Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]12[NH:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][C:21]1[CH:20]=[CH:19][C:18]([NH:27][C:28]3[N:33]=[C:32]([NH:34][C:35]4[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=4[C:37]([NH:39][CH3:40])=[O:38])[C:31]([Cl:45])=[CH:30][N:29]=3)=[CH:17][C:16]2=1.[CH3:46][C:47]([CH3:49])=O.ClC(Cl)C>C(O)(=O)C>[Cl:45][C:31]1[C:32]([NH:34][C:35]2[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=2[C:37]([NH:39][CH3:40])=[O:38])=[N:33][C:28]([NH:27][C:18]2[CH:19]=[CH:20][C:21]3[CH2:22][CH:23]4[N:26]([CH:47]([CH3:49])[CH3:46])[CH:15]([CH2:25][CH2:24]4)[C:16]=3[CH:17]=2)=[N:29][CH:30]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2C(C)C)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
Sodium triacetoxyborohydride (100 mg, 0.47 mmol) was added to a solution of 2-[2-(12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (100 mg, 0.23 mmol), acetone (0.034 mL, 0.47 mmol), acetic acid (1 drop) and dichloroethane (5 mL). The reaction was stirred at room temperature for 18 h. The reaction was then quenched with saturated aqueous NaHCO3 (5 mL), extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered, and concentrated to afford the title compound as off-white solid (89 mg, 82%). 1HNMR (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 9.3 (s, 1H), 8.8-8.7 (m, 2H), 8.2 (s, 1H), 7.8 (d, 1H, J=7.8 Hz), 7.5 (appt t, 1H, J=8.1 Hz), 7.4 (d, 1H, J=8.6), 7.3 (s, 1H), 7.1 (appt t, 1H, J=7.6 Hz), 6.9 (d, 1H, J=8.3 Hz), 3.9 (m, 1H), 3.6 (m, 1H), 3.0 (dd, 1H, J=17.2, 4.6 Hz), 2.8 (d, 3H, J=4.3 Hz), 2.4 (m, 1H), 2.2 (d, 1H, J=17.2 Hz), 2.1-2.0 (m, 2H), 1.6 (m, 1H), 1.5 (m, 1H), 1.1 (d, 3H, J=5.9 Hz), 0.9 (d, 3H, J=5.9 Hz); MS (m/e) 477 (M+1); mp 202-205° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1)=O.C([BH3-])#N.[Na+].C(Cl)Cl>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=3)[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOC(=O)c1ccc(CCCN2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCCN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1899.1 %

Procedure:
A solution of (1R,2S)-2-phenylcyclopropanamine (1.051 g, 7.89 mmol) and ethyl 4-(3-(4-formylpiperidin-1-yl)propyl)benzoate (1.9 g, 6.26 mmol) in methanol (50 mL) was heated to reflux for 5 minutes. The reaction was cooled to room temperature and sodium cyanoborohydride (0.590 g, 9.39 mmol) was added. The reaction was stirred at room temperature for 16 hours. After concentrating, dichloromethane was added and the solution was washed with water followed by brine and dried over MgSO4, filtered and concentrated. The residue was purified via Biotage (0% to 100% EtOAc:Hex; to get off impurity then 0% to 20% MeOH:DCM to get off product 50 g-HP—silica gel column) to yield 1.18 g 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-1.18 (m, 2H), 1.20-1.36 (m, 2H), 1.40 (t, J=7.07 Hz, 4H), 1.66-1.80 (m, 2H), 1.81-2.02 (m, 5H), 2.24-2.45 (m, 3H), 2.56-2.79 (m, 4H), 2.95 (d, J=10.86 Hz, 2H), 4.38 (q, J=7.24 Hz, 2H), 6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.21-7.38 (m, 5H), 7.97 (d, 2H) MS (ES); [M+H]+421.3
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=1[O:2][CH3:1])=[O:7])[CH2:49][CH2:50][CH3:51]
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,3-dimethoxybenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.86-0.95 (m, 3 H) 1.27-1.38 (m, 2 H) 1.71-1.77 (m, 2 H) 2.48 (s, 3 H) 3.75 (s, 3 H) 3.80 (s, 3 H) 4.10-4.14 (m, 2 H) 6.45 (s, 1 H) 7.08-7.19 (m, 3 H); MS (ESI) m/z 335 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C@@:16]1([OH:57])[CH2:33][C@H:32]([O:34][C@@H:35]2[O:49][C@@H:48]([CH3:50])[C@H:38]3[O:39][C@H:40]4[N:45]([C@H:37]3[CH2:36]2)[CH2:44][CH2:43][O:42][C@@H:41]4[O:46][CH3:47])[C:31]2[C:18](=[C:19]([OH:56])[C:20]3[C:21](=[O:55])[C:22]4[C:27]([C:28](=[O:52])[C:29]=3[C:30]=2[OH:51])=[C:26]([O:53][CH3:54])[CH:25]=[CH:24][CH:23]=4)[CH2:17]1)[CH2:3][O:4][C:5]1([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O[N:59]1[C:63](=[O:64])[CH2:62][CH2:61][C:60]1=[O:65].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:1]=[C:2]([C@@:16]1([OH:57])[CH2:33][C@H:32]([O:34][C@@H:35]2[O:49][C@@H:48]([CH3:50])[C@H:38]3[O:39][C@H:40]4[N:45]([C@H:37]3[CH2:36]2)[CH2:44][CH2:43][O:42][C@@H:41]4[O:46][CH3:47])[C:31]2[C:18](=[C:19]([OH:56])[C:20]3[C:21](=[O:55])[C:22]4[C:27]([C:28](=[O:52])[C:29]=3[C:30]=2[OH:51])=[C:26]([O:53][CH3:54])[CH:25]=[CH:24][CH:23]=4)[CH2:17]1)[CH2:3][O:4][C:5]1([O:11][CH2:12][C:13]([O:15][N:59]2[C:63](=[O:64])[CH2:62][CH2:61][C:60]2=[O:65])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C1CCC(=O)N1O
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1(OCC(=O)O)CCCCC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1(OCC(=O)ON2C(=O)CCC2=O)CCCCC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the acid intermediate 46 (4 mg, 0.005 mmol) in dry Dichloromethane (2 mL) kept at +5° C., N-hydroxysuccinimide (2 mg, 0.017 mmol) and N,N′-dicyclohexylcarbodiimide (2 mg, 0.01 mmol) were added. The solution was stirred at room temperature for 6 h, the solvent evaporated under vacuum and the residue treated with ethyl ether (5 mL). The suspension was stirred for 30 minutes, the solid removed by filtration and organic solution concentrated in vacuo. Purification of the crude by flash chromatography (DCM/Acetone 80:20) yield 1.5 mg (y=33%) of 47 as a red solid. MS (ESI): 895 [M+H]+. Retention time=3.22 min. Method 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH:12](O)=[O:13]>>[CH:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:13]
Reactant: O=CO
Reactant: Cc1ccc(C(=O)O)cc1N
Product: Cc1ccc(C(=O)O)cc1NC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-amino-4-methylbenzoic acid (13) (22.139 g, 146.5 mmol) and 90% aqueous formic acid (200 mL) is heated at reflux for about 2 hours. The mixture is cooled to ambient temperature, added to ice water (400 mL) and stirred for about 15 minutes. The solids obtained are filtered and dried to obtain 3-(formylamino)-4-methylbenzoic acid (17), as a light flaky purple-pink solid (23.213 g, 88% yield).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].C[O-].[Na+].[Na].[CH:10]12[O:15][CH:11]1[CH2:12][CH2:13][CH2:14]2>CO>[OH:15][C@@H:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: C1CC2OC2C1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(O)CS[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Mercaptoacetic acid (22.5 g 0.244 mole) was added to a cold (+5° C.) solution of sodium methoxide [prepared from sodium (11.2 g, 0.488 mole)]in methanol (125 ml). After stirring for 20 minutes, cyclopentene oxide (19.5 g, 0.23 mole) was added dropwise over 20 minutes to the cold solution. The ice bath was removed and the reaction was refluxed for 45 minutes. The reaction was cooled to room temperature and made acidic by the addition of 4N hydrochloric acid. Water (100 ml) was added and the mixture was extracted twice with 150 ml of diethyl ether. The combined diethyl ether extracts were washed with water (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@@H:4]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].ClC1[N:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][N:34]=1>ClCCl>[CH2:39]([C:36]1[CH:35]=[N:34][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C@H:4]3[CH2:5][C@H:3]3[CH2:2][OH:1])[CH2:11][CH2:10]2)=[N:38][CH:37]=1)[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CO)CC1
Reactant: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CO)CC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.), stirred solution tert-butyl 4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]piperidine-1-carboxylate (intermediate 4, 5.0 g, 19.58 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (100 mL) slowly over 10 minutes. After being stirred at 0° C. for 1 h, the mixture was concentrated under vacuum. Residual TFA was further removed by stripping twice from dichloromethane followed by drying in vacuum. The resulting residue was dissolved in DMF (40 ml) followed by the addition of cesium carbonate (35.09 g, 107.69 mmol) and 2-chloro-5-ethylpyrimidine (5.6 g, 39.15 mmol). The mixture was stirred at RT for 15 h before being quenched with H2O. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with H2O (2×), brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 2:1→1:1 hexane:ethyl acetate) to yield the title compound. H NMR (500 MHz, CDCl3) δ 8.18 (s, 2H), 4.74-4.65 (m, 2H), 3.74-3.67 (m, 2H), 2.89-2.81 (m, 2H), 2.47 (q, J 7.6 Hz, 2H), 1.91-1.82 (m, 2H), 1.46-1.34 (m, 2H), 1.23-1.16 (M, 4H), 1.16-1.07 (m 1H), 0.77-0.70 (m, 2H), 0.09-0.04 (m, 1H). MS (ESI) m/z 262 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:21][C:22](O)=[O:23])[C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[CH3:26]>>[CH2:25]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[C:22](=[O:23])[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)[CH3:26]
Reactant: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)c1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1cccc(C)c1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([O:19][C:20]3[CH:21]=[C:22]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=3)=[O:24])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[N:9]1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[NH:8]1[CH:12]=[C:11]([C:13]2[C:14]([O:19][C:20]3[CH:21]=[C:22]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=3)=[O:24])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[N:9]1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Oc1ncccc1-c1cnn(Cc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Oc1ncccc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(3-(1-benzyl-1H-pyrazol-4-yl)pyridin-2-yloxy)-N-(3-isopropylphenyl)-4-methylbenzamide (65 mg, 0.13 mmol) in EtOAc (4 mL) and MeOH (4 mL) was added Pd/C (10%, 300 mg). The reaction was purged with hydrogen gas and then stirred at rt under a balloon of hydrogen for 16 hours. The reaction was filtered through Celite with EtOAc, concentrated, and purified by Gilson reverse-phase HPLC (0.1% TFA in water/acetonitrile). After a basic workup involving CH2Cl2 and saturated sodium bicarbonate, 3-(3-(1H-pyrazol-4-yl)pyridin-2-yloxy)-N-(3-isopropylphenyl)-4-methylbenzamide was obtained as a white solid. MS m/z=413 [M+1]+. Calc'd for C25H24N4O2: 412.50.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[N:22]1([C:20]([C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCOCC2)(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCOCC1)C1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.3 %

Procedure:
4-(Morpholin-4-ylcarbonyl)-4-phenyl-1-piperidinecarboxylic acid tert-butyl ester (907 mg) was dissolved in methylene chloride (6 ml) and trifluoroacetic acid (1 ml) was added thereto. The mixture was stirred at room temperature for 10 hr. After completion of the reaction, a 10% aqueous sodium hydroxide solution was added, and the mixture was extracted three times with methylene chloride. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(morpholin-4-ylcarbonyl)-4-phenylpiperidine (600 mg, yield 91%).
Reaction SMILES: O.NN.[C:4]([C:6]1[C:7]([N:17]2C(=O)C3=CC=CC=C3C2=O)=[N:8][CH:9]=[C:10]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:11]=1)#[N:5]>CO>[NH2:17][C:7]1[C:6]([C:4]#[N:5])=[N:11][C:10]([CH:12]([O:15][CH3:16])[O:13][CH3:14])=[CH:9][N:8]=1
Reactant: COC(OC)c1cnc(N2C(=O)c3ccccc3C2=O)c(C#N)n1
Agent: NN
Solvent: O
Solvent: CO
Product: COC(OC)c1cnc(N)c(C#N)n1
Yield: 75.1 %

Procedure:
0.2 g of hydrazine hydrate were added dropwise to a suspension of 2 g of 3-cyano-5-dimethoxymethyl-2-phthalimidopyrazine in 40 ml of absolute methanol at 40° C. Immediately after the addition, the solution became clear, and crystals were precipitated after a few minutes. Chromatography over silica gel gave 0.9 g (75%) of 2-amino-3-cyano-5-dimethoxymethylpyrazine. 1H-NMR (270 MHz, DMSO-d6): δ3.3 (s, 6H), 5.0 (s, 1H), 8.35 (s, 1H).
Reaction SMILES: CN1C=C(C(C=CC(O)=O)=O)C=N1.N1CCC[C@H]1C(O)=O.[CH3:22][N:23]1[CH:27]=[C:26]([C:28]([CH:30]=[CH:31][C:32]([N:34]2[CH2:41][CH2:40][CH2:39][C@H:35]2[C:36]([OH:38])=[O:37])=[O:33])=[O:29])[CH:25]=[N:24]1.[C:42]([OH:45])(=[S:44])[CH3:43]>>[C:42]([S:44][CH:31]([CH2:30][C:28]([C:26]1[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=1)=[O:29])[C:32]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33])(=[O:45])[CH3:43]
Reactant: Cn1cc(C(=O)C=CC(=O)N2CCC[C@H]2C(=O)O)cn1
Reactant: CC(O)=S
Agent: Cn1cc(C(=O)C=CC(=O)O)cn1
Agent: O=C(O)[C@@H]1CCCN1
Product: CC(=O)SC(CC(=O)c1cnn(C)c1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
As for Example 29, 3-(1-methyl-4-pyrazolylcarbonyl)acrylic acid is coupled to L-proline and the resulting 1-[3-(1-methyl-4-pyrazolylcarbonyl)acryloyl]-L-proline is reacted with thioacetic acid to give the product of the Example as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:28])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4]([Cl:28])=[O:5]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)Cl)c(Cl)cc2F)c1=O
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To a stirred solution of 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid (4 g) in chloroform (100 ml) were added oxalyl chloride (1.8 g) and a few drops of N,N-dimethylformamide (DMF) at ambient temperature. The resulting mixture was stirred for three hours at same temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure to give the titled compound (4.3 g) as a brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:16]([OH:18])=[CH:15][CH:14]=[C:13]([CH:19]=O)[C:12]=2[CH2:11][CH2:10][C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([CH:19]=[C:26]3[S:22][C:23](=[O:28])[NH:24][C:25]3=[O:27])[CH:14]=[CH:15][C:16]=2[OH:18])[CH2:11][CH2:10][C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(O)c2c1CCC(=O)N2Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(O)c3c2CCC(=O)N3Cc2ccccc2)S1
Yield: 99.8 %

Procedure:
2.0 g of 1-benzyl-8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde and 0.874 g of 2,4-thiazolidinedione were suspended in 20 ml of toluene. Ten drops of piperidine and ten drops of acetic acid were added, followed by heating and refluxing for 8 hours. The resultant was allowed to cool to precipitate a solid, and the precipitated solid was collected by filtration and dried, giving 2.7 g (92% yield) of 5-(1-benzyl-8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethylidene)thiazolidine-2,4-dione as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[OH:32][CH2:33][C:34]1[S:35][CH:36]=[C:37](B(O)O)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:37]3[CH:38]=[C:34]([CH2:33][OH:32])[S:35][CH:36]=3)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: OCc1cc(B(O)O)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2csc(CO)c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
To a solution of Example 57c (0.300 g, 0.568 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), 2-hydroxymethyl-4-thiopheneboronic acid (0.133 g, 0.853 mmoles) and sodium carbonate (0.180 g, 1.70 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.033 g, 0.028 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as light brown solid (0.042 g, 14% yield). MP: 154-156° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05 (s, 1H), 8.04 (dd, J=7.9, 1.4 Hz, 1H), 7.85 (m, 1H), 7.67 (d, J=6.4 Hz, 1H), 7.66 (s, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.29 (br s, 1H), 7.20 (s, 1H), 7.06 (dt, J=8.8, 2.1 Hz, 1H), 6.98 (br s, 2H), 6.02 (q, J=6.9 Hz, 1H), 5.54 (t, J=5.8 Hz, 1H), 4.68 (d, J=5.7 Hz, 2H), 1.88 (d, J=7.0 Hz, 3H). Mass: 514.19 (M++1).
Reaction SMILES: [O:1]=[S:2]1(=[O:24])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[NH:17]C(=O)C(F)(F)F)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].O.[OH-].[Li+].Cl>CO.O>[O:1]=[S:2]1(=[O:24])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[NH2:17])[CH2:4][CH2:3]1
Reactant: COc1ccc(CC2CCS(=O)(=O)CC2)c(NC(=O)C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(CC2CCS(=O)(=O)CC2)c(N)c1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
N-{2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]-5-methoxyphenyl}-2,2,2-trifluoroacetamide (890 mg; 2.44 mmol; 1 eq) is suspended in MeOH (15 mL). To the yellow-brown suspension is added dropwise a solution of potassium carbonate (403.98 mg; 2.92 mmol; 1.2 eq) in water (4 mL). Immediately, the suspension lighted up. Stirring is continued at room temperature for 1 h. No conversion is observed. Lithium hydroxide monohydrate (112.44 mg; 2.68 mmol; 1.1 eq) is added leading to a turbid solution. Stirring is allowed to continue at room temperature overnight. No conversion is observed. Additional lithium hydroxide monohydrate (511.08 mg; 12.18 mmol; 5 eq) is added as a solution in water (5 mL). Stirring is continued at room temperature for 4 days. The suspension is cooled with an ice-bath and 5 N HCl is added until pH=1. The resulting solution is concentrated under reduced pressure until precipitation started (approx. 5 mL of solution left). n-Heptane is added as anti-solvent and the biphasic system is cooled with an ice-bath. The beige solid obtained is filtered off, rinsed twice with diethyl ether and dried under high vacuo to afford 580 mg (78%) of the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 9.80 (br s, 2H), 7.17 (d, J=8.7 Hz, 1H), 6.94 (d, J=2.6 Hz, 1H), 6.83 (dd, J=8.7 Hz, 2.6 Hz, 1H), 3.73 (s, 3H), 3.03-2.99 (m, 4H), 2.61-2.58 (m, 2H), 2.10-1.98 (m, 1H), 1.91-1.86 (m, 2H), 1.72-1.61 (m, 2H). HPLC (max plot) 95.5%; Rt 1.55 min. LC/MS: (ES+): 270.1.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][CH:23]([F:25])[F:24])=[CH:16][N:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[F:24][CH:23]([F:25])[CH2:22][O:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH3:13])=[N:15][CH:16]=1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ncc1OCC(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (91 mg, colorless solid) from 4-chloro-2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.27 mmol, Intermediate-76, single enantiomer) and phenyl formate (66 mg, 0.54 mmol) in a similar manner to Intermediate-91.