Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.O1C=CN=C1C(O)(C#C)C.[N:38]1[CH:43]=[CH:42][CH:41]=[N:40][C:39]=1[C:44]([OH:48])([C:46]#[CH:47])[CH3:45]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:47]#[C:46][C:44]([OH:48])([C:39]4[N:40]=[CH:41][CH:42]=[CH:43][N:38]=4)[CH3:45])[CH:15]=3)[C:10]([C:18]([N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C(=O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12)c1ccccn1
Reactant: C#CC(C)(O)c1ncccn1
Agent: C#CC(C)(O)c1ncco1
Product: CN(C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ncccn3)ccc12)c1ccccn1

Procedure:
The title compound was prepared according to the procedure described in Example 70-b, by substituting 4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine with 1-(2-aminopyrimidin-4-yl)-6-iodo-N-methyl-N-(pyridin-2-yl)indazole-3-carboxamide and 2-(1,3-oxazol-2-yl)but-3-yn-2-ol with 2-(pyrimidin-2-yl)but-3-yn-2-ol in Step 2: 1H NMR (500 MHz, DMSO) delta 1.91 (3H, s), 3.54 (3H, s), 6.25 (1H, s), 6.28 (1H, d, J=5.5 Hz), 7.10 (2H, s), 7.25 (1H, dd, J=6.9, 5.1 Hz), 7.37 (1H, dd, J=8.4, 1.0 Hz), 7.41 (1H, d, J=8.1 Hz), 7.50 (1H, t, J=4.9 Hz), 7.80 (1H, td, J=7.8, 1.8 Hz), 8.00 (1H, d, J=8.4 Hz), 8.19 (1H, d, J=5.4 Hz), 8.32 (1H, d, J=3.4 Hz), 8.80 (1H, s), 8.86-8.96 (2H, m); LC-MS: m/z=+492.15 (M+H)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:13]([C:10]2[CH2:9][C:8]3([CH2:7][CH2:6][CH:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:17][CH2:16]3)[O:12][N:11]=2)=[O:15])=[CH:27][CH:28]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)C2=NOC3(CCC(C(C)(C)C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid (220 mg, 0.91 mmol), 4-tert-butylaniline (137 mg, 0.91 mmol), 4-methylmorpholine (279 mg, 2.76 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (528 mg, 1.20 mmol) (HBTU) were dissolved in DMF (10 ml) and stirred overnight under a nitrogen atmosphere at RT. The solvent was removed under vacuum, the residue taken up in EtOAc and sat. aq. NaHCO3 solution and the phases were separated. The aqueous phase was extracted several times with EtOAc and the combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. After purification by column chromatography (silica gel, ether/hexane 2:1), the desired product 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid-(4-tert-butylphenyl)amide was obtained as a diastereomer mixture in a yield of 80 mg (24% of the theoretical amount).
Reaction SMILES: [S:1]([C:5]1[S:16][C:8]2[CH2:9][N:10](C(=O)C)[CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CO>[OH-].[Na+]>[S:1]([C:5]1[S:16][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: CC(=O)N1CCc2cc(S(N)(=O)=O)sc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc2c(s1)CNCC2
Temperature: 80 °C
Yield: 91.1 %

Procedure:
A suspension of 2-sulfamoyl-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (9.61 g, 37 mmol) in 20% sodium hydroxide solution (75 ml) was warmed at 80° C. for 3 hours. The resultant clear solution was cooled, acidified with concentrated hydrochloric acid, and then made basic with saturated sodium carbonate solution. The product was isolated by exhaustive extraction into ethyl acetate/methanol. The dried solution was evaporated to give 7.36 g (91% yield) of product. Recrystallization from ethyl acetate/methanol gave pure product; m.p. 172°-175° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7]2[S:8][C:9](=[O:11])[S:10][C:6]=2[C:5](=O)[C:4](=O)[O:3]1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>>[CH3:1][C:2]1([CH3:14])[O:3][C:4]2[C:5](=[N:21][C:16]3[C:15]([N:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]2[S:10][C:9](=[O:11])[S:8][C:7]1=2
Reactant: CC1(C)OC(=O)C(=O)c2sc(=O)sc21
Reactant: Nc1ccccc1N
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Product: CC1(C)Oc2nc3ccccc3nc2-c2sc(=O)sc21

Procedure:
4,4-Dimethyl-4H-[1,3]dithiolo[4,5-c]pyran-2,6,7-trione (5) (150 mg, 0.65 mmol), o-phenylenediamine (75 mg, 0.65 mmol) and montmorillonite KSF (100 mg) were mixed in a mortar until a homogeneous solid was obtained then the solid mixture was transferred into a test tube and irradiated with microwaves for 4 min. The resulting mixture was purified by chromatography (silica gel, CH2Cl2) to give pure 4,4-dimethyl-4H-5-oxa-1,3-dithia-6,11-diaza-cyclopenta[a]anthracen-2-one (7). Yield: 90 mg (45%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1.[C:30]([NH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([N:41]3[CH2:40][CH2:39][CH:38]([NH:37][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:43][CH2:42]3)=[CH:7][CH:6]=2)[CH2:9][C:10]([C:20]([C:22]([F:24])([F:23])[F:25])([C:26]([F:28])([F:27])[F:29])[OH:21])=[N:11]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
5-(4-Bromo-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (300.0 mg, 0.60 mmol) prepared in Step 4 of Preparation 17, 4-(N-BOC-amino)-piperidine (180.0 mg, 0.90 mmol), Pd2(dba)3 (27.0 mg, cat.), BINAP (37.0 mg, cat.) and sodium t-butoxide (115.0 mg, 1.20 mmol) were added to toluene (5.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 210.0 mg of the titled compound as a white liquid.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(Cl)=[O:12]>C(OC(=O)C)C.C1(C)C=CC=CC=1>[C:2]1([C:1]2[O:8][C:11](=[O:12])[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2ccccc2)o1
Temperature: 25 °C

Procedure:
Into a stirred slurry of 25 g (0.18 mole) benzoylhydrazine in ethylacetate, 142.5 g (0.18 mole) 12.5% phosgene in toluene was dropped in. The reaction mixture was refluxed about 3 hours, and then allowed to stir over the weekend at ambient temperature. The flask was hooked to an aspirator and placed under vacuum to remove any possible peroxides. The mixture was filtered to give the above-identified product as a solid, melting point 133°-135° C.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][N:15]=1.CCN=C=NCCCN(C)C.[NH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>C(Cl)Cl>[O:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH:36]1[O:35][NH:34][C:20]([C:17]1[CH:16]=[N:15][C:14]([N:2]2[CH2:3][CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[N:19][CH:18]=1)=[O:21]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a stirred solution of 2-(1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)pyrimidine-5-carboxylic acid (400 mg) in DCM (10 mL) was added EDCI (390 mg, mmol) at 0° C. After stirring the reaction mixture at 0° C. for 15 min. NH2OTHP (160 mg, mmol) was added. After stirring overnight, the reaction was diluted with DCM (30 mL). The organic layer was washed with saturated sodium bicarbonate and water. The crude product obtained on removal of solvent was purified by column chromatography using EtOAc in hexanes (50%) to obtain N-(tetrahydro-2H-pyran-2-yloxy)-2-[1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (250 mg, 46.8% yield), m/e=394 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH:4]=[CH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:12][CH2:11][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: Cn1ccc2ccc(C#N)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ccc2ccc(CN)cc21
Temperature: 50 °C
Yield: 90.9 %

Procedure:
Dissolve 1-methylindole-6-carbonitrile (0.97 g, 6.18 mmol) in anhydrous THF (10 mL) and add slowly to 1M lithium aluminum hydride in THF (1.24 mL, 1.24 mmol) at ambient temperature. Heat the reaction mixture at 50° C. for 17 h and cool to ambient temperature. Quench the reaction mixture with water until a granular precipitate starts to form and filter through a pad of Celite®. Evaporate the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.9 g, 91%). GC-MS m/z: 160 (M+).
Reaction SMILES: O.[OH-].[Li+].O.[F:5][C:6]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]2[C:7]=1[C:8](=[O:37])[C:9]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[CH:10][N:11]2[CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26]>C(#N)C>[F:5][C:6]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]2[C:7]=1[C:8](=[O:37])[C:9]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[CH:10][N:11]2[CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCSCCC(=O)OC)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCSCCC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Lithium hydroxide mono-hydrate (31 mg, 0.74 mmol) and water (5 ml) were added to an acetonitrile solution (10 ml) of methyl 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionate (175 mg, 0.37 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with ethyl acetate, and then 2N hydrochloric acid was added to the water layer to make the mixture acidic. The generated insoluble matter was separated, washed with water and then dried, giving a white powder of 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionic acid (140 mg, yield: 82%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1F.[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:26][OH:27].Cl>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1[O:27][CH2:26][C:16]1[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:19][C:15]=1[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1oc(-c2ccccc2)nc1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Sodium hydride (60% in oil, 2.2 g) was added portionwise, at 0° C., to a solution of 3,4-difluoronitrobenzene (8.8 g) and 5-methyl-2-phenyl-4-oxazolyl methanol (10.0 g) in N,N-dimethylformamide (DMF) (100 ml). The mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into ice-water, which was acidified with 2N HCl. Then, resulting crystalline precipitate was collected by filtration, which was recrystallized from dichloromethane-methanol to give 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)nitrobenzene (14.0 g, 81%) as colorless prisms, m.p.155-156° C.
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.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[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:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=1)[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)=[CH:34][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(NCc2ccc(N3CCOCC3)cc2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CCc1ccc(N(Cc2ccc(N3CCOCC3)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 70.8 %

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 (0.63 g) and (4-ethylphenyl)[(4-morpholinophenyl)methyl]amine (0.56 g) as starting materials, 5-benzyloxy-N-(4-ethylphenyl)-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound, N-(4-ethylphenyl)-5-hydroxy-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.51 g) was obtained. melting point: 200° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([I:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([I:15])=[C:13]([O:16][C:19](=[O:21])[CH3:20])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(O)c1I
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc2ccc(F)cc2c(OC(C)=O)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a stirred solution of (6-fluoro-4-hydroxy-3-iodo-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 1.4 mmol) and 4-dimethylaminopyridine (34 mg, 0.28 mmol) in pyridine (3 mL) was added acetic anhydride (160 μL, 1.7 mmol). After being stirred at room temperature overnight, the resulting mixture was diluted with 10% hydrochloric acid (20 mL), and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (elution with 20% ethyl acetate in petroleum ether) to afford (4-acetoxy-6-fluoro-3-iodo-naphthalen-2-yl)acetic acid methyl ester (300 mg, 53%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[C:16]([O:20]C)=[CH:17][CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[C:16]([OH:20])=[CH:17][CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1cccc2cc(-c3cnc4ccc(Cl)nn34)sc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1cccc2cc(-c3cnc4ccc(Cl)nn34)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
To a solution of 6-chloro-3-(7-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (103 mg, 0.326 mmol, 1.0 equiv) in dichloromethane at −78° C. was added boron tribromide (2.27 mL, 1.0 M solution in dichloromethane, 7.0 equiv). The reaction mixture was stirred at the reduced temperature for 10 min then warmed to room temperature and stirred for 15 h. Methanol (2 mL) was added to quench the reaction and extracted with dichloromethane. Purification by column chromatography using 5% methanol in dichloromethane elution gave 70 mg of the yellow solid, 70%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:29](=[O:31])[NH2:30])([CH2:15][C:16]([O:18][CH:19]1[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][CH:21]([CH3:28])[CH2:20]1)=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:29](=[O:31])[NH2:30])([CH2:15][C:16]([O:18][CH:19]1[CH:24]([CH:25]([CH3:26])[CH3:27])[CH2:23][CH2:22][CH:21]([CH3:28])[CH2:20]1)=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(CC(=O)OC1CC(C)CCC1C(C)C)(NC(=O)OC(C)(C)C)C(N)=O
Solvent: CC(C)=O
Product: CCOC(=O)[C@](CC(=O)OC1CC(C)CCC1C(C)C)(NC(=O)OC(C)(C)C)C(N)=O
Yield: 11.9 %

Procedure:
Ethyl 2-(tert-butoxycarbonylamino)-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (737 mg, 1.67 mmol) was dissolved in acetone (3.69 g) and the solution was placed at 5-10° C. The precipitated crystals were filtered to give ethyl (2R)-2-(tert-butoxycarbonylamino)-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (88 mg) as a white crystal. mp. 176° C., optical purity: 82.6% d.e.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:3])[CH3:2].S(Cl)([Cl:17])(=O)=O>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][C:9]=1[Cl:17])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cscc1NC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1csc(Cl)c1NC(C)=O
Temperature: 0 °C

Procedure:
40 g. of methyl 4-acetylamino-3-thiophene carboxylate are dissolved in 1 liter of absolute chloroform, and a solution of 27 g. of sulfuryl chloride in 100 ml. of absolute chloroform is then added dropwise within 20 minutes. The reaction solution is then boiled under reflux for 1 hour. The brownish colored solution obtained is cooled and when its temperature is 10°, 1 liter of ice water is added. The organic solution is then washed with 200 ml. of 5% sodium bicarbonate solution, dried over sodium sulfate, and evaporated to dryness in vacuo. The oily residue is triturated with 100 ml. of ether, whereupon crystallization takes place. The product is suction filtered and recrystallized from ethyl acetate, and methyl 4-acetylamino-5-chloro-3-thiophene carboxylate having a melting point of 119°-121° is obtained. The ethereal filtrate and the mother liquor from the ethyl acetate recrystallization are combined, evaporated to dryness, and the oil that remains is chromatographed on 300 g. of silica gel using methylene chloride/ethyl acetate (4:1) as eluent. An additional portion of methyl 4-acetylamino-5-chloro-3-thiophene carboxylate having a melting point of 119°-121° is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:11]2[C:12](=[O:14])[N:13]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[O:14]=[C:12]1[N:11]2[CH2:15][CH2:16][NH:17][C:10]2=[CH:9][C:8]([O:7][CH2:6][C:5]2[CH:4]=[C:3]([CH:27]=[CH:26][CH:25]=2)[C:1]#[N:2])=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cccc(C#N)c1)nc2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(COc2cc3n(c(=O)n2)CCN3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A solution of tert-butyl 7-((3-cyanobenzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrim-idine-1(5H)-carboxylate (20 mg, 0.054 mmol) in dichloromethane (DCM) (4 mL) was added TFA (0.5 mL, 6.49 mmol) at room temperature. The reaction mixture was stirred at rt overnight, then concentrated to remove solvent, diluted with sat. NaHCO3 (5 mL) solution and EtOAc (15 mL). Separated organic part was dried over Na2SO4, filtered and concentrated. Purification via MDAP (Gilson GX-281, mobile phase: 0.01% NH4HCO3, CH3CN/water, 50˜95%) afforded the title product (9 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16].[OH-].[Na+]>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: COc1ccccc1CN
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1CNc1ncccc1C(=O)O
Temperature: 25 °C
Yield: 74.5 %

Procedure:
7.00 g (44.2 mmol) of 2-chloronicotinic acid and 12.13 g (88.4 mmol) of 2-methoxybenzylamine were heated at 140° C. for 4 hours. The mixture was left to cool to room temperature, and then a 10% aqueous solution of sodium hydroxide was added to the reaction mixture. The resulting mixture was washed with chloroform. Concentrated hydrochloric acid was added to the aqueous phase to adjust the aqueous phase to pH 6 to 7, and a solid precipitated therefrom was separated by filtration and dried. Thus, 8.50 g (yield: 74%) of the title compound was obtained as a pale yellow powder.
Reaction SMILES: CCCCCC.C([Li])CCC.O1CCCC1.Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1I>C(OCC)(=O)C.Cl.[Cl-].[Zn+2].[Cl-]>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Fc1ccccc1I
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
1.6M-n-Butyllithiumhexane solution (30 ml) is added to tetrahydrofuran (30 ml), the tetrahydrofuran is chilled to −78° C. under a nitrogen environment beforehand. Subsequent to this addition, a tetrahydrofuran (30 ml) solution of 4-bromotoluene (8.33 g) is added. Then, the solution is stirred for one hour at −78° C. A tetrahydrofuran (30 ml) solution of zinc chloride (6.64 g), which had been heat-dissolved and dehydrated under reduced pressure, is added to the solution at −78° C. and the solution is stirred for one hour at room temperature. This solution is added to a tetrahydrofuran (30 ml) solution of 2-fluoroiodobenzene (7.22 g) and tetrakis(triphenylphosphyne)palladium (0.52 g) at room temperature, and the solution is stirred for a day and a night. The reaction solution is diluted with ethyl acetate (300 ml), 10% hydrochloric acid is added, and extraction is performed. After the organic layer is washed with a saturated saline solution and dried, it is concentrated. The residue is purified using silica gel column chromatography (eluate: hexane) and thus, oily 2-fluoro-4′-methylbiphenyl (6.05 g) is obtained. 1H-NMR (CDCl3, δ): 2.39 (3H, s), 7.10-7.30 (5H, m), 7.39-7.49 (3H, m).