Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[C:4](I)[N:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4](/[CH:19]=[CH:18]/[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:3][C:2]=1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1nc(I)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(/C=C/C(=O)OC(C)(C)C)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
To a solution of 828 mg (2.55 mmol) of 2-methyl-3-benzyloxy-6-iodopyridine (from Step B), 746 μL (5.09 mmol) of tert-butyl acrylate, 535 mg (6.37 mmol) of sodium bicarbonate, 708 mg (255 mmol) of tetrabutylammonium chloride, and 20 mg of crushed 4 A molecular sieve in 10 mL of DMF was added 29 mg (0.13 mmol) of palladium acetate. After stirring at 60° C. for 5 h, the reaction mixture was cooled to rt, diluted with EtOAc (20 mL), and filtered through a cake of Celite. The filtrate was washed with brine (100 mL), H2O (3×100 mL), and brine (100 mL). The organic layer was dried over Na2SO4 and concentrated. Chromatography on a Biotage 40M cartridge using 2:23 v/v EtOAc/hexanes as the eluant afforded 703 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.52 (s, 9H), 2.53 (s, 3H), 5.09 (s, 2H), 6.70 (d, J=15.6, 2H), 7.06 (d, J=8.5, 1H), 7.18 (d, J=8.5, 1H), 7.37-7.42 (m, 5H), 7.52 (d, J=15.8, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:22])[CH:9]=[C:10]([C:11]3[CH:21]=[CH:20][C:14]4[O:15][CH2:16][CH2:17][N:18]([CH3:19])[C:13]=4[CH:12]=3)[C:3]=12.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[N:25]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH3:22])[CH:9]=[C:10]([C:11]4[CH:21]=[CH:20][C:14]5[O:15][CH2:16][CH2:17][N:18]([CH3:19])[C:13]=5[CH:12]=4)[C:3]=23)(=[O:31])=[O:30])=[N:25]1
Reactant: CN1CCOc2ccc(-c3cn(C)c4nccc(Br)c34)cc21
Reactant: Cn1ccc(S(N)(=O)=O)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: CN1CCOc2ccc(-c3cn(C)c4nccc(NS(=O)(=O)c5ccn(C)n5)c34)cc21
Temperature: 130 °C
Yield: 45.4 %

Procedure:
6-(4-Bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (344 mg, 0.960 mmol), 1-methyl-1H-pyrazole-3-sulfonamide (D94) (186 mg, 1.152 mmol), xantphos (111 mg, 0.192 mmol), palladium(II) acetate (21.56 mg, 0.096 mmol) and cesium carbonate (939 mg, 2.88 mmol) were dissolved in 1,4-dioxane (10 mL) and refluxed at 130° C. overnight. The mixture was cooled and then acidified with 1M HCl till pH7-8. Water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified on normal phase silica eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give an impure fraction which was further triturated with MeOH and followed by purification on reverse phase eluting with acetonitrile and water (+0.2% formic acid) to give the title compound (191 mg). LCMS (A): m/z (M+H)+ 439, C21H22N6O3S requires 438 (acidic).
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][N:19]2[CH2:23][C@H:22]3[C:24]4[CH:25]=[C:26]([C:32]#[N:33])[CH:27]=[CH:28][C:29]=4[O:30][CH2:31][C@@H:21]3[CH2:20]2)[CH2:13][CH2:12]1)C.[NH3:34].[ClH:35]>C(O)C.C(#N)C>[ClH:35].[NH2:34][C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][N:19]2[CH2:23][C@H:22]3[C:24]4[CH:25]=[C:26]([C:32]#[N:33])[CH:27]=[CH:28][C:29]=4[O:30][CH2:31][C@@H:21]3[CH2:20]2)[CH2:13][CH2:12]1
Reactant: CCOc1c(N[C@H]2CC[C@H](CCN3C[C@H]4COc5ccc(C#N)cc5[C@@H]4C3)CC2)c(=O)c1=O
Reactant: N
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](Nc4c(N)c(=O)c4=O)CC3)C[C@H]1CO2

Procedure:
A solution of 1.17 g of the compound obtained in Step A of Example 20 (2.61 mmol) in 13 ml of ethanol is treated with 13 ml of a saturated solution of ammonia in acetonitrile for 16 hours. The solid obtained is filtered off and then washed with ethyl acetate to finally yield, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][O:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=2[O-])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:14][C@@H:13]1[NH:8][CH2:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[O:11][CH2:12]1
Reactant: [H][H]
Reactant: C[C@H]1COC(c2cccc[n+]2[O-])CN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1COC(c2ccccn2)CN1
Yield: 30.1 %

Procedure:
To a suspension of 10% palladium-on-carbon (2 g) in ethanol (30 mL) was added a solution of 2-((5S)-4-benzyl-5-methylmorpholin-2-yl)pyridine 1-oxide (3.5 g, 13.06 mmol) in ethanol (10 mL). The mixture was subjected to a hydrogen atmosphere using a balloon filled with hydrogen gas for 2 h. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford (5S)-5-methyl-2-(pyridin-2-yl)morpholine (0.7 g). MS (ES+) (M+H) 179.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH:13]=O)=[C:8]([Cl:15])[CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[O:22].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[NH:17][C:18]3[CH:19]=[C:20]([C:21](=[O:22])[NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=4)[CH:32]=[CH:33][C:34]=3[N:35]=2)=[C:8]([Cl:15])[CH:7]=1
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: COC(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc(C)c(C)c4)cc3[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,5-dichloro-4-formylphenoxy)-acetic acid methyl ester (524 mg, 2.0 mmol) and 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (510 mg, 2.0 mmol) (Example 5-1, step 6) in DMSO (15 mL) was added Yb(OTf)3 (248 mg, 0.4 mmol) and the solution was stirred at ambient temperature overnight. The mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4, filtered and concentrated. Purification by HPLC (0-80% MeCN/water) gave {3,5-dichloro-4-[6-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-phenoxy}-acetic acid methyl ester as a white solid. MS (m/z) 498.1 (M+1); 1H-NMR (Methanol-d4, 400 MHz): δ 8.36 (d, 1H), 8.09 (dd, 1H), 7.87 (dd, 1H), 7.49 (d, 1H), 7.46 (dd, 1H), 7.31 (s, 2H), 7.16 (d, 1H), 4.93 (s, 2H), 3.83 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: Cc1cc(-c2cccnc2)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2cccnc2)ncc1N
Yield: 82.1 %

Procedure:
A mixture of 4-methyl-5-nitro-2,3′-bipyridine (215 g, 1 mol), Pd/C (10 g, 10%) and MeOH (1000 mL) was stirred at room temperature for 16 h under 10 atm of hydrogen. After reaction, the mixture was filtered. The filtrate was evaporated at reduced pressure to afford 4-methyl-2,3′-bipyridin-5-amine as a yellow solid (152 g, 82%)
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[C:67]([CH:79]=[CH:80][CH:81]=4)[CH2:68][CH:69]4[CH2:74][CH2:73][N:72]([CH2:75][C:76]([NH2:78])=[O:77])[CH2:71][CH2:70]4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:92]=[CH:93][CH:94]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[C:67]([CH:79]=[CH:80][CH:81]=4)[CH2:68][CH:69]4[CH2:74][CH2:73][N:72]([CH2:75][C:76]([NH2:78])=[O:77])[CH2:71][CH2:70]4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCN(CC(N)=O)CC5)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CN1CCC(Cc2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c2)CC1
Yield: 43.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidin-1-yl) acetamide (30 mg, 0.044 mmol) was hydrolyzed by lithium hydroxide (18 mg, 0.44 mmol) in THF/methanol/water (2/2/1 ml) to yield 10 mg (43.4% yield) of the titled compound. 1H NMR (DMSO-d6, 400 MHz): δ 8.516-8.512 (d, 1H), 8.43 (s, 1H), 8.347-8.343 (d, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.59-7.54 (m, 2H), 7.42-7.38 (t, 2H), 7.17-7.09 (m, 5H), 5.41 (s, 2H), 2.78 (s, 4H), 2.65-2.55 (m, 2H), 1.99-1.93 (t, 2H), 1.59-1.56 (m, 3H), 1.31-1.23 (m, 3H). MS: m/z=523.4 (M+1), HPLC: 91.01% in method B.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][CH:16]3[CH2:18][O:19][CH2:20][CH:15]3[N:14]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][CH:16]3[CH2:18][O:19][CH2:20][CH:15]3[N:14]=2)=[CH:8][C:3]=1[C:4]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:5]
Reactant: COC(=O)c1cc(C2=NC3COCC3N2)c(C)cc1C
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C2=NC3COCC3N2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 8 h
Yield: 12.1 %

Procedure:
Into around-bottom flask, was placed a solution of 2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-c]imidazol-2-yl)benzoic acid (compound 466.5, 80.0 mg, 0.250 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 82.0 mg, 0.350 mmol, 1.20 equiv), 4-dimethylaminopyridine (76.0 mg, 0.620 mmol, 2.00 equiv), and EDC.HCl (116 mg, 0.610 mmol, 2.00 equiv) were added and the resulting solution was stiffed overnight at room temperature. The mixture was diluted with ethyl acetate (30 mL) and washed with brine (3×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (15% CH3CN up to 50% in 9 min, up to 100% in 1 min, down to 15% in 1 min); Detector, Waters 2489 254 nm & 220 nm. The fractions containing pure product were combined and lyophilized to obtain the title compound as a white solid (13 mg, 12%). m/z (ES+) 429 (M+H)+. 1H-NMR (300 MHz, CD3OD): δ 7.70 (d, 2H), 7.53-7.36 (m, 4H), 5.09 (s, 2H), 4.17 (d, J=10.8 Hz, 2H), 3.77 (d, J=10.5 Hz, 2H), 3.60-3.44 (m, 1H), ˜3.3 (m, partially overlapped with water, 1H), 3.10-2.92 (m, 2H), 2.48 (s, 3H), 2.45 and 2.35 (2 singlets, amide rotamers, Ar—CH3, 3H), 2.10-1.97 (m, 1H), 1.92-1.52 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:34])/[C:10](/[CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.O.[OH-].[Li+]>O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:34])/[C:10](/[CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc(/C=C(\COc2cccc3ccccc23)C(=O)NC2CCN(C)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(NC(=O)/C(=C/c2ccc(C(=O)O)cc2)COc2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
Methyl (E)-4-(3-(1-methylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxo-prop-1-enyl)benzoate (300 mg, 0.65 mM) obtained in Example (1-1-1) was dissolved in water (1 ml), and lithium hydroxide monohydrate (LiOH.H2O) (82 mg, 1.95 mM) was added thereto. The resulting mixture was stirred at room temperature for 10 mins, and further stirred at 50° C. for 3 hrs. After the completion of reaction, the reaction mixture was cooled to room temperature and ice water was poured thereinto, followed by removing the solvent under reduced pressure. Then, the resultant was cooled to 5, acidified with 2N hydrochloride solution to pH 4, extracted with chloroform/methanol (4/1) 3 times. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 281 mg of the title compound (yield 97%).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1)#[N:7].O>C(Cl)Cl>[C:6]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][S:1]([CH3:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1)#[N:7]
Reactant: N#Cc1ccc(OCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCOc1ccc(C#N)cc1
Reaction time: 4 h

Procedure:
Mesylchloride (2.32 mL; 30 mmol) was added to a stirred 0° C. solution of 4-(4-cyanophenoxy)-1-butanol (5.2 g; 29.7 mmol; from step (c) above) and TEA (4.35 mL) in CH2Cl2 (50 mL), and the reaction mixture was stirred for 4 h. H2O (150 mL) was added and the organic layer separated, dried and concentrated to give the sub-title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)=[C:30]=[O:31].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:19][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]1[NH:8][C@H:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([NH:1][C:30]([NH:29][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[O:31])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: COc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(NC(=O)Nc2ccc(C[C@@H]3CC[C@H]([C@H](O)c4ccccc4)N3)cc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 30 mg (0.078 mmol) of tert-butyl (2S,5R)-2-(4-aminobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (i-13a) in CH2Cl2 (0.5 mL) was added 14 mg (0.094 mmol) of 1-isocyanato-3-methoxybenzene. The reaction mixture was stirred at ambient temperature for 2.5 h. It was then added TFA (0.4 mL) and was stirred at ambient temperature for another 3 h. After removal of the volatiles, it was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-80% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give the title compound as a white solid. LC/MS 432.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:15]([CH3:17])[CH3:16])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C1C(=O)N([I:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:15]([CH3:16])[CH3:17])=[N:7][C:8]3[C:9]([I:27])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC(C)c1nc2cc[nH]c(=O)c2c2cc(Br)ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of 9-bromo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one (81 mg, 0.26 mmol) in DMF (1.5 ml) was added NIS (86 mg, 0.38 mmol), and stirred for 24 hours at room temperature. The reaction mixture was diluted with EtOAc until a solution was formed, and washed with a mixture of 10% aqueous sodium thiosulfate and 1N NaOH. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was adsorbed on to silica gel and purified by silica gel chromatography using an EtOAc/Hexanes gradient to afford 9-bromo-4-iodo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one. LRMS (ESI) calc'd for (C15H12BrIN2O) [M+H]+, 442.9; found 442.8.
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[C:15]([Cl:17])[C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[C:8]([Cl:18])[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:53][C:54]([F:66])([F:65])[C:55]1[CH:56]=[C:57]([CH:62]=[CH:63][CH:64]=1)[C:58](=[N:60]O)[NH2:59]>CN(C=O)C.O.C1C=CC2N(O)N=NC=2C=1>[Cl:19][C:2]([Cl:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([Cl:18])[C:9]([O:10][CH2:11][C:12]2[O:14][N:60]=[C:58]([C:57]3[CH:62]=[CH:63][CH:64]=[C:55]([C:54]([F:53])([F:65])[F:66])[CH:56]=3)[N:59]=2)=[C:15]([Cl:17])[CH:16]=1
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2noc(COc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)n2)c1
Temperature: 25 °C
Yield: 184 %

Procedure:
To a stirred solution of 0.129 gram (0.00037 mole) of 2-(4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy)acetic acid in 1.9 mL of DMF was added 0.141 gram (0.00037 mole) of HBTU, 0.008 gram (0.00006 mole) of HOBT and 0.24 gram (0.0019 mole) of DIEA. The reaction mixture stirred for 10 minutes at which time 0.075 gram (0.00037 mole) of 3-(trifluoromethyl)benzamidoxime was added. Upon completion of addition the reaction mixture was stirred at ambient temperature then heated to 112° C. where it stirred for four hours. After this time the reaction mixture was cooled to ambient temperature, diluted with water and extracted with a mixture of hexanes and ethyl acetate (70:30). The extract was washed in succession with two 5 mL portions of water, one 5 mL portion of an aqueous hydrochloric acid solution and one 5 mL portion of aqueous sodium bicarbonate, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using a mixture of hexanes and ethyl acetate as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.35 gram of the subject compound as an off-white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](O)(=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29].O>ClCCl>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=C(O)CCC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(2-Phenylchroman-6-yloxy)pyridin-3-ylamine (example 35) (270 mg) and succinic acid (151 mg) were dissolved in dichloromethane (16 ml). 1-(3-Dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (245 mg) was added into a reaction mixture and it was stirred at room temperature for 3 hours. Water was added and the mixture was filtered. The precipitate was collected and treated with methanol and filtered again. The methanol-filtrate was evaborated to dryness to yield N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid. 1H NMR (400 MHz, d6-DMSO) δ: 12.0 (bs, 1H), 10.08 (s, 1H), 8.29 (d, 1H, J 2.4 Hz), 8.01 (dd, 1H, J 8.8, 2.4 Hz), 7.46-7.32 (m, 5H), 6.93 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (d, 1H, J 8.6 Hz), 2.96 (m, 1H), 2.70 (m, 1H), 2.56-2.52 (m, 4H), 2.16 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH:9](O)=[O:10]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:9]=[O:10])=[N:3][CH:4]=1
Reactant: O=CO
Reactant: Nc1ccc(Cl)cn1
Product: O=CNc1ccc(Cl)cn1

Procedure:
Was prepared according to Example 2 from 2-amino-5-chloropyridine and formic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]1[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:20][CH:19]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccncc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccncc4)cc23)CC1
Yield: 69.8 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.1 mg (0.09 mMol) pyridine-4-carboxylic acid, 7.0 mg of the title compound were recovered.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[CH3:11][O:12][C:13](=[CH2:16])[C:14]#[N:15].[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH2:17]([N:24]1[CH2:25][CH2:16][C:13]([C:14]#[N:15])([O:12][CH3:11])[CH2:30]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C(C#N)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(C#N)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.2 g triflouroacetic acid and 1.2 g triethylamine in 200 ml dry dichloromethane 8.3 g (90 mmol, 90% proof) 2-methoxyacrylonitrile (J. Chem. Soc. 520, 1942) are added. Thereafter 28.5 g N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)-amine (Chem. Letters 1117, 1984) are added, and the mixture is stirred overnight at room temperature. The mixture is treated with a saturated solution of sodium hydrogencarbonate, dried with magnesiumsulfate, and finally the organic solvents are removed in vacuo and the residue is destilled.