Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([C:17](O)=[O:18])[C:11]=2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:20])[N:14]=[CH:15][C:16]([C:17](=[O:18])[NH:28][CH:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)=[C:11]2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Reactant: NC1CCOCC1
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NC3CCOCC3)c12

Procedure:
Prepared in a similar manner to Example 11 (b) from 7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1,4-dicarboxylic acid 1-tert-butyl ester and using tetrahydro-pyran-4-ylamine (195 mg) instead of morpholine. The title compound was further purified by trituration with ether/isohexane to give an off-white solid (324 mg).
Reaction SMILES: [CH:1]1([N:4]2[S:8](=[O:10])(=[O:9])[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:1]1([N:4]2[CH2:5][CH2:6][NH:7][S:8]2(=[O:10])=[O:9])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CC2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)NCCN1C1CC1
Reaction time: 2 h
Yield: 165.8 %

Procedure:
400 mg of tert-butyl 5-cyclopropyl-1,1-dioxo-[1,2,5]thiadiazolidine-2-carboxylate were dissolved in 10 ml of CH2Cl2/trifluoroacetic acid 1:1 and left to stand for 2 hours. The volatile constituents were removed in vacuo and coevaporated twice with 50 ml of CH2Cl2 each time. 410 mg of pale yellow oil were obtained and were directly employed further.
Reaction SMILES: [CH2:1]([C@H:8]1[C:12](=[O:13])[NH:11][CH:10]([CH2:14][CH2:15][C:16]([O:18]CC(C)C)=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[N:9]2[C:16](=[O:18])[CH2:15][CH2:14][CH:10]2[NH:11][C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)COC(=O)CCC1NC(=O)[C@H](Cc2ccccc2)N1
Solvent: Cc1ccccc1
Product: O=C1NC2CCC(=O)N2[C@H]1Cc1ccccc1
Yield: 50.4 %

Procedure:
A solution of isobutyl (4S)-4-benzyl-5-oxo-2-imidazolidinepropanoate (2.3 g, 7.33 mmol) in toluene (100 ml) was refluxed for 8 days. After evaporation of the solvent, the residue was chromatographed over silica gel (dichlorometane-methanol 9:1). The appropriate fractions were collected and evaporated; the residue was triturated with diethyl ether to afford 850 mg (50%) of the title compound, m.p. 141°-145° C. NMR (CDCl3): deltaH =7.25 (s, 5H, PhH); 7.02 (b.s., 1H, NH); 4.52 (t, J=4.5 Hz, 1H, PhCH2CH); 4.37 (t, J=5 Hz, 1H, NCHNH); 3.13 (d, J=4.5 Hz, 2H, PhCH2); 2.80-1.6 (c.a., 4H, CH2CH2). MS (E.I., 70 eV, 1.5 mA) m/z 230 (M+), 139 (M--C7H7)+, 91 (C7H7)+, 84 (C4H6NO)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](B(O)O)[CH:36]=2)[CH:31]=[CH:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][NH:29]2)=[CH:33][CH:34]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added (1H-indol-6-yl)boronic acid (65 mg, 0.41 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 272 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (50% to 100%, hexane-ethyl acetate) to obtain 125 mg (94% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1([CH2:26][OH:27])[CH2:14][CH2:13][N:12]([C:15](=[O:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)=[O:8].[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1)[CH3:33]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:42])[O:27][CH2:26][C:9]2([C:7](=[O:8])[NH:6][CH2:5][C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[C:3]=3[CH3:31])[CH2:14][CH2:13][N:12]([C:15](=[O:25])[CH2:16][NH:17][C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:11][CH2:10]2)=[CH:36][CH:35]=1)[CH3:33]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: Cc1c(F)cccc1CNC(=O)C1(CO)CCN(C(=O)CNC(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OCC2(C(=O)NCc3cccc(F)c3C)CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a solution of crude tert-butyl 2-(4-(3-fluoro-2-methylbenzylcarbamoyl)-4-(hydroxymethyl)piperidin-1-yl)-2-oxoethylcarbamate (185 mg, ˜0.422 mmol, 1.0 equiv.) in THF (2 mL) were added DMAP (10 mg, 0.085 mmol, 0.2 equiv.) and 4-ethylphenylisocyanate (61 μL, 0.422 mmol, 1.0 equiv.). The reaction mixture was stirred overnight, and then concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (1-(2-(tert-butoxycarbonylamino)acetyl)-4-(3-fluoro-2-methylbenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (12 mg, 5% for three steps). LRMS (M-Boc+H+) m/z 485.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](O)=[O:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:32])=O>>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH:10]([CH2:11][CH2:12][Cl:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1OC1CCN(Cc2ccccc2)C1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2OC(CCCl)CN1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
To 85.7 g (0.29 mole) of 2-[(1-benzyl-3-pyrrolidinyl)oxy]-benzoic acid was added 150 ml of thionyl chloride. The solution stood for 15 min and was then refluxed 30 min. and concentrated in vacuo. The residue was twice treated with 250 ml of chloroform and concentrated in vacuo. The residue was dissolved in 500 ml of chloroform and 101 g (1 mole) of triethylamine added slowly with stirring. The solution was refluxed 1 hr. and concentrated in vacuo. The residue was partitioned between 50% ethyl acetate-50% isopropyl ether and dilute hydrochloric acid. The organic layer was washed with dilute sodium hydroxide and concentrated. The residue was crystallized 5 times from isopropyl ether-ethyl acetate. Yield of product was 23.8 g (26%), m.p. 145.0°-147° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([Br:19])[CH:13]=1.O>C1COCC1>[CH2:1]([O:8][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[C:14]([Br:19])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104 %

Procedure:
Benzylalcohol (9.7 ml, 94 mmol) was added dropwise to a suspension of NaH (4.0 g of a 60% suspension in mineral oil, 100 mmol) in THF (150 ml) at room temperature and the mixture was stirred at room temperature for 1 h before 1,3-dibromo-5-fluorobenzene (15.9 g, 62.5 mmol) was added. The reaction was stirred at room temperature for 12 h. Water was added carefully and the THF was evaporated under reduced pressure. The residue was extracted with iso-hexane (×3) and the combined organic extracts were washed with NaOH solution (1M aq). water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 1-benzyloxy-3,5-dibromobenzene (14.7 g, 65 mmol) as a colourless liquid in 69% yield. 1H NMR (CDCl3) δ 7.45-7.33 (m, 5H), 7.30-7.28 (m, 1H), 7.10-7.08 (m, 2H), 5.02 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[S:32]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:38][CH2:37][C:34]1[CH:35]=[CH:36][S:32][CH:33]=1)=[O:5]
Reactant: NCc1ccsc1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ccsc1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 35.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), thiophen-3-ylmethanamine (11.8 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(thiophen-3-ylmethyl)acetamide (12.9 mg, 0.025 mmol, 35.2% yield): LCMS=527.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.53 Hz), 7.52-7.76 (7 H, m), 7.26 (1 H, dd, J=5.02, 1.25 Hz), 6.85-7.01 (2 H, m), 5.16 (1 H, s), 4.60 (2 H, s); HPLC peak RT=3.0 min (Method E).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH2:4]C)([CH3:3])C.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.ClCCl>N1C=CC=CC=1>[CH:1]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH3:16])[CH:21]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)([CH3:3])[CH3:4]
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 4-t-pentylbenzenesulfonyl chloride (0.028 g, 0.13 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.023 g, 0.10 mmol) in pyridine (1.0 mL) was heated at 80° C. for 18 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.05 mmol, 50%). 1H NMR (400 MHz, CDCl3) δ 9.02 (d, J=4.4 Hz, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.87-7.33 (m, 2H), 7.72-7.70 (m, 3H), 7.35 (s, 1H), 7.33 (s, 1H), 5.94 (s, 1H), 3.04-2.98 (m, 1H), 2.32 (s, 3H), 1.29 (s, 6H); MS: (ES) m/z calculated for C22H23N4O2S [M+H]+ 407.2. found 407.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CC1(C)CCCOc2c(N)cccc21
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Product: Cn1ccnc1-c1ccccc1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine in an analogous manner to Example 179 heating at 130° C. Product was isolated as a pink foam (42 mg, 57%). LCMS (m/e) 475 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 8.60 (d, 1H, J=8.3 Hz), 8.32 (d, 1H, J=7.8 Hz), 8.05 (s, 1H), 7.78 (s, 1H), 7.43 (m, 2H), 7.21 (m, 2H), 6.95 (m, 3H), 4.01 (m, 2H), 3.76 (s, 3H), 2.07 (m, 2H), 1.69 (m, 2H), 1.39 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](Cl)=[O:38]>C(#N)C>[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])[CH2:19]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:17])=[O:38]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)CC(C)(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (500 mg, 1.1 mmol) in acetonitrile (5 mL) was added 3,3-dimethyl-butyryl chloride (0.2 mL, 1.4 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[2-(3,3-dimethyl-butyryloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (360 mg, 59% yield): mp, 118-120° C.; 1H NMR (DMSO-d6) δ 0.87-0.89 (m, 4H, 2CH2), 0.98 (s, 9H, 3CH3), 1.31 (t, J=7 Hz, 3H, CH3), 1.73-1.80 (m, 1H, CH), 2.27 (s, 2H, CH2), 3.03-3.06 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.97-4.03 (m, 2H, CH2), 4.18 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.67 (t, J=0.8 Hz, 1H, NCH), 6.86-6.94 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.49 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=8 Hz, 1H, Ar), 10.55(s, 1H, NH), 11.82 (s, 1H, NH); 13CNMR (DMSO-d6) δ 7.75, 14.70, 15.46, 29.12, 30.53, 34.67, 44.24, 46.62, 51.11, 55.47, 63.80, 111.94, 112.09, 116.78, 117.33, 117.48, 119.25, 131.23, 132.73, 136.98, 142.26, 147.95, 148.56, 166.54, 168.06, 169.34, 171.70; Anal Calcd for C30H37N3O7+0.1H2O: C, 65.11; H, 6.78; N, 7.59. Found: C, 64.87; H, 6.87; N, 7.48.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[Na+].[I-:14]>I>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1[I:14]
Reactant: [I-]
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Agent: I
Agent: [Na+]
Product: COC(=O)c1cnc(I)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of methyl 5-bromo-6-chloro-3-pyridinecarboxylate (4500 mg, 17.97 mmol) in HI (30 ml) was added NaI (3501 mg, 23.36 mmol). The mixture was stirred at 50° C. overnight. Reaction was cooled at 0° C. and the precipitated solid was isolated by filtration and washed with 15 ml of MeOH. The obtained solid was suspended in 25 ml of water and pH was adjusted to 9 with NaOH 6N (1.5 ml). The aqueous phase was extracted twice with DCM and once with DCM/MeOH (5%). Organic layers were dried over Na2SO4. Volatiles were removed under vacuum to afford 2.505 g (40%) of the desired compound as a white solid. The solution of HI and MeOH was dissolved in water and pH was adjusted to 9 with NaOH 6N. The organic phase was extracted twice with DCM and once with DCM/MeOH (5%). Organic layers were dried over Na2SO4. Volatiles were removed under vacuum to afford an additional quantity of the desired compound (649 mg, 10%) as beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][C:15]3([CH3:18])[CH2:17][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C1COCC1>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:16][C:15]3([CH3:18])[CH2:17][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]3)=[O:9])=[CH:6][CH:7]=1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)cc2)C1
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)CCl)cc2)C1
Reaction time: 1.25 h
Yield: 85.9 %

Procedure:
To a solution of (4-amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (3.0 g, 11.01 mmol) and TEA (3.1 ml, 22.03 mmol) in dry THF (100 ml) was added dropwise chloroacetyl chloride (1.05 ml, 13.22 mmol). The mixture was stirred for 75 min. and evaporated followed by addition of water 75 (ml). The aqueous phase was extracted with EtOAc (2×50 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was dissolved in EtOAc (40 ml) and filtered through a 2.5 cm path of silicagel. The filtrated was evaporated to dryness affording 3.3 g (86%) of 2-chloro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acetamide as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:20][CH2:21][C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH:18]=[CH2:19])=[CH:17][C:7]2=1.[H][H]>CO.[Pd]>[CH2:18]([C:16]1[C:15]([O:20][CH2:21][C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:14][C:8]2[N:9]([CH3:13])[C:10](=[O:12])[C:11]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][CH:4]=[N:3][C:2]=3[CH3:1])[CH3:19]
Reactant: [H][H]
Reactant: C=Cc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 54.2 %

Procedure:
A solution of (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-9-vinyl-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.107 mmol) in MeOH (3 mL) was degassed with nitrogen for 5 min, then palladium on carbon (1.143 mg, 10.74 μmol) was added. The reaction mixture was allowed to stir under a balloon of hydrogen for 16 h. The reaction mixture was then filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (2% MeOH in MDC) to afford (S)-tert-butyl (1-((9-ethyl-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (31 mg, 0.058 mmol, 54% yield) as pale yellow solid. LC/MS, (ESI) m/z 468.5 [(M+H)+, calcd for C27H38N3O4 468.3]; LC/MS retention time (method D): tR=1.31 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[CH:30]1([NH2:33])[CH2:32][CH2:31]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:33][CH:30]2[CH2:32][CH2:31]2)=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: NC1CC1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3CC3)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with cyclopropylamine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=453.1 [M+H]+.
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.Br[CH2:21][C:22]#[C:23][C:24]([O:26][CH3:27])=[O:25]>O1CCCC1>[CH3:27][O:26][C:24]([C:23]#[C:22][CH2:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1)=[O:25]
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Reactant: COC(=O)C#CCBr
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)C#CCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 30 ml of 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0°-5° is added dropwise over 30 minutes a solution of 10.0 g of 2-(3-pyridyl)indole in 60 ml of tetrahydrofuran. The mixture is stirred fo 0.5 hour at 0°-5° followed by the dropwise addition of 10.6 g of methyl bromotetrolate (J. Chem. Soc. 1950, 3646) in50 ml of tetrahydrofuran. The mixture is stirred for an additional 2 hours, at 0° poured into ice water, and extracted with ether. The aqueous phase is extracted with ether. The ether extract is washed with water, brine, and dried over anhydrous magnesium sulfate. Concentration in vacuo yields 3-(3-methoxycarbonyl-prop-2-ynyl)-2-(3-pyridyl)indole.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>>[N+:8]([C:7]1[C:2]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: [O-]c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Na+]
Product: O=[N+]([O-])c1cccnc1Oc1ccccc1

Procedure:
In step (3) of Reaction Scheme I, a 2-chloro-3-nitropyridine of Formula XII is reacted with sodium phenoxide to provide a 3-nitro-2-phenoxypyridine of Formula XIII. Phenol is reacted with sodium hydride in a suitable solvent such as tetrahydrofuran to form the phenoxide. The phenoxide is then reacted at an elevated temperature with a compound of Formula XII.