Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(O)c1
Reactant: COCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(C(=O)OC)ccc1C

Procedure:
A solution of 3-hydroxy-4-methyl-benzoic acid methyl ester (7.7 g, 32.43 mmol), potassium carbonate (6.72 g, 48.65 mmol) and 1-iodo-3-methoxy propane (7.14 g, 35.68 mmol) in acetonitrile (125 mL) is stirred at reflux for 26 h. The solvent is concentrated under reduced pressure, H2O (100 mL) is added, and the aqueous layer is extracted with ether (50 mL×4). The combined organic extracts are washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title which is used without further purification in the next step. TLC, Rf (hexane/AcOEt 2:1)=0.65. 1H-NMR (CDCl3, 300 MHz): δ=2.10 (p, 2H), 2.3 (s, 3H), 3.38 (s, 3H), 3.62 (t, 2H), 3.9 (s, 3H), 4.15 (t, 2H), 7.15 (d, 1H), 7.45 (s, 1H), 7.55 (d, 1H) ppm.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]1[CH:32]=[C:31]([CH2:33][C:34](O)=[O:35])[O:30][N:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][C:31]3[O:30][N:29]=[C:28]([CH3:27])[CH:32]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)on1

Procedure:
The title compound, off-white solid (84 mg, 74%), MS (ISP) m/z=450.3 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-(3-methyl-isoxazol-5-yl)-acetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])[CH:12]=[CH:11][C:10]=1[CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35]>CN(C=O)C.C(N(CC)CC)C>[CH2:2]([N:39]1[CH2:38][CH2:37][N:36]([C:34](=[O:35])[CH2:33][CH2:32][C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:26][C:25]4[CH:24]=[N:23][N:22]([CH3:27])[C:21]=4[NH:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)=[O:16])=[CH:14][C:9]=2[CH3:8])[CH2:41][CH2:40]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCN1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-1-piperazin-1-yl-propan-1-one from Example E47 (2.29 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=543.4
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[S:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[S:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:14]([C:17]([NH2:18])=[O:32])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 3-methylisothiazol-5-amine hydrochloride (50 mg, 0.332 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 5 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg, 0.219 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (44 mg). MS 384.2 (M+H); UV 209.0, 270.7, 321.3 nm; t 0.362 min.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[S:11][C:10]([N-:12][CH2:13][CH2:14][C:15](=O)[CH3:16])=[N:9][N:8]=1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:6][C:7]1[S:11][C:10]2=[N:12][C:13](=[O:2])[CH:14]=[C:15]([CH3:16])[N:9]2[N:8]=1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)CC[N-]c1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(=O)nc2sc(Br)nn12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To concentrated sulfuric acid (10 ml) heated to 60° C. was added the compound (1.3 g) obtained in Step 2 in divided portions, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was poured into ice (100 g), and the mixture was neutralized with an aqueous solution (100 ml) of sodium carbonate (20 g). The organic layer was extracted with chloroform (50 ml), and dried to give the title compound (810 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)=[O:24])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCc1cccc(C)n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:17]([N:19]([C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH3:16].C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:17]([N:19]([C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH3:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N(CC(=O)O)c1ccsc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N(CC(=O)O)c1ccsc1

Procedure:
2-Oxo-4-phenylbutyric acid and L-alanyl-N-(3-thienyl)glycine are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-alanyl-N-(3-thienyl)glycine.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A solution of Compound 35 (3 g, 16.57 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 729 mg, 18.22 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (2.28 mL, 18.23 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 3.23 g (67%) of white solids. M.P. 107° C. 1H NMR (DMSO-d6): δ 5.27 (s, 2H), 7.19 (m, 2H), 7.29 (dd, J=3.9, 9.0 Hz, 1H), 7.47 (m, 2H), 7.65 (td, J=5.5, 9.0 Hz, 1H), 7,81 (dd, J=2.9, 7.9 Hz, 1H). Anal. (C15H9F2NO3) C, H, N.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[N:5]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13](OC)=[O:14])=[C:6]=[S:7]>O1CCCC1>[CH2:1]([N:4]1[C:13](=[O:14])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[NH:5][C:6]1=[S:7])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: COC(=O)c1sccc1N=C=S
Solvent: C1CCOC1
Product: CCCn1c(=S)[nH]c2ccsc2c1=O
Reaction time: 16 h

Procedure:
In a sulfonation flask, 1.7 g (0.028 mol) of n-propylamine are added dropwise to 30 ml of tetrahydrofuran and 5.2 g (0.026 mol) of methyl 3-isothiocyanatothiophene-2-carboxylate, dissolved in 30 ml of tetrahydrofuran, such that the internal temperature does not rise above 35° C. The reaction mixture is then stirred for 16 hours at reflux temperature and the tetrahydrofuran is then removed in a water-jet vacuum. The residue is taken up in ethyl acetate and extracted three times with water. The organic phase is then dried over sodium sulfate and the solvent is removed in the water-jet vacuum, giving the 3-propyl-2-thioxo-2,3-di-hydro-1 H-thieno[3.2-d]pyrimidin-4-one crude product which can be purified by digestion in tert-butylmethyl ether. The slightly brownish powder (5.3 g) has a melting point of >230° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:3]1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:9]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC(C)(C)C3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(3,3-dimethylpiperidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120 mg, 0.31 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (61 mg, 1.52 mmol, 4.99 equiv), and water (2 mL). The resulting solution was stirred for 2 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 60 mg (52%) of 3-(3,3-dimethylpiperidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]1[CH2:19][C@H:15]2[O:16][CH2:17][CH2:18][C@@:14]2([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[OH:34])=[O:21])[CH2:13]1.C=O.O.[C:38]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[CH:26][C:25]2[O:34][CH2:38][N:22]([C:20]([C@:14]34[CH2:13][C@H:12]([N:3]5[C:4](=[O:11])[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[C:2]5=[O:1])[CH2:19][C@H:15]3[O:16][CH2:17][CH2:18]4)=[O:21])[CH2:23][C:24]=2[CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C

Procedure:
A solution of the product of Step C (7.97 g, 15.5 mmol, 1 eq), paraformaldehyde (9.28 g, 310 mmol, 20 eq) and p-toluenesulfonic acid hydrate (2.94 g, 15.5 mmol, 1 eq) in toluene (300 mL) was heated to 130° C. for 18 hours in a flask equipped with a Dean-Stark trap. The solution was cooled to rt and concentrated. Purification by chromatography (200 g column) eluting with 25 to 60 to 100% ethyl acetate/heptane afforded the product of Step D. Calculated for C25H21F3N2O5: 487.1 (M+1). found: 487.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28](=[O:31])[CH2:29]Cl)[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:28](=[O:31])[CH2:29][N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCl)c1
Reactant: c1cn[nH]c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cn2cccn2)c1

Procedure:
Prepared according to the procedure described in Example 37, Step 2, using the following starting materials: (2′-{[(2-chloro-acetyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and pyrazole.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]#[N:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18].[OH-].[K+]>C(O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14](=[N:17][OH:18])[NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: CSc1ccc(-c2ccc(C#N)o2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ccc(-c2ccc(C(N)=NO)o2)cc1
Reaction time: 8 h

Procedure:
A mixture of 13 g (0.060 mole) of 5-(p-methylthiophenyl)-2-furonitrile, 4.5 g (0.065 mole) of hydroxylamine hydrochloride, 4.2 g (0.065 mole) of KOH, and 160 ml of absolute ethanol was refluxed for 11/2 hours and then kept overnight at room temperature. The insoluble material was removed by filtration and discarded. The filtrate was added to ice/water and the resulting solid was dissolved in refluxing ethyl acetate, Darcoed, and filtered. The filtrate was heated to reflux and hexane was added to the cloud point. This mixture was cooled in an ice bath with the resulting solid being filtered and air dried to yield 10 g (67%). An analytical sample was prepared by drying a sample in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 148°-150°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:24][CH:25]([C:27]1[S:28][CH:29]=[C:30]([CH2:32][NH2:33])[N:31]=1)[CH3:26]>>[CH:25]([C:27]1[S:28][CH:29]=[C:30]([CH2:32][NH:33][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[N:31]=1)([CH3:26])[CH3:24]
Reactant: CC(C)c1nc(CN)cs1
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Product: CC(C)c1nc(CNC(=O)c2ccc(OCC3CC3)c(-c3ccc(Cl)cc3)n2)cs1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 2-(1-methylethyl)-4-thiazole-methanamine dihydrochloride (CAN 1171981-10-4) as starting materials, LC-MS (peak area/EIC) 97.9%, 442.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:20]>C(O)C.[Pd]>[ClH:20].[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][NH:5][C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:3]1
Reactant: Cc1nc(N2CCOCC2)nnc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1N=C(N2CCOCC2)NN=C1c1ccccc1

Procedure:
5-Methyl-3-morpholino-6-phenyl-1,2,4-triazine (2.32 g) was dissolved in ethanol (40 ml) containing anhydrous hydrogen chloride and hydrogenated over 10% palladium on carbon (0.33 g) under an atmospheric pressure at room temperature. After the theoretical amount of hydrogen gas was absorbed, the catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residual solid was recrystallized from ethanol to give crystals of 5-methyl-3-morpholino-6-phenyl-2,5-dihydro-1,2,4-triazine hydrochloride, mp 213°~215.5° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[CH:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([O:31]C)=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[CH:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC=CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC=CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 40 °C
Reaction time: 6 h
Yield: 92.9 %

Procedure:
In THF (4.4 ml)/methanol (4.4 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-crotyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.22 g). To the solution was added 1N sodium hydroxide solution (2.2 ml), and the mixture was stirred at 40° C. for 6 hours. pH was adjusted to approximate 5 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate=8/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-crotyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (198 mg).
Reaction SMILES: O([CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])S(C(F)(F)F)(=O)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:57]=[CH:58][CH:59]=1)[NH:26][C:27]1[N:32]=[C:31]([C:33]2[N:34]=[CH:35][N:36](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:37]=2)[CH:30]=[CH:29][N:28]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:57]=[CH:58][CH:59]=1)[NH:26][C:27]1[N:32]=[C:31]([C:33]2[N:34]([CH2:9][CH2:10][N:11]3[C:15](=[O:16])[C:14]4=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]4[C:12]3=[O:21])[CH:35]=[N:36][CH:37]=2)[CH:30]=[CH:29][N:28]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOS(=O)(=O)C(F)(F)F
Reactant: Clc1cccc(Nc2nccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2)c1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Reaction time: 0.08 h
Yield: 40 %

Procedure:
2-Phthalimidoethyl triflate (660 mg, 2.04 mmol) was added to solution of the 2-(3-chloroanilino)-4-(1-triphenylmethylimidazol-4-yl)pyrimidine Method 2; 1.00 g, 1.95 mmol) in DCM (5 ml) and the reaction mixture stirred for 4 hours. The solvent was removed by evaporation and MeOH (6 ml) and 2M hydrochloric acid (1.5 ml) was added to the residue. The mixture was stirred for 5 minutes, the volatiles were removed by evaporation and the residue partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution. The resulting precipitate was collected by filtration, washed with water and EtOAc and dried to give the title compound 350 mg, (40%) as a solid. NMR: 3.81-3.96 (m, 2H), 4.77-4.92 (m, 2H), 6.98 (d, 1H), 7.06 (d, 1H), 7.31 (t, 1H), 7.37 (d, 1H), 7.63-7.80 (m, 6H), 7.92 (s, 1H), 8.27 (d, 1H), 9.50 (s, 1H); m/z: 443.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:24])=[O:5])C.[OH-].[Na+].O.Cl>C(#N)C>[C:22]([C:18]1[CH:17]=[C:16]([CH:11]2[CH2:10][C:9]([CH3:25])([CH3:24])[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)#[N:23]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C#N)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(c2cccc(C#N)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
A mixture of 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.0 g, 7.96 mmol), sodium hydroxide (1.8 g, 44.9 mmol), water (15 mL) in acetonitrile (30 mL) was stirred at 60° C. for 4 h. The mixture was neutralized with a 3 mol/L aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.65 g, 60%) as a white solid which was used for next step without further purification: MS (ESI) M+1=307.2.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C1(C)C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:33])[O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: CCCCCCCCCCCCCCCCCCCCO
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCOC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, n-eicosanol (182 g) was dissolved in toluene (1250 ml) in a nitrogen atmosphere. To the solution, p-nitrophenyl isocyanate (100 g) was gradually added, and the mixture was stirred at room temperature for 10 minutes and then heat-refluxed for 30 minutes. When the reaction liquid was cooled to room temperature, crystals precipitated. The crystals were collected by filtering and washed with toluene. n-eicosyl p-nitrophenylcarbamate (270 g) was obtained at a yield of 96%.