Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7](=[O:9])[CH3:8].[Li+].[BH4-]>C1COCC1>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[CH:7]([OH:9])[CH3:8]
Reactant: CC(=O)c1cc(-c2ccccc2)sc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)cc1C(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanone (1.08 g, 5.00 mmole) in THF (20 mL), is added to LiBH4 (0.327 g, 15.0 mmole) in one portion at 0° C. The reaction is kept at 0° C. for 30 minutes and warmed up to room temperature for 2 hours. The reaction is quenched using NH4Cl(aq) (50 mL) at 0° C. The THF is removed on rota vapor, the aqueous solution is then extracted with ethyl acetate (3×50 mL). The combined organic solution is dried over Na2SO4 and concentrated to provide the titled compound as white solid, which is used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]([OH:18])[C:19]#[N:20])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
A solution of 3-(4-(benzyloxy)phenyl)propanal (S49, 700 mg, 3.07 mmol, 1 equiv) in THF (13 mL) and H2O (18 mL) was treated with KCN (2.30 g, 35.3 mmol, 11.5 equiv). After stirring for 50 h at 25° C., the reaction was quenched with H2O and extracted with ether. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to afford S50 (755 mg, 2.96 mmol, 96%) as a white solid: 1H NMR (CDCl3, 400 MHz) 7.47-7.33 (m, 5H), 7.14 (d, 2H, J=8.8 Hz), 6.95 (d, 2H, J=8.8 Hz), 5.06 (s, 2H), 4.39 (t, 1H, J=6.9 Hz), 2.82-2.77 (m, 2H), 2.17-2.10 (m, 2H); 13C NMR (CDCl3, 100 MHz) 157.3, 136.9, 131.9, 129.4, 128.5, 127.9, 127.4, 119.9, 115.0, 70.0, 60.2, 36.6, 29.7; IR (film) νmax 3444, 2927, 2865, 2250, 1611, 1583, 1514, 1454, 1382, 1246, 1177, 1079, 1024, 912, 830, 738, 695 cm−1.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]([CH2:18][CH3:19])[CH2:12][C:13]#[C:14][C:15]([OH:17])=O)[CH3:10].CN1CCOCC1.N#N.[NH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34]([C:40]#[N:41])=[C:33]2[NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[C:45]([Cl:50])[CH:44]=1>N1C=CC=CC=1>[Cl:50][C:45]1[CH:44]=[C:43]([NH:42][C:33]2[C:32]3[C:37](=[CH:38][CH:39]=[C:30]([NH:29][C:15](=[O:17])[C:14]#[C:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:18][CH3:19])[CH:31]=3)[N:36]=[CH:35][C:34]=2[C:40]#[N:41])[CH:48]=[CH:47][C:46]=1[F:49]
Reactant: CCN(CC)CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CCN(CC)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.061 g, 0.448 mmol) was dropwise added into an ice cold solution of 4-diethylamino-2-butynoic acid (0.104 g, 0.672 mmol) and N-methylmorpholine (0.068 g, 0.672 mmol) in 10 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.1 g (0.32 mmol) of 6-amino-4-[(3-chloro-4-fluorophenyl)-amino]-3-quinolinecarbonitrile in 1.5 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 1.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.046 g (32%) of light brown solid; ESMS m/z 450.2, (M+H+); mp 117-120° C.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11](OC)=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[NH3:16]>>[SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([NH2:16])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[NH3:5]
Reactant: COC(=O)c1nc2nc(C)cc(S)n2n1
Agent: N
Product: Cc1cc(S)n2nc(C(N)=O)nc2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 2.50 g of methyl 7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxylate (Euro. Pat. Publ. 150,507) in 25 ml of 25 percent aqueous ammonia was stirred at room temperature for 6 hours. The mixture was filtered and the solid was dried at 50° in a vacuum. There was obtained 7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide as a 1:1:1 adduct with water and ammonia.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:31])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)ccc43)cc2s1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)ccc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of 6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.64 g, 1.9 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.472 g, 2.3 mmol) in DCM (3 mL). The mixture was stirred at 0° C. for 2 h. The solution was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.63 g, 94%) as a yellow solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.02-8.05 (m, 2H), 7.78 (s, 1H), 7.51 (dd, J=9.6, 2.4 Hz, 1H), 7.38 (dd, J=8.4, 1.8 Hz, 1H), 7.20 (m, 1H), 7.00 (dt, J=9.0, 2.4 Hz, 1H), 5.52 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 346 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([S:26][CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([S:26]([CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)=[O:9])[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1
Reactant: CCOC(=O)c1c(SCc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)Cc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reaction time: 3 h
Yield: 70.2 %

Procedure:
m-Chloroperbenzoic acid (80%, 1,4 g) was added under ice-cooling to a solution of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1-methylimidazol-2-ylmethylthio)quinoline-3-carboxylate (3.0 g) in dichloromethane (90 ml), and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was washed successively with an aqueous saturated NaHSO3 solution, aqueous saturated sodium bicarbonate solution and water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/dichloromethane (4:1, v/v) gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1-methylimidazol-2-ylmethylsulfinyl)quinoline-3-carboxylate (2.17 g, 70%). mp. 151°-152° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C(OCC)(=O)C>[CH2:9]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCCN1Cc1ccccc1
Reaction time: 5 h

Procedure:
14.4 g (0.33 mol) of 50% sodium hydride dispersion in oil are added in batches to 25.5 g (0.3 mol) of 2-pyrrolidone in 300 ml of absolute dimethylsulphoxide. The mixture is then stirred for 5 hours at 40° to 50° C. and at 25°-30° C. 56.4 g=39.2 ml (0.33 mol) of benzyl bromide are added dropwize. After stirring for 10 hours at ambient temperature the reaction mixture is dissolved in 500 ml of ethyl acetate and extracted several times with water. The organic phase is separated off, dried over magnesium sulphate and the solvent is eliminated in vacuo. The residue obtained is purified over 900 g of aluminium oxide (neutral, activity II) with methylene chloride and 0.1% ethanol. Yield: 35.6 g (67.7% of theory), Rf value: 0.77 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.C(O)=O.C=O.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Cl)c1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: CN1CCC[C@H]1COc1cncc(Cl)c1
Yield: 62.9 %

Procedure:
To 5-chloro-3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)pyridine (0.600 g, 1.92 mmol), from Example 15b, was added a solution of formic acid/formaldehyde (1:2, 3 mL). The mixture was heated at reflux for 3 hours, then basified with sat. K2CO3. The aqueous phase was extracted with CH2Cl2 (3×) then the organic layer was dried (MgSO4) and concentrated. The crude product was purified by chromatography over silica gel eluted with CHCl3/MeOH to afford 0.274 g (63%) of the title compound as a pale yellow oil. TLC Rf =0.23 (10%MeOH/CHCl3). MS (DCI/NH3) m/e: 227 (M+H)+ with 35Cl and 229 (M+H)+ with 37Cl. 1H NMR (CDCl3, 300 MHz) δ: 8.22 (d, J=2.6 Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.22 (t, J=2 Hz, 1H), 4.00 (dd, J=9, 5.50 Hz, 1H), 3.92 (dd, J=9, 5.20 Hz, 1H), 3.14-3.08 (m, 1H), 2.69-2.64 (m, 1H), 2.47 (s, 3H), 2.36-2.27 (m, 1H), 2.07-1.97 (m, 1H), 1.88-1.69 (m, 3H).
Reaction SMILES: [F-:1].[K+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@@H:15](O)[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)CO>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([F:1])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [F-]
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Agent: [K+]
Solvent: OCCO
Product: O=C(OCc1ccccc1)N1CC[C@H](F)C1

Procedure:
A stirred mixture of 20.85 g (0.360 moles) of potassium fluoride spray-dried and 18.0 g (0.048 moles) of (3R)-N- benzyloxycarbonyl-3-hydroxypyrrolidine in 160 ml of freshly distilled ethylene glycol was kept at 85° C. for 15 h under nitrogen atmosphere.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:33][CH3:34])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCN(CC)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.021 mole), 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of N,N-diethylethylenediamine (7.32 g, 0.063 mole) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was evaporated to a solid. The solid was triturated with water (50 ml), filtered, and the filter cake was rinsed twice with water, twice with a 5% potassium hydroxide solution and twice with water. The resulting solid was dissolved in hot isopropyl alcohol, filtered hot and cooled to room temperature. Addition of water caused a white solid to form. The solid was collected by filtration and rinsed with water to give 4.21 g (52%) of a white solid A 1.0-g sample of the solid was dried under high vacuum at room temperature to give a white solid, mp 142°-143° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:39])=[C:7]([CH:38]=1)[CH2:8][N:9]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:23]([CH3:29])=[N:24][CH:25]=[N:26][C:27]=2[CH3:28])=[O:21])[CH2:12][CH2:11]1)#[N:2].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:45]([O:44][C:42](=[O:43])[CH2:41][O:37][C:34]1[CH:33]=[CH:32][C:31]([N:9]([CH2:8][C:7]2[CH:38]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[F:39])[CH:10]2[CH2:11][CH2:12][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:27]([CH3:28])=[N:26][CH:25]=[N:24][C:23]=3[CH3:29])=[O:21])[CH2:14][CH2:15]2)=[CH:36][CH:35]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(OCC(=O)OC(C)(C)C)cc2)CC1
Temperature: 80 °C
Yield: 72.6 %

Procedure:
A mixture of COMPOUND 233 (100 mg, 0.188 mmol), t-butyl bromoacetate (37 mg, 0.19 mmol) and K2CO3 (39 mg, 0.28 mmol) in DMF (1.9 mL) were heated at 80° C. for 18 h to give COMPOUND 235 as a yellow foam (88 mg, 72%) following work-up and purification. 1H NMR (CDCl3) δ 0.92-1.03 (m, 1H), 1.01 (d, 3H, J=6.6 Hz), 1.08-1.20 (m, 1H), 1.46 (s, 9H), 1.52-1.63 (m, 1H), 1.76 (m, 3H), 2.16 (m, 1H), 2.50 (s, 6H), 2.54 (m, 1H), 2.68-2.95 (m, 3H), 3.31-3.46 (m, 2H), 3.82 (m, 1H), 3.92 (s, 2H), 4.41 (s, 2H), 6.58 (m, 2H), 6.73 (m, 2H), 7.16 (m, 1H), 7.51 (m, 2H), 8.30 (m, 1H), 8.83 (s, 1H). ES-MS m/z 645 (M+H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7](=[O:10])(O)[O-:8].[Na+]>C(Cl)Cl.CCOCC>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:8][CH:7]1[CH2:5][CH2:4][CH2:3][CH2:2][O:10]1
Reactant: O=C([O-])O
Reactant: C1=COCCC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C1CCC(OC2CCCCO2)OC1

Procedure:
A solution of 1.15 g of the ketone, 1.2 ml of dihydropyran and 10 mg of p-toluolsulfonic acid in 40 ml of methylene chloride is stirred for 30 minutes at 0° C. The product is then diluted with ether, shaken with dilute sodium bicarbonate solution, washed with neutral water, dried via magnesium sulfate and concentrated by evaporation in a vacuum. 1.65 g of the bis-tetrahydropyranyl ether is obtained, which is used without any further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16]C(OC(C)(C)C)=O)=[N:13][C:12]=1[CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CN2CCOCC2)c(C(=O)NCc2ccccc2)s1
Agent: Cl
Solvent: CO
Product: Nc1nc(CN2CCOCC2)c(C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A solution of crude 2-(tert-butoxycarbonylamino)-4-morpholin-4-ylmethylthiazole-5-carboxylic acid benzylamide (0.18 mmol) from the previous step in methanol (5 mL) was treated with hydrochloric acid solution (3 mL, 4 M solution in dioxanes) and the reaxtion mixture was stirred at ambient temperature until the reaction was completed. The mixture was then concentrated and purified by preparative HPLC (acetone/water gradient) to afford 2-amino-4-morpholin-4-ylmethylthiazole-5-carboxylic acid benzylamide (0.030 g).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:12]([C:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:22][CH:23]=1
Reactant: CC(=O)N1CC=C(c2cccnc2Oc2ccc(N)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCC(c2cccnc2Oc2ccc(N)cc2)CC1

Procedure:
A solution of 1-(4-(2-(4-aminophenoxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.98 g, 3.17 mmol) in ethanol (16 mL) was added palladium, 10 wt. % on carbon (0.1 g, 0.094 mmol) and hydrogenated (double-walled balloon pressure) at room temperature for 18 h. The reaction mixture was filtered via a pad of Celite, and the filtrate was concentrated in vacuo and chromatographed via flash column chromatography (20% to 80% EtOAc/Hexanes) to give 1-(4-(2-(4-aminophenoxy)pyridin-3-yl)piperidin-1-yl)ethanone as a light tan solid. MS (ESI, pos. ion) m/z: 312.0 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:8]([CH3:9])=[CH:7][S:6][C:5]=1[C:10]1([C:15]2[N:16]([CH3:21])[C:17](=[S:20])[NH:18][N:19]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C1COCC1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][S:20][C:17]1[N:16]([CH3:21])[C:15]([C:10]2([C:5]3[S:6][CH:7]=[C:8]([CH3:9])[C:4]=3[Cl:3])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:19][N:18]=1
Reactant: Clc1ccccc1CBr
Reactant: Cc1csc(C2(c3n[nH]c(=S)n3C)CCCC2)c1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1csc(C2(c3nnc(SCc4ccccc4Cl)n3C)CCCC2)c1Cl
Reaction time: 0.08 h

Procedure:
Sodium hydride (55%, 24 mg) was added to a THF (10 ml) solution of 5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-thione (154 mg) at 0° C. and the whole was stirred for 5 minutes. Then, 2-chlorobenzyl bromide (0.07 ml) was added thereto, followed by stirring at 0° C. for 3 hours. The reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with brine, dried over anhydrous sodium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by column chromatography (hexane:ethyl acetate=1:1) to obtain 200 mg of 3-[(2-chlorobenzyl)thio]-5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-4H-1,2,4-triazole (pale yellow foam). It was converted into an ethyl acetate (5 ml) solution and 4M hydrogen chloride-ethyl acetate (0.23 ml) was added, followed by removal of the solvent by evaporation under reduced pressure. The resulting solid washed with ether to obtain 185 mg of 3-[(2-chlorobenzyl)thio]-5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-4H-1,2,4-triazole hydrochloride (colorless solid).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:13]4[S:18][C:17]([CH2:19][N:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[O:32]1[CH:34]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33]1>CN(C=O)C.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[C:13]4[S:18][C:17]([CH2:19][N:20]5[CH2:21][CH2:22][N:23]([CH2:33][CH:34]([OH:32])[CH2:35][O:36][C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:24][CH2:25]5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)c2cn[nH]c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OC(COc1ccccc1)CN1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Treatment of 4-[2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester with HCl in DCM/MeOH yielded 2-(1H-indazol-4-yl)-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine. A mixture of 2-(1H-indazol-4-yl)-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (150 mg) and 1,2-epoxy-3-phenoxypropane (40 mg) was suspended in 50% DMF/0.1M sodium phosphate buffer (2 mL) and shaken at 55° C. overnight. After stirring for 24 h the reaction mixture was then diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography.
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][S:5][CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1.[H-].[K+].Cl>CO.O>[CH2:6]([S:5][CH2:4][C:3]([OH:12])=[O:2])[C:7]1[O:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CSCc1ccco1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)CSCc1ccco1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of methyl-2-(furfurylthio)acetate was dissolved in 60 ml of methanol, and the solution prepared by dissolving 4.25 g of 85% potassium hydride in 15 ml of water was added dropwise. The mixture was stirred for 2 hours at room temperature, and pH was adjusted to 5 by adding 2N aqueous hydrochloric acid. Water and methanol were evaporated under reduced pressure. 100 ml of ethyl acetate and 100 ml of water were added to the residue and extraction was carried out. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evapoated in vacuo to obtain the captioned 2-(furfurylthio)acetic acid. Yield: 9.2 g.
Reaction SMILES: [OH:1][C:2](C)([CH3:31])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.NC1C=CN(C[C@H]2[O:66][C:65](=O)[NH:64]C2)N=1>ClCCl>[O:66]=[C:65]1[NH:64][CH2:31][C@@H:2]([CH2:3][N:4]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]3[CH2:20][C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])=[CH:18][C:17]3=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]2)[O:1]1
Reactant: Nc1ccn(C[C@@H]2CNC(=O)O2)n1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2CNC(=O)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 425 mg, 1.30 mmol) in dichloromethane (20 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt (275 mg, 1.45 mmol), 1-hydroxybenzotriazole (195 mg, 1.45 mmol) and (S)-5-(3-amino-pyrazol-1-ylmethyl)-oxazolidin-2-one (285 mg, 1.57 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen and then diluted with dichloromethane, washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 10% methanol/dichloromethane) to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((S)-2-oxo-oxazolidin-5-ylmethyl)-1H-pyrazol-3-yl]-amide (370 mg, 58%) as a white powder: LR-ES-MS m/z calculated for C23H26ClN5O5 [M]+ 487, observed 488 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.35-1.50 (m, 1H), 1.50-1.66 (m, 1H), 1.68-1.87 (m, 1H), 3.28 (dd, J=8.8, 6.0 Hz, 1 H), 3.55 (t, J=8.9 Hz, 1H), 4.21 (d, J=18.4 Hz, 1H), 4.27 (d, J=5.1 Hz, 2H), 4.61 (d, J=18.4 Hz, 1H), 4.79 (s, 1H), 4.80-4.95 (m, 2H), 6.47 (d, J=2.1 Hz, 1H), 7.37 (td, J=7.8, 1.2 Hz, 1H), 7.42-7.50 (m, 1H), 7.50-7.57 (m, 2H), 7.61 (d, J=2.1 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 10.85 (s, 1H).