Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])=[O:6].[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1>CCCCCC.CN(C=O)C>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])[C:5](=[O:6])[C:4]([F:18])([F:19])[F:3])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1ccc(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C(=O)C(F)(F)F)c2ccc(C)cc2[N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A portion of 60% NaH in mineral oil (2.9 g, 71.8 mmol, 1.1 eq) was pre-washed with hexane and suspended in dry DMF under nitrogen. The slurry was cooled in an ice bath and a solution of 2,2,2-trifluoro-N-(4-methyl-2-nitrophenyl)-acetamide (16.2 g, 65.3 mmol, 1.0 eq) in dry DMF was added dropwise over 15 min. The cooling bath was removed and the mixture was stirred for 30 min. The reaction mixture was cooled again and a solution of 4-bromomethylbenzoic acid methyl ester (20 g, 65.3 mmol, 1.0 eq) in dry DMF was added dropwise over 10 min. The reaction mixture was stirred at room temperature for 18 h and evaporated under reduced pressure to give a residue. The residue was partitioned between ethyl acetate and water. The organic layer was washed sequentially with water and brine, dried (Na2SO4) and concentrated to give a yellow solid. The yellow solid was purified by column chromatography. (Silica gel 230-400 mesh: eluent CHCl3 MeOH:0→5%) to give 4-{[(4-methyl-2-nitrophenyl)-(2,2,2-trifluoroacetyl)amino]methyl}benzoic acid methyl ester, yield: 59%. 1H NMR (400 MHz, CDCl3): 7.97 (m, 3H); 7.27 (m, 3H); 6.76 (d, J=8 Hz, 1H); 5.66 & 4.26(2H); 3.92 (s, 3H); 2.46(s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[S:17])=[CH:11][C:10]=2[F:28])[CH:5]=[CH:4][N:3]=1.CN1CC[O:33][CH2:32]C1.ClC(OC1C=CC=CC=1)=O.[N:46]1([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48][CH2:47]1>O1CCCC1.CN(C)C=O>[F:28][C:10]1[CH:11]=[C:12]([NH:15][C:16]([NH:18][C:19](=[O:27])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[S:17])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:32]([N:54]2[CH2:55][CH2:56][CH:51]([N:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)[CH2:52][CH2:53]2)=[O:33])[CH:7]=1
Reactant: CN1CCOCC1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Nc1cc(Oc2ccc(NC(=S)NC(=O)Cc3ccccc3)cc2F)ccn1
Agent: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
2-Amino-4-{2-fluoro-4-[3-(2-phenylacetyl)thioureido]phenoxy}pyridine (66.6 mg) was dissolved in tetrahydrofuran (2.0 ml) under a nitrogen atmosphere, and then N-methylmorpholine (0.0462 ml) and phenyl chloroformate (0.0527 ml) in this order were added dropwise thereto while cooling in an ice bath, followed by raising the temperature up to room temperature and stirring for 15 min. The solvent was evaporated to give a residue, which was dissolved in N,N-dimethylformamide (2.0 ml), and then 4-(pyrrolidin-1-yl)piperidine (136 mg) was added thereto at room temperature, followed by stirring for 2 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (46.3 mg, 48%) as white powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C@H:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[CH:23]=2)[C:18]([OH:20])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:37][C:34]1[N:35]=[CH:36][C:31]([NH:30][C:18](=[O:20])[C:17]2[CH:21]=[C:22]([O:24][C@H:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[CH:23]=[C:15]([O:14][CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:16]=2)=[N:32][CH:33]=1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCOC3)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Oxalyl chloride (1.9 mL, 22.2 mmol) and DMF (1 drop) were added to a solution of 3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (5.8 g, 18.5 mmol) in DCM (100 mL) and the mixture stirred at RT for 16 hours. The mixture was evaporated in vacuo to a residue which was redissolved in DCM (25 mL) and added to a stirred mixture of 2-amino-5-methylpyrazine (2.22 g, 20.35 mmol) and pyridine (1.81 mL, 22.2 mmol) in DCM (100 mL) at 5° C.-10° C. The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo to give a residue which was partitioned between water (50 mL) and ethyl acetate (125 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 60% ethyl acetate in isohexane, to give the desired material (5.1 g). 1H NMR δ (CDCl3): 2.1-2.2 (m, 2H), 2.5 (s, 3H), 3.8-3.95 (m, 4H), 4.9 (m, 1H), 5.0 (s, 2H), 6.6 (s, 1H), 6.95 (s, 1H), 7.05 (s, 1H), 7.35 (m, 5H), 8.05 (s, 1H), 8.3 (s, 1H), 9.5 (s, 1H); m/z 406 (M+H)+.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:18]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CC(O)C>[C:18]1([CH2:24][CH2:25][CH2:26][NH:27][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCc1ccccc1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccccc4)CC3)cc2o1
Reaction time: 4 h

Procedure:
To a solution of ketone 5 (0.50 g, 2.0 mmol) in 2-propanol (30 mL) was added 3 Å molecular sieves and 3-phenyl-1-propylamine 10 (0.39 g, 2.0 mmol). The reaction mixture was stirred for 4 hours. Sodium borohydride (0.11 g, 2.83 mmol) was added, and the reaction mixture was stirred overnight, quenched with MeOH, and concentrated under reduced pressure. Purification by flash chromatography (silica, 9.5:5:1 CH2Cl2:MeOH:NH4OH) gave 6-[trans-4-(3-phenylpropylamino)-cyclohexyl]-3H-benzoxazol-2-one (0.30 g, 42%): mp 166-170° C.; IR (KBr): 2933, 1761, 1653, 1582 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 9.09 (s, 1H), 7.30-7.19 (m, 6H), 7.03 (d, J=9 Hz, 1H), 6.68 (d, J=9 Hz, 1H), 2.66 (m, 1H), 2.55 (t, J=8 Hz, 2H), 2.37 (tt, J=10, 2 Hz, 1H), 1.98 (d, J=10 Hz, 1H), 1.96 (d, J=10 Hz, 1H), 1.76 (d, J=3 Hz, 1H), 1.56 (m, 1H), 1.45 (m, 1H), 1.39 (m, 1H), 1.18-1.05 (m, 6H); CI-MS (methane) (m/z): 351 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C22H26N2O2, 351.2072; found, 351.2178; HPLC: method A, 7.66 minutes (96.9%); method B, 14.14 minutes (97.7%); Anal. Calcd for C22H26N2O2.H2O: C, 71.71; H, 7.66; N, 7.60. Found: C, 71.70; H, 7.62; N, 7.20.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:13]2[C:22]3[N:23]=[C:24]([CH2:30][CH2:31][CH2:32]O)[N:25]([CH2:26][O:27][CH2:28][CH3:29])[C:21]=3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:5]1([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:13]2[C:22]3[N:23]=[C:24]([CH2:30][CH2:31][CH2:32][Cl:3])[N:25]([CH2:26][O:27][CH2:28][CH3:29])[C:21]=3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOCn1c(CCCO)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOCn1c(CCCCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Yield: 95.4 %

Procedure:
Thionyl chloride (5 mL, 68 mmole) was added to N,N-bis(phenylmethyl)-2-(3-hydroxypropyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (1 g, 2.1 mmole) and the reaction mixture was stirred rapidly until thin layer chromatography (silica gel, 10% ethyl acetate in methylene chloride v/v) indicated that the reaction was complete. The reaction mixture was diluted with methylene chloride then neutralized with 10% sodium hydroxide and sodium bicarbonate. The methylene chloride layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with 10-30% ethyl acetate in hexanes v/v) to provide 1 g of N,N-bis(phenylmethyl)-2-(3-chloropropyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[CH:7]([CH3:9])[CH3:8].O.C([O-])(O)=O.[Na+].[C:23]1([CH3:29])C=CC=C[CH:24]=1>>[Cl:4][CH:11]([C:6](=[O:10])[C:7]1[CH:9]=[CH:29][CH:23]=[CH:24][CH:8]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of sulfuryl chloride (12.4 mmol) in toluene (5 mL) was added dropwise via an additional funnel to a solution of ethyl isobutyrylacetate (12.4 mmol) in toluene (20 mL) over 5 minutes at rt. The resulting mixture was stirred at rt overnight. Water was added slowly. The resulting two-phase mixture was basified with saturated NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. sodium sulfate, and removed in vacuo to afford 2.2 g (84%) of product as a pale yellow oil. MH+=227.0, retention time (LC-MS)=2.77 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[N:7][C:6]=1[Br:12])[CH3:2].[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21]N=2)[CH:17]=[CH:16][CH:15]=1.[CH:24](=[O:27])CC.[C:28]([CH2:30][C:31]([O:33][CH2:34]C)=O)#N>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[N:7][C:6]=1[Br:12])[CH3:2].[CH3:24][O:27][C:21]1[CH:16]=[CH:17][C:18]([CH2:23][NH2:14])=[CH:19][CH:20]=1.[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[N:7][C:6]=1[NH:14][CH2:15][C:16]1[CH:28]=[CH:30][C:31]([O:33][CH3:34])=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: c1cnc2ncccc2c1
Reactant: CCC=O
Agent: CCOC(=O)c1cc(C)cnc1Br
Product: CCOC(=O)c1cc(C)cnc1NCc1ccc(OC)cc1
Product: COc1ccc(CN)cc1

Procedure:
2-Bromo-5-methyl nicotinic acid ethyl ester, depicted by formula 31 in Scheme 12, was used as a starting material to prepare compounds with methyl substitution at 6-position of naphthyridine moiety. This starting material was prepared by condensation of propionaldehyde with ethyl cyanoacetate followed by cyclisation of resulted intermediate as shown in Scheme 12. Amination of 2-bromo-5-methyl nicotinic acid ethyl ester by p-methoxy benzyl amine gave 5-methyl-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester, depicted by formula 32 in Scheme 12, which was then converted into 6-methyl-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione, depicted by formula 33 in Scheme 12, by reacting with trichloromethyl chloroformate as shown in Scheme 12.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:15]=1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Fc1ccc2[nH]cc(CCn3cnc4ccccc43)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (7.26 g, 30 mmol), benz-imidazole (3.54 g, 30 mmol) and ethyl-diisopropylamine (5.1 ml, 30 mmol) in abs. chloroform (80 ml) was boiled under reflux for 20 h. The reaction solution was then washed twice with water, dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (50:1).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([Br:21])=[CH:13][CH:12]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C1(C)C=CC=CC=1>[Br:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:13]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: Brc1ccc(-c2ccccc2)c2ccccc12
Temperature: 78 °C
Reaction time: 24 h
Yield: 41.1 %

Procedure:
Under an argon gas atmosphere, 128.0 g (1.049 mol) of phenylboronic acid, 300.0 g (1.163 mol) of 1.4-dibromonaphthalene, 24.2 g (21.0 mmol) of tetrakis(triphenylphosphine)palladium(0), 4.3 L of dimethoxyethane and 1.60 L of 2M sodium carbonate solution were mixed, and stirred for 24 hours at 78 degrees C. The reaction mixture was further added with toluene and water, and then aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. By refining residue thereof by silica-gel column chromatography and by recrystallizing the residue by hexane, 122 g of 1-bromo-4-phenyl naphthalene was obtained with an yield of 41%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:34])[CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[CH:22][CH:21]=4)=[O:18])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.[CH3:35][I:36]>CN(C=O)C>[I-:36].[CH3:34][N+:27]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)([CH3:35])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([C:14]2[CH:15]=[CH:16][C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:12][C:11]=3[CH:13]=2)=[O:18])=[CH:21][CH:22]=1
Reactant: CI
Reactant: Cc1ccc(-c2cc3cc(C(=O)Nc4ccc(CN(C)C5CCOCC5)cc4)ccc3o2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3cc(C(=O)Nc4ccc(C[N+](C)(C)C5CCOCC5)cc4)ccc3o2)cc1
Product: [I-]
Reaction time: 24 h

Procedure:
To a solution of 2-(4-methylphenyl)-N-[4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)phenyl]benzofuran-5-carboxamide (120 mg) in DMF (20 ml) was added at room temperature methyl iodide (0.04 ml), and the mixture was stirred for 24 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added ethanol. The resulting crystals were collected by filtration to give yellow crystals of N,N-dimethyl-N-[4-[[2-(4-methylphenyl)benzofuran-5-carbonyl]amino]-benzyl]-4-tetrahydropyranyl ammonium iodide (Compound 281) (142.1 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17]([C:20](O)=[O:21])=[CH:16]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.Cl.[C:24]([S:43][CH2:44][CH2:45][NH2:46])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17]([C:20]([NH:46][CH2:45][CH2:44][S:43][C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:21])=[CH:16]3)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 7-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indole-2-carboxylic acid (0.84 g), 2-(tritylthio)ethylamine hydrochloride (0.85 g), 1H-1,2,3-benzotriazol-1-ol (0.35 g), triethylamine (0.36 mL) and N,N-dimethylformamide (20 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.50 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.41 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point>197° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:19]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH2:20][CH3:21].O>C(Cl)Cl>[CH2:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][C:25](=[O:26])[CH2:24][O:23][C:19](=[O:22])[CH2:20][CH3:21])[C:3]=1[C:4]#[N:5])[CH3:12]
Reactant: CCNc1cccc(N)c1C#N
Reactant: CCC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCNc1cccc(NC(=O)COC(=O)CC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzonitrile (2.3 g) in methylene chloride (50 ml) is added pyridine (1.6 ml), and thereto is added dropwise propionyloxyacetyl chloride (3.0 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol to give the title compound (1.6 g) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=1.[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23][Br:24]>>[Br-:24].[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23][N:3]1[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N+:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCn1nc(C)cc1C
Reactant: Clc1ccc(CBr)c(Cl)c1
Product: CCCCCCCCCCCC[n+]1c(C)cc(C)n1Cc1ccc(Cl)cc1Cl
Product: [Br-]

Procedure:
Reaction of 3,5-dimethyl-1-dodecyl-pyrazole with 2,4-dichlorobenzylbromide yields 2-(2,4-dichlorobenzyl)-3,5-dimethyl-1-dodecyl-pyrazolium bromide; m.p. 139°-140.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][NH:11]C2CCCC2)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].ClC1N=C(Cl)C([N+]([O-])=O)=CN=1.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][NH2:11])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:4]
Reactant: COC(=O)C1(CNC2CCCC2)CCCC1
Agent: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1(CN)CCCC1

Procedure:
Methyl1-[(cyclopentylamino)methyl]cyclopentane-1-carboxylate (Intermediate 258; 1.60 g, 7.10 mmol), 2,4-dichloro-5-nitropyrimidine (Aldrich; 1.66 g, 8.52 mmol) and triethylamine (1.2 mL, 8.52 mmol) were stirred in acetonitrile (50 mL) for 4 hours. The reaction mixture was evaporated and the residue dissolved in DCM, washed with water, dried (MgSO4) and evaporated. The residue was purified on a silica column eluting with 1% methanol/DCM to yield the title compound as a yellow oil that crystallised on standing (945 mg, 35%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:10].[CH3:20][O:21][C:22](=[O:49])[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([O:32][C:33]2[C:34]3[C:41](Br)=[C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[O:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:27]1>CS(C)=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>[CH3:20][O:21][C:22](=[O:49])[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([O:32][C:33]2[C:34]3[C:41]([C:14]4[CH:15]=[CH:16][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=4)=[C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[O:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:27]1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)CCCN1CCC[C@H](Oc2ncnc3oc(-c4ccccc4)c(Br)c23)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H]4CCCN(CCCC(=O)OC)C4)c23)cc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
Add 5.2 mg (0.007 mmol) of bis(triphenylphosphine)palladium(II) chloride,. 30.6 mg (0.221 mmol) of potassium carbonate, 0.04 ml of methanol and 31 mg (0.207 mmol) of 4-ethylbenzeneboronic acid successively under argon to a solution of 70 mg (0.148 mmol) of (+)-4-{(3S)-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]piperidin-1-yl}butanoic acid methyl ester in 0.4 ml of DMSO. Stir the mixture at 80° C. for a total of 3.5 h. After cooling, purify the reaction mixture directly by preparative RP-HPLC (eluent: acetonitrile/water gradient). 37.3 mg (50.6% of theory) of the target compound are isolated.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:19][O:20][C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:22].O>N1C=CC=CC=1>[CH3:19][O:20][C:21](=[O:22])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:18][C:16]2[S:17][C:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=3)=[N:14][N:15]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: CCCCCOc1ccc(-c2nnc(N)s2)cc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCOc1ccc(-c2nnc(NC(=O)c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of 5-(4-pentyloxyphenyl)-1,3,4-thiadiazol-2-yl-amine (20 g) in pyridine (200 ml) was added 4-methoxycarbonylbenzoylchloride (15 g) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried to give N-[5-(4-pentyloxyphenyl)-1,3,4-thiadiazol-2-yl]terephthalamic acid methyl ester (30.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Clc1ccc(NCc2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
A 4.37 g. portion of 3-(4-chlorophenylaminomethyl)pyridine was dissolved in 20 ml. of dichloromethane, and 4.1 g. of potassium carbonate and 3.8 g. of ethanesulfonyl chloride were added. The mixture was stirred under gentle reflux overnight, and was then allowed to stand for several days at ambient temperature. The mixture was extracted with water, dried over magnesium sulfate and filtered. The residue was taken up in chloroform and purified over silica gel, eluting with chloroform. The product-containing fractions were collected and evaporated under vacuum to obtain 1 g. of the desired product, m.p. 104°-106°.