Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+](=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N-]>C1(C)C(C)=CC=CC=1>[CH2:28]([O:27][C:25]([CH:24]1[CH2:20][CH:19]1[C:17]1[CH:18]=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:21])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CC1c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 54.4 %

Procedure:
1-(Toluene-4-sulfonyl)-5-vinyl-1H-pyrrolo[2,3-b]pyridine, (200 mg, 0.67 mmol), and ethyl diazoacetate, (730 μL, 7.0 mmol), were combined in 3 mL xylene and heated to 95° C. for 30 min, then to 115° C. for 4 hours. The solvent was evaporated onder vacuum and the residue purified by silica chromatography, (eluent: methylene chloride), affording 140 mg, (50%), 2-[1-(Toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl ]-cyclopropanecarboxylic acid ethyl ester as a mixture of cis and trans isomers. MS ES+385.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(C)cc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
A solution of 3,5-dimethyl benzoic acid (25 g, 0.17 mol) in methanol (250 ml) was treated with sulfuric acid (1 ml, cat. amount) and heated to reflux. After 10 hours, the solution was cooled to room temperature, concentrated to approximately 1/2 volume and poured into 200 ml of crushed ice. The mixture was extracted twice with 200 ml portions of diethyl ether. The organic phase was extracted with saturated aqueous sodium carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting solid was recrystallized from hexanes to yield the product (24.5 g, 90% yield) as volatile white plates. mp=32°-35° C. (lit. mp=35°-36° C.)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[CH3:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[C:23]([CH2:22][O:21][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[CH3:39])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]3)[CH:32]=2)[CH2:27][CH2:28][C:29]1=[O:38]
Reactant: Cc1ccccc1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4C)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.099 g of 14-bromobutoxy)-2-methylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.33 (2:1 EtOAc-heptane); Rt=6.34.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)[N:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH:10]=[CH:9][C:3]=1[C:4]([NH:6]CC)=[O:5].ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl.O>[C:4]([C:3]1[CH:9]=[CH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N+:29]([O-:41])=[CH:28][CH:27]=[CH:26]5)[N:20]=[N:21][C:16]3=[CH:15][CH:14]=2)=[CH:12][C:2]=1[Cl:1])(=[O:5])[NH2:6]
Reactant: CCNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5c(ccc[n+]5[O-])c4)c3n2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of example 119 (0.060 g, 0.135 mmol) in dichloromethane (1 ml), 3-chloroperbenzoic acid (0.46 g, 0.270 mmol) was added and stirred at RT for 12 h. The mixture was diluted with water, extracted with dichloromethane, the organic layer dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane as the eluent to afford the title compound as a grey solid. (0.016 g, 26%). M.P.: 212-215° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.71 (d, J=8.8 Hz, 1H), 8.68 (d, J=9.1 Hz, 1H), 8.56 (m, 2H), 8.30 (d, J=1.5 Hz, 1H), 8.24 (m, 2H), 8.12 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.86 (dd, J=9.1, 1.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.48 (dd, J=8.4, 6.0 Hz, 1H), 6.20 (s, 2H), 3.28 (m, 2H), 1.14 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].Cl.CN(C)[CH2:25][CH2:26][CH2:27][N:28]=[C:29]=NCC.O.ON1[C:40]2C=CC=C[C:39]=2N=N1.CN1CCOCC1>CN(C)C=O>[CH:27]1([N:28]([CH3:29])[C:11](=[O:13])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:26][CH2:25][CH2:40][CH2:39]1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N(C)C1CCCC1
Yield: 72.6 %

Procedure:
To a solution of (S)-3-(4-cyanophenyl)-2-(butyloxycarbonyl-amino)propionic acid (0.7 g, 2.41 mmole) in dimethylformamide (DMF, 6 ml) were added, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC, 0.7 g) and 1-hydroxybenzotriazole hydrate(HOBT, 0.4 g) at 0° C. The mixture was stirred until they are completely dissolved therein. To this reaction mixture were added the compound (0.4 g, 2.96 mmole) prepared in Preparation 1 and N-methylmorpholine(1.0 ml) and then the reaction temperature was slowly elevated to room temperature. The reaction solution was stirred for 3.5 hours. After the reaction is completed, the reaction solution was concerntrated under reduced pressure to remove the volatile substances and the remaining residue was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified by column chromatography (ethyl acetate: hexane=7:3 (v/v)) to obtain the purified title compound (0.65 g, Yield: 73.0%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:48]=[N:49][N:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=23)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:47]3[CH:48]=[N:49][N:50]4[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=34)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC1(C)OB(c2cnn3ccccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (100 mg, 0.182 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (53.4 mg, 0.219 mmol), sodium carbonate (48.3 mg, 0.455 mmol) and tetrakis(triphenylphosphine)palladium (21.05 mg, 0.018 mmol) in DME (1 mL) and H2O (0.333 mL) was stirred at 85° C. for 3 h. Following reaction, the mixture was filtered and the filtrate was diluted with EtOAc and H2O. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound (53 mg, 46.1%). 1H NMR (500 MHz, CDCl3) δ ppm 1.17-2.03 (m, 17H), 3.74-3.81 (m, 3H), 3.84-3.89 (m, 3H), 4.04 (br s, 1H), 4.26 (br s, 2H), 4.46 (br s, 1H), 4.71 (br s, 2H), 6.36-6.55 (m, 2H), 6.83 (d, J=5.86 Hz, 1H), 7.18-7.31 (m, 2H), 8.42 (br s, 1H), 8.47-8.57 (m, 1H), 9.42 (br s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1CCN>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: NCCc1ccccc1Cl
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: CN(C)C=O
Product: S=C(NCCc1ccccc1Cl)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl]imidazole (2.1 g, 8 mmol) and 2-(2-chlorophenyl)-ethylamine (1.25 g, 8 mmol) in N,N-dimethylformamide (30 mL) was stirred at 100° C. for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2].[CH2:34]([NH:36][CH3:37])[CH3:35]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:36]([CH2:34][CH3:35])[CH3:37])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2]
Reactant: CCNC
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(N(C)CC)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A solution of 6-chloro-4-(2-chloro-benzyl)-8-fluoro-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (108 mg, 0.205 mmol, Eq: 1.00) and ethyl-methyl-amine (12.7 mg, 18.5 μl, 0.215 mmol, Eq: 1.05) in DMSO (1.5 ml) was heated to 40° C. for 65 h. Additional ethyl-methyl-amine (60.6 mg, 88.1 μl, 1.02 mmol, Eq: 5) was added and the solution was heated to 80° C. for 1.5 h. The solution was cooled to RT, diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×) and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 96.5:3.5) to afford the title compound as yellow solid (48 mg). MS (ESI): 435.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[C:33](=[O:34])[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[N:26]=[CH:25]5)[C:19]=4[CH3:35])=[CH:16][N:15]=[C:14]([C:36]([NH2:38])=[O:37])[C:10]=3[NH:11]2)=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].O>ClCCl.O1CCCC1>[CH3:35][C:19]1[C:20]([N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25]2)=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[C:9]2[C:8]3[C:12](=[CH:13][C:5]([O:4][CH2:3][CH:2]=[O:1])=[CH:6][CH:7]=3)[NH:11][C:10]=2[C:14]([C:36]([NH2:38])=[O:37])=[N:15][CH:16]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCCO)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCC=O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.6 %

Procedure:
To a solution of 7-(2-hydroxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (152 mg, 0.301 mmol) in dichloromethane (10 mL) and tetrahydrofuran (10.00 mL) at room temperature was added Dess-Martin periodinane (191 mg, 0.451 mmol) in one portion. The mixture was stirred at room temperature for 16 hr. To the mixture was added saturated NaHCO3 solution (10 mL) and water (10 mL). The mixture was stirred at room temperature for 20 min and extracted with ethyl acetate (3×40 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (178 mg, 0.354 mmol, 118% yield) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][C:22]([NH:24][C:25]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)=[O:23])=[CH:13][CH:12]=1.[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46][C:47](Cl)=[O:48]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:47](=[O:48])[CH2:46][O:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccncc3N)c3ccccc23)cc1
Reactant: COCCOCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCOCC(=O)Nc1cnccc1CCOc1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.2 %

Procedure:
To 1-(4-(2-(3-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate E) (50 mg, 0.094 mmol) and DMAP (5.71 mg, 0.047 mmol) in DCM (3.0 mL) was added 2-(2-methoxyethoxy)acetyl chloride (30 μl, 0.281 mmol) at 0° C. and the reaction mixture stirred at RT for 1.5 hr. The solvent was removed in vacuo and the residue subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The residue was purified by column chromatography (4.0 g) gradient elution with 0-8% MeOH in DCM and the product fractions concentrated in vacuo to give N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide (Example 22) as a light purple solid (35 mg, 56%): m/z 651 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.25 (9H, s), 2.40 (3H, s), 3.26 (5H, m), 3.50 (2H, m), 3.70 (2H, m), 4.15 (2H, s), 4.40 (2H, t), 6.35 (1H, s), 6.98 (1H, d), 7.35 (2H, m), 7.42 (2H, m), 7.50 (3H, m), 7.62 (1H, d), 7.87 (1H, d), 8.07 (1H, dd), 8.36 (1H, d), 8.56 (1H, br s), 8.60 (1H, s), 8.76 (1H, br s), 9.55 (1H, br s).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].[I:20]I.Cl>O.C1COCC1>[OH:13][C:9]1[C:10]([I:20])=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12]2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc2ccc(O)cc2c1
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2ccc(O)c(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 7-cyano-2-naphthol (22.3 g, 131.8 mmol), sodium carbonate (29.3 g, 277 mmol) and I2 (31.8 g, 125.2 mmol) in water (500 mL) and THF (80 mL) at 0° C. was stirred at room temperature for 3 h, acidified with 1M HCl and extracted with ethyl acetate. The extracts were washed with saturated Na2S2O3 and brine, dried (Na2SO4) and concentrated. The product was recrystallized from ethyl acetate to yield 33 g of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=O)C.[C:10]([C:12]1[CH:18]=[C:17]([F:19])[C:15](N)=[C:14]([F:20])[CH:13]=1)#[N:11].O.[BrH:22]>[Cu]Br>[Br:22][C:15]1[C:17]([F:19])=[CH:18][C:12]([C:10]#[N:11])=[CH:13][C:14]=1[F:20]
Reactant: N#Cc1cc(F)c(N)c(F)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(F)c(Br)c(F)c1
Temperature: 25 °C

Procedure:
4 g of sodium nitride was added to 30 ml of concentrated sulfuric acid and chilled to a temperature of 10° C. and 38 ml of acetic acid was added thereto. 8.9 ml of 4-cyano-2,6-difluoroaniline was added gradually to maintain the solution at a temperature of 20° to 25° C. The reaction mixture was added dropwise to a solution a 10 g of copper (I) bromide dissolved in 30 ml of concentrated hydrobromic acid. After the dropwise addition was completed, the reaction mixture was stirred for one and one half hours at room temperature. Water was added to the reaction mixture, the reaction mixture was extracted with chloroform and washed with water. The organic layer was removed by distillation, and the residue was recrystallized with a mixture of methanol and acetone to yield 6.6 g of 2-bromo-5-cyano-1,3-difluorobenzene.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][N:7]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)nc3)CC2)cc1
Yield: 15.8 %

Procedure:
By reaction and treatment in the same manner as in Example 40 and using (6-bromopyridin-3-yl)(4-p-tolyloxypiperidin-1-yl)methanone (1.2 g) described in Preparation Example 28 and (R)-4-methyloxazolidin-2-one (364 mg) described in Preparation Example 25, the title compound (200 mg) was obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=1)[O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1.[NH2:45][C:46]1[N:55]=[C:54]([N:56]2[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]2)[C:53]2[C:48](=[CH:49][C:50]([C:63](O)=[O:64])=[CH:51][CH:52]=2)[N:47]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:45][C:46]1[N:55]=[C:54]([N:56]2[CH2:57][CH2:58][N:59]([CH3:62])[CH2:60][CH2:61]2)[C:53]2[C:48](=[CH:49][C:50]([C:63]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=3)[O:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[O:64])=[CH:51][CH:52]=2)[N:47]=1
Reactant: COC(=O)c1ccc(Oc2cccc(CN)c2)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Oc2cccc(CNC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)c2)cc1
Reaction time: 1 h
Yield: 73 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of methyl 4-[3-(aminomethyl)phenoxy]benzoate-HCl (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-Dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified without workup by RP-HPLC (pH=10) to give the desired product (0.020 g, 50%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): δ 9.16 (m, 1H), 7.89 (d, 2H), 7.70 (m, 2H), 7.36 (m, 2H), 7.14 (d, 1H), 6.99 (d, 2H), 6.95 (m, 2H), 6.39 (bs, 2H), 4.44 (d, 2H), 3.75 (s, 3H), 3.50 (bs, 4H), 3.29 (s, 4H), 2.18 (s, 3H); Analytical LCMS (M+H)+: m/z=527.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(OC([N:19]1[CH2:24][CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[CH2:21][CH2:20]1)=O)(C)(C)C>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[NH:19]1[CH2:20][CH:21]=[C:22]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cccc(C2=CCNCC2)c1
Yield: 103.4 %

Procedure:
3-Cyanophenyl boronic acid (3.0 g, 20.4 mmol) and 4-(trifluoromethanesulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.0 g, 21.1 mmol) are dissolved in acetonitrile (100 ml) and 0.4 M aqueous sodium carbonate (100 ml). The solution is degassed and treated with palladium tetrakistriphenylphosphine (1.2 g, 1.04 mmol) at 90° C. for 1 hour. The reaction is cooled, filtered and the filtrate is concentrated to an oil. The oil is extracted with methylene chloride (3×) and the solvent is removed under vacuum. The residue is chromatographed (15% ethyl acetate/hexane) to give the title compound as a white solid (6.0 g, 21.1 mmol). This material is treated with methylene chloride (100 ml) and 40% TFA/methylene chloride (100 ml) at ambient temperature for 2 h. The solvents are removed under vacuum and the residue is chromatographed (NH4OH/MeOH/CH2Cl2, 1:5:94) to give title compound as a brown solid contaminated with inorganic salts (4.6 g).1H NMR (CDCl3, 300 MHz) δ7.87 (s, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.58 (t, 1H), 6,28 (m, 1H), 3.90 (m, 2H), 3.49 (t, 2H), 2.83 (m, 2H). EI MS M+ 184.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:14]C(OC(C)(C)C)=O)[CH2:8]2)(=[O:3])[CH3:2].[ClH:22].O1CCOCC1>C(O)(=O)C>[ClH:22].[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH2:14])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc2c(c1)CC(N)C2

Procedure:
Using 5-acetoxy-2-(tert-butoxycarbonylamino)indan (120 mg, 0.40 mmol), 4N hydrochloric acid-dioxane (2 ml) and acetic acid (6 ml), a similar procedure to Production Example 213 was carried out to obtain 5-acetoxy-2-aminoindan hydrochloride (86 mg, 0.38 mmol) having the following physical properties: