenzylamine instead of dopamine.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:11][C:12]2[NH:13][CH2:14][CH2:15][N:16]=2)[CH:3]=1.[Br:17]Br.N>CO.CCOC(C)=O>[Br:17][C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[C:2]([Br:1])=[CH:3][C:4]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: BrBr
Reactant: Brc1cc(NC2=NCCN2)cc2[nH]cnc12
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: Brc1cc(NC2=NCCN2)c(Br)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.4 %

Procedure:
To a solution of 7-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.6 g, 2.1 mmol) in 10 ml of ACOH was added Br2 (0.057 ml, 1.1 mmol) in a portion. The resulting reaction mixture was stirred for 1 h at 25° C. Concentration of reaction mixture in vacuo yields a brown oil which was subjected to column chromatography (30% NH3 sat'd MeOH/EtOAc) to provides 0.28 g (1.5 mmol, 71%) of the desired product. The product obtained was recrystallized from MeOH to afford 0.22 g (56%) of the product as a light brown solid: mp 320-321° C.; Anal. Calc. for C10H9N5Br2 requires C, 33.45; H, 2.53; N, 19.51. Found: C, 33.93; H, 4.05; N, 19.01.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:60]=[CH:59][C:15]2[NH:16][C:17]([CH2:19][CH2:20][CH:21]3[CH2:24][CH:23]([N:25]([CH2:27][C@@H:28]4[C@H:32]5[O:33]C(C)(C)[O:35][C@H:31]5[C@H:30]([N:38]5[C:42]6[N:43]=[CH:44][N:45]=[C:46]([NH:47]CC7C=CC(OC)=CC=7OC)[C:41]=6[CH:40]=[CH:39]5)[CH2:29]4)[CH3:26])[CH2:22]3)=[N:18][C:14]=2[CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C([SiH](CC)CC)C>O>[NH2:47][C:46]1[C:41]2[CH:40]=[CH:39][N:38]([C@@H:30]3[CH2:29][C@H:28]([CH2:27][N:25]([CH:23]4[CH2:22][CH:21]([CH2:20][CH2:19][C:17]5[NH:16][C:15]6[CH:59]=[CH:60][C:12]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:13][C:14]=6[N:18]=5)[CH2:24]4)[CH3:26])[C@@H:32]([OH:33])[C@H:31]3[OH:35])[C:42]=2[N:43]=[CH:44][N:45]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Reaction time: 8 h
Yield: 40.3 %

Procedure:
Trifluoroacetic Acid (5 ml) added to a mix lure of Water (0.5 ml) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.20 g, 0.28 mmol) at RT. The reaction was allowed to proceed overnight upon which it was quenched with Triethylsilane (0.088 ml, 0.55 mmol). The volatiles were removed in vacuo and resulting residue was partitioned between saturated NaHCO3 and DCM/MeOH (10:1). Aqueous extracted 3× more with DCM/MeOH (10:1) and combined organics were dried over MgSO4, filtered, concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 87:13) to give the desired product as an off-white foam (0.060 g). MS (ESI+) for C30H41N7O2 m/z 532.3 [M+H]+; MS (ESI−) for C30H41N7O2 m/z 530.4 [M−H]−; HPLC purity >94% (ret. time, 2.723 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.079 (s, 1H), 7.500 (s, 1H), 7.418-7.398 (m, 1H), 7.310-7.307 (m, 1H), 7.230-7.216 (m, 1H), 6.619-6.610 (m, 1H), 4.355-4.316 (m, 1H), 3.926-3.887 (m, 1H), 3.088-3.017 (m, 0.5H (methine of trans isomer)), 2.879-2.809 (m, 2H), 2.745-2.685 (m, 0.5H (methine of cis isomer), 2.532-2.512 (m, 1H), 2.446-2.373 (m, 2H), 2.294-2.276 (m, 2H), 2.202-2.012 (m, 5H), 1.685-1.603 (m, 1H), 1.545-1.504 (m, 1H), 1.383 (s, 1H). Retention time: 2.723 mins HPLC Conditions: Agilent Zorbax Exlipse XDB-C18 column, 4.6×50 mm (1.8 um packing), Solvent A—Water (0.1% TFA), Solvent B—Acetonitrile (0.07% TFA) 6 min gradient from 5 to 95% B; 1 min hold; then recycle.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12]>CC#N.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][CH2:11][C:13](=[O:14])[CH3:15]
Reactant: C=CC(C)=O
Reactant: Fc1ccc2[nH]ccc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: CC(=O)CCc1c[nH]c2ccc(F)cc12
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of 5-fluoroindole (10.5 g, 78 mmol) in MeCN (150 mL) at 0° C. is treated with methyl vinyl ketone (9.5 mL, 117 mmol) and Sc(OTf)3 (383 mg, 0.78 mmol) and stirred for 1 h. The mixture is then stirred an additional 6 h at rt. The mixture is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-50% EtOAc in heptane to afford 4-(5-fluoro-1H-indol-3-yl)-butan-2-one (11.1 g, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].O[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: OCc1ccccn1
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O)cc1F
Product: CCOC(=O)C(OCC)c1c(F)cc(OCc2ccccn2)cc1F

Procedure:
In analogy to example 22.1 (RS)-(2,6-difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (example L6) was reacted with 2-(hydroxymethyl)pyridine to give (RS)-[2,6-difluoro-4-(pyridin-2-ylmethoxy)-phenyl]-ethoxy-acetic acid ethyl ester as a yellow semisolid. This material was hydrolysed in analogy to example 101.3 to give (RS)-[2,6-difluoro-4-(pyridin-2-ylmethoxy)-phenyl]-ethoxy-acetic acid. White solid. MS 324.1 ([M+H]+)