Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[CH2:4][C@H:3]1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12]1)=O.O1CCCC1.C(O)(=O)C>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([CH2:9][C@@H:3]3[CH2:4][S:5](=[O:7])(=[O:8])[CH2:6][C@H:2]3[NH2:1])[CH2:12]2)=[CH:23][CH:22]=1
Reactant: N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N[C@@H]1CS(=O)(=O)C[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reaction time: 16.5 h
Yield: 61.2 %

Procedure:
[(3R,4S)-4-Amino-1,1-dioxo-tetrahydrothiophen-3-yl]-[(S)-3-(4-fluorobenzyl)-piperidin-1-yl]-methanone (560 mg, 1.46 mmol) was treated with borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M; 58 mL, 58 mmol) and stirred for 16.5 h . The mixture was treated slowly with 20% acetic acid in methanol (38 mL), and the resulting mixture was stirred at room temperature for 5.5 h . The solvents were removed, and the residue was dissolved in water, made basic (pH 11) with 50% sodium hydroxide, and extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated to provide a gum. This was purified by flash column chromatography (4% methanol/dichloromethane, containing 0.4% ammonium hydroxide) to provide the product (304 mg, 61%) as a white solid. 1H NMR (300 mHz, CD3OD) δ7.13 (m, 2H), 6.96 (m, 2H), 3.36 (m, 3H), 2.87 (m, 3H), 2.78 (m, 1H), 2.56 (m, 1H), 2.49 (m, 2H), 2.40 (m, 2H), 1.95 (m, 1H), 1.8-1.6 (m, 4H), 1.50 (m, 1H), 0.95 (m, 1H), ESI MS: (M+H)+=341.2.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28](OC)=[O:29])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[OH:33][CH2:34][CH2:35][NH2:36]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28]([NH:36][CH2:35][CH2:34][OH:33])=[O:29])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1
Reactant: NCCO
Product: O=C(NCCO)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with 2-hydroxyethylamine yielded N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.07 (d, 1H, J=1.2 Hz), 7.86 (d, 1H, J=3.9 Hz), 7.43 (d, 2H, J=1.5 Hz), 7.38 (s, 1H), 7.29 (d, 1H, J=2.4 Hz). 6.98 (dd, 1H, J=2.1 and 9 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.23 (s, 4H), 3.72 (t, 2H, J=5.7 Hz), 3.53 (t, 2H, J=6.0 Hz); LCMS: ret. time: 16.21 min.; purity: 97%; MS (m/e): 466 (MH+).
Reaction SMILES: O.[C:2]([NH:9][C:10](=[NH:19])[NH:11]C(OC(C)(C)C)=O)([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]>CC(OC)(C)C>[C:5]([O:4][C:2]([NH:9][C:10]([NH2:19])=[NH:11])=[O:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)NC(=N)N
Temperature: 57.5 °C

Procedure:
After addition of water (200.00 g) the resultant mixture was evaporated to yield a solid comprising the crude product together with inorganic salts and a small amount of bis-Boc-guanidine. The solids were suspended in 2-Me-THF (344.00 g), the suspension was stirred and heated to reflux and maintained at reflux for about 1 h. The suspension was then cooled to about 55-60° C. and filtered warm to remove the inorganic salts. Evaporation of the 2-MeTHF yielded a solid. This solid was re-suspended in MTBE (37.00 g) and the resultant suspension was stirred at ambient temperature for ˜1 h. The suspension was filtered, and the solid was washed with MTBE (18.5 g). The MTBE treatment was repeated again and the resultant product was air dried for several hours at ambient temperature. The product—N-(t-butyloxycarbonyl)-guanidine—was isolated as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[NH:17]2)(=[O:11])=[O:10].[OH-].[Li+].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[NH:17]2)(=[O:11])=[O:10]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C)cc2c1NS(=O)(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a room temperature solution of 1.4 (1.00 g, 1.82 mmol) dissolved in a mixture of methanol (5 mL) and water (5 mL) was added lithium hydroxide (190 mg, 7.90 mmol). The reaction mixture was stirred at room temperature for 1 h then poured into aqueous 1N hydrochloric acid solution. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed twice with water then brine, stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a yellow solid. The product was isolated by semi-preparative reversed phase HPLC to afford a colorless solid. LC-MS ESI (neg.) m/z: 533.0 (M−H). 1H NMR (400 MHz) (d6-DMSO) δ 12.30 (br s, 1H); 10.95 (s, 1H); 9.73 (s, 1H); 7.63 (d, J=8.4 Hz, 1H); 7.52 (d, J=2 Hz, 1H); 7.30 (dd, J=2.0 & 8.5 Hz, 1H); 7.09 (d, J=8.6 Hz, 1H); 6.87 (d, J=1.4 Hz, 1H); 6.57 (d, J=8.3 Hz, 1H); 6.31 (d, J=8.6 Hz, 1H); 6.22 (d, J=8.0 Hz, 1H); 6.13 (s, 1H); 3.69 (s, 3H); 3.50 (s, 2H); 2.37 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of methyl 5-chloro-2-hydroxybenzoate (2.35 g, 12.6 mmol), 2-chloro-5-nitropyridine (2.00 g, 12.6 mmol), and potassium carbonate (5.23 g, 37.8 mmol) in N,N-dimethylformamide (50 mL) was stirred at 120° C. for 1 h. The reaction mixture was poured into water and the aqueous mixture was extracted with a mixture (3/1) of ethyl acetate and toluene. The organic extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to afford 3.79 g (97%) of the title compound: 1H-NMR (CDCl3) δ 8.94 (1H, d, J=2.8 Hz), 8.52 (1H, dd, J=9.0, 2.8 Hz), 8.05 (1H, d, J=2.8 Hz), 7.60 (1H, dd, J=8.6, 2.8 Hz), 7.18 (1H, d, J=8.6 Hz), 7.14 (1H, d, J=9.0 Hz), 3.73 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:35][CH2:34][CH2:33][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:32])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:47])C=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:35][CH2:34][CH2:33][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:32])[CH2:21][S:22]([C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)=[O:47])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CSc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CS(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(4-nitrophenylthio)ethyl]pyrrolidine (1.50 g) was subjected to oxidation as in Example 2-A) in dichloromethane using 1.1 equivalent of m-chloroperbenzoic acid to give 894 mg of the title compound.
Reaction SMILES: [H-].[Na+].C([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=O)C1C=CC=CC=1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>O1CCCC1>[Cl:18][C:16]1[CH:17]=[C:12]2[C:13]([C:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:29]([C:30]([O:32][CH3:33])=[O:31])[NH:11]2)=[CH:14][CH:15]=1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1-c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a mixture of a 50% sodium hydride suspension in mineral oil (52.5 g) (which was extracted with dry heptane) and dry tetrahydrofuran (250 ml) was added a solution of N-benzoyl 5-chloro-2-(4-fluorobenzoyl)aniline (129 g) in dry tetrahydrofuran (500 ml) during 0.5 h at 20° C. (ice bath). After 1 h methyl 2-bromoacetate (101 ml) was added during 0.5 h at 20° C. (ice bath) and the mixture was stirred for another 1 hour. The solvents were evaporated in vacuo. The remaining oil was diluted with methanol (250 ml) and 5.4M sodium methoxide in methanol (670 ml) was added carefully. After 1 h at room temperature the solvents were evaporated in vacuo and water (0.5 l) was added. The thus obtained mixture was extracted with ethyl acetate (2×0.75 l) and the combined organic phases were washed with brine and dried (Na2SO4). Evaporation of the solvents in vacuo afforded the title compound, which was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:3) and crystallized from heptane. Yield: 33 g, mp 172°-183° C.
Reaction SMILES: [CH3:1][O:2]N=C1C(COS(C)(=O)=O)(CO)CN(CC2C=CC=CC=2)C1.[CH2:24]([N:31]1[CH2:35][CH:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33](=[O:41])[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+].C=O>C(O)(C)C>[CH2:24]([N:31]1[CH2:35][C:34]([CH2:1][OH:2])([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33](=[O:41])[CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=O
Reactant: CON=C1CN(Cc2ccccc2)CC1(CO)COS(C)(=O)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOC(=O)C1(CO)CN(Cc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
1-benzyl-4-methanesulfonyloxymethyl-4-hydroxymethyl-pyrrolidine-3-one-O-methyloxime 50 g of 1-benzyl-4-ethoxycarbonyl-pyrrolidine-3-one was dissolved in 300ml of isopropanol and thereto 4 ml of 10% NaOH and 20.7 ml of formalin were added successively. The mixture was stirred for 30 minutes at room temperature and concentrated under the reduced pressure. 200 ml of water was added to the concentrated residue. The resulting solution was extracted twice with each 200 ml of ethylether, dried with magnesium sulfate, filtered and concentrated under the reduce pressure to give 46 g of 1-benzyl-4-hydroxymethyl-4-ethoxycarbonyl-pyrroline-3-one(yield : 82.0%). The obtained compound was dissolved in 400 ml of pyridine and thereto methoxylamine hydrochloride was added and stirred for 1 hour at room temperature. The reaction mixture was concentrated under the reduced pressure, diluted with 400 ml of dichloromethane, washed with water and saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 43 g of 1-benzyl-4-hydroxymethyl-4-ethoxycarbonyl-pyrroline-3-one-O-methyloxime (yield: 84.6%). Thus obtained compound was dissolved in a solution of 22 ml of triethylamine and 400 ml of dichloromethane and cooled to 0-5° C. and thereto 10 ml of methanesulfonylchloride was added dropwise and the reaction temperature was slowly increased up to room temperature. The reaction mixture was stirred for 1 hour, washed with water and saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 50 g of 1-benzyl-4-methanesulfonyloxymethyl-4-ethoxycarbonyl-pyrroline-3-one-O-methyloxime (yield : 92.6%). It was dissolved in 200 ml of tetrahydrofuran and thereto 13 g of sodium borohydride and 400 ml of ethyl alcohol were added successively at room temperature and 11 g of lithium chloride was added slowly. The reaction mixture was stirred for 5 hours and poured into 300 ml of ice water. The resulting solution was adjusted to pH 5-6 with diluted hydrochloric acid, concentrated under the reduced pressure to remove most organic solvents therefrom, then extracted twice with each 200 ml of ethylether, dried with magnesium sulfate, filtered and concentrated under the reduced pressure. The residue was purified by silicagel column chromatography(ethylacetate:normal hexane=2:1) to give 42 g of the titled liquid compound (yield: 94.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Br[C:31]1[C:32](=[O:41])[NH:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[N:36][CH:35]=2.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:31]3[C:32](=[O:41])[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][CH:37]=[N:36][CH:35]=4)=[CH:10][CH:9]=2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OC(=O)N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@H]1c1ccccc1
Reactant: O=c1[nH]c2cnccc2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cc4ccncc4[nH]c3=O)cc2)[C@H]1c1ccccc1
Yield: 19.12 %

Procedure:
A microwave vial was charged with (S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (0.100 g, 0.254 mmol), 3-bromo-1,7-naphthyridin-2(1H)-one (0.063 g, 0.280 mmol), sodium carbonate (0.081 g, 0.763 mmol), dioxane (2.0 mL), and water (0.400 mL). Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (DCM adduct) (0.021 g, 0.025 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was irradiated at 100° C. in the microwave for 1 hour. The reaction mixture was then filtered through Celite® brand filter aid, and the filtrate was concentrated to afford a brown oil. The oil thus obtained was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-10% MeOH-EtOAc) to afford Example 88 ((S)-5,5-dimethyl-3-(4-(2-oxo-1,2-dihydro-1,7-naphthyridin-3-yl)phenyl)-4-phenyloxazolidin-2-one) (0.020 g, 0.049 mmol, 19.12% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (br. s., 3H), 1.65 (br. s., 3H), 5.52 (br. s., 1H), 7.09-7.49 (m, 5H), 7.49-7.93 (m, 5H), 8.08 (br. s., 1H), 8.20-8.50 (m, 1H), 8.50-8.83 (m, 1H), 12.18 (br. s., 1H). m/z (ESI) 412.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8](Br)[CH:7]=1)=[O:5])[CH3:2].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccnc(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CCOC(=O)c1ccnc(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
Electrospray MS (positive ion): (M+H) 272.8; from 2-bromo4-pyridinecarboxylic acid ethyl ester (900 mg), tetrakis(triphenylphosphine)paliadium (136 mg), and 3-nitrophenylboronic acid (783 mg).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>O1CCCC1>[C:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:36])=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-acetylphenyl isocyanate (196 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 278 mg (84.0%) of the desired product as a solid.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1.O.[OH-].[Li+].C(OC1C=CC(C(O)=O)=CC=1)CCCCCCCCCCCCCCCCC>CO>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:21])=[O:2])=[CH:9][CH:8]=1)/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCC/C=C/COc1ccc(C(=O)OC)cc1
Agent: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCC/C=C/COc1ccc(C(=O)O)cc1

Procedure:
The ester 35g 565 mg, 1.95 mmol), and lithium hydroxide monohydrate (817 mg, 19.5 mmol) in 20 ml methanol were reacted according to the procedure for compound 36a. The yield was 482 mg (89% of a white powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH2:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]([CH3:33])[CH3:32])[CH:18]=[CH:17]2)#[N:13].[OH-].[K+]>C(OCC)(=O)C.O>[NH2:13][CH2:12][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH2:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]([CH3:33])[CH3:32])[CH:18]=[CH:17]2
Reactant: CC(C)c1nccn1CCCn1ccc2cc(C#N)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1nccn1CCCn1ccc2cc(CN)ccc21
Temperature: 0 °C
Yield: 87.1 %

Procedure:
To 2.3 g of lithium aluminum hydride was added 100 ml of tetrahydrofuran, under stirring condition, and 6 g of 5-cyano-1-[3-(2-isopropyl-imidazol-1-yl)propyl]indole was gradually added thereto. The mixture was refluxed for 4 hours, then after confirmation of that the reaction was finished, under cooling at 0° C., 2.3 ml of water, 2.3 ml of 10% aqueous solution of potassium hydroxide and 7 ml of water were gradually added thereto. The reaction mixture was diluted with ethyl acetate, then filtrated with Celite, and the solvent was removed by distillation, 5.3 g of 5-aminomethyl-1-[3-(2-isopropylimidazol-1-yl)propyl]indole was obtained in the form of yellow oily product.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:21][C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)=O.C(OC(N1CCC(C(O)=O)CC1)=O)(C)(C)C.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([O:12][C:13]2[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:21]=[C:22]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[N:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ncccc1Oc1cc(NC(N)=S)ncc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)cs2)ncc1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
1-(5-Bromo-4-(2-methylpyridin-3-yloxy)pyridin-2-yl)thiourea (1.48 g, 4.4 mmol), tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (1.41 g, 4.60 mmol, prepared from 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid utilizing the procedure from Example 1, steps A-C), and triethylamine (0.93 mL, 6.56 mmol) were diluted in ethanol (130 mL). The reaction was stirred at 70° C. overnight and then concentrated. Water was added and the solution was extracted with ethyl acetate, dried and concentrated to give the title compound (2.37 g, 94% yield) as light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C/c1ccc([C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc([C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 4 h
Yield: 99.4 %

Procedure:
(R)-2-[4-((E)-2-Methoxycarbonyl-vinyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.4 g, 7.242 mmol) was dissolved in ethanol (100 mL), and wet 10% Pd/C added. The reaction mixture was placed under an atmosphere of hydrogen for 4 hrs (Parr apparatus, 25 psi) then filtered through a plug of celite and concentrated to dryness to give (R)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil (2.4 g, 7.2 mmol, >99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>C(Cl)(Cl)(Cl)Cl>[Cl:14][S:15]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:17])=[O:16]
Reactant: CCOC(=O)c1ccc(OC)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 4-methoxybenzoate (10.25 g, 57 mmol) in CCl4 (40 ml) is cooled to −15° C. and treated dropwise with chlorosulfonic acid (10.4 ml, 156 mmol) in the course of 15 min, the temperature rising to −10° C. After addition is complete, the reaction mixture is warmed to RT with stirring in the course of 30 min and then stirred at 40-50° C. for 1.5 h. The heating is removed and the reaction mixture is stirred at RT in a gentle stream of argon for 64 h to complete the chlorination. The reaction mixture is added to a suspension of ice (25 g) in CCl4 (50 ml) with ice-cooling and vigorous stirring. It is stirred vigorously for 3 min. The organic phase is separated off and the aqueous phase is extracted 3 times with further CH2Cl2 (150 ml). The combined organic extracts are washed with saturated NaCl solution, dried over Na2SO4 sicc. and concentrated: a crystalline, white residue of a mixture of ester and free acid in the ratio 1:1 remains, which is dried on an oil pump, yield 6.7 g (42%)