Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1.I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:29]1([CH2:28][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([S:16][CH2:15][O:14][CH3:13])=[CH:18][CH:19]=2)[C:24]([OH:26])=[O:25])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COCSc1ccc(CC(=O)O)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COCSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A solution of diisopropylamine (0.37 mL, 2.62 mmol) in tetrahydrofuran (2 mL) was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (1.05 mL, 2.62 mmol). This solution was stirred at −78° C. for 30 min and then treated with a solution of (4-methoxymethylsulfanyl-phenyl)-acetic acid (223 mg, 1.05 mmol) in tetrahydrofuran (1.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL). The reaction mixture was allowed to stir at −78° C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (328 mg, 1.56 mmol). The reaction mixture was allowed to slowly warm to 25° C. where it was stirred for 18 h. At this time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and then concentrated in vacuo. The residue was treated with a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The aqueous layer was then acidified with concentrated hydrochloric acid. This solution was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methoxymethylsulfanyl-phenyl)-propionic acid (202 mg, 65%) as an off-white solid: mp 167-170° C.; EI-HRMS m/e calcd for C16H22O3S (M+) 294.1290, found 294.1288.
Reaction SMILES: I[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]=1.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].C([N-]C(C)C)(C)C.[Li+]>CN1C(=O)N(C)CCC1>[CH2:23]([O:22][C:19](=[O:21])[CH2:20][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]=1)[CH3:24]
Reactant: CCOC(C)=O
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)CCc1cc(-c2ccc(C(F)(F)F)cc2)nn1C

Procedure:
In analogy to the procedure described in example 20 b], 5-iodomethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole was reacted with ethyl acetate in the presence of lithium diisopropylamide and DMPU to obtain 3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propionic acid ethyl ester as yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+].O>CO>[CH3:5][O:4][C:2]([N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]1)=[O:3]
Reactant: c1ccncc1
Reactant: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)N1C=CC=CC1
Reaction time: 2 h

Procedure:
Methyl chloroformate (30.9 mL/400 mmol) was added via syringe to a mixture of pyridine (31.6 g/400 mmol) and sodium borohydride (16.0 g/420 mmol) in methanol (150 mL) at -78° C. Stirred for two hours then poured in to water then extracted with diethyl ether (3×300 mL). The extracts were dried over NaCl/Na2SO4 then evaporated. The residue was purified by preparative chromatography using silica gel eluting with ethyl acetate/hexanes to yield the 1-(methoxycarbonyl)-1,2-dihydropyridine, 1A (20.2 g/130 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5].P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][C:15]1[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Solvent: ClC(Cl)Cl
Product: COCC(=O)c1cnc2c(OC)cccc2c1Cl
Yield: 45.8 %

Procedure:
3-Methoxyacetyl-8-methoxy-4-(1H)-quinolone (39 g, 0.16 mol) was heated under reflux in a mixture of phosphoryl chloride (150 ml) and chloroform (200 ml) for 45 minutes. The solvent was evaporated and the mixture ws partitioned between chloroform and sodium hydrogen carbonate solution. The aqueous layer was separated and extracted with chloroform. The combined organic solutions were washed with sodium hydrogen carbonate solution and brine. Evaporation gave an oil which afforded yellow crystals of 4-chloro-8-methoxy-3-methoxyacetylquinoline (19.2 g, 45.8%), m.p. 96°-8°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[Cl:17][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=3)[CH:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2nc(Cl)cc(C3CC3)n2)c1
Reactant: Nc1ccc(CCO)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 120 °C
Yield: 72.6 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.100 g, 0.38 mmol) and 4-aminophenethyl alcohol (0.103 g, 0.75 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was cooled, diluted with water (20 mL) affording a solid. The solid was isolated by filtration and purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as eluent to afford the title compound (0.101 g, 73%) as a white solid. MW=365.86. M.p. 124-126° C. 1H NMR (DMSO-d6, 500 MHz) δ 9.46 (s, 1H), 8.27-8.21 (m, 2H), 7.62-7.51 (m, 4H), 7.21 (d, J=8.5 Hz, 2H), 6.62 (s, 1H), 4.61 (br s, 1H), 3.60 (t, J=7.0 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.06-1.99 (m, 1H), 1.11-1.06 (m, 2H), 1.02-0.95 (m, 2H); ESI MS m/z 366 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH3:25]>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH3:25])[CH3:23])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A2) (1.62 g, 5.0 mmol) and dimethylamine (5.6 N in EtOH, 4.47 mL, 25.0 mmol) in DMSO (10 mL) at 23° C. according to the general procedure C and obtained as a yellow solid (1.48 g).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][N:7]=1
Reactant: CSc1ccc(C(O)c2ccc(F)nc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(Cc2ccc(F)nc2)cc1
Reaction time: 0.08 h
Yield: 89 %

Procedure:
A solution of (6-fluoropyridin-3-yl)(4-(methylthio)phenyl)methanol (1.716 g, 6.88 mmol) in DCM (3.0 mL) was treated with trifluoroacetic acid (2.56 mL, 34.4 mmol) resulting in a green solution. The mixture was stirred for 5 min, and then triethylsilane (3.30 mL, 20.65 mmol) was added dropwise. The green color dissipated rapidly to give a straw colored solution, and a brief exotherm was observed (DCM started refluxing). The mixture was stirred for 30 min, and then extracted into DCM from saturated aqueous NaHCO3. The DCM extracts were dried (MgSO4) and purified by flash chromatography (5% to 7.5% EtOAc/hexane) to give 2-fluoro-5-(4-(methylthio)benzyl)pyridine (89% over 2 steps) as a colorless oil. 1H NMR (400 MHz, d6-DMSO) δ 8.15 (s, 1H); 7.81 (t, J=8.22 Hz, 1H); 7.20 (s, 4H); 7.10 (d, J=8.41 Hz, 1H); 3.94 (s, 2H); 2.44 (s, 3H). 19F NMR (376 MHz, d6-DMSO) 6-72.37 (s, 1 F). m/z (ESI, +ve ion) 234.0 (M+H)+.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:12](Cl)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl>O1CCOCC1>[NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:12]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Reactant: C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(N3CCCCC3)cc(C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (100.0 mg, 0.241 mmol) in dioxane (2.5 mL) was added piperdine (40.9 mg, 0.481 mmol). The mixture was left to stir at 80° C. overnight. The mixture was cooled to room temperature, poured into 1N HCl (1 mL) and extracted with CH2Cl2. The organic extracts were combined, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was purified by Biotage silica gel chrmoatography (1:1 EtOAc:Hex) to provide 2-anilino-1-phenyl-7-(1-piperidinyl)-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (89.5 mg, 80%) as a pale yellow solid: LCMS RT: 2.76 min, MH+: 465.5.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15](=[CH:18]N(C)C)[C:16](=O)[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:23]([C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)[C:24]([NH2:26])=[NH:25].[OH-].[Na+]>C(O)(C)C.O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15]3[CH:18]=[N:25][C:24]([NH:23][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:34])(=[O:35])[NH2:36])[CH:28]=4)=[N:26][C:16]=3[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1CCc2sc(C(=O)OC(C)(C)C)cc2C1=O
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc2c(s1)CCc1cnc(Nc3cccc(S(N)(=O)=O)c3)nc1-2
Temperature: 25 °C
Yield: 53.1 %

Procedure:
5-Dimethylaminomethylene-4-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid tert-butyl ester (6.21 g, 20.20 mmol), 3-guanidinophenylsulphonamide hydrochloride (5.07 g, 20.20 mmol) and sodium hydroxide (0.81 g, 20.20 mmol) were suspended in isopropanol (250 mL) and stirred at reflux overnight. The reaction was allowed to cool to room temperature and diluted with water (˜200 mL). The resulting precipitate was isolated by filtration and the solid obtained was washed with water (1×100 mL), isopropanol (1×50 mL), diethyl ether (2×50 mL) and pentane (3×100 mL). Air drying gave an ochre powder (4.92 g, 53% yield). MS (ES+)459. δH (d6 DMSO) 1.5-1.6 (9H, s), 2.9-3.0 (2H, m), 3.1-3.2 (2H, m), 7.2-7.3 (2H, br s), 7.3-7.5 (2H, m), 7.7-7.8 (1H, m), 8.1 (1H, s), 8.4 (1H, s), 8.6 (1H, s), 9.9 (1H, s).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCCC.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:46])[CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CC#N>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:46])[CH2:39][N:40]2[CH2:41][CH2:42][N:43]([C:6](=[O:8])[C:5]3[CH:4]=[C:3]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]([OH:1])=[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=3)[CH2:44][CH2:45]2)=[CH:34][CH:33]=1
Reactant: O=C(CN1CCNCC1)c1ccc(Cl)cc1
Reactant: CCCCCCCCCOc1cc(C(=O)O)cc(OCCCCCCCCC)c1O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCCCCOc1cc(C(=O)N2CCN(CC(=O)c3ccc(Cl)cc3)CC2)cc(OCCCCC)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To 4-hydroxy-3,5-bis-nonyloxy benzoic acid (98 mg, 0.23 mmol), 1-(4-chlorophenyl)-2-piperazine-1-yl-ethanone (111 mg, 0.46 mmol), EDCI (89 mg, 0.46 mmol) and HOBT (63 mg, 0.46 mmol) was added MeCN (3 ml) and stirred for 1 hour at room temperature. The solution was added with NaHCO3 to finish the reaction. The solution was extracted with EtOAc, dried over anhydrous Na2SO4 and filtered. The obtained filterate was vacuum concentrated to give the residue, which was purified by column chromatography (Hexane:EtOAc=1:10), yielding 98 mg (66%) of 1-(4-chlorophenyl)-2-[4-(4-hydroxy-3,5-bis-pentyloxybenzoyl)piperizine -1-yl]ethanone.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH:12]=[C:13]([N:15]([CH:17]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:16])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].CI.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:29][C:27]1[CH:28]=[C:23]([CH:17]([N:15]([CH3:16])[C:13]2[CH:14]=[C:9]([CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:41])=[O:2])[CH:10]=[C:11]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][CH:32]=3)[CH:12]=2)[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:24]=[C:25]([F:30])[CH:26]=1
Reactant: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(C)C(CCC(C)C)c2cc(F)cc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: CC(C)CCC(c1cc(F)cc(F)c1)N(C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)O)c1
Temperature: 80 °C
Yield: 50 %

Procedure:
A solution of 2-(5-{[1-(3,5-Difluoro-phenyl)-4-methyl-pentyl]-methyl-amino}-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester, compound 29e, (0.25 g, 0.4 mmol), MeI (0.3 ml, 4 mmol), Cs2CO3 (0.72 g) and acetonitrile in a sealed reaction tube was heated to 80° C. overnight. The solvent was removed by vacuum and the crude was purified by preparative TLC to give the title compound (50% yield). Calcd. MW 575.67 Found MH+ 576.3.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[C@H:12]1[OH:17].[NH3:18]>>[NH2:18][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[C@H:12]1[OH:17]
Reactant: N
Reactant: O[C@@H]1[C@H](O)CC[C@H]1n1cnc2c(Cl)ncnc21
Product: Nc1ncnc2c1ncn2[C@@H]1CC[C@@H](O)[C@H]1O

Procedure:
(±)-(1R*,2S*,3R*)-3-(6-Chloro-9H-purin-9-yl)-1,2-cyclopentanediol (4.00 g, 15.7 mmol) and ammonia (1, 100 ml) were stirred in a Parr bomb at 25° C. for 18 hours. Evaporation and neutralization with 1N NaOH (16 ml), followed by elution of a silica gel column with MeOH:CHCl3 /1:4 gave title compound as white crystals, recrystallized from 95% ethanol (3.54 g, 96%); mp 201°-202° C.; 1H-NMR (Me2SO-d6) δ8.19 and 8.12 (both s, 2, purine H-2, H-8), 7.18 (br s, 2, NH2), 4.98 (d, J=6.6, 1, 2-OH), 4.76-4.64 (m) overlapping 4.70 (d, J=3.4, 2, H-3 and 1-OH), 4.42-4.34 (m, 1, H-2), 4.04-3.97 (m, 1, H-1), 2.5-1.9 and 1.7-1.6 (both m, 4, two CH2).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1.O>[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(C(CO)CO)N(C(=O)c1ccccc1)CC2
Yield: 95 %

Procedure:
0.01 mole (2.7 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is dissolved in 50 ml of benzene under slight warming, and the solution obtained is admixed with a solution of 0.015 mole (0.6 g) of sodium hydroxide in 10 ml of water. 0.011 mole (1.5 g) of benzoyl chloride is added dropwise to the reaction mixture under cooling and stirring. When the addition is complete, the reaction mixture is stirred at room temperature for an additional hour, the organic phase is separated, and the aqueous phase is extracted twice with chloroform. The organic phases are combined, dried and evaporated to yield the aimed compound with a melting point of 161° to 163° C. (methanol/ether).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH3:16]>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:21]([NH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])=[S:22])=[CH:11][CH:12]=1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)N=C=S
Solvent: CC(C)OC(C)C
Product: CCOC(=O)NC(=S)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
In 150 ml of isopropyl ether was dissolved 13.51 g of 4-amino-benzoic acid t-butyl ester. To the solution was added, while stirring at room temperature, 9.83 g of ethoxycarbonyl isothiocyanate. The mixture was stirred for two hours, then the resulting crystalline precipitate was collected by filtration, followed by recrystallization from isopropyl ether to give 21.83 g of the title compound as colorless needles.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:30][CH2:31][C@@H:32]4[CH2:36][CH2:35][CH2:34][O:33]4)[C:16]4[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.Cl>CO>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:30][CH2:31][C@@H:32]4[CH2:36][CH2:35][CH2:34][O:33]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@@H]3CCCO3)c2C1
Agent: Cl
Solvent: CO
Product: c1ncc(-c2ccc(Nc3nc4c(c(NC[C@@H]5CCCO5)n3)CNCC4)cc2)o1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
(S)-tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate was dissolved in methanol (3 mL). Hydrochloric acid was added and the reaction mixture was stirred at 75° C. for 1 h. The solvent was evaporated under reduced pressure and the crude was used as such in the next step. MS (ES+) m/z 393.2 (M+H)+
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].CS([O-])(=O)=O.Cl.[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33][C:34](=[O:36])[NH2:35])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CO.N1C=CC=CC=1>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=3)[C:29]=2[CH2:33][C:34](=[O:36])[NH2:35])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
100 Milliliters of 20% hydrous pyridine was added to 3.0 g of 4-guanidinobenzoic acid.methanesulfonate, 3.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride and 4.5 g of DCC, followed by stirring for 2 hours under cooling with ice and then 2 days at room temperature. The precipitate was filtered and 1 g of active carbon was added to the filtrate, followed by stirring for 30 minutes under cooling with ice, and insoluble matter was filtered off. The filtrate was slowly added dropwise to 4 liters of ether under cooling with ice, followed by stirring for 2 hours. The precipitate was collected by filtration and washed with 100 ml of acetone to obtain a crude product. Then, the product was dissolved in 150 ml of methanol. Thereafter, 2.5 g of active carbon was added to the solution, followed by stirring for 30 minutes under cooling with ice, and insoluble matter was filtered off. The filtrate was slowly added dropwise to 1 liter of acetone under cooling with ice, followed by stirring for 2 hours. The precipitate was collected by filtration to obtain 2.9 g of the desired product.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:17]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][CH2:19][NH2:20])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([N:17]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][CH2:19][NH:20][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN(CCN)CCCC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCN(CCCC)CCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N-dibutylethane-1,2-diamine as starting materials to give the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2nc(C3CCCN(S(C)(=O)=O)C3)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of crude methyl 4-(3-amino-6-(piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (38 mg, 0.114 mmol) in DCM (2 mL) in an ice bath was added DIEA (79 μL, 0.454 mmol) followed by methanesulfonyl chloride (9.73 μL, 0.125 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product (50% purity) was proceeded to next step. LCMS (m/z): 409.1 (MH+), 0.721 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SCC(C)CC.BrCC1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](C3C=CC=CC=3OC)[CH:38]=2)[NH:33]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].CC(CC)CS>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])([CH3:20])[CH:13]=[C:12]2[CH2:21][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: CCC(C)CSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: CCC(C)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-(2-methylbutylsulfanylmethyl)-1,2-dihydroquinoline 60 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 27 μL of 2-methyl-1-butanethiol reacted to give 4 mg of the title compound as an oil.