Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:4][CH:3]=1.C1(SSC2C=CC=CC=2)C=CC=CC=1>C1CCCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2=NCCc3c(Cl)cccc32)cc1
Agent: c1ccc(SSc2ccccc2)cc1
Solvent: C1CCCCC1
Product: Cc1ccc(-c2nccc3c(Cl)cccc23)cc1
Yield: 78.2 %

Procedure:
1-(4-Methylphenyl)-5-chloro-3,4-dihydroisoquinoline (29 g) and 24.7 g of diphenyl disulfide were reacted over an oil bath at 220° C. The reaction mixture was dissolved in cyclohexane, and extracted with a 4 N aqueous solution of hydrochloric acid. The aqueous layer was neutralized with an aqueous solution of sodium hydroxide. The resulting oily product was extracted with benzene, washed in water, and dried. The solvent was distilled off, and the residue was recrystallized from benzene to afford 22.5 g of 1-(4-methylphenyl)-5-chloroisoquinoline as colorless needles having a melting point of 88.6° to 89.1° C.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>S(Cl)(Cl)=O>[ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:1])=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1
Yield: 196.6 %

Procedure:
4-(3-Piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2) (0.23 g) in thionyl chloride (5 ml) was heated under reflux for 1 h. The reaction mixture was then evaporated to a minimum and co-evaporated from DCM (3×10 ml) to give the title compound (D3) as a white powder (0.24 g).
Reaction SMILES: [O-:1][P:2]([O-:5])([O-:4])=[O:3].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[P:22]([O-])([O-])([O-])=[O:23].P([O-])([O-])([O-])=O.[Ca+2].P([O-])([O-])([O-])=O.[Ca+2].[Ca+2]>>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:15][P:22]([O:9]3)([O:4]1)=[O:23])(=[O:13])[O:1]2)=[O:8]
Reactant: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Agent: [F-]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Yield: 3 %

Procedure:
Phosphate rock in Florida is a typical sedimentary siliceous phosphate consisting of calcium phosphate in form of apatite together with clay, sand and other gangue minerals. The appropriately sized flotation feed with typical grade of 3 to 10% P2O5 is obtained through logging, washing, desliming and sizing. The feed in thick slurry is conditioned with pH modifier, fatty acids, fuel oil, and other co-collectors at pH 8.5 to 10. Sodium silicate sometimes is added as a silica depressant. The slurry is subsequently floated by conventional froth flotation routes. A rougher concentrate with typical grade of 20 to 30% P2O5 and 15-40% silica sand is acid-scrubbed, rinsed free of reagents, and subjected to a reverse cationic flotation to further remove the silica sand at pH 6.5 to 7.5. The final phosphate concentrate is produced with the double flotation process with typical grade ranging from 30 to 34% P2O5 with 10-4% sand (acid insoluble). Therefore, the alkaline pH modifier and silica depressant are only applied in the first stage, the rougher flotation.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[CH:10]3[CH2:11][N:12](C(C4CCCCC4)=O)[CH2:13][C:14](=[O:15])[N:9]3[CH2:8][CH2:7][C:5]=2[CH:6]=1.COC(OC)CNCC(NCCC1C=CC=CC=1)=O>>[O:15]=[C:14]1[N:9]2[CH2:8][CH2:7][C:5]3[C:4]([CH:10]2[CH2:11][NH:12][CH2:13]1)=[CH:3][CH:2]=[CH:1][CH:6]=3
Reactant: O=C(C1CCCCC1)N1CC(=O)N2CCc3ccccc3C2C1
Agent: COC(CNCC(=O)NCCc1ccccc1)OC
Product: O=C1CNCC2c3ccccc3CCN12

Procedure:
Further embodiments disclosed herein provide a process for the preparation of Praziquantel of formula I by cyclisation of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide using an acid in the presence of a solvent to obtain 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline; and acylation of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline with cyclohexanoylchloride in presence of a base and a solvent to obtain Praziquantel.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].[OH-].[Na+].CCOCC>C(O)C>[CH2:1]([O:3][C:4]([CH:5]1[CH2:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:7]([CH3:8])[C:6]1=[O:9])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccccn1)C(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1CC(c2ccccn2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A solution of the diketoester 20b (3.1 g, 11.19 mmol) in dry ethanol (35 ml) was added dropwise to a solution of sodium hydroxide (0.447 g, 11.19 mmol) in dry ethanol (15 ml) with vigorous stirring. The solution was stirred at room temperature overnight. Ether (200 ml) was added and the organic phase was washed with 2 N HCl (3×100 ml). The aqueous layer was cooled to 0° C. and made slightly basic by addition of sodium bicarbonate. The aqueous layer was then extracted with ethyl acetate (3×300 ml) and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give an oil that was purified by flash column chromatography (EtOAc/hexanes, 1:10) to give the cyclic β-ketoester 21b (2.115 g, 73%) as a yellow oil: TLC Rf=0.35 (silica gel, 33% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.62-7.60 (m, 1H), 7.54-7.52 (m, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.56 (dd, J=2.8 Hz, 7.2 Hz, 1H), 3.42-3.25 (m, 2H), 2.41 (s, 3H), 2.12 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 203.2, 169.5, 164.4, 151.4, 150.6, 136.8, 136.5, 134.2, 123.3, 61.7, 51.1, 32.5, 18.6, 14.3, 10.6; HRMS calcd for C15H17NO3+Na+ 282.1106; found 282.1109 [M+Na+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.Cl[C:17]1[CH:18]=CC([N+]([O-])=O)=[C:21]([CH:23]=1)N.ICl.CC([O-])=O.[Na+].[N-]=[N+]=[N-].[Na+].C(Cl)(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COC1CCC(OC)O1>CC(O)=O.CS(C)=O.C1COCC1>[I:15][C:3]1[C:2]([N:1]2[CH:21]=[CH:23][CH:17]=[CH:18]2)=[CH:7][C:6]([NH2:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CC(=O)Nc1cc(N)c(I)cc1[N+](=O)[O-]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: COC1CCC(OC)O1
Agent: ClI
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)Cl
Product: Nc1cc(-n2cccc2)c(I)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from N-(5-amino-4-iodo-2-nitro-phenyl)-acetamide (228 mg, 0.71 mmol) [prepared from commercially available 5-chloro-2-nitroaniline by the following sequence: i.) iodination with iodine monochloride, NaOAc in HOAc according to Wilson, J. Gerald; Hunt, Frederick C. Aust. J. Chem. 1983, 36, 2317-25; ii.) nucleophilic aromatic substitution with NaN3 in DMSO at 80° C. for 15 h; iii.) acetylation with AcCl in HOAc at 120° C. for 2 h according to Eur. J. Med. Chem. 1988, 23, 553; iv.) Staudinger-reduction with PPh3/H2O in THF at 23° C. for 1 h] and 2,5-dimethoxytetrahydrofuran (0.14 mL, 1.08 mmol) in HOAc (10 mL) at 95° C. for 2 h according to the general procedure F. Obtained as a yellow solid (221 mg). Deacetylation of this material (371 mg, 1.0 mmol) was perfomed by stirring with 1 N NaOH (2.0 mL, 2.0 mmol) in THF (3.4 mL) at 60° C. for 21 h. Obtained as a yellow solid (312 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]=[CH:9][CH:10]=[CH2:11]>C1C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([O:5][CH:8]=[CH:9][CH2:10][CH2:11][CH2:11][CH2:10][CH:9]=[CH2:8])=[O:4]
Reactant: C=CC=C
Reactant: O=C(O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: C=CCCCCC=COC(=O)C(F)(F)F

Procedure:
1,7-Octadienyl trifluoroacetate was prepared by reacting 1 g of palladium acetate in 20 ml of benzene with 102 g of trifluoroacetic acid and 0.96 M butadiene in a 300 ml autoclave at ambient temperature for 4 days.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:26]=[N:27][N:28]([CH3:30])[N:29]=4)[CH:20]=3)[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:26]=[N:27][N:28]([CH3:30])[N:29]=4)[CH:20]=3)[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnn(C)n4)c3)csc12
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnn(C)n4)c3)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(2-methyl-2H-tetrazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.15 g, 0.35 mmol) (from Example 31 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-[3-(2-methyl-2H-tetrazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.11 g, 79%).
Reaction SMILES: [NH2:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][S:14][CH2:15][C:16](O)=[O:17]>>[CH3:13][S:14][CH2:15][C:16]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CSCC(=O)O
Product: CCOC(=O)C(NC(=O)CSC)C(=O)OCC
Yield: 68.4 %

Procedure:
Diethyl 2-aminomalonate (3.5 g) and methylsulfenylacetic acid (2.2 g) are treated in the same manner as described in Reference Example 1 to give diethyl 2-[(methylsulfenylacetyl)amino]malonate (3.6 g), m.p. 56°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[C:13](=O)[CH3:14].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14]
Reactant: CC(=O)c1ccc(OCC(F)F)cc1Cl
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)F)cc1Cl
Yield: 55 %

Procedure:
The title compound is prepared in 55% yield (990 mg, clear colorless oil) from 1-(2-chloro-4-(2,2-difluoroethoxy)phenyl)ethanone (1.2 g, 5.2 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[F:12])[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1ccccc1F
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2F)Oc2ccc(Br)cc21
Yield: 66.6 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15 g, 70.1 mmol), 2-fluorobenzaldehyde (8.7 g, 70.1 mmol), and borax (26.7 g, 70.1 mmol) in ethanol (90 mL) and H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(2-fluorophenyl)chroman-4-one (15 g, 50%). 1HNMR (CDCl3): 2.8 (d, 1H), 3.0 (t, 1H), 5.7 (d, 1H), 6.7 (d, 1H), 6.9 (t, 1H), 7.2 (m, 2H), 7.3 (m, 2H), 7.5 (m, 2H), 7.9 (t, 1H), 8.1 (d, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1.[Cl:16][C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.CCCCCC>[CH:10]1[C:9]2[CH:8]=[CH:7][C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[N:15]([C:17]([Cl:16])=[O:19])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1=Cc2ccccc2Nc2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Cl)N1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 247.6 %

Procedure:
A solution of 2.8 g of iminostilbene (34) in 100 mL of dichloromethane was treated with 1.5 g of triphosgene followed by 3 mL of pyridine and stirred at room temperature overnight. Thin layer chromatography in 40% ethyl acetate-hexane indicated formation of one product. The reaction mixture was washed with water and concentrated in vaccuo. The residue was chromatographed on silica using 10% ether/dichloromethane to yield 3.2 g of 5H-dibenz[b,f]azepine-5-carbonylchloride (35) as an off-white powder. NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH2:20][CH:19]([O:22][CH2:23][C:24](N4CCOCC4)=[O:25])[CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH2:20][CH:19]([O:22][CH2:23][CH:24]([OH:25])[CH3:32])[CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: O=C(COC1CCc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2C1)N1CCOCC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)COC1CCc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-((2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-5-yl)oxy)-1-(morpholin-4-yl)ethanone (6.22 g) in THF (25 mL) was added methylmagnesium bromide (1 M THF solution, 20.9 mL). To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue in a mixed solvent of THF (10 mL)-methanol (10 mL) was added sodium tetrahydroborate (527 mg), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.82 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1.[C:19]1(C)C=CC(S(O)(=O)=O)=C[CH:20]=1>C(O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1n[nH]c2ccc(-c3ccc(C(=O)O)o3)cc12
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc3[nH]nc(N)c3c2)o1
Yield: 26.9 %

Procedure:
100 mg of 5-(3-amino-1H-indazol-5-yl)furan-2-carboxylic acid and 78 mg of p-toluenesulfonic acid are heated at 75° C. for 3 days in 5 ml of ethanol. The batch is evaporated, water is added, and the mixture is neutralised. The mixture is extracted three times with EA, the combined org. phases are washed with water, dried and evaporated to dryness. Purification by RP chromatography gives 30 mg of ethyl 5-(3-amino-1H-indazol-5-yl)furan-2-carboxylate, corresponding to a yield of 27%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH3:19]>CN(C)C=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH2:17][CH2:18][CH3:19])=[CH:3][C:2]=1[F:1]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a solution of 3,4-difluoro-phenol (20 g, 154 mmol) in N,N-dimethylformamide (70 mL) was added potassium carbonate (30 g, 217 mmol) and iodopropane (50 g, 293 mmol, Aldrich). The reaction mixture was heated at refluxing for 48 h. The crude was cooled to room temperature and filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:8) to give 1,2-difluoro-4-propoxy-benzene as a colorless oil (Yield 17 g, 100%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+]>C(O)C>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]3[N:18]=[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]4[CH:2]=3)=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2ccc(-c3cn4ccccc4n3)cc2)cc1
Yield: 84 %

Procedure:
Dissolving 6.7 g (19 mmol) of 2-bromo-1-(4′-bromo-biphenyl-4-yl)-ethanone into 50 milliliter of ethanol, adding 2.1 g (22 mmol) of 2-aminopyridine and 5.0 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining yellow crystals of 2-(4′-bromo-biphenyl-4-yl)-imidazo [1,2-a] pyridine in an amount of 5.5 g (yield: 84%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CN(C=O)C.CC(O)=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1cccc(-c2ccncc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: c1ccc(NCc2cccc(-c3ccncc3)c2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(pyridin-4-yl)benzaldehyde from Example 1 Step 1 (2 g, 10.9 mmol, 1 equiv) in DMF/AcOH (20/2 mL), aniline (1.02 g, 11.0 mmol, 1 equiv) and NaBH3CN (2.62 g, 41.6 mmol, 4 equiv). The resulting solution was stirred 2 h at 110° C. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 1:1 ethyl acetate/petroleum ether) to give N-(3-(pyridin-4-yl)benzyl)benzenamine as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:25]1([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1nc(I)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccccc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 120 °C
Yield: 55.6 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-1-iodo-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (117 mg, 0.27 mmol), phenyltributyltin (0.11 mL, 0.32 mmol), and PdCl2(PPh3)2 (38 mg, 0.054 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under N2 atmosphere. After the mixture was cooled to r.t., EtOAc (30 mL) and brine (10 mL) were added. 1 M HCl was added with stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-35% EtOAc/hexanes) to give 58 mg of the title compound. MS: (+) m/z 387.07 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=O)[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])(=[O:3])[CH3:2]>P(Cl)(Cl)(Cl)=O>[C:1]([O:4][CH2:5][C@@H:6]([C:14]1[N:22]2[C:18]([S:19][CH:20]=[CH:21]2)=[CH:17][N:16]=1)[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](NC(=O)C(F)(F)F)C(=O)NCc1nccs1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OC[C@H](NC(=O)C(F)(F)F)c1ncc2sccn12
Temperature: 25 °C
Yield: 66.6 %

Procedure:
To 0.506 g of the above-obtained 2-[(O-acetyl-N-trifluoroacetyl-D-seryl)amino]methylthiazole was added 10 ml of phosphorus oxychloride. The mixture was refluxed for 5 hours, cooled to room temperature, and then concentrated to dryness under reduced pressure. To the residue was added 50 ml of methylene chloride, and the mixture was thoroughly stirred. To this was added 30 ml of a saturated aqueous solution of sodium hydrogencarbonate with ice-cooling, and the mixture was stirred for an additional 30 minutes. Insoluble matters were removed by filtration. The organic layer was separated, and the aqueous layer was extracted with 30 ml of methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel, eluting with a 2:1 mixture of ethyl acetate and hexane to give 0.319 g (yield 67%) of 5-[(R)-2-acetoxy-1-(trifluoroacetyl-amino)ethyl]imidazo[5,1-b]thiazole. NMR (CDCl3) d: 2.08 (3H, s), 4.53 (1H, dd, J=11.6 Hz, 5.3 Hz), 4.57 (1H, dd, J=11.6 Hz, 7.8 Hz), 5.67 (1H, td, J=7.8 Hz, 5.3 Hz), 6.92 (1H, d, J=4.3 Hz), 7.05 (1H, s), 7.56 (1H, d, J=4.3 Hz), 7.64-7.74 (1H, br)
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[OH-].[Na+].Cl.Cl[CH:11]([CH3:14])[CH2:12][NH2:13].O>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:14][CH2:11][CH2:12][NH2:13])[CH:4]=[CH:5][N:6]=1
Reactant: CC(Cl)CN
Reactant: Cc1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1CCCN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
A solution of 2-methylimidazole (0.820 g, 10.0 mmol) in DMF (10 mL) was cooled in an ice/water bath and sodium hydroxide (1.00 g, 25.0 mmol) added. The resulting mixture was stirred for 30 min, then 2-chloropropylamine hydrochloride (1.30 g, 10.0 mmol) added in one portion. The resulting suspension was then stirred for 16 h during which time the reaction slowly warmed to room temperature. After this time the mixture was poured into water (500 mL) and the mixture extracted with ether (3×100 mL). The combined ether extracts were dried over sodium bicarbonate, filtered and concentrated under reduced pressure to afford 0.726 g (52% yield) of 3-(2-methylimidazol-1-yl)propylamine as a yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.00 (d, J=1.4 Hz, 1H), 6.79 (d, J=1.4 Hz, 1H), 3.97 (t, J=7.3 Hz, 2H), 2.63 (t, J=7.1 Hz, 2H), 2.35 (s, 3H), 1.87 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](CN)C1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
(S)-tert-butyl 3-(azidomethyl)piperidine-1-carboxylate (5.38 g, 22.40 mmol) was dissolved in MeOH (50 ml), and then Pd/C (5% mol) was added, followed by stirring at room temperature under H2 (gas) for 9 hours. After the completion of the reaction, the reaction mixture was filtered through celite, followed by filtration and concentration under reduced pressure, and then the next reaction was advanced without purification.