Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH2:35][CH3:36])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Li+]>C1COCC1.CO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([CH2:35][CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)C[C@@H](CC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of 36.2 (0.056 g, 0.114 mmol) in THF/MeOH (2/1) (1.5 mL) was added a solution of 1 M lithium hydroxide (0.50 mL, 0.50 mmol). The resulting mixture was stirred overnight at 23° C., and then quenched with excess 1N HCl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford a 36 (0.046 g, 87% yield). MS ESI (neg.) m/e: 463.3 (M−H)+.
Reaction SMILES: COC1C=C(OC)C=C(OC)C=1C[NH:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=1.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].COCCOCCOC>O>[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:32][C:11]1[N:10]=[CH:9][N:8]=[C:7]([NH2:6])[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COc1cc(OC)c(CNc2cc(Cl)ncn2)c(OC)c1
Solvent: O
Solvent: COCCOCCOC
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 160 °C
Reaction time: 4 h
Yield: 25.1 %

Procedure:
A mixture of N-(2,4,6-trimethoxybenzyl)-6-chloropyrimidin-4-amine (2.2 g, 7.11 mmol), 2-fluoro-4-nitrophenol (1.1 g, 7.0 mmol), and 2-methoxyethyl ether (50 mL) was heated at 160° C. for 60 h. The reaction mixture was cooled to RT and poured into H2O (200 mL). The solid was collected, washed with 2 M aqueous Na2CO3 and H2O, and then vacuum dried on a Büchner funnel. The crude product was treated with TFA (20 mL) in dioxane (40 mL) and stirred at RT for 4 h. The reaction mixture was concentrated, the residue partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc phase was separated, dried (MgSO4), concentrated and the crude product purified by flash chromatography using 1-2% MeOH in CH2Cl2 as the eluent to give 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (440 mg, 31%). 1H NMR (DMSO-d6) δ 8.31 (dd, 1H, J=10.4, 2.5 Hz), 8.14 (dd, 1H, J=9.8, 2.0 Hz), 8.04 (s, 1H), 7.61 (dd, 1H, J=8.3, 8.3 Hz), 7.07 (s, 2H), 6.02 (s, 1H); MS(ESI+) m/z 251.15 (M+H)+.
Reaction SMILES: C1N(P(N2CC2)(NC(C2C(I)=CC=CC=2)=O)=O)C1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][N:27]=2)[CH2:22][CH2:21]1.I[C:35]1[C:43]2[C:38](=[CH:39][C:40]([CH:44]=[O:45])=[CH:41][CH:42]=2)[N:37]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:36]=1>>[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]2[N:27]=[CH:28][C:29](/[CH:32]=[CH:33]/[C:35]3[C:43]4[C:38](=[CH:39][C:40]([CH:44]=[O:45])=[CH:41][CH:42]=4)[N:37]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:36]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1
Reactant: C=Cc1ccc(N2CCN(C)CC2)nc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: O=C(NP(=O)(N1CC1)N1CC1)c1ccccc1I
Product: CN1CCN(c2ccc(/C=C/c3nn(COCC[Si](C)(C)C)c4cc(C=O)ccc34)cn2)CC1

Procedure:
The title compound was synthesized according to the method of Example A103, utilizing 1-methyl-4-(5-vinylpyridin-2-yl)piperazine (65 mg, 0.32 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.25 mmol). Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange material (46 mg, 39%). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1H), 8.34 (d, J=2.26 Hz, 1.0H), 8.24-8.28 (m, 2H), 8.00 (dd, J=8.91, 2.38 Hz, 1H), 7.80 (d, J=8.78 Hz, 1H), 7.51 (d, J=16.56 Hz, 1H), 7.36 (d, J=16.56 Hz, 1H), 6.97 (d, J=9.29 Hz, 1H), 5.85 (s, 2H), 3.77-3.87 (m, 4H), 3.63 (t, J=7.91 Hz, 2H), 3.06-3.15 (m, 4H), 2.75 (s, 3H), 0.88 (t, J=8.03 Hz, 2H), −0.09 (s, 9H); MS ESI 478.3 [M+H]+, calcd for [C26H35N5O2Si+H]+ 478.7.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:28])[CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20](C(OC)=O)=[CH:19][CH:18]=1>>[CH3:12][O:13][C:14](=[O:28])[C:22]1([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[O:28]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: COC(=O)CC(=O)c1ccc(C(=O)OC)cc1
Product: COC(=O)C=CC1C=CC=CC1(Nc1ccc(OC(C)C)cc1)C(=O)OC

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 1 from p-isopropoxyaniline and 4-methoxycarbonylbenzoyl acetic acid methyl ester.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(OC1CCCCO1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A mixture of 7 g. of 4-(8-cyclohexyloctylamino)benzoic acid, 2 g. 2,3-dihydropyran and 100 mg. anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and condensed. The residue is crystallized from methylcyclohexane to white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(C(C)C)C(C)C.[Cl-].[Cl-].[O:20]=[S:21]1(=[O:32])[CH2:25][CH2:24][CH:23]([NH+:26]2[CH2:31][CH2:30][NH2+:29][CH2:28][CH2:27]2)[CH2:22]1.Cl>C(O)CCC>[O:32]=[S:21]1(=[O:20])[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:28][CH2:27]2)[CH2:22]1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=S1(=O)CCC([NH+]2CC[NH2+]CC2)C1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1cc(N2CCN(C3CCS(=O)(=O)C3)CC2)ncn1

Procedure:
7-2 (0.23 g, 1.79 mmol), DIEA (0.69 g, 5.37 mmol) and 1-(1,1-dioxidotetrahydrothien-3-yl)piperazinediium dichloride (the bis HCl salt of 39-1) (0.49 g, 1.79 mmol) were stirred at 150° C. in n-butanol for 18 hours overnight. Upon cooling, the solid was filtered off and washed with n-butanol and ethyl ether to afford 39-2. Hi-Res MS: calc: 298.1132 found: 298.1357. 1H-NMR (CD3OD): 7.97(s, 1H); 5.72(s, 1H); 3.55(t, 4H); 3.27(complex, 2H); 3.07(complex, 2H); 2.77(complex, 1H); 2.67(m, 2H); 2.59(m, 2H); 2.47(m, 1H); 2.12(m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:22]1([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.N1C=CC=CC=1>C1COCC1>[OH:32][CH:29]([CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH2:30][O:31][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:21])=[O:19]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Reactant: OCC(O)CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CN3CCOCC3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol), 3-morpholin-4-yl-propane-1,2-diol, and pyridine in 3.0 mL of THF was stirred at room temperature for 15 min and filtered. The solid was then washed with ethyl acetate and ether to give 116 mg (55%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-morpholin-4-yl-propyl ester as an orange solid. 1HNMR (400 MHz, DMSO-d6) δ 12.06 (s, br, 1H, NH-1′), 10.47 (s, br, 1H, OH), 7.86–7.88 (m, 1H, H-4), 7.79–7.81 (m, 1H, H-7), 7.66 (s, 1H, H-vinyl), 7.19–7.23 (m, 2H, H-5, 6), 6.12 (d, J=2.34 Hz, 1H, H-4′), 4.35–4.45 (m, 3H), 3.75–3.98 (m, 4H), 3.26–3.51 (m, 7H), 2.37 (s, 3H, CH3), and 2.34 (s, 3H, CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][CH:31]3[S:35][C:34](=[O:36])[NH:33][C:32]3=[O:37])=[CH:38][CH:39]=2)[CH3:18])=[CH:13][CH:12]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)c(OC)c1
Agent: Cl
Product: COc1ccc(-c2ccc(C(C)=NOCCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c(OC)c1
Yield: 89.8 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 256 mg of 4'-(2,4-dimethoxyphenyl)acetophenone and 382 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 467 mg of the title compound, melting at 186-188° C., were obtained.
Reaction SMILES: CS(O)(=O)=O.[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1.[CH3:14][C:15]1[N:24]=[C:23]2[N:17]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[CH:22]2O)[C:16]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:14][C:15]1[N:24]=[C:23]2[N:17]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[CH:22]2[O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[C:16]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1CCC(O)CC1
Reactant: Cc1nc2n(c1-c1ccccc1)CCc1ccccc1C2O
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2n(c1-c1ccccc1)CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methanesulfonic acid (1.5 mL) and 4-hydroxy-N-methylpiperidine (658 mg, 5.72 mmoles) in CHCl3 (1 mL) cooled at 0° C. is added a solution of 2-methyl-1-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-4-ol (example 123B) (166.1 mg, 0.573 mmole) in CHCl3 (2 mL) dropwise. The reaction mixture is allowed to slowly reach room temperature and is stirred at room temperature for 2 hours. The reaction mixture is poured into a solution of saturated Na2CO3 (final pH 9-10). The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) with a gradient from (100:0:0) to (95:5:0.5) to give 2-methyl-4-(1-methylpiperidin-4-yloxy)-1-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([O:16]CC)=O.[NH2:19][NH2:20]>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:14]([NH:19][NH2:20])=[O:16]
Reactant: NN
Reactant: CCOC(=O)c1nc(-c2ccc(C)cc2)[nH]c1C
Solvent: O
Product: Cc1ccc(-c2nc(C(=O)NN)c(C)[nH]2)cc1

Procedure:
A mixture of 4.9 g of the above ester and 15 ml of anhydrous hydrazine was stirred and refluxed overnight. Water was added, the mixture was evaporated and the residue recrystallized from ethanol, giving 3.45 g of 5-methyl-2-(4-methylphenyl)-1H-imidazole-4-carboxylic acid, hydrazide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=1.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C>[N:27]1[CH:28]=[CH:29][C:24]([CH:22]=[CH:23][C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Reactant: C=Cc1ccncc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(C=Cc2ccncc2)c1
Yield: 79 %

Procedure:
A mixture of 5-bromo-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine (440 mg, 1.25 mmol), 4-vinylpyridine (0.267 mL), Pd(OAc)4 (30 mg), tris(o-tolyl)phosphine (160 mg), and triethylamine (3.5 mL) in acetonitrile (4 mL) was heated at reflux for 16 hours. The solution was then concentrated, and the residue was washed with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:EtOAc 1:3 to afford the title compound (440 mg, 79% yield). MS (CI/NH3) m/z 382 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.49 (s, 3H), 1.85-2.12 (m, 4H), 3/26 -3.55 (m, 2H), 3.86-4.08 (m, 1H), 4.08--4.34 (m, 1H), 7.20-7.30 (m, 2H), 7.36-7.42 (m, 2H), 7.71 (br s, 0.5 H), 8.22-8.42 (m, 1.5 H), 8.58-8.69 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[F:25].CN1C(=O)N(C)CCC1.C(O[Li])(C)(C)C.[C:41]([CH2:45]OS(C(F)(F)F)(=O)=O)([F:44])([F:43])[F:42]>C1COCC1>[CH3:1][C@H:2]1[N:7]([CH2:45][C:41]([F:44])([F:43])[F:42])[C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[F:25]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C[C@H]1NC(=O)C(NC(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1F
Agent: [Li]OC(C)(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)CC(NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
To a solution of 46 (50 g, 0.14 mol) and DMPU (7.2 g, 0.06 mol) in THF (500 mL) was added tert-BuOLi (8.6 g, 0.11 mol) in portions at 20° C. for 0.5 h. After the mixture was degassed for 30 min at 20° C., CF3CH2OTf (37.5 g, 0.14 mol) was added at 20-25° C. The solution was stirred for 24 h at 20-25° C. After the reaction was complete, the mixture was quenched by water, and then partitioned with water and EtOAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (2-10% EtOAc/PE) to give product 47 (50 g, 82% yield). 1H (DMSO-d6, 400 MHz): δ 7.52 (m, 1H), 7.22-6.91 (m, 1H), 4.65 (m, 1H), 3.85 (br, 1H), 3.38-3.37 (m, 2H), 1.40 (s, 9H), 0.90 (m, 3H); MS (ESI) m/e [M+H]+: 441.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1.[H-].[Na+].[Cl:31]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Cl:31][C:17]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere, to a mixture of ethyl 3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (3.1 g) in DMF (30 mL) was added sodium hydride (60%, 0.34 g) at 0° C., and the mixture was stirred at room temperature for 30 min. N-Chlorosuccinimide (1.14 g) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (1.9 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3O)[N:9]=1)[CH3:2].[NH2:29][CH2:30][CH2:31][OH:32]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3[NH:29][CH2:30][CH2:31][OH:32])[N:9]=1)[CH3:2]
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4O)no2)cc1OCC
Reactant: NCCO
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4NCCO)no2)cc1OCC

Procedure:
Prepared using General Procedure 14 using 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol 60 and 2-aminoethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=O)=[O:5]>C(O)(=O)C>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]=[C:25]1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:5]
Reactant: O=C(Nc1ccccc1Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12)c1cccnc1
Solvent: CC(=O)O
Product: O=C(Nc1cccc2c(-n3c(-c4cccnc4)nc4ccccc43)ccnc12)c1c(Cl)cccc1Cl
Yield: 93.9 %

Procedure:
A solution of 8-(2,6-dichlorobenzoylamino)-4-[2-(3-pyridinecarboxamido)phenylamino]quinoline (150 mg) in acetic acid was refluxed for 60 hours. After cooling, the mixture was concentrated in vacuo and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from acetonitrile and collected by filtration to give 8-(2,6-dichlorobenzoylamino)-4-[2-(3-pyridyl)-1H-benzimidazol-1-yl]quinoline (136 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10](OC)=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][N:8]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH:10]=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][N:8]=1
Reactant: COC(=O)c1nc(C)cnc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1ncc(C)nc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
After dissolving 300 mg of methyl 3-methoxy-6-methylpyrazine-2-carboxylate in a mixture of 5 ml toluene/5 ml dichloromethane, the solution was cooled to −78° C. Next, 1.21 ml of diisobutylaluminium hydride (1.5 M, toluene solution) was added dropwise and the mixture was stirred for 1 hour. After adding 10 ml of 1N hydrochloric acid dropwise to the reaction solution, extraction was performed with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, a saturated sodium bicarbonate solution and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (118 mg, 47% yield).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].C1C(=O)N([Br:30])C(=O)C1>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:30])=[CH:18][C:17]=1[Cl:22]
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.82 g, 5.39 mmol) in DMF (10 mL) was added NBS (1.0 g, 5.65 mmol). After stirring for 4 h at ambient temperature, the reaction was quenched by saturated NH4Cl (aq.). The solution was extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL) successively, dried over Na2SO4 and concentrated in vacuo to give the desired product (yellow solid, 2.02 g, 90.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 8.60 (d, 1H), 7.59 (d, 1H), 7.29 (m, 1H), 6.77 (m, 1H), 4.04 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C@H:13]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=1)[CH3:14].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([C:4]([NH:12][C@H:13]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:17][CH:16]=2)[CH3:14])=[O:6])=[CH:7][C:8]([Cl:11])=[CH:9][N:10]=1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a stirred solution of 2,5-dichloronicotinic acid (Syn. Commun. 1989, 19, 553–9, 1.92 g, 10 mmol) and tert-butyl 4-[(1S)-1-aminoethyl]benzoate (example 44 step 3, 2.02 g, 9.1 mmol) in dichloromethane (20 mL) were successively added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.59 g, 13.5 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (2.07 g, 13.5 mmol), and triethylamine (4 mL). After being stirred overnight, the reaction was quenched by the addition of saturated sodium bicarbonate aqueous solution (100 mL). The aqueous layer was extracted with dichloromethane (50 mL×3) and the combined organic layers were washed with brine (100 mL), dried (sodium sulfate), and evaporated. The remaining residue was purified by flush column chromatography on silica gel (100 g) eluting with dichloromethane/ethyl acetate (20/1) to afford 2.51 g (70%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.41 (1H, d, J=2.6 Hz), 8.09 (1H, d, J=2.6 Hz), 7.99 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz), 6.81 (1H, d, J=7.2 Hz), 5.33 (1H, dq, J=7.2, 7.0 Hz), 1.62 (3H, d, J=7.0 Hz), 1.58 (9H, s).