Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([CH:27]5[CH2:30][CH2:29][CH2:28]5)=[O:32])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (81 mg, 79%), MS (ISP) m/z=411.4 [(M+H)+], mp 197° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[C:5]([F:12])=[C:4]([CH3:13])[N:3]=1.[S:14]1[C:18]([C@:19]23[CH2:27][NH:26][CH2:25][C@H:24]2[CH2:23][S:22][C:21]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:20]3)=[CH:17][CH:16]=[N:15]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:12][C:5]1[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:7][C:2]([N:26]2[CH2:25][C@@H:24]3[C@@:19]([C:18]4[S:14][N:15]=[CH:16][CH:17]=4)([N:20]=[C:21]([NH:28][C:29](=[O:36])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[S:22][CH2:23]3)[CH2:27]2)=[N:3][C:4]=1[CH3:13]
Reactant: Cc1nc(Cl)nc(C(C)(C)O)c1F
Reactant: O=C(NC1=N[C@@]2(c3ccns3)CNC[C@H]2CS1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccns3)C2)nc(C(C)(C)O)c1F
Temperature: 110 °C
Reaction time: 0.05 h
Yield: 17.8 %

Procedure:
2-(2-Chloro-5-fluoro-6-methyl-pyrimidin-4-yl)propan-2-ol (104 mg, 0.51 mmol) is dissolved in 1,4-dioxane (3 mL). N-[(4aR,7aR)-7a-Isothiazol-5-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (125 mg, 0.36 mmol) is added followed by diisopropylethylamine (158 μL, 0.91 mmol). The reaction is heated via microwave irradiation in a sealed microwave vessel to 110° C. for 1 hr. The reaction is concentrated to give the crude product. The crude product is purified via HPLC using a Waters XBridge 5 μm C18 OBD 30×75 mm column and eluted with a gradient of: 36% β isocratic for 3 min followed by 36-51% B over 5 min where solvent A is 10 mM ammonium bicarbonate in water with 5% MeOH and solvent B is acetonitrile. The desired fractions are combined and diluted with saturated NaHCO3 (aq, 100 mL). The mixture is extracted with 4:1 CHCl3: isopropanol (3×100 mL). The organic layers are combined, washed with brine (1×50 mL), dried over MgSO4, filtered and concentrated to give the title compound (33 mg, 0.064 mmol): EZ/MS (m/z): 513 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].O1CCCCC1[O:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][N:30]=1>CCO>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:33]2[C:32]2[CH:31]=[N:30][C:29]([CH2:28][OH:27])=[CH:36][CH:35]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=Cc1ccc(COC2CCCCO2)nc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(CO)nc3)nc3ccccc3c2=O)cc1
Yield: 40 %

Procedure:
2-amino-N-(4-sec-butylphenyl)benzamide (0.250 g, 0.92 mmol) and 6-((tetrahydro-2H-pyran-2-yloxy)methyl)nicotinaldehyde (0.77 mmol) were mixed in anyhydrous EtOH (40 mL) and anyhydrous CuCl2 (0.310 g, 2.3 mmol) was added. After heating at reflux for 1.5 hours, and concentrating, ethyl acetate (150 mL) was added, the mixture was washed with water (2×125 mL), dried (MgSO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 50% ethyl acetate/heptane to 100% ethyl acetate, plus re-chromatographing with 30% ethyl acetate/CH2Cl2 to 100% ethyl acetate, afforded the title compound as a white solid (40%). 1H-NMR (300 MHz, DMSO-6): δ8.47 (d, J=1.6 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 7.89-7.94 (m, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.60-7.72 (m, 2H), 7.26-7.29 (m, 3H), 7.14-7.18 (m, 2H), 5.42 (t, J=5.8 Hz, 1H), 4.45 (d, J=5.7 Hz, 2H), 2.55-2.64 (m, 1H), 1.37-1.58 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 0.64 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 386 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10]2[NH:9][C:8](=O)[CH:7]=[CH:6][C:5]=2[C:4](=[O:13])[CH2:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:4](=[O:13])[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:11][C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)CC(=O)c2ccc(=O)[nH]c2C1
Product: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Yield: 60 %

Procedure:
In analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsikl. Soedin. 1991, (1) 86-92.) 7,7-dimethyl-7,8-dihydro-1H,6H-quinoline-2,5-dione was treated with phosphoryl chloride (POCl3) to give the title compound as a gray solid in 60% yield.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[O:9][C:11]3[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]=3[C:5]=2[CH:4]=1
Reactant: NOc1ccc(Br)cc1
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Product: O=C1CCCc2oc3ccc(Br)cc3c21
Yield: 34.8 %

Procedure:
The product of Example 29, step A (1.0 g, 4.45 mmol) and cyclohexane-1,3-dione (750 mg, 6.68 mmol) were reacted following the procedure of Example 44, step A. Purification by flash column chromatography (SiO2, 90:10 hexanes/ethyl acetate) provided 8-bromo-3,4-dihydrodibenzo[b,d]furan-1(2H)-one (410 mg, 35%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.20 (d, J=1.8 Hz, 1H), 7.42 (dd, J=8.7, 2.1 Hz, 1H), 7.33 (dd, J=8.7, 2.7 Hz, 1H), 3.04 (t, J=6.3 Hz, 2H), 2.61 (t, J=6.0 Hz, 2H), 2.28 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:24][C:17]=12.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:24][C:17]=12
Reactant: CN1CCC(c2cc3c(-c4cc(NC(=O)OC(C)(C)C)ccc4F)ccnc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(c2cc3c(-c4cc(N)ccc4F)ccnc3[nH]2)CC1
Reaction time: 2 h

Procedure:
To a solution of Example 179C (102 mg, 0.24 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred for 2 hours. Concentration and purification by HPLC (Zorbax XDB C-18 (32) using a gradient of 5-40% acetonitrile/water (containing 0.1% trifluoroacetic acid) afforded the title compound. LCMS: 325 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][CH2:37][CH2:36][NH:35][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: NCCCCO
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCCO)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 60 mg, 0.126 mmol) and 4-amino-butan-1-ol (1 mL) using a similar method to that employed in Example 48 (17 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH2:26][CH2:27][OH:28])=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=1
Reactant: Nc1ccc(NCCO)nc1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(NCCO)nc1)C1CC1
Yield: 67.2 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 2-(5-aminopyridin-2-ylamino)ethanol (230 mg, 1.5 mmol) to afford the desired product (287 mg, 67%) as a yellow solid: ESI MS m/z 427 [C20H19BrN4O2+H]+.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:20]2[CH2:19][CH:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)C1C=CC=CC=1>CO.C(Cl)Cl>[NH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH2:19][CH:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:16]2
Reactant: CS(=O)(=O)NC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)NC1CCc2cccc(N)c2C1
Yield: 71.8 %

Procedure:
The title compound was prepared using the procedure as described in Example 20E substituting the product of Example 23A (280 mg, 0.748 mmol) for the product Example 20D. Flash chromatography (5% to 10% CH3OH/CH2Cl2) gave 129 mg (72%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.20 (d, J=7.5 Hz, 1H), 6.79 (t, J=7.8 Hz, 1H), 6.43 (m, 1H), 6.30 (m, 1H), 4.74 (s, 2H), 3.55 (m, 1H), 2.99 (s, 3H), 2.75 (m, 3H), 2.22 (m, 1H), 1.95 (m, 1H), 1.58 (m, 1H); MS (DCI+) m/z 241 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1.Cl>C(O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:7]2\[O:8][C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:13]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CCO
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Temperature: 75 °C
Reaction time: 5 h
Yield: 105.4 %

Procedure:
The synthesis was performed with reference to the known literature (International Patent Publication WO1998/30556). A solution of 6-hydroxybenzofuran-3(2H)-one (2.0 g, 13 mmol) and 1H-indole-3-carboxaldehyde (2.3 g, 16 mmol) in ethanol (100 mL) was added with concentrated hydrochloric acid (10 mL), and the mixture was stirred at 75° C. for 5 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol and water to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (3.8 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:15])=[CH:12][C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.FC1C=CC2NC(=O)N([C:40](=[S:51])[C@H:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42])C=2C=1>CN(C=O)C.O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:14]([C:13]1[N:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:40](=[S:51])[C@@H:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH3:42])[N:10]=[C:11]([C:26]([F:28])([F:29])[F:27])[CH:12]=1)=[O:15]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN)c1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=S)n1c(=O)[nH]c2ccc(F)cc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNC(=S)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of 58 (62 mg, 0.153 mmol) in dry DMF (0.3 mL) at 0° C. was added (R)-tert-butyl 1-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-thioxopropan-2-ylcarbamate (57.2 mg, 0.169 mmol; J. Med. Chem.1999, 42, 2046-2052) in two equal portions over 10 minutes and the reaction was stirred at 0° C. for 2 hours and then at room temperature for 16 h. It was then diluted with water (˜15 mL) and extracted into dichloromethane using an “IST phase-separator.” The DCM extracts were combined and concentrated and the crude material purified by silica gel chromatography (Biotage 12M, 20% to 30% to 40% ethyl acetate in hexanes) to give 134 (35 mg, 0.059 mmol, 38.6% yield) as white solid. LRMS(ESI): (calc.) 529.3 (found) 614.3 (MNa)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]([CH2:12][CH:13]=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][C:5]2=[N:4][O:3]1.B.CO>O1CCCC1>[OH:14][CH2:13][CH2:12][CH:7]1[N:6]2[C:2](=[O:1])[O:3][N:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CCC1CCCCc2noc(=O)n21
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=c1onc2n1C(CCO)CCCC2
Yield: 70.6 %

Procedure:
To a solution of the product of Example 8 (3.0 g, 0.015 mol) in tetrahydrofuran (20 mL) was added a borane.THF complex (20 mL, 0.020 mol). The reaction stirred for 2 hours upon which methanol (19 mL) was added. The solvent was removed under reduced pressure. The resulting oil was partioned between CH2Cl2 (40 mL) and water (2×20 mL). The organic layer was dried over magnesium sulfate and all solvent was removed under reduced pressure. The residue was chromatographed eluting with 1:1 ethyl acetate/hexane to produce 2.1 g (69%) of the title material.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)=[O:29]>C1COCC1.CO>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[O:29])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccccn4)c3C2=O)C(=O)N1
Yield: 39.6 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added pyridine-2-carbonyl chloride hydrochloride (0.71 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in a biphasic mixture of diethyl ether (20 ml)/20% NH4OH (20 ml) and filtered to give an off-white solid. The solid was re-slurried in methanol (20 ml) and filtered to give 0.30 g (40%) of product: mp 336–338° C.; 1H NMR (DMSO-d6) δ 11.83 (s, 1H), 11.20 (s, 1H), 8.92 (d, J=8.4 Hz, 1H), 8.81 (d, J=3.6 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H), 8.15 (t, J=7.4 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.77–7.72 (m, 1H), 7.65 (d, J=7.2 Hz, 1H), 5.22 (dd, J=5.2 and 12.5 Hz, 1H), 3.00–2.86 (m, 1H), 2.69–2.52(m, 2H), 2.15–2.11 (m, 1H); 13C NMR (DMSO-d6) δ 172.67, 169.67, 168.20, 166.61, 162.69, 148.83, 148.19, 138.45, 136.50, 136.16, 131.39, 127.72, 124.23, 122.46, 118.29, 116.32, 48.96, 30.91, 21.98; Anal. Calcd. For C19H14N4O5: C, 60.32; H, 3.73; N, 14.81. Found: C, 60.05; H, 3.57; N, 14.45.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].O.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1cccc(Br)c1
Reaction time: 48 h

Procedure:
A magnetically stirred solution of 3-bromobenzaldehyde (86.5 g, 0.468 mol) and malonic acid (107 g, 1.03 mol) in pyridine (200 ml) was treated with peiperidine (4.0 ml, 40.45 mmol) and heated at ~90° C. for 90 min then under reflux for 30 min. The cooled mixture was poured onto ice (200 g) and water (300 ml) then acidified to ph=1 with conc. hydrochloric acid. Filtration afforded a white solid which was washed with water (4×200 ml), dried by suction and placed in an oven at 70° C. for 48 h until constant weight was obtained (96.02 g, 90%); Vmax (nujol)/cm-1 3400-2000 (br. OH), 1684.5, 1631.5, 1587.0; δH (270 MHz) 6.45 (1H, d, 2-H, 3J2,3 =16,2 Hz); 7.28 (1H, t, 5'-H, Jo =7.8 Hz); 7.48 (1-H, dt, 4'-H, Jo =7.9, Jm =1.3 Hz); 7.54 (1-H, dt, 6'-H, Jo =7.9, Jm =1.0 Hz); 7.70 (1-H, t, 2'H, Jm =1.8 Hz); 7.71 (1H, d, 3-H, 3J3,2 =15.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[NH:14][CH2:15][CH2:16][OH:17])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[NH:14][CH2:15][CH2:16][OH:17]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1NCCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cccc(C(F)(F)F)c1NCCO
Temperature: 60 °C
Yield: 89.9 %

Procedure:
To a solution of 2-{[2-nitro-6-(trifluoromethyl)phenyl]amino}ethanol (0.72 g, 2.88 mmol) in methanol (30 mL) a suspension of 85% sodium hydrosulfite (2.0 g, 9.8 mmol) in water (6 mL) was added. Additional water (4 mL) was added, and the mixture was heated at 60° C. for 15 min. The reaction mixture was cooled and concentrated in vacuo. The residue was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate. The solvent was removed in vacuo affording 0.57 g of 2-{[2-amino-6-(trifluoromethyl)phenyl]amino}ethanol: MS (ES) m/z 219 [M−H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:8].[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)([OH:26])=[O:25].[BH4-].[Na+]>C(O)(=O)C>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([C:7]([NH:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][CH2:30][C:29]3[CH:28]=[C:27]([CH:34]=[CH:33][CH:32]=3)[C:24]([OH:26])=[O:25])[CH:23]=[CH:22][CH:21]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Nc1cccc(CNC(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cccc(CNc2cccc(CNC(=O)c3ccc(-c4ccccc4)cc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
N-(3-aminobenzyl)-1,1′-biphenyl-4-carboxamide (20 mg, 0.07 mmol) was dissolved in acetic acid (0.5 ml). 3-Carboxybenzaldehyde (14 mg, 0.09 mmol) was added and then sodium borohydride (11 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 2 hours and evaporated to dryness. DCM was added into the residue. The mixture was loaded on a column (ISOLUTE® SI, 500 mg/3 ml). It was eluted with DCM, MeOH/DCM (0.5:99.5) and then MeOH/DCM (1:99). The product fractions were combined and the solvent was removed, Re-chromatography of the residue on a column (ISOLUTE® SI, 1 g/6 ml) using DCM, MeOH/DCM (0.5:99.5) and then MeOH/DCM (1:99) as eluant gave 9 mg the desired product, yield 31%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[I-].[CH2:13]([O:20][C:21]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:22]=1[N:28]1[S:32](=[O:34])(=[O:33])[N:31]([CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:30](=[O:41])[CH2:29]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O.[Zn]>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][C:25]1[CH:24]=[CH:23][C:22]([N:28]2[CH2:29][C:30](=[O:41])[N:31]([CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[S:32]2(=[O:34])=[O:33])=[C:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCI
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [I-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (3 g, 46 mmol) is placed in a flask and heated under vacuum to remove traces of water. DMF (25 mL) is then added under nitrogen atmosphere. Dibromoethane (cat. 0.25 mL) is added and the mixture heated until effervescence occurs. The reaction is allowed to cool to RT over 30 min and chlorotrimethylsilane (cat 0.3 mL) is added, followed after 30 min with (2-iodoethyl)-carbamic acid tert-butyl ester (4.5 g, 16.5 mmol) dissolved in 10 mL of DMF. After 30 min, TLC indicates the iodide has been consumed and Pd2(dba)3 (0.20 g) and tri-o-tolylphosphine (0.30 g) are added, followed by the dropwise addition of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (5 g, 9.2 mmol) dissolved in 25 mL of DMF. The reaction mixture is stirred for 14 h and then diluted with EtOAc and filtered through Celite. The filtrate is washed with 1M HCl, brine and water, dried over MgSO4, filtered through a short plug of silica and concentrated to afford the title compound as a light yellow oil.
Reaction SMILES: Br[CH:2]([CH2:18]C)[C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[O:23]1[CH2:24][CH2:25][N:20]([CH:2]([CH3:18])[C:3]([C:5]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]3[C:6]=2[CH2:7][CH2:8][C:9](=[O:17])[NH:10]3)=[O:4])[CH2:21][CH2:22]1
Reactant: CCC(Br)C(=O)c1ccc(OC)c2c1CCC(=O)N2
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C(=O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1

Procedure:
5 g of 5-(α-bromopropionyl)-8-hydroxy-3,4-dihydrocarbostyril (IV) was suspended in 30 ml of benzene, and 4.2 ml of morpholine (III) was added to the suspension followed by allowing the mixture to react for 4 hours while heating under refluxing. The reaction mixture was filtered and the filtrate was washed with water followed by concentration under reduced pressure to remove any remaining water. The resulting residue was dissolved in 50 ml of isopropanol, and the solution was adjusted to a pH of 2 - 3 with concentrated hydrochloric acid. The viscous precipitate formed upon ice-cooling was separated and dissolved in acetone by heating. After allowing the solution to cool, the precipitate formed was dissolved in 30 ml of water and adjusted to a pH of 7.5 - 8 with sodium bicarbonate. The precipitate formed upon ice-cooling was filtered and dissolved in 10 ml of a 47% aqueous hydrobromic acid followed by concentration under reduced pressure. The residue thus obtained was washed with 10 ml of ethanol and recrystallized from ethanol to obtain 2.6 g of white amorphous 5-(α-morpholinopropionyl)-8-hydroxy-3,4-dihydrocarbostyril (IIb) hydrobromide monohydrate having a melting point of 235° - 236° C (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[N:34]=[N:35][N:36]([CH2:38][C:39](O)=[O:40])[CH:37]=1>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][N:36]3[CH:37]=[C:33]([C:32]([F:42])([F:31])[F:43])[N:34]=[N:35]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Reactant: O=C(O)Cn1cc(C(F)(F)F)nn1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)nn3)c2)c2cnccc21

Procedure:
Prepared according to Method Z (Preparation 8) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 28) and [4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetic acid (Preparation 90).