Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)c1ccccc1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and benzoyl chloride (21 mg, 150 μmol). Yield 19 mg (82%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=O)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[CH3:39][S:40]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:36])([F:37])[F:38])=[N:33][N:34]=5)[N:31]=4)[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=[O:42])=[O:41]
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 24 %

Procedure:
Obtained in 24% yield by an analogous method to Example 26, starting from 6-[4-[4-[3-(piperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 4.1, preparation of starting materials) and methanesulfonyl chloride.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[CH2:28]([N:30]([CH2:33]C)[CH2:31]C)[CH3:29].CN(C)CCO>C(Cl)Cl>[CH3:31][N:30]([CH3:33])[CH2:28][CH2:29][O:11][C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)CCO
Solvent: ClCCl
Product: CN(C)CCOC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
To a solution of boc-glycine (1.0 g, 5.7 mmol), DCC (1.82 g, 8.84 mmol), and triethylamine (0.84 ml, 6.05 mmol) in CH2Cl2 at 0° C. was added 2-(dimethylamino)-ethanol (1.5 ml, 14.6 mmol). The mixtures were allowed to warm to room temperature. After stirring for 12 h, the solution was filtered, extracted with 1% HCl, saturated NaHCO3, water, and brine subsequently. The extracted CH2Cl2 solution was dried with anhydrous MgSO4 and evaporated to dryness. The white residue was purified by chromatography on silica gel (ethyl acetate/methanol 9:1) to give 4 (1.03 g, 74%) as a white solid; 1H NMR (C6D6, 400 MHz): 5.51 (t, 1H, J=5.90 Hz, NH), 4.01 (t, 2H, J=5.88 Hz), 3.75 (d, 2H, J=5.90 Hz), 2.22 (t, 2H, J=5.88 Hz), 1.98 (s, 6H), 1.40 (s, 9H); 13C NMR (C6D6, 100 MHz): 170.4, 156.0, 79.1, 62.8, 57.7, 45.4, 42.7, 28.4; Electrospray-ion trap-MS: Calcd for C11H22N2O4+: m/z 246.2. Found: m/Z 247.0 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[C:22]([C:23]([O:25]C)=O)=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O.[NH4+:28]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[C:22]([C:23]([NH2:28])=[O:25])=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][CH:9]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc2nc(-c3ccc(CN4CCNCC4)cc3)oc12
Reactant: [NH4+]
Solvent: O
Product: NC(=O)c1cccc2nc(-c3ccc(CN4CCNCC4)cc3)oc12
Yield: 33 %

Procedure:
Methyl 2-(4-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate in ammonium water (10 mL) was stirred at 30° C. for 17 hr, cooled, and filtered; then the cake was washed with water, dried under reduced pressure to obtain 2-(4-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (80 mg, yield 33% for two steps). 1H NMR (400 MHz, DMSO-d6) δ 2.32 (s, 4H), 2.69-2.72 (t, J=4 Hz, 4H), 3.53 (s, 2H), 3.98 (s, 1H), 7.45-7.49 (t, J=8 Hz, 1H), 7.54-7.56 (d, J=8 Hz, 2H), 7.79-7.80 (d, J=7.2 Hz, 1H), 7.86-7.89 (d, J=10.4 Hz, 2H), 7.93-7.95 (d, J=8 Hz, 1H), 8.23-8.25 (d, J=8 Hz, 2H); LC-MS (ESI) m/z 337 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][NH:17]3)=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc2cc[nH]c2c1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted to provide 2-chloro-5-fluoro-N4-[(1H)-indol-6-yl]-4-pyrimidineamine. LCMS: purity: 92%; MS (m/e): 263 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:35][C:36](OC(C)=O)=[O:37]>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:36]([O:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:6]=1)(=[O:37])[CH3:35]
Reactant: OCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Some starting materials may be obtained from Adesis Inc., New Castle, Del.) A mixture of (2-chloro-5-(4-morpholinoquinolin-6-yl)pyridin-3-yl)methanol (63 mg, 177 μmol), Hunig's Base (300 μl, 1718 μmol), and Ac2O (17 μl, 177 μmol) in DCM (10 mL) was stirred at rt. A small amount of DMF (10 drops) was added. After 2 h, a tiny amount of DMAP was added. After an additional 1 h, the solvent was removed under vacuum and the residue was treated with water. The slurry was extracted with DCM containing MeOH (2%). The organic phase was dried over Na2SO4, concentrated, and purified on silica using 1% MeOH in DCM to give a film (70 mg). LCMS (ESI, pos. ion): calc'd for C21H20ClN3O3: 397.1; found: 398.1 (M+1). 1H NMR (400 MHz, TFA-CHLOROFORM-d) δ ppm 2.26 (s, 3 H) 3.97 (d, J=4.02 Hz, 4 H) 4.11 (d, J=4.52 Hz, 4 H) 5.39 (s, 2 H) 7.10 (d, J=7.03 Hz, 1 H) 8.10-8.19 (m, 1 H) 8.17-8.28 (m, 2 H) 8.33 (s, 1 H) 8.60 (d, J=6.52 Hz, 1 H) 8.91 (d, J=2.01 Hz, 1 H) 13.20 (s, 1 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].ClC1C2C(=CC=C(C(C3N(C)C(C)=NC=3)O)C=2)N=C(OC)C=1CC1C=NC(C(F)(F)F)=CC=1.[F:47][C:48]([F:59])([F:58])[O:49][C:50]1[CH:57]=[CH:56][C:53]([CH:54]=O)=[CH:52][CH:51]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH2:54][C:53]1[CH:56]=[CH:57][C:50]([O:49][C:48]([F:47])([F:58])[F:59])=[CH:51][CH:52]=1)=[C:5]2[OH:13]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Solvent: c1ccncc1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a dark solution of 6-bromo-4-hydroxyquinolin-2(1H)-one (1.0 g, 4.25 mmol, Intermediate 45: step a) and 4-(trifluoromethoxy)benzaldehyde (0.67 mL, 4.67 mmol) in pyridine (7.5 mL) was added diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.08 g, 4.25 mmol). The resulting mixture was warmed with stirring in a 100° C. oil bath for a period of 5 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue diluted with acetonitrile. The semi-solid mixture was sonicated and filtered, rinsing further with acetonitrile, to provide the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16](Cl)=[C:17]([F:22])[CH:18]=2)[N:13]([CH2:24][CH3:25])[CH:12]=1)=[O:10]>N1C=CC=CC=1>[CH3:7][O:8][C:9]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:17]([F:22])[CH:18]=2)[N:13]([CH2:24][CH3:25])[CH:12]=1)=[O:10]
Reactant: CCn1cc(C(=O)OC)c(=O)c2cc(F)c(Cl)cc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)OC)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reaction time: 5 h
Yield: 94.2 %

Procedure:
A mixture of 1.7 g of anhydrous piperazine and 1.4 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester in 3 ml of pyridine was refluxed with stirring for 5 hrs. The reaction mixture was cooled to give crude crystals. The crude crystals were recrystallized from a mixture of methylene chloride and methanol to give 1.55 g (77.5% yield) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester. mp: 179°-181° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1Cl>CN(C=O)C.O>[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[O:15][CH:13]1[CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:14]1
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Reactant: Clc1ccncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnccc1OC1CN(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2, step 1; 320 mg, 1.60 mmol) in DMF (10 mL) was added Cs2CO3 (1.04 g, 3.2 mmol) and 3-bromo-4-chloropyridine (307 mg, 1.60 mmol). The mixture was stirred at 90° C. overnight and then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in petroleum ether) to give the title product (350 mg, 0.98 mmol, 61% yield) as white solid. ESI-MS (M+1): 356 calc. for C17H14BrN3O 355.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]=1[C:8]([OH:10])=O.[F:11][C:12]1[CH:20]=[CH:19][C:15](C(O)=O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:8]([C:3]2[NH:4][C:5](=[O:7])[NH:6][C:2]=2[CH3:1])=[O:10])=[CH:14][CH:13]=1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)O
Reactant: O=C(O)c1ccc(F)cc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
2,3-Dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylic acid (71.0 g, 0.5 mol) and 4-fluorobenzoic acid (105 g, 0.75 mol) are mixed together then covered with polyphosphoric acid (1.6 Kg). The mixture is rapidly heated to 60° C. with stirring, then gradually heated to 110° C. over 2.5 hr. with continued stirring. After stirring at ca. 110° C. for an additional 2 hr. the mixture is cooled to 60° C. and mixed with crushed ice (3.5 Kg). After all the ice has melted, the mixture is filtered and the solid washed with water. The filter cake is suspended in water (800 mL) and the pH raised to approximately 8 by the gradual addition of 10% aqueous sodium hydroxide solution, and the mixture stirred overnight. The pH is adjusted to 8-9, the solid collected by filtration, washed thoroughly with water and dried. Recrystallization from isopropanol-water affords the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 33.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.088 mmol), 4-aminobutyric acid (726 mg, 7.0 mmol) and NaOMe solution (10.6 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 15.5 mg of the title compound as a light yellow solid. MS: (+) m/z 526.26 (M+1).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>>[OH:1][CH:2]([CH2:16][NH:20][CH:17]([CH3:19])[CH3:18])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: O=c1[nH]ncc2ccc(OCC3CO3)cc12
Product: CC(C)NCC(O)COc1ccc2cn[nH]c(=O)c2c1

Procedure:
7-(2,3-Epoxypropoxy)-1(2H)-phthalazinone was reacted with isopropylamine in a similar manner to that described in Example 1(iv) to give 7-(2-hydroxy-3-isopropylaminopropoxy)-1(2H)-phthalazinone, the hydrochloride of which had m.p. 232°-235°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]2)[C:6]([N+:26]([O-])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:26][C:6]1[C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]2)=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCCN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(NCCN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Yield: 100.8 %

Procedure:
A solution of 1,1-dimethylethyl [1-(2-{[6-(methyloxy)-3-nitro-2-pyridinyl]amino}ethyl)-4-piperidinyl]carbamate (3.0 g, 7.6 mmol) in ethanol (500 ml) was hydrogenated for 2 hours over 10% palladium on charcoal (50% dispersion with water, 1.5 g). The mixture was filtered, evaporated, and azeotroped with chloroform to afford a purple oil (2.8 g, 100%).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5](=[S:10])[S:6][C:7]=1[CH2:8]Br.[C:11]1(=[O:18])[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>[I-].C([N+](CC)(CC)CC)C.C(#N)C>[S:10]=[C:5]1[S:4][C:3]2[CH:2]=[C:12]3[C:13](=[CH:8][C:7]=2[S:6]1)[C:14](=[O:17])[CH:15]=[CH:16][C:11]3=[O:18]
Reactant: S=c1sc(CBr)c(CBr)s1
Reactant: O=C1C=CC(=O)C=C1
Agent: CC[N+](CC)(CC)CC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [I-]
Solvent: CC#N
Product: O=C1C=CC(=O)c2cc3sc(=S)sc3cc21
Yield: 78 %

Procedure:
In a vessel, the 4,5-bis(bromomethyl)-1,3-dithiol-2-thione: 1-3 (1.10 g), tetraethylammonium iodide (0.38 g), p-benzoquinone (2.77 g), and acetonitrile (60 mL) were charged, and then refluxed for 1 hour. Thereafter, dichloro dicyano benzoquinone (1.62 g) was added in the resultant mixture, and then refluxed for 7 hours. After completion of the reflux, the solvent was distilled away, and methanol was added in the vessel, and then the precipitate was recovered through filtration. The precipitate was washed with methanol, distilled water, and ether in this order, the obtained residue was dissolved in chloroform, and then filtered. The obtained filtrate was recrystallized, to thereby obtain 2-thioxonaphth[2,3-d] [1,3]dithiol-5,8-dione: 1-4 in a yield of 78%. The target compound was identified through NMR analysis: 1H-NMR (CDCl3, TMS) σ: 7.04 (s, 2H), 8.15 (s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:27])=[C:19]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:28])[CH:10]=[CH:11]3)[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>>[F:27][C:18]1[CH:17]=[C:14]2[C:13]3[N:8]([CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16])[CH:9]([CH3:28])[CH:10]=[CH:11][C:12]=3[C:19]=1[N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: CCOC(=O)c1cn2c3c(c(N4CCN(C)CC4)c(F)cc3c1=O)C=CC2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1C=Cc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 17 h
Yield: 60.4 %

Procedure:
To 3.85 g (0.01 mole) of 9-fluoro-5-methyl-8- (4-methyl-1-piperazinyl) -1-oxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was added 50 ml of a 1N aqueous solution of sodium hydroxide. This mixture was stirred at 20°-25° C. for 17 hours to hydrolyze the starting material. The resulting reaction solution was adjusted to pH 6-7 by the addition of 1N hydrochloric acid under cooling with ice. The adjusted solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography [using a chloroform-methanol mixture (with a volume ratio of 2:1) as the developing solvent]. The fraction containing the desired product was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol to obtain 2.16 g (60.4% yield) of 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl) -1-oxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid in the form of pale-yellow crystals. These crystals had a melting point of 190°-195° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>O1CCCC1>[F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][S:21]([CH3:20])(=[O:23])=[O:22])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(F)c([N+](=O)[O-])cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-fluoro-2-methoxy-5-nitroaniline (0.16 g) and pyridine (0.21 mL) in tetrahydrofuran (3 mL) was added methanesulfonyl chloride (0.074 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours, and then stirred at 50° C. overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/3) to give 5-fluoro-2-methanesulfonylamino-4-nitroanisole (0.1 g). This material was dissolved in N,N-dimethylformamide (3 mL). To the solution were added potassium carbonate (68 mg) and 2,3-difluoro-6-methoxybenzyl bromide (99 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=½) to give 5-fluoro-2-[N-(2,3-difluoro-6-methoxybenzyl)-N-methanesulfonylamino]-4-nitroanisole (0.14 g). This material was dissolved in tetrahydrofuran (2 mL). To the solution was added 10% palladium-carbon powder (13 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=½) to give the title compound (80 mg).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Temperature: 110 °C
Yield: 63.8 %

Procedure:
A stirred mixture of 6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.33 g, 3.14 mmol), (1R,2R)-2-aminocyclohexanol (1.09 g, 9.43 mmol), DIEA (1.62 g, 12.58 mmol) and DMA (40 mL) was heated in a sealed vial at 110° C. for 15 h. The mixture was cooled to rt and then partitioned between water and EtOAc. The organic layer was separated and washed sequentially with water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residual solid was purified by trituration with a 6:1 mixture of diethyl ether and DCM to afford (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (952 mg, 64%) as a tan solid. A 90 mg portion was further purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (15 mg) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.98 (d, J=10.0 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.54 (m, 1H), 7.33 (m, 1H), 7.29 (d, J=10.0 Hz, 1H), 7.08 (m, 1H), 5.52 (s, 2H), 4.75 (d, J=5.0 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.59-1.64 (m, 2H), 1.16-1.30 (m, 4H); LCMS (ESI) m/z 475 and 477 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]2[CH2:16][CH2:17][C:12]1([C:18]([OH:20])=O)[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[NH2:21][C:18]([C:12]12[N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:20]
Reactant: c1ccncc1
Reactant: O=C(OCc1ccccc1)N1C2CCC1(C(=O)O)CC2
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)C12CCC(CC1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A stirred solution of 7-[(benzyloxy)carbonyl]-7-azabicyclo[2.2.1]heptane-1-carboxylic acid (C-35) in dioxane was treated with pyridine (0.8 eq.) and Boc2O (1.5 eq.), then ammonium bicarbonate (1.46 eq.) was added and the mixture was stirred at room temperature for 15 hours. Dioxane was concentrated and the residue was taken up in ethyl acetate, washed with HCl 1N and brine and dried over Na2SO4 to give, after filtration and concentration, the titled compound (C-36).