Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([OH:40])=O)([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:64][S:61]([CH:58]6[CH2:60][CH2:59]6)(=[O:63])=[O:62])=[O:40])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C)n3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C)n3)nc2c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
A mixture of the acid 17-[2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yl-oxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (102, 28 mg, 0.046 mmol) and CDI (15 mg, 0.092 mmol) in dry THF (3 mL) was heated at reflux for 2 h under nitrogen. The activation was monitored by LC-MS. The reaction mixture was cooled at room temperature and cyclopropylsulfonamide (17 mg, 0.137 mmol) was added. Then, DBU (16 μL, 0.105 mmol) was added and the reaction was heated at 55° C. After 24 h, the pH of the reaction mixture was adjusted to 3 with citric acid (5%). Then, the solvent was evaporated, and the residue partitioned between AcOEt and water. The crude material was purified by preparative HPLC to give 17 mg (52%) of the target compound 103: m/z=716 (M+H)+.
Reaction SMILES: C([C@H]1COC(=O)N1C(=O)[C@@H:15]([O:40][CH2:41][CH3:42])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]([CH3:39])[C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:24]=2)=[CH:19][CH:18]=1)C1C=CC=CC=1.C1[CH2:48][O:47]CC1.[OH-:49].[Li+]>O>[CH2:41]([O:40][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]([CH3:39])[C:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:38])[CH:24]=2)=[CH:21][CH:22]=1)[C:48]([OH:47])=[O:49])[CH3:42]
Reactant: [OH-]
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: [Li+]
Solvent: O
Product: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)O
Reaction time: 1 h
Yield: 47 %

Procedure:
600 mg (1 mmol) of N-{4′-[(S)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide and 10 ml of THF are introduced into a round-bottomed flask. At 0° C., 4.2 ml (2 mmol) of an aqueous lithium hydroxide solution (0.5M) are added and the mixture is stirred for one hour. The reaction medium is poured into water, acidified to pH 1 and extracted with ethyl acetate, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (50/50). 200 mg (47%) of (S)-2-ethoxy-3-(3′-{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-yl)propionic acid, with a melting point of 53-54° C., are obtained.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH:8]2[O:10][CH:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O.C(=O)=O>C(O)C>[C:1]1([C:7](=[O:17])[C:8](=[O:10])[CH2:9][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C1OC1c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(Cc1ccccc1)C(=O)c1ccccc1
Reaction time: 0.03 h
Yield: 65 %

Procedure:
To a boiling solution of 30 g 1,3-diphenyl-2,3-epoxy-1-propanone in 500 ml ethanol was rapidly added a hot solution of 30 g potassium t-butoxide in 500 ml ethanol. The mixture was kept boiling on a steambath for 2 minutes. It was then diluted with 3 l. water. The aqueous solution was saturated with carbon dioxide by the addition of small pieces of dry ice. The resulting emulsion was extracted with ether. The ether extracts were diluted with benzene, dried over sodium sulfate and evaporated under reduced pressure. The remaining dark oil was distilled in high vacuum to afford 19.5 g 1,3-diphenyl-1,2-propanedione; b.p. 136°-138° /0.1 mm.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]([CH3:10])[CH3:9].[OH:11][C:12]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[C:24]([CH3:27])([CH3:26])[CH3:25]>C(O)C>[OH:11][C:12]1[C:19]([C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:18][C:15]([CH:16]=[N:2][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]([CH3:10])[CH3:9])=[CH:14][C:13]=1[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)c1nccn1N
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCO
Product: CC(C)c1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.65 g of the above crude 1-amino-2-isopropylimidazole hydrochloride is dissolved in 30 ml of ethanol, 0.94 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde is added and the mixture is stirred at room temperature for 2 hours. The resulting solution is evaporated in a vacuum. The residue is partitioned between methylene chloride and water. The aqueous phase is treated with sodium bicarbonate solution up to a neutral reaction (pH=7) and the methylene chloride phase is separated, dried, filtered and evaporated. The residue is stirred with ether, whereupon the solid is removed by filtration and dried; there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-isopropylimidazole of m.p. 159°-160°.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH2:17][C@@H:18]([C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[O:21])[N:19]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[O:21])[N:19]=2)=[CH:13][CH:14]=1
Reactant: COc1cc(C(=O)[C@@H]2CSC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)=N2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C(=O)c2csc(-c3ccc(O)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
At 0° C., to a solution of 58a (0.2 mmol) in 5 mL CH2Cl2 was added a solution of tetrabutylammonium fluoride in THF (1 N, 0.6 mmol) and stirred at RT for around 14 h until reaction was finished by TLC monitor. 67.0% yield. 1H NMR (500 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.51 (s, 1H), 7.85 (d, 2H, J=8.50 Hz), 7.62 (s, 2H), 6.91 (d, 2H, J=8.5 Hz), 3.86 (s, 6H), 3.79 (s, 3H). MS (ESI) m/z 394.1 (M+Na)+, 369.9 (M−H)−.
Reaction SMILES: Cl.CN1C2=CCC(=O)C=C2[O:5][CH:4]1[CH2:13]CN.Cl.[CH3:17][N:18]1[C:22]2=[CH:23][CH2:24][C:25](=[O:27])[CH:26]=[C:21]2[S:20][CH:19]1[CH2:28][CH2:29][NH2:30]>>[CH3:17][N:18]1[C:22]2=[CH:23][CH2:24][C:25](=[O:27])[CH:26]=[C:21]2[S:20][CH:19]1[CH2:28][CH2:29][NH:30][C:4](=[O:5])[CH3:13]
Reactant: CN1C2=CCC(=O)C=C2OC1CCN
Reactant: CN1C2=CCC(=O)C=C2SC1CCN
Agent: Cl
Product: CC(=O)NCCC1SC2=CC(=O)CC=C2N1C

Procedure:
By replacing 2-(3-methyl-6-benzoxazolinonyl)-ethylamine hydrochloride in Example 61 by 2-(3-methyl-6-benzothiazolinonyl)ethylamine hydrochloride, described in French Patent Application 90/11,866, the product of the title is obtained.
Reaction SMILES: FC1C=C(CN)C=NC=1.[F:10][C:11]1[C:12]([CH2:17][NH2:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[CH:19]1([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34]([NH:18][CH2:17][C:12]4[C:11]([F:10])=[CH:16][CH:15]=[CH:14][N:13]=4)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])[CH2:20][CH2:21]1
Reactant: NCc1ncccc1F
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ncccc1F
Yield: 60 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (3-fluoropyridin-2-yl)methanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid in 60% yield: mp 142-144° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.38-8.31 (m, 2H), 7.69-7.62 (m, 1H), 7.39-7.33 (m, 1H), 4.51-4.54 (m, 2H), 4.00-3.95 (m, 2H), 3.64-3.59 (m, 2H), 3.06 (d, J=6.0 Hz, 2H), 2.44 (s, 3H), 0.96-0.87 (m, 1H), 0.49-0.42 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.2, 159.1, 157.9, 155.7, 151.2, 146.2, 145.4, 124.5, 123.6, 118.2, 48.2, 42.5, 42.3, 40.8, 17.5, 9.3, 3.6; MS (ES+) m/z 389.9 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:32])=O>>[CH:30]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:28][CH2:27]1)([CH3:32])[CH3:29]
Reactant: c1cc(C2(CN3CCNCC3)CCOCC2)ccc1OCCCN1CCCC1
Reactant: CC(C)=O
Product: CC(C)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 44 %

Procedure:
The title compound (78 mg, 44%) was prepared from 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine and acetone similarly to the procedure used for example 54. 1H NMR (400 MHz, CDCl3) δ 0.98 (d, 6H), 1.77-1.80 (m, 4H), 1.86-1.93 (m, 2H), 1.98-2.02 (m, 2H), 2.06-2.09 (m, 2H), 2.20-2.22 (m, 4H), 2.34-2.36 (m, 6H), 2.50-2.54 (m, 5H), 2.62 (t, 2H), 3.52 (t, 2H), 3.71-3.75 (m, 2H), 4.02 (t, 2H), 6.85 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 430.3417 [MH]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C.BrN1C(=O)CCC1=O>[Br:16][C:7]1[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCOCCN(CC)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCN(CC)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a solution of N-ethyl-N-(2-propoxyethyl)aniline (10.18 g) in DMF (50 ml) was added at room temperature a solution of N-bromosuccinimide (7.45 g) in DMF (50 ml) for 40 minutes, and the mixture was stirred for 3 hours. To the mixture was added a solution of N-bromosuccinimide (0.2 g) in DMF (10 ml), and the mixture was stirred for 15 hours. The reaction mixture was added to water, and the mixture was extracted with diethylether. The organic layer was washed with water (twice) and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was distilled under reduced pressure (0.7 mmHg, 134° C.) to give pale yellow oil of 4-bromo-N-ethyl-N-(2-propoxyethyl)aniline (9.49 g).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8]>>[Cl:1][CH:2]([Cl:6])[C:3](=[O:4])[CH:8]=[CH:7][O:9][CH2:10][CH3:11]
Reactant: C=COCC
Reactant: O=C(Cl)C(Cl)Cl
Product: CCOC=CC(=O)C(Cl)Cl
Reaction time: 5 h
Yield: 68 %

Procedure:
At about 0° C., dichloroacetyl chloride (95% pure, 16.5 g, 0.11 mol) and ethyl vinyl ether (99% pure, 48.7 g, 0.67 mol) were added and stirred for 5 h. The mixture was then stirred at 22° C. for about 11 h. Most of the excess ethyl vinyl ether was then removed by distillation under reduced pressure (40° C./300-400 mbar). The product was separated off from the residue (18.7 g) by flash distillation (oil bath 100° C./0.7 mbar; transition 72° C.). The distillate obtained was a product mixture (15.6 g). This consisted to 80% (GC area %) of the desired product. Furthermore, the product mixture consisted to about 5% (GC area %) of 1,1-dichloro-4,4-diethoxy-2-butanone. Including the corresponding diethyl acetal, the yield was about 68%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH2:9][O:10][C:11]([CH:13]1[C:17](=O)[CH2:16][CH2:15][CH2:14]1)=[O:12].[Cl-].[Ca+2].[Cl-]>C1COCC1>[NH:1]([C:14]1[CH2:15][CH2:16][CH2:17][C:13]=1[C:11]([O:10][CH2:9][CH3:8])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(Nc2ccccc2)CCC1

Procedure:
A mixture of aniline (6.0 g, 64.5 mmol), ethyl cyclopentanone-2-carboxylate (Aldrich Chemicals) (10.0 g, 64.1 mmol) and calcium chloride (7.6 g, 68.5 mmol) in THF (100 ml) was heated under reflux for 24 hours. After being allowed to cool, the suspension was filtered and the solvent was removed from the filtrate under reduced pressure. Kugelrohr distillation of the residue (125° C., 0.02 mmHg) gave the title product as a pale yellow liquid.
Reaction SMILES: Br[C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:37]1[C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=[N:38]1>>[OH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:3]2[C:2]([C:39]3[NH:38][N:37]=[CH:41][CH:40]=3)=[CH:24][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:20])([F:19])[F:21])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:26]1
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 19.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford an off-white solid. HPLC (Condition 4) tR=4.86 min, UPLC-MS (Condition 3) tR=0.97 min, m/z=484.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.92 (m, 2H) 2.94 (d, J=1.00 Hz, 1H) 3.18-3.34 (m, 2H) 3.37-3.51 (m, 1H) 4.13-4.22 (m, 1H) 4.70-4.91 (m, 1H) 6.37 (br. s, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.86 (m, J=9.00 Hz, 3H) 8.01 (br. s, 1H) 8.65-8.83 (m, 1H) 10.17 (s, 1H) 12.84-13.11 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[S:7])([CH3:3])[CH3:2].S(Cl)(Cl)=[O:14].[C:17]1([CH3:23])C=CC=C[CH:18]=1>>[CH:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH:17]1[CH2:23][O:14][CH2:18]1)=[S:7])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ncccc1C(O)=S
Product: CC(C)c1ncccc1C(=S)OC1COC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 19.7 g of 2-isopropylthionicotinic acid prepared according to Example 1 and 22 ml of thionyl chloride in 100 ml of absolute toluene is stirred for 3 hours at 80° C. When evolution of gas has ceased, the reaction mixture is filtered and the mother liquor is concentrated to dryness under vacuum. The residual crude product (20.8 g of 2-isopropylthionicotinyl chloride as a yellow oil) is dissolved in 70 ml of absolute toluene and treated slowly at a temperature of 20°-25° C. with a mixture of 8.8 g of oxetan-3-ol and 8.5 ml pyridine dissolved in 20 ml of toluene. After stirring for 12 hours at a temperature of 20°-25° C., 100 ml of ice-water and 200 ml of diethyl ether are added, the organic phase is separated, and the aqueous phase is extracted with 2×100 ml of diethyl ether. The combined organic phase is dried and concentrated to give 27.4 g of oxetan-3-yl 2-isopropylthionicotinate in the form of a pale yellow oil. Purification by distillation at a bath temperature of 145°-150° C., 4×10-2 bar) gives 19.7 g of an oil.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21](SC3C=CC=CC=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9](CC#C)[CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-:32].[Cs+].[Cs+].[F:37][C:38]([F:48])([F:47])[O:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1>CN(C)C=O>[ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:32][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[O:39][C:38]([F:48])([F:47])[F:37])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(NO)C1(S(=O)(=O)c2ccc(Oc3ccccc3OC(F)(F)F)cc2)CCNCC1

Procedure:
Part A: To a solution of the product of Example 9, Part D (1.5 g, 3.61 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and 4-(trifluoromethoxy)phenol (0.70 mL, 5.41 mmol). The solution was heated to ninety degrees Celsius for 20 hours. The solution was partitioned between ethyl acetate and H2O and the organic layer was washed with saturated NaCl and dried over Na2SO4. Filtration through a silica pad (ethyl acetate) provided the phenoxyphenol as a yellow oil (2.11 g, quantitative yield). MS (CI) MNa+ calculated for C26H30NO8SF3: 596, found 596.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:23][O:24]C3CCCCO3)=[O:22])=[N:17][CH:18]=2)[CH2:8]1.[ClH:34].CCO.C(OCC)(=O)C>C(O)C>[ClH:34].[ClH:34].[OH:24][NH:23][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:15]=[N:14][C:13]([NH:12][C@@H:9]2[CH2:10][CH2:11][N:7]([CH2:6][C:5]3[CH:31]=[CH:32][CH:33]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:8]2)=[CH:18][N:17]=1
Reactant: COc1cccc(CN2CC[C@@H](Nc3cnc(/C=C/C(=O)NOC4CCCCO4)cn3)C2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc(CN2CC[C@@H](Nc3cnc(/C=C/C(=O)NO)cn3)C2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (240 mg) in ethanol (3.6 mL) was added 2N HCl-EtOH (10.1 mL), which was stirred at room temperature for 1 hour. To the resultant was added ethyl acetate (9.6 mL), which was stirred for 1 hour. The precipitate was filtered to give (2E)-N-hydroxy-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride (223 mg) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:11])[NH:9][NH:10][C:4]=2[CH:3]=1.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:11])[NH:9][N:10]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:4]=2[CH:3]=1
Reactant: O=c1[nH][nH]c2cc(Cl)ncc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]n(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 50 °C
Reaction time: 30 h

Procedure:
Into a 2000-mL 4-necked round-bottom flask was placed 6-chloro-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (Intermediate 1B, Step 2; 100 g, 589.73 mmol), Trt-Cl (328 g, 1.18 mol), potassium carbonate (244 g, 1.77 mol), and DMSO (1200 mL). The resulting solution was stirred for 30 h at 50° C. The reaction mixture was cooled to room temperature, then quenched by the addition of water/ice (4 L). The resulting solution was diluted with EtOAc (12 L). The solid was collected by filtration and washed with MeCN (1.5 L) to give 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one, which was carried onto the next step without further purification. MS ESI calc'd. for C25H18ClN3O [M+1]+ 412. found 412.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1.[CH2:36](O)C>N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH2:33][CH3:36])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: CCO
Solvent: C1CCNCC1
Product: CCc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-bromo-phenyl)2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-ethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (96 mg, 74%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][CH2:19][CH:20]1[O:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[NH4+].[Cl-]>ClCCl>[CH2:11]([O:18][CH2:19][CH:20]1[O:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1CCC(COCc2ccccc2)OC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCC(COCc2ccccc2)OC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMSO (1.15 mL, 16.2 mmol) was added to a stirred solution of oxalyl chloride (1 mL, 10.8 mmol) in dichloromethane (60 mL) at −78° C. After 10 minutes, a dichlotomethane solution of 6-(benzyloxymethyl)tetrahydro-2H-pyran-3-ol (14) (1.20 g, 5.40 mmol) was added. Stirring was continued for one hour then triethylamine (3.8 mL, 27 mmol) was added and slowly warmed to 0° C. The reaction was poured into saturated NH4Cl solution and the organic phase was washed with brine and dried (NaSO4). The residue was purified over silica gel using EtOAc and hexanes to give 6-(benzyloxymethyl)dihydro-2H-pyran-3(4H)-one (15).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.[NH2:12][C:13]1[N:17]([C:18]([NH2:20])=[O:19])[N:16]=[C:15]([CH3:21])[C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[CH3:30].C(OC)(OC)(OC)C.O>C(#N)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:14]2[C:15]([CH3:21])=[N:16][N:17]3[C:18]([OH:19])=[N:20][C:1]([CH3:2])=[N:12][C:13]=23)=[C:23]([CH3:30])[CH:24]=1
Reactant: COc1ccc(-c2c(C)nn(C(N)=O)c2N)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(C)(OC)OC
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2c(C)nn3c(O)nc(C)nc23)c(C)c1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
p-Toluenesulfonic acid (29.2 g, 154 mmol) in acetonitrile (100 mL) was added to the reaction mixture described in Example 3 containing 5-amino-4-(4-methoxy-2-methylphenyl)-3-methylpyrazole-1-carboxylic acid amide. The resulting mixture was heated to 85–90° C. and trimethyl orthoacetate (160 mL, 1.26 mol) was added over 5 minutes during the heating. The reaction was held for about 45 minutes in the desired range with a total of 1.5 hours of heating time from the initiation of the heating cycle. Reaction progress was monitored by HPLC. Water (1.50 L) was added over 5 minutes with a temperature drop to about 60° C. The resulting mixture was cooled to about 20° C. over 1 hour and the product isolated by filtration. The yield was 136 g (78.0% with a purity of 99.5 A %).