Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)(=[O:7])=[O:6].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]3[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=3)[CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=4)[CH2:28][CH2:27]3)=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(NCCO)c1ccc(B(O)O)cc1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCO)cc4)cc3)CC2)n1
Yield: 2 %

Procedure:
The title compound (4 mg, 2%) was prepared as a white solid from (4-{[(2-hydroxyethyl)amino]sulfonyl}phenyl)boronic acid (98 mg, 0.4 mmol), 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (prepared as in Example 24, Step 1, 152 mg, 0.4 mmol), Pd(PPh3)2Cl2 (100 mg, 0.14 mmol), 2M Na2CO3 (2 mL) and DME (2 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, 2H, J=8.6 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.8 Hz), 4.84 (t, 1H, J=6.1 Hz), 4.26-4.16 (m, 2H), 3.89 (d, 2H, J=6.2 Hz), 3.76-3.70 (m, 2H), 3.20-3.07 (m, 4H), 2.98-2.85 (m, 1H), 2.38-2.18 (m, 1H), 2.10-2.04 (m, 1H), 2.03-1.93 (m, 2H), 1.57-1.40 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 501 (M+H).
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:43])[C:24]2[C:32]3[CH:31]=[N:30][CH:29]=[N:28][C:27]=3[N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=2)=[C:19]([CH3:44])[N:18]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][NH:7][C:17]2[N:18]=[C:19]([CH3:44])[C:20]([C:23]([C:24]3[C:32]4[CH:31]=[N:30][CH:29]=[N:28][C:27]=4[NH:26][CH:25]=3)=[O:43])=[CH:21][CH:22]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncncc34)c(C)n2)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncncc34)c(C)n2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To {5-[hydroxy-(7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-6-methyl-pyridin-2-yl}-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (75, 0.317 g, 0.501 mmol) dissolved in 15.0 mL of 1,2-dichloroethane, triethylsilane (1.00 mL, 6.26 mmol) was added, followed by trifluoroacetic acid (0.482 mL, 6.26 mmol). The reaction was stirred at 70° C. overnight, then concentrated under vacuum and combined with 1 N aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, then dried with sodium sulfate, filtered and the filtrate adsorbed onto silica. This was purified by silica gel column chromatography eluting with 50-100% ethyl acetate in hexanes. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (P-0019, 57.5 mg). 1H NMR was consistent with the compound structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:28])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:29][C:10]1([CH3:30])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:28])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N(C)C(=O)N(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N(C)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 60 °C
Reaction time: 36 h
Yield: 26.2 %

Procedure:
A mixture of 3,3-dimethyl-2-[3-(trimethyl-ureido)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (409 mg, 1 mmol) in methanol (5 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (5 mL) was stirred at 60° C. for 36 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-[3-(trimethyl-ureido)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 26%) as a yellow solid: LC/MS m/e calcd for C22H27N3O3 (M+H)+: 382.48, observed: 382.1.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].O1CCOCC1.Cl[C:19]1[CH:24]=[C:23]([CH:25]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:22]([Cl:42])=[CH:21][N:20]=1>C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Cl:42][C:22]1[C:23]([CH:25]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])=[CH:24][C:19]([NH:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
In a small amount of a saturated aqueous solution of potassium carbonate was dissolved β-alanine t-butyl ester hydrochloride (1.5 g), followed by extraction with methylene chloride. The extract was dried and concentrated into 720 mg of β-alanine t-butyl ester in the free form. The resulting ester and a 1,4-dioxane (2.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (300 mg, 0.72 mmol) obtained in Example 54 was stirred at 120° C. for 4 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The diluted mixture was washed with water and brine, dried and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (79 mg, 16%) as an oil.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)=[O:3].Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:16][CH:15]=1>>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CS(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)=O)cc3)cc2)CC1
Yield: 15.9 %

Procedure:
The title compound (6.6 mg, 16%) was prepared from (±)-[4-(methylsulfinyl)phenyl]boronic acid (18.4 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 416 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: Nc1cccnc1
Product: O=C(N1CCc2ccc(Cl)c(Nc3cccnc3)c2CC1)C(F)(F)F
Yield: 7.7 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.7 mmol) with 3-aminopyridine (75 mg, 0.85 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to give 7-chloro-6-[(3-pyridyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (20 mg, 8%). MS (ES+) m/z: 370 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH2:30])[CH3:29].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH:30][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: CC(N)c1ccc(F)cc1-c1cc(F)ccc1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccc(F)cc2-c2cc(F)ccc2F)cc1
Yield: 87.8 %

Procedure:
The title compound was prepared from 4-methoxybenzenesulfonyl chloride (153 mg, 0.74 mmol), 1-(-2′,5′,5-trifluoro-1,1′-biphenyl-2-yl)ethylamine (177 mg, 0.70 mmol), and triethylamine (147 μL, 1.1 mmol) according to the procedure and in the same manner as described in Example 105, step c. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (259 mg, 91%) as a white solid;
Reaction SMILES: [Na].[CH3:2][N:3]1[CH:7](P(OCC)(=O)OCC)[C:6](=[O:16])[NH:5][C:4]1=[O:17].[CH:18]1([N:24]([CH3:42])[C:25](=[O:41])[CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([CH:39]=O)[CH:31]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH:18]1([N:24]([CH3:42])[C:25](=[O:41])[CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([CH:39]=[C:7]3[N:3]([CH3:2])[C:4](=[O:17])[NH:5][C:6]3=[O:16])[CH:31]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Reactant: CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Agent: [Na]
Solvent: CCO
Product: CN1C(=O)NC(=O)C1=Cc1cc(OCCCC(=O)N(C)C2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
Sodium (0.079 g, 0.003 g atom) was dissolved in ethanol (20 mL) and diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate (0.86 g, 3.4 mmol) added. After 5 minutes, N-cyclohexyl-4-(3-formyl-4-nitrophenoxy)-N-methylbutanamide (1 g, 2.9 mmol) was added and the mixture stirred at room temperature for 90 minutes. The solvent was evaporated and the residue diluted with water and extracted with dichloromethane to give a foam. Crystallization from hexane/dichloromethane afforded N-cyclohexyl-N-methyl-4-[3-[(1-methyl-2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxy]butanamide (0.96 g, 75%) as a 3:1 mixture of geometrical isomers, m.p. 149°-154° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[O:4][N:3]=1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:15](=[O:16])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:4][N:3]=1
Reactant: Cc1noc(N)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: Cc1noc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 215° C. and MS: m/e=293 (M+) was prepared in accordance with the general method of example 44a from 3-methyl-[1,2,4]oxadiazol-5-ylamine (Helv. Chim. Acta, 49(1966), 1430-1432) and 2,2-diphenylacetic acid chloride.
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[CH2:19][C:18]([CH3:32])([C:27](OCC)=[O:28])[C:17]2=[O:33])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>O>[Cl:26][C:23]1[CH:24]=[C:25]2[C:20]([CH2:19][C:18]([CH2:27][OH:28])([CH3:32])[C:17](=[O:33])[N:16]2[CH:13]2[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[CH2:11][CH2:12]2)=[N:21][CH:22]=1
Reactant: CCOC(=O)C1(C)Cc2ncc(Cl)cc2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(CO)Cc3ncc(Cl)cc32)CC1
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a methanol solution (4 ml) of ethyl 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-7-chloro-3-methyl-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate (163 mg) was added at 0° C. calcium chloride (162 mg), followed by stirring for 15 minutes. Then, sodium borohydride (115 mg) was added, and stirred for 2 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The collected organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography to afford tert-butyl 4-[7-chloro-3-(hydroxymethyl)-3-methyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl]piperidine-1-carboxylate (30.8 mg).
Reaction SMILES: CO.Cl.[CH2:4]([N:6]([CH2:22][CH3:23])[C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][CH:21]=1)[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH3:5]>>[NH2:11][CH2:10][C:9]1[CH:8]=[C:7]([CH:21]=[CH:20][CH:19]=1)[N:6]([CH2:4][CH3:5])[CH2:22][CH3:23]
Reactant: CCN(CC)c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: CCN(CC)c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.4 %

Procedure:
MeOH.HCl (1.25 M, 11 ml, 13.9 mmol, 10 eq) was added to a flask charged with tert-butyl 3-(diethylamino)benzylcarbamate (0.3875 g, 1.4 mmol, 1 eq) at 0° C. under Ar. After stirring for 1.5 h at 0° C. the ice-bath was removed. After stirring at room temperature for 6 h, the solvent was removed in vacuo. The residue was stirred with saturated aqueous NaHCO3 for 30 min and extracted with CH2Cl2 (×2). The combined organics were dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo to yield 0.191 g (1.07 mmol, 77% yield) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([C:7]([N:9](C(=O)C2C=CC(OC)=CC=2)[C:10]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:16]=3)[N:11]=2)=[O:8])=[CH:5][CH:4]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C.[OH-].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:16]=3)[N:11]=2)=[O:8])=[CH:47][CH:48]=1
Reactant: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N4CCN(C)CC4)cc3c(NCc3ccccc3)c2C#N)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2nc3ccc(N4CCN(C)CC4)cc3c(NCc3ccccc3)c2C#N)cc1

Procedure:
To the solution of 2.3 g of 4-methoxy-N-(4-methoxybenzoyl)-N-(6-(4-methylpiperazino)-4-benzylamino-3-cyanoquinolin-2-yl)benzamide in 15 mL of acetonitrile, 4 mL of 1N methanolic potassium hydroxide solution is added. The reaction mixture is heated under reflux conditions for 10 minutes, 1 mL of glacial acetic acid is added to it, then it is neutralized with 12 mL of 1M sodium hydrogen carbonate solution. The precipitate is filtered off, the yellow crystalline material is recrystallized from the mixture of 15 mL of methanol and 35 mL of water. After drying 1.1 g of the title compound is obtained, m.p.: 173° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:22]=[C:18]([C:19](O)=[O:20])[C:17]([NH2:23])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:22]=[C:18]2[C:17](=[CH:16][CH:15]=1)[N:23]=[C:2]1[NH:3][C:4]3[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=3[N:6]1[C:19]2=[O:20]
Reactant: Cc1cc2nc(Cl)[nH]c2cc1C
Reactant: Nc1ccc(Br)cc1C(=O)O
Product: Cc1cc2[nH]c3nc4ccc(Br)cc4c(=O)n3c2cc1C

Procedure:
2-Bromo-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 2-chloro-5,6-dimethylbenzimidazole and 5-bromoanthranilic acid.
Reaction SMILES: C(OC([NH:8][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]1[N:29]2[N:30]=[C:31]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)[C:32]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[N:34]=3)=[C:28]2[CH:27]=[CH:26][CH:25]=1)=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:40]1([NH:39][C:35]2[N:34]=[C:33]([C:32]3[C:31]([C:45]4[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=4)=[N:30][N:29]4[C:24]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:9]([NH2:10])=[NH:8])=[CH:25][CH:26]=[CH:27][C:28]=34)[CH:38]=[CH:37][N:36]=2)[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COc1ccc(-c2nn3c(NCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(NCCCCNC(=N)N)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 32.4 %

Procedure:
To a solution of N,N″-di-tert-butoxycarbonyl-N′-(4-{[3-[2-(cyclopentylamino)-pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)-guanidine (42 mg, 0.06 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL). The resultant solution was stirred for 8 hours and then concentrated in vacuo. The residue was dissolved in dichloromethane and saturated aqueous sodium bicarbonate was added. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration provided N-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)guanidine (10 mg, 33%) as a yellow solid. MS m/z 514 (M+1).
Reaction SMILES: Br[CH:2]=[C:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.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>[F:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:2]=[C:3]2/[CH:4]=[CH:5][C:6](=[O:8])[O:7]/2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1C=CC(=CBr)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C/C(=C/c2ccc(F)cc2)O1

Procedure:
A mixture containing 5-bromomethylene-2(5H)furanone (0.175 g, 1 mmol), 4-fluorophenylboronic acid (0.168 g, 1.2 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.035 g, 0.05 mmol), tetrabutylammonium iodide (0.018 g, 0.05 mmol) and cesium fluoride (0.456 g, 3 mmol) in toluene (10 mL) and water (10 mL) were stirred at reflux for 24 hours under nitrogen. After cooling, brine (50 mL) was added and the product extracted with ethyl acetate (50 mL×3). The organic fractions were combined, washed with brine (50 mL×3), dried over anhydrous sodium sulfate and evaporated to dryness to give a brown solid. The resulting solid was chromatographed (silica gel: eluent 50:50 dichloromethane/light petroleum) giving the desired product 28 as a white powder. Yield 0.164 g (86%), m.p. 140-142° C., UV-Vis λmax (MeOH) 225(22535), 330(56424) nm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[CH:2]=1>[Pt](=O)=O>[CH3:14][O:13][C:11]([C:3]1[CH:2]=[N:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)=[O:12]
Reactant: COC(=O)c1cnc2ccccc2c1
Agent: O=[Pt]=O
Product: COC(=O)c1cnc2c(c1)CCCC2
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Representative procedure for small scale hydrogenation reactions. To a 2 or 3-neck, 100 ml round bottom flask containing a stir bar was added methyl quinoline-3-carboxylate (170 mg, 0.908 mmol) and platinum(IV) oxide (10.3 mg, 5 mol %). The flask was equipped with two outlets sealed with rubber septa and containing Teflon stopcocks. Trifluoroacetic acid (3.0 mL), which was purged with argon gas to remove oxygen, was added via a plastic syringe into the reaction flask under an atmosphere of nitrogen. The stirred reaction mixture was flushed and the flask filled with hydrogen gas via a needle from a balloon through one of the septa-sealed outlets. The Teflon stopcocks were closed and the reaction mixture was warmed to 60° C. and stirred for 5 hours. The progress of the reaction was monitored by GC and TLC. The reaction mixture was cooled to room temperature and aqueous saturated sodium bicarbonate solution was added until the mixture was neutral. The mixture was then extracted with CH2Cl2 (3×30 mL), dried (MgSO4), and the solvent was removed in vacuo. The crude material thus obtained was separated by flash chromatography (silica gel, 10% EtOAc in hexanes). The title compound was obtained as a yellowish liquid (121 mg, 70%) which displayed: 1H NMR (CDCl3, 300 MHz): δ 1.80-2.00 (m, 4H), 2.79-2.85 (m, 2H), 2.90-3.00 (m, 2H), 3.91 (s, 3H), 7.95 (s, 1H), 8.93 (s, 1H); 13C NMR (CDCl3): δ 22.8, 23.1, 28.9, 30.0, 33.1, 52.5, 123.7, 132.5, 138.0, 148.2, 162.6, 166.5; MS m/z: 192 (M+H+). 1,2,3,4-Tetrahydroquinoline-3-carboxylic acid methyl ester also was isolated (19 mg, 11%).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[C:8]2[CH:16]=[CH:15][NH:14][C:9]=2[N:10]=[C:11]([Cl:13])[CH:12]=1)=[O:6].Cl>CO>[Cl:13][C:11]1[CH:12]=[C:7]([C:5]([OH:6])=[O:4])[C:8]2[CH:16]=[CH:15][NH:14][C:9]=2[N:10]=1
Reactant: COC(=O)c1cc(Cl)nc2[nH]ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
In a 100 ml round-bottomed flask, 7.5 ml of a 1M aqueous solution of lithium hydroxide are added, at ambient temperature, to a suspension of 527 mg of 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester obtained according to the preceding stage, in 15 ml of methanol. After stirring for 2.5 hours at ambient temperature, 7.5 ml of 1N hydrochloric acid are added dropwise. After stirring for ½ hour, the solid is filtered off, washed with 25 ml of water and dried. 475 mg of 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O1CCOCC1>[C:12]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:14])[CH3:13]
Reactant: COC(=O)c1cnccc1N
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cnccc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
A mixture of methyl 4-aminopyridine-3-carboxylate (100 g, 0.6 mol) and acetic anhydride (240 g, 2.4 mol) in anhydrous 1,4-dioxane (1.2 L) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and diluted with water (800 mL). The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate to pH 7. The formed solid was collected by filtration and dried in vacuo to afford 50 g of methyl 4-(acetylamino)pyridine-3-carboxylate as a white solid.