Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(C)cccc1C
Reactant: NC(CO)CO
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1c(C)cccc1C

Procedure:
The product of Example 122, and serinol were reacted by the procedure of Example 60 to afford the title compound 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 1.91 (s, 6H), 2.14 (s, 3H), 3.45 (br s, 4H), 3.93 (br s, 1H), 6.20 (br s, 1H), 6.31 (d, 1H, J=9.7 Hz), 6.93 (m, 2H), 7.11 (m, 5H). LC MS (m/e)=449.0 (MH+). Rt=1.62 min
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(C)C.[Si]([O:30][C@H:31]1[C:36](=[CH2:37])[C@H:35]([O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:34][C:33](=O)[CH2:32]1)(C(C)(C)C)(C)C>O1CCCC1>[Si:39]([O:38][C@H:35]1[C:36](=[CH2:37])[C@H:31]([OH:30])[CH2:32]/[C:33](=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:34]1)([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C1[C@H](O)C/C(=C\C(=O)OCC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of diisopropylamine (1.2 mL, 9.4 mmol) in 10 mL of tetrahydrofuran was cooled to −78° C.; n-butyllithium (2.5 M in hexanes, 3.6 mL) was added, followed after 5 minutes by ethyl trimethlysilylacetate (1.7 mL). The resultant solution was stirred at −78° C. for 30 minutes, and then a solution of the compound of Example 13E (2.0 g, 4 mmol) in 10 mL of tetrahydrofuran was added over 5 minutes. Stirring was continued for 4 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl; the mixture was warmed to ambient temperature, the partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl and brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 5% to 10% ethyl acetate in hexanes. The product (1.9 g) was dissolved in 17 mL of ethanol; 1.3 mL of concentrated HCl was added, and the resultant solution was stirred overnight at ambient temperature. The solvents were removed in vacuo, the residue was taken up in saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was concentrated in vacuo and purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 2% to 3% dichloromethane in acetonitrile. The title compound was isolated as the slower-eluting material (0.62 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.C([Li:16])CCC>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH:6]2[Li:16]
Reactant: [Li]CCCC
Reactant: Cc1ccc(C)c2c1C=CC2
Solvent: C1CCOC1
Product: [Li]C1C=Cc2c(C)ccc(C)c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
38.2 g (265 mmol) of 4,7-dimethylindene were dissolved in 350 ml of tetrahydrofurane and the temperature of the solution was cooled to 0° C. Then, 165 ml of n-butyllithium (1.6M in hexane, 264 mmol) were added, dropwise for 2.5 hours. After having again heated up to room temperature and stirred the whole for 4 hours, a purple-red solution of 4,7-dimethyl-indenyl-lithium was obtained. This solution was cooled to -70° C. and treated, dropwise for 35 minutes, with 25.3 g of 1,2-dibromoethane (135 mmol) in 15 ml of tetrahydrofurane. After having heated up to room temperature, a slight yellow solution was obtained to which water was added. The organic phase was collected ed dried on Na2SO4. The solvent was then evaporated under vacuum and 20 g of product were obtained (yield 48%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3([CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][CH2:17]3)[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)n1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)n1ncc2c1-c1ccccc1OC21CCNCC1
Yield: 101.8 %

Procedure:
Benzyl 1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.1 g, 2.6 mmol) was stirred in methanol (14.4 mL) with Pd/C (140.3 mg, 0.1318 mmol) under a balloon of hydrogen for 16 h. The reaction was filtered through a syringe filter and the solvent evaporated to give 1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (750 mg, 100%). ESI-MS m/z calc. 283.2. found 284.3 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[C:36]2[N:35]=[N:34][N:33]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[C:32]=2[CH:31]=[CH:30][C:29]=1[C:41]1[CH2:46][CH2:45][CH:44]([CH2:47]O)[CH2:43][CH:42]=1>O1CCCC1>[Cl:27][C:28]1[C:36]2[N:35]=[N:34][N:33]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[C:32]=2[CH:31]=[CH:30][C:29]=1[C:41]1[CH2:46][CH2:45][CH:44]([CH2:47][I:25])[CH2:43][CH:42]=1
Reactant: OCC1CC=C(c2ccc3c(nnn3CC3CC3)c2Cl)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1c(C2=CCC(CI)CC2)ccc2c1nnn2CC1CC1
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran solution (2 mL) of triphenylphosphine (94 mg, 0.36 mmol, 1.1 equiv) was added imidazole (0.11 g, 1.6 mmol, 5 equiv) and iodine (86 mg, 0.34 mmol, 1.05 equiv). After stirring for 10 minutes, a tetrahydrofuran solution (1.5 mL) of {4-[4-chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]cyclohex-3-en-1-yl}methanol (Example 2, 0.10 g, 0.32 mmol) was added and the mixture was stirred for 1 hour. In a separate flask, a tetrahydrofuran solution (2 mL) was prepared containing triphenylphosphine (94 mg, 0.36 mmol, 1.1 equiv), imidazole (0.11 g, 1.6 mmol, 5 equiv) and iodine (86 mg, 0.34 mmol, 1.05 equiv), which was added to the reaction mixture after stirring for 10 minutes. After stirring for an additional 1 hour, an additional tetrahydrofuran solution (2 mL) containing triphenylphosphine (94 mg, 0.36 mmol, 1.1 equiv), imidazole (0.11 g, 1.6 mmol, 5 equiv) and iodine (86 mg, 0.34 mmol, 1.05 equiv) was added to the reaction mixture. After stirring for an additional 30 minutes, the mixture was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethly acetate), providing the titled compound as a light yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[N:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[N:33]=[CH:32][C:31]([CH2:34][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(Sc2ccc(C=O)cn2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cc1ccc(Sc2ccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cn2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-(4-methylphenyl)sulfanylpyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[6-(4-methylphenyl)sulfanylpyridin-3-yl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]1([CH:7]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][Cl:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=O>C1C=CC=CC=1>[C:1]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]2[CH2:15][CH:16]([CH2:17][Cl:18])[O:19][CH2:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: OC(CCl)CNC(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClCC1CN(C(c2ccccc2)c2ccccc2)CO1

Procedure:
A mixture of 27.6 g of 1-diphenylmethylamino-2-hydroxy-3-chloropropane, 10 ml of a 37% strength solution of formaldehyde and 200 ml of benzene is heated to the reflux temperature, while continuously separating off water. The mixture is then evaporated in vacuo and 3-diphenylmethyl-5-chloromethyloxazolidine is obtained as a yellowish oil which, without purification, is heated together with the reacton solution obtained according to Example 43 from 2.3 g of sodium, 100 ml of ethanol and 17.8 g of 4-trans-propenylguaethol, to 100° in an autoclave for 12 hours. After cooling, the sodium chloride which has precipitated is filtered off. 50 ml of 4 N hydrochloric acid are added to the resulting alcoholic solution of 3-diphenylmethyl-5-(2-ethoxy-5-trans-propenyl-phenoxymethyl)-oxazolidine and the mixture is left to stand for 4 hours at room temperature.
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:21](OC)(OC)(OC)[CH3:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH3:21][C:22]1[O:20][C:19]2[C:2]([N:1]=1)=[CH:3][C:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=1[CH:18]=2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: Cc1nc2cc3c(cc2o1)CCN(C(=O)OC(C)(C)C)CC3
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (1.7 g) and trimethyl orthoacetate (1.2 ml) in the presence of pyridinium para-toluenesulfonate (0.16 g) were heated in dry DMF (20 ml) for 90 min at 70° C. followed by 2 h at 105° C. Volatiles were evaporated under reduced pressure to give the title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][S:15]([C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:13]=1.[CH2:30](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[C:4]([NH:14][S:15]([C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)(=[O:16])=[O:17])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:30])[CH2:9][CH2:8][C:7]=2[CH:13]=1
Reactant: COc1cc2c(cc1NS(=O)(=O)c1ccc(-c3ccc(Cl)cc3)s1)CCNCC2
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc2c(cc1NS(=O)(=O)c1ccc(-c3ccc(Cl)cc3)s1)CCN(C)CC2
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a suspension of the amine hydrochloride salt D9 (0.96 g, 0.00198 moles) in 1,2-dichloroethane (50 ml) at room temperature was added triethylamine (5 ml, excess) followed by 37% aqueous formaldehyde (5 ml, excess). After vigorous stirring for 5 minutes, sodium triacetoxyborohydride (5 g, excess) was added portionwise over 5 minutes and the resultant solution stirred for a further 2 hours. The reaction was partitioned between water and dichloromethane and the organic phase washed with water, brine and dried over anhydrous MgSO4. The solution was evaporated to dryness affording the title compound E1 as a pale yellow solid (0.993 g, 100%). M-H 461. 1H NMR: δ CDCl3 2.67–2.88 (6H, m), 3.60–3.95 (8H, m), 6.58 (1H, s), 7.07 (1H, S), 7.13 (1H, d), 7.33–7.50 (6H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[N+:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5]2[O:7][N:23]=[C:16]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:15]=2)=[CH:3][C:2]=1[OH:1])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: O=[N+]([O-])c1ccc(-c2nc(-c3cccnc3)no2)cc1O

Procedure:
The title compound was prepared according to Method C using 3-hydroxy-4-nitrobenzoic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.76 (dd, J=8.5, 1.8 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.45 (dt, J=7.9, 2.0 Hz, 1H), 8.83 (dd, J=4.8, 1.6 Hz, 1H), 9.26 (d, J=1.2 Hz, 1H)) ppm; MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][CH3:27])=[O:25].FC(F)(F)C(O)=O>CC(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([NH:26][CH3:27])=[O:25])[CH:7]=3)[CH2:9]2)=[CH:14][CH:15]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Fc1ccc(OC2CN(c3ccnc(Cl)c3)C2)cc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cccc(Nc2cc(N3CC(Oc4ccc(F)cc4)C3)ccn2)c1
Temperature: 92 °C
Yield: 58.1 %

Procedure:
To 2-chloro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (90 mg, 0.323 mmol) and 3-amino-N-methylbenzamide (72.7 mg, 0.484 mmol) in 2-propanol (3.00 mL) in a disposable sealed tube at RT was added trifluoroacetic acid, (0.075 mL, 0.969 mmol). The resulting reaction mixture was heated at 84° C. for 5 days and 92° C. for 20 days, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 100% 90/10 CH2Cl2-MeOH in CH2Cl2) giving 3-(4-(3-(4-fluorophenoxy)azetidin-1-yl)pyridin-2-ylamino)-N-methylbenzamide (73.6 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:31]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([F:31])=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a cooled (-15° C.) solution of t-butoxycarbonyltryptophan (1.2 g, 4 mmol) and pyridine (0.35 ml, 4 mmol) in methylene chloride (10 ml) is dropped cyanuric fluoride (0.72 ml, 36 mmol) and the mixture is stirred at -15° C. for 1 hour. The reaction mixture is diluted with methylene chloride and ice, and filtered on Celite. The filtrate is diluted with ice water and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonyltryptophan fluoride.
Reaction SMILES: CC(=O)CC.[OH:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[N:32]([CH3:38])[C:31]1=[O:39].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:38][N:32]1[C:33]([CH3:37])([CH3:36])[C:34](=[O:35])[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][O:6][C:7]2[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]3[C:10]([C:11]([C:21]([F:24])([F:22])[F:23])=[CH:12][C:13](=[O:20])[O:14]3)=[CH:9][CH:8]=2)[C:31]1=[O:39]
Reactant: CN1C(=O)N(CCCCBr)C(=O)C1(C)C
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCN2C(=O)N(C)C(C)(C)C2=O)ccc2c(C(F)(F)F)cc(=O)oc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
A 2-butanone (2 mL) solution of 7-hydroxy-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (30 mg, 0.11 mmol), 3-(4-bromobutyl)-1,5,5-trimethylimidazolidine-2,4-dione (30.5 mg, 0.11 mmol), and potassium carbonate (22.8 mg, 0.165 mmol) was heated and stirred overnight at 80° C. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using thin-layer silica-gel chromatography (hexane:ethyl acetate=1:1), and 53.5 mg of the title compound (yield 100%) was obtained as colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1)=[O:2]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Nc1ccc(Br)cc1F
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: C1CCOC1
Product: Nc1ccc(-c2ccccc2C=O)cc1F

Procedure:
4-(2′-N,N-Dimethylaminomethylphenyl)-2-fluoroaniline: To a solution of 2-formylphenylboronic acid (5 g, 33 mmol) in THF (80 mL) was added 4-bromo-2-fluoroaniline (4.2 g, 22 mmol) and sodium carbonate (2 M, 80 mL) and then was bubbled with nitrogen for 10 min. After Pd(PPh3)4 (1.54 g, 1.33 mmol) was added, the resulting mixture was refluxed under nitrogen for 4 h. The THF layer was separated and filtered through a pad of silica gel. The pad was washed with THF to give an 80 mL solution of 4(2′-formylphenyl)-2-fluoroaniline in THF. To the filtrate (15 mL from total 80 mL) was added Me2NH.HCl (0.68 g, 8.3 mmol) and the resulting mixture was refluxed for 2 h. The mixture was cooled to rt and MeOH (5 mL) was added followed by NaBH4 (0.32 g, 8.3 mmoL). After being stirred at 50° C. for 1 hour, the mixture was cooled to rt and quenched with 1 N HCl to pH 1. The aqueous layer was separated, neutralized with 50% NaOH to pH 12, and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated, and purified by SiO2 chromatography eluted with EtOAc to give 54a (0.89 g, 88% yield); [M+H]+=245.2; 1H NMR (CDCl3) δ 7.49 (dd, J=8.8 Hz, J=1.8 Hz, 1H), 7.31-7.21 (m, 3H), 7.14 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.97 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 6.80 (t, J=8.8 Hz, 1H), 3.76 (bs, 2H), 3.34 (s, 2H), 2.17 (s, 6H); 19F NMR (CDCl3) δ-136.19. This material was converted to the bis-HCl salt by dissolving a sample in a minimum volume of methanol and adding 2.2 equivalents of 1.0 M HCl in diethyl ether followed by removal of the solvent under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOc1ccc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: COCCOc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 46.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and (4-isopropylphenyl)([6-(2-methoxyethoxy)pyridin-3-yl]methyl)amine (0.60 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-([6-(2-methoxyethoxy)pyridin-3-yl]methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].CS([C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1)(=O)=O>CN(C)C=O>[CH3:27][O:26][C:20]1[CH:21]=[C:22]([O:24][CH3:25])[N:23]=[C:18]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[S:2][CH3:1])[N:19]=1
Reactant: CSc1nc2ccccc2[nH]1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(-n2c(SC)nc3ccccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
2-Methylthiobenzimidazole (0.50 g) was dissolved in dimethylformamide (10 ml), and sodium hydride (60% purity, oily) (0.13 g) was added thereto at room temperature. After stirring for 1 hour, 2-methylsulfonyl-4,6-dimethoxypyrimidine (0.67 g) was added at room temperature, followed by stirring for 8 hours. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.80 g of the desired product as a white powder (m.p. 135-137° C.).
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]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([NH:41]C(OC(C)(C)C)=O)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C(O)(C(F)(F)F)=O>CO>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][C:25]2[S:24][C:23]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[C:13]([C:11](=[O:12])[NH:10][C:2]5[S:1][C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[N:3]=5)[CH:14]=[CH:15][CH:16]=4)[CH2:21]3)=[N:27][C:26]=2[C:28]([OH:30])=[O:29])=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound 5-(3-(4-aminophenoxy)propyl)-2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylic acid (6) was prepared by the following procedure: To 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(tert-butoxycarbonylamino)phenoxy)propyl)thiazole-4-carboxylic acid (4) (20 mg, 0.029 mmol) in MeOH (1 mL) was added TFA (1 mL, 13 mmol) and stirred at rt for 2 hours. The reaction mixture was purified by HPLC (Preparative reverse phase HPLC was performed on an automated Gilson HPLC system, using a SymmetryPrep Shield RP18 prep cartridge, 250 mm×21.20 mm i.d., 10 um, and a flow rate of 25 mL/min; λ=214, 245 nm; mobile phase A, 0.1% TFA in H2O; mobile phase B, CH3CN; linear gradient 0-70% of B in 40 minutes) to provide the desired product 5-(3-(4-aminophenoxy)propyl)-2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylic acid in 48% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (1H, s), 9.04 (1H, s), 8.03 (1H, d), 7.79 (1H, d), 7.67 (1H, d), 7.47 (2H, m), 7.37 (2H, m), 7.09 (2H, d), 6.92 (2H, m), 4.83 (2H, s), 3.95 (2H, t), 3.72 (2H, t), 3.17 (2H, m), 3.03 (2H, t), 1.99 (2H, m). MS (ESI(+)): m/z 586 (M+H).