Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=1)=[N:6]2.[CH3:33][N:34](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:4]1[N:5]2[C:10]([CH:9]=[N:8][C:7]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)=[CH:16][CH:17]=3)=[N:6]2)=[C:2]([C:33]#[N:34])[CH:3]=1
Reactant: COc1ccccc1-c1cc(Br)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Reactant: CN(C)C=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Product: COc1ccccc1-c1cc(C#N)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12

Procedure:
Into a Microwave vial, [5-Bromo-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.151 g, 0.000306 mol), Zinc Cyanide (0.0719 g, 0.000612 mol), Copper(I) iodide (5.8 mg, 0.000031 mol) and Tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.000031 mol) were added and purged with nitrogen for 10 minutes. N,N-Dimethylformamide (3.00 mL, 0.0387 mol) was added. The reaction was microwaved on 300 watts, 150° C. for 60 minutes. The solvent was removed under vacuum. The reaction was purified via ISCO column chromatography with DCM and MeOH as eluant (0 to 10% methanol). The collected fractions afforded 7-(2-Methoxy-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile a yellow solid (62 mg, 46%). LCMS (E/I+) 440.18M+H). NMR 1H (DSMO-d6)-9.59 (s, 1H), 9.20 (s, 1H), 7.72 (dd, 1H, J=1.64, 6.00 Hz), 7.46-7.57 (m, 3H), 7.43 (s, 1H), 7.42 (d, 1H, J=8.33 Hz), 7.13 (t, 1H, J=7.56 Hz), 6.80 (d, 2H, J=9.13 Hz), 3.79 (s, 3H), 3.04 (t, 4H, J=4.64, 2.43 (t, 4H, J=4.84), 2.21 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.ClC1C=CC=CN=1.ClC1N=C(C2C=CC=CC=2)C(C(OCC)=O)=CC=1.N[C:57]1[N:62]=[C:61]([NH:63][CH2:64][CH2:65][NH:66][C:67]2[CH:72]=[CH:71]C(C3NC=CN=3)=C(C3C=CC(Cl)=CC=3Cl)[N:68]=2)[CH:60]=[CH:59][C:58]=1[N+:86]([O-:88])=[O:87]>C1(C)C=CC=CC=1.CC(N(C)C)=O.C1COCC1.C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:71][CH:72]=[C:67]([NH:66][CH2:65][CH2:64][NH:63][C:61]3[CH:60]=[CH:59][C:58]([N+:86]([O-:88])=[O:87])=[CH:57][N:62]=3)[N:68]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CC(=O)c1ccc(C#N)cc1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: CCOC(=O)c1ccc(Cl)nc1-c1ccccc1
Agent: Clc1ccccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(C#N)cc1

Procedure:
ethyl 2-(4-cyanophenyl)-6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyridine-3-carboxylate (62258) was prepared from ethyl 3-(4-cyanophenyl)-3-oxopropanoate (ref. Wemple, J.; et. al. Synthesis 1993, 290-292.) as the starting material and THF/ethanol ratio of 1:5 as the solvent in the first step. The oxidation uses DDQ in toluene. The final product is achieved directly from the chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3-carboxylate with 2-(2-aminoethylamine)-5-nitropyridine in DMA and Hüing's base at 120° C. for 18 hours. The procedures are analogous to the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [CH2:1](Br)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:29][O:30][C:31]1[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([O:40][CH3:41])[C:32]=1[CH:33]=O>O1CCCC1>[CH3:41][O:40][C:35]1[CH:36]=[C:37]([OH:39])[CH:38]=[C:31]([O:30][CH3:29])[C:32]=1[CH2:33][CH2:1][CH3:2]
Reactant: CCBr
Reactant: COc1cc(O)cc(OC)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(OC)cc(O)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
Anhydrous tetrahydrofuran (36 ml) was added to triphenylphosphine ethyl bromide (12.3 g) prior to stirring at room temperature for 20 minutes. To the resulting mixture was added potassium tert-butoxide (4.5 g), for stirring at room temperature for 30 minutes. Then, 2,6-dimethoxy-4-hydroxybenzaldehyde (3.0 g) was added to the resulting mixture for stirring at room temperature for 2 hours. The resulting solution was partitioned between ethyl acetate and dilute hydrochloric acid, and the resulting ethyl acetate phase was washed in water and subsequently in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:hexane:ethyl acetate=2:1), followed by addition of a catalytic amount of platinum dioxide for hydrogenation, to recover 3,5-dimethoxy-4-propylphenol (1.8 g; yield of 55%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[C:4]1=[O:17])[CH3:2].S1C=CC=C1.CO.[H][H]>C(O)C.[Pd]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][N:3]([CH2:1][CH3:2])[C:4]2=[O:17])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CCO
Solvent: CO
Product: CCN1CCN(c2ccc(N)cc2)C1=O
Yield: 93 %

Procedure:
A mixture of 12 parts of 1-ethyl-3-(4-nitrophenyl)-2-imidazolidinone, 1 part of a solution of thiophene in ethanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 9.6 parts (93%) of 1-(4-aminophenyl)-3-ethyl-2-imidazolidinone (18).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][N:26]5[C:31](=[O:32])[CH:30]=[CH:29][C:28]([C:33]6[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=6)=[N:27]5)[CH:23]=4)[N:18](C(OC(C)(C)C)=O)[N:17]=3)[N:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].CN(C=O)C.CCO.Cl>[OH-].[Na+]>[O:32]=[C:31]1[N:26]([CH2:25][C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:14]2[N:13]=[N:12][N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)[CH:15]=2)[N:27]=[C:28]([C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)[CH:29]=[CH:30]1
Reactant: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(Cn5nc(-c6ccncc6)ccc5=O)cc34)nn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5nc(-c6ccncc6)ccc5=O)cc34)nn2)cc1
Temperature: 80 °C
Yield: 132.5 %

Procedure:
tert-butyl 3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-[(6-oxo-3-pyridin-4-ylpyridazin-1(6H)-yl)methyl]-1H-indazole-1-carboxylate (88 mg; 0.10 mmol; 1.0 eq.) was suspended in NaOH (5N solution, 0.50 mL), DMF (6 mL) and EtOH (6 mL). The suspension was heated in MW at 80° C. for 10 min. The reaction mixture was allowed to cool to RT and brought to pH 6 by addition HCl (1N solution). The resulting solution was passed through an SCX-2 column and concentrated to give the title compound as a yellow solid (65 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 9.28 (s, 1H), 8.70 (dd, J=1.6, 4.5 Hz, 2H), 8.50 (s, 1H), 8.17 (d, J=9.8 Hz, 1H), 8.04 (d, J=8.7 Hz, 2H), 7.99-7.88 (m, 4H), 7.58 (d, J=9.0 Hz, 2H), 7.55-7.47 (m, 1H), 7.17 (d, J=9.8 Hz, 1H), 5.54 (s, 2H). HPLC (Condition A): Rt 2.34 min (purity 93.1%). MS (ESI+): 491.3, MS (ESI−): 489.4.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][C:10](=[O:27])[CH2:11][C@H:12]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[C:13]([O:15]C(C)(C)C)=[O:14]>ClCCl>[CH3:8][S:9][C:10](=[O:27])[CH2:11][C@H:12]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[C:13]([OH:15])=[O:14]
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SC)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCC(=O)N[C@@H](CC(=O)SC)C(=O)O
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 83.1 %

Procedure:
Trifluoroacetic acid (0.684 ml, 9.20 mmol) was added to a solution of (S)-tert-butyl 4-(methylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1e-IA, 69.3 mg, 0.23 mmol) in dichloromethane (1.2 ml), and the mixture was stirred at room temperature for 6.5 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=100/0→60/40) to afford (S)-4-(methylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-IA) (46.9 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=4)[C:22](O)=[O:23])[C:11]3=[O:28])[CH2:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([N:60]5[CH2:65][CH2:64][O:63][CH2:62][CH2:61]5)=[O:23])[CH:20]=4)[C:11]3=[O:28])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.3 %

Procedure:
A mixture of (1S,2S) and (1R,2R)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)benzoic acid (117 mg, 0.3 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU)(145 mg, 0.45 mmol), N,N-Diisopropylethylamine (DIPEA) (154 μL, 0.9 mmol) and morpholine (79 μL, 0.9 mmol) in DMF (2 mL) was stirred at room temperature for 14 hours. Purification by preparative HPLC gave desired product as a white solid (83 mg, 60%). LC/MS m/e calcd. for C27H23ClN2O3: 458, observed (M+H)+: 459.2 1H NMR (400 MHz, MeOD-d4) δppm 2.23-2.31 (m, 2 H) 3.28-3.32 (m, 1 H) 3.77 (br. s., 8 H) 6.16 (d, J=7.58 Hz, 1 H) 6.81 (t, J=7.58 Hz, 1 H) 6.93 (d, J=7.83 Hz, 1 H) 7.11-7.19 (m, 1 H) 7.26-7.33 (m, 2 H) 7.33-7.38 (m, 2 H) 7.56 (d, J=7.58 Hz, 1 H) 7.60-7.67 (m, 2 H) 7.68-7.76 (m, 1 H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH4+].[OH-]>CO.C1COCC1.[Ni]>[NH2:20][CH2:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH2:5][CH2:6]3)[S:11][C:12]=2[CH:18]=1
Reactant: N#Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carbonitrile (1 g, 3.52 mmol) in MeOH-THF (120 mL, 5:3) was added NH4OH (15 mL) and Raney Ni (200 mg). The mixture was stirred for 12 h at rt under 50 psi H2 atmosphere. After filtration, the mixture was concentrated to give 6-aminomethyl-2-(4-cyclopropylpiperazin-1-yl)benzothiazole (500 mg, 49.3%), which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:38]([F:39])=[CH:37][C:10]3[N:11](CC4C=CC(C5C=CC=CC=5)=CC=4)[C:12]([O:14][CH:15]4[CH2:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:40])=[CH:3][CH:2]=1.C1CC=CCC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:1]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:38]([F:39])=[CH:37][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:40])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCC=CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1

Procedure:
To a solution of ethyl 3-{[5-(biphenyl-4-yl)-1-(biphenyl-4-ylmethyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclobutanecarboxylate (0.160 g, 0,260 mmol) and Pd(OH)2 (0.048 g, 0.068 mmol) in 2.5 mL of EtOAc and 1.25 mL of EtOH was added 1,4-cyclohexadiene (0.630 mL, 6.70 mmol). The resulting black suspension was microwaved at 130° C. for 2 h. Then the reaction was filtered through a Celite™ pad, washed with 100% EtOAc, and the filtrate was concentrated in vacuo. Purification of the resulting residue by reverse phase Gilson™ HPLC (50-100% MeCN/H2O) afforded the title compound as a white solid. LCMS: calculated for C26H22F2N2O3 448.46, observed m/e 449.0 (M+H)+ (Rt 2.27/4 min).
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][C:5]12[CH2:12][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH:9]1[CH2:8][CH2:7][O:6]2>O.C(O)(C)(C)C>[CH2:13]([N:11]1[CH2:12][C:5]2([CH2:4][NH:3][C:7]([O:6][C:5]([CH3:12])([CH3:9])[CH3:4])=[O:1])[CH:9]([CH2:8][CH2:7][O:6]2)[CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: NCC12CN(Cc3ccccc3)CC1CCO2
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCC12CN(Cc3ccccc3)CC1CCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 g of NaOH in 45 ml of water are added to 10.4 g (44.7 mmol) of 1-aminomethyl-7-benzyl-2-oxa-7-azabicyclo[3.3.0]octane in 56 ml of tert-butanol, and 10.2 g (47 mmol) of di-tert-butyl pyrodicarbonate are then added dropwise. The mixture is stirred at room temperature for 15 hours, and then extraction with chloroform, drying over potassium carbonate, concentration and distillation are carried out. Yield: 12.2 g (82% of theory) Boiling point: 170° C./0.15 mbar The product is 94% pure by gas chromatography.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14]C)[CH:12]=3)[C:7]([C:16]#[N:17])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=3)[C:7]([C:16]#[N:17])=[CH:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1ccc2c(C#N)cn(C3CCC3)c2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1cn(C2CCC2)c2cc(O)ccc12
Temperature: -20 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
1-cyclobutyl-6-methoxy-1H-indole-3-carbonitrile (100 g, 442 mmol) was dissolved in CH2Cl2 (700 mL) and cooled to −20° C. Boron tribromide (300 g, 1.2 mol) was added dropwise over 2.5 hours to the cooled solution. The reaction was poured into ice water (2 L), neutralized to pH 7 with 5 N aq. sodium hydroxide and stirred overnight at room temperature. The remaining organic solvent was evaporated and the resulting suspension was filtered. The solid was washed with water (2×200 mL), 1/1 hexane/ethyl ether (2×125 mL) and dried in a stream of nitrogen to give 1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile as a beige powder (90.0 g, 96%).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:23][CH:24]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: CCS(=O)(=O)Nc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Nc1ccc(CNC(=O)COc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a N,N-dimethylformamide (DMF) (5 ml) solution of (4-tert-butylphenoxy)acetic acid (330 mg, 1.50 mmol) and N-[4-(aminomethyl)phenyl]ethanesulfonamide hydrochloride (451 mg, 1.80 mmol, Journal of Medicinal Chemistry 2003, 46(14), 3116–3126), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (431 mg, 2.25 mmol), 4-(dimethylamino)pyridine (DMAP) (46 mg, 0.38 mmol) and triethylamine (506 mg, 5.0 mmol) were added and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=100/1 to furnish the title compound. Further, the title compound was recrystallized from ethyl acetate and hexane to furnish 341 mg (56% yield) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:2]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Temperature: 92.5 °C
Yield: 82.1 %

Procedure:
A mixture of methyl 2-chloro-4-nitrobenzoate (44.2 g, 205 mmol), phenylboronic acid (27.5 g, 226 mmol), sodium carbonate (2.0 M in water, 123 mL, 246 mmol), and bis(triphenylphosphine)palladium(II) chloride (2.8 g, 4 mmol) in dioxane (300 mL) was degassed by nitrogen, and heated at 90-95° C. for 20 hours. The reaction mixture was diluted with ether (500 mL) and ethyl actate (500 mL), washed with water (2 times, 200 mL each) and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystalized from hexane-ethyl acetate (1/1) to give 2-phenyl-4-nitrobenzoic acid methyl ester as a white solid (43.3 g). The mother liquid from the recrystalization was concentrated in vacuo, and the residue was purified by column chromataography (80:15:5 hexane-chloroform-ethyl acetate) to yield an additional 5.2 g of the desired compound (total yield 48.5 g, 92%). 1H NMR (300 MHz, CDCl3) δ 8.25 (d, 1H), 8.24 (dd, 1H), 7.94 (dd, 1H), 7.44 (m, 3H), 7.35 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: NCc1ccccc1Br
Reactant: COC(=O)C(OC)OC
Product: COC(OC)C(=O)NCc1ccccc1Br
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Into a sealed tube were added methyl dimethoxyacetate (1.0 g, 7.5 mmol) and 2-bromobenzylamine (1.1 g, 5.8 mmol), this mixture was stirred at 50° C. for 16 h. The completed reaction was transferred to a flask and re-crystallized from heptane yielding the desired product as an off-white solid. MS (ES+): m/z=288.04/289.69 [MH+]. HPLC: tR=2.93 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[ClH:12].[CH3:13][O:14][C:15]1[C:23]2[O:22][C:21]([CH3:25])([CH3:24])[CH2:20][C:19]=2[C:18]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([C:37]3[CH:42]=[CH:41][C:40]([C:43](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:44])=[CH:39][CH:38]=3)[N:27]=2)=[CH:17][CH:16]=1>>[ClH:12].[ClH:12].[CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:43]([C:40]2[CH:41]=[CH:42][C:37]([N:28]3[N:27]=[C:26]([C:18]4[C:19]5[CH2:20][C:21]([CH3:25])([CH3:24])[O:22][C:23]=5[C:15]([O:14][CH3:13])=[CH:16][CH:17]=4)[C@@H:35]4[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]4)[C:29]3=[O:36])=[CH:38][CH:39]=2)=[O:44])[CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCNCC1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CCN(C)C)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A2 and 1-(2-dimethylaminoethyl)-piperazine as described for compound 8. M.p. 245° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:8]([NH:14][CH2:15][CH3:16])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=O.[C:20]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21]1.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[N:14]([CH2:15][CH3:16])[C:24](=[O:25])[C:23]=2[CH2:22][CH2:21][C:20]([OH:26])=[O:27])[CH:17]=[CH:18][CH:19]=1
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Br)c1
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Solvent: O
Product: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Br)c2)c2ccc(C)nc21
Temperature: 150 °C
Yield: 64.1 %

Procedure:
A mixture of 1.2 g of 3-(3-bromobenzoyl)-2-ethylamino-6-methylpyridine and 2.1 g of glutaric anhydride was stirred under heating at 150° C. for 15 hours. After cooling to room temperature, 10 ml of 1M hydrochloric acid was added thereto and the whole was heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. To the residue was added 50 ml of ethanol and 0.5 ml of concentrated sulfuric acid, followed by heating under reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. The residue was purified by a silica gel column chromatography (chloroform). Thereafter, similar operations to those in Example 2 were carried out to obtain 1.00 g of 3-[4-(3-bromophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[S:46]1[C:50](B(O)O)=[CH:49][C:48]2[CH:54]=[CH:55][CH:56]=[CH:57][C:47]1=2.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:50]2[S:46][C:47]3[CH:57]=[CH:56][CH:55]=[CH:54][C:48]=3[CH:49]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cc3ccccc3s2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using 19 (83.4 mg, 0.123 mmol), benzo[b]thiophene-2-boronic acid (109 mg, 0.613 mmol), Pd(PPh)3Cl2 (4.32 mg, 0.00615 mmol), 2 M Na2CO3 (aq., 0.185 mL, 0.369 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of 20-100% CH3CN in 0.05% aqueous formic acid) afforded the product (56.4 mg, 62%) as a white solid.