Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:57][CH2:56][CH2:55][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:24]([NH:26][C@H:27]([C@H:32]([CH2:34][C:35]([NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C@H:48]([CH2:50][C:51](OC)=[O:52])[OH:49])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:41])[CH3:39])=[O:36])[OH:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH3:58]>>[NH:1]1[CH2:57][CH2:56][CH2:55][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:24]([NH:26][C@H:27]([C@H:32]([CH2:34][C:35]([NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C@H:48]([CH2:50][C:51]([NH2:58])=[O:52])[OH:49])[CH2:44][CH:45]([CH3:46])[CH3:47])=[O:41])[CH3:39])=[O:36])[OH:33])[CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: N
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1)[C@@H](O)CC(N)=O
Reaction time: 48 h

Procedure:
40 mg of H-Pro-Phe-His-Sta-Ala-Sta-OMe are dissolved in 10 ml of saturated methanolic ammonia solution. The solution is left to stand for 48 hours at room temperature, then the solvent is removed in a rotary evaporator and the residue is chromatographed over silica gel in the system chloroform/methanol/concentrated aqueous ammonia solution (40:10:1). The main fractions are combined and concentrated by evaporation. After drying the residue in a high vacuum, H-Pro-Phe-His-Sta-Ala-Sta-NH2 (cf. Example 9) is obtained in the form of a colourless powder; Rf (chloroform/methanol/concentrated ammonia solution [40:10:1])=0.27.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:17]=2)[CH2:9]1.[CH2:35]([O:37][C:38]([CH:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)=[O:39])[CH3:36]>>[CH2:35]([O:37][C:38]([CH:40]1[CH2:45][CH2:44][CH:43]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=4)[N:18]([CH2:29][C:30]([F:31])([F:32])[F:33])[N:17]=3)[CH2:9]2)[CH2:42][CH2:41]1)=[O:39])[CH3:36]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: O=C(CNc1nn(CC(F)(F)F)c2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(CC(F)(F)F)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-(azetidin-3-yl)-2-((1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1H-indazol-3-yl)amino)acetamide TFA salt (as prepared in the previous step) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][NH:13][C:12](=[O:15])[C@@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][CH2:9][C@H:10]1[CH2:14][NH:13][C:12](=[O:15])[C@@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1NC[C@H](COCc2ccccc2)[C@H]1c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1NC[C@H](CO)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.6 %

Procedure:
10% Palladium-carbon (1.7 g) was added to a solution of (3S,4R)-4-[(benzyloxy)methyl]-3-phenyltetrahydro-1H-2-pyrrolone (1.73 g, 6.2 mmol) in methanol (40 ml). The mixture was stirred at room temperature under a hydrogen stream for 15 hours and further stirred at 60° C. for 3 hours. The reaction mixture was filtered and was subjected to distillation under reduced pressure. Ether was added to the residue and the precipitates were filtered out to yield the title compound as a white solid (1.05 g). 1H-NMR (CDCl3) δ(ppm) 1.90 (1H, brs), 2.69 (1H, m), 3.32 (1H, dd, J=10.0 Hz, 8.0 Hz), 3.46 (1H, d, J=9.2 Hz), 3.56 (1H, t, J=8.8 Hz), 3.67 (1H, m), 3.75 (1H, m), 6.50 (1H, brs), 7.19-7.30 (3H, m), 7.32-7.38 (2H, m)
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[CH:31]([C:34]1[CH:35]=[CH:36][C:37]([O:51][CH3:52])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([CH3:50])=[CH:47][CH2:48]O)=[CH:42][CH:41]=2)[CH:39]=1)([CH3:33])[CH3:32]>C1C=CC=CC=1.O.C(OCC)(=O)C>[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:48]/[CH:47]=[C:46](/[C:43]2[CH:42]=[CH:41][C:40]([C:38]3[CH:39]=[C:34]([CH:31]([CH3:32])[CH3:33])[CH:35]=[CH:36][C:37]=3[O:51][CH3:52])=[CH:45][CH:44]=2)\[CH3:50])=[CH:28][CH:29]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(C)=CCO)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)C)ccc3OC)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.74 ml, 0.61 g, 3.0 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.50 g, 2.10 mmol) and 3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol (0.593 g, 2.0 mmol) in dry benzene (15 ml), the mixture warmed to room temperature, and stirred for 4 h. The resulting mixture was diluted with water (100 ml) and ethyl acetate (50 ml), the aqueous layer collected and further extracted with ethyl acetate (50 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica (10% ethyl acetate in n-heptane eluent) to give (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate as a colourless oil; 0.67 g (65%).
Reaction SMILES: [OH:1][CH:2]([P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH3:5].C/C(/[O-])=C/C(C)=O.C(OO)(C)(C)C>ClC1C=CC=CC=1>[C:2]([P:6](=[O:13])([O:7][CH2:8][CH3:9])[O:10][CH2:11][CH3:12])(=[O:1])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)P(=O)(OCC)OCC
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)OO
Solvent: Clc1ccccc1
Product: CCCC(=O)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
To 16.2 g (77 mmol) of diethyl α-hydroxybutylphosphonate and 0.4 g (1.5 mmol) of vanadyl(IV) bis-acetylacetonate in 100 g of chlorobenzene there were added 30.4 g (0.24 mol) of 70 wt % strength aqueous tert-butylhydroperoxide and the mixture was stirred for 4 days. The solvent was removed in vacuo. Yield (in the residue ): 25%
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[Mg].[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:21]
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc2ccccc2c1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1C(O)c1ccccc1
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
A solution of 10 g (45 mmol) of 1-bromo-2-methylnaphthalene in 75 mL of THF was refluxed with 1.2 g (50 mmol) of magnesium turnings for three hours. The reaction was cooled on ice and 4.8 mL (43 mmol) of benzaldehyde was added. The ice was removed, the reaction was stirred 45 minutes and quenched with 5 mL of 1N HCl followed by 50 mL of water. The reaction was extracted into ethyl acetate, dried over sodium sulfate and flash chromatographed through silica gel with 5-10% ethyl acetate in hexane to provide 8.4 g (75%) of 2-methyl-a-phenyl-1-naphthalenemethanol as a pale yellow gum.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([NH:17][C:18]1[C:19](=[O:36])[N:20]([C:24]2[CH:25]=[C:26]([CH:31]=[C:32]([F:35])[C:33]=2[CH3:34])[C:27]([O:29]C)=[O:28])[CH:21]=[CH:22][N:23]=1)([CH3:16])[CH3:15].Cl>O.C1COCC1>[Cl:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([NH:17][C:18]1[C:19](=[O:36])[N:20]([C:24]2[CH:25]=[C:26]([CH:31]=[C:32]([F:35])[C:33]=2[CH3:34])[C:27]([OH:29])=[O:28])[CH:21]=[CH:22][N:23]=1)([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc(F)c(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCCl)c2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)O)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
Lithium hydroxide monohydrate (0.177 g) in water (5.00 mL) was added to methyl 3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1 (2H)-yl]-5-fluoro-4-methylbenzoate (Example 316b, 1.17 g) in THF (10 mL) and the reaction mixture was stirred for 4 h at room temperature. Water was added and the solution acidified with 2M HCl. This was extracted into ethyl acetate (2×). The combined organics were dried (MgSO4), filtered and evaporated to afford the subtitle compound as a solid (1 g).
Reaction SMILES: [CH2:1]([C@@H:4]1[C@@H:8](/[CH:9]=[CH:10]/[C@@H:11]([O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C@H:7]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:6][C:5]1=[O:40])[CH:2]=[CH2:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[CH2:1]([C@@H:4]1[C@@H:8](/[CH:9]=[CH:10]/[C@@H:11]([O:24][Si:25]([CH2:26][CH3:27])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C@H:7]([O:32][Si:33]([C:36]([CH3:38])([CH3:37])[CH3:39])([CH3:35])[CH3:34])[CH2:6][C@@H:5]1[OH:40])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](COc1cccc(C(F)(F)F)c1)O[Si](CC)(CC)CC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@H](/C=C/[C@H](COc2cccc(C(F)(F)F)c2)O[Si](CC)(CC)CC)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A 500 ml three-necked flask was flame dried and allowed to be cooled under nitrogen. (2R,3R,4R)-2-allyl-4-(tert-butyldimethylsilyloxy)-3-((R,E)-3-(triethylsilyloxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)cyclopentanone (2.68 g, 4.48 mmol) and 30 ml tetrahydrofuran were added to the reaction flask, followed by dropwise addition of L-Selectride (4 ml, 1M in tetrahydrofuran) at −70° C. Then, the reaction mixture was warmed to room temperature and quenched by 30 ml saturated aqueous ammonium chloride. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off and organic solvent was evaporated off under vacuum. The crude product was purified by chromatography and then concentrated under reduced pressure to provide 2.5 g of the title compound (93% yield).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]=2[CH:15]=1)=[N+]=[N-].[ClH:24]>C(O)C.[Pd]>[ClH:24].[CH2:17]([O:16][C:7]1[C:8]2[O:12][C:11]([CH3:13])([CH3:14])[O:10][C:9]=2[CH:15]=[C:5]([CH2:4][NH2:1])[CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)Oc2cc(CN=[N+]=[N-])cc(OCc3ccccc3)c2O1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(C)Oc2cc(CN)cc(OCc3ccccc3)c2O1
Reaction time: 18 h

Procedure:
A solution of 6-azidomethyl-4-benzyloxy-2,2-dimethyl-benzo[1,3]dioxole (2.0 mmol maximum) in ethanol (20 mL) and 6 M aqueous hydrochloric acid (2 mL) is hydrogenated at 50 psi over 5% Pd/C. After 18 hours, the reaction mixture is filtered through a Celite pad and concentrated under reduced pressure to give C-(7-benzyloxy-2,2-dimethyl-benzo[1,3]dioxol-5-yl)-methylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[C:5]2[CH2:20][CH2:21][CH2:22][CH2:23][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:45]=[CH:44][C:37]2[NH:38][C:39]([C@@H:41]([NH2:43])[CH3:42])=[N:40][C:36]=2[CH:35]=1.ClCl>CN(C)C=O>[Cl:33][C:34]1[CH:45]=[CH:44][C:37]2[NH:38][C:39]([C@@H:41]([NH:43][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([N:6]4[C:5]5[CH2:20][CH2:21][CH2:22][CH2:23][C:4]=5[N:3]=[C:2]4[CH3:1])=[C:8]([C:16]([F:18])([F:19])[F:17])[CH:9]=3)[CH3:42])=[N:40][C:36]=2[CH:35]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1nc2c(n1-c1ccc(C(=O)O)cc1C(F)(F)F)CCCC2
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(n1-c1ccc(C(=O)N[C@@H](C)c3nc4cc(Cl)ccc4[nH]3)cc1C(F)(F)F)CCCC2
Yield: 45 %

Procedure:
Prepared analogously to Example 1d from 4-(2-methyl-4,5,6,7-tetrahydrobenzimidazol-1-yl)-3-trifluoromethylbenzoic acid, PFTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 45%; C25H23ClF3N5O (501.938); mass spectrum: (M−H)−=500/502 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COCCOCCOCCOCCC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCC(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To tert-butyl 2,5,8,11-tetraoxatetradecan-14-oate (65 g, 222.6 mmol) (example-1), was added p-toluenesulfonic acid (21.16 g, 111 mmol) and water (31.7 mL). The contents were heated to 80° C. and stirred at that temperature for 2 h. The completion of the reaction was monitor by TLC. The reaction mixture was cooled to 0° C. and basified to pH 10 to 11 using sodium hydroxide solution (17.7 g dissolved in 65 mL water). The contents were stirred at 25-30° C. for 10 minutes. Added Ethyl acetate (65 mL×2), stirred and separated the layer. The aqueous layer was cooled to 0 to 5° C. and the pH was adjusted to 3.5 to 4 using 11 N HCl solution and the product was extracted to methylene chloride (120 ml×2). The combined organic layer was washed with water, brine solution and dried over sodium sulphate. The solvent was removed under vacuum to afford 2,5,8,11-tetraoxatetradecan-14-oic acid (40.5 g, 77.1%).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Br:11][C:4]1[N:3]=[C:2]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1CCN(c2nc(Br)ccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Yield: 65.6 %

Procedure:
A mixture of 2,6-dibromo-3-nitropyridine (Duffy, J., et al, J. Org. Chem. 56, (9), 3006, (1991)) (282 mg, 1.00 mmol), 4-methylpiperidine (118 μL, 1.00 mmol) and K2CO3 (138 mg, 1.00 mmol) in toluene (10 mL) was heated at 50° C. for 3 h. Toluene was removed in vacuo and the residue obtained was purified on silica (2% EtOAc/hexane) to obtain the title compound (197 mg, 66%). 1H-NMR (CDCl3; 400 MHz): δ 8.32 (d, 1H J=8.2 Hz), 7.94 (d, 1H J=8.2 Hz), 3.82 (m, 2H), 3.04 (m, 2H), 1.85 (m, 3H), 1.3 (m, 2H), 0.99 (d, 3H, J=6.4 Hz).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B1OC(C)(C)C(C)(C)O1.Br[C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:25]([NH:36][C:37]([C:39]2[CH:40]=[N:41][CH:42]=[C:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:44]=2)=[O:38])[CH:24]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O.C(O)C.C1(C)C=CC=CC=1>[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[C:25]([NH:36][C:37]([C:39]2[CH:40]=[N:41][CH:42]=[C:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:44]=2)=[O:38])[CH:24]=1
Reactant: Cn1cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
Ethanol (0.62 mL), water (0.31 mL), sodium carbonate (70 mg), 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (55 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg) were added to a toluene (2.1 mL) solution of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then sodium carbonate (23 mg), 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (46 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 3 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then toluene (1.0 mL), ethanol (0.31 mL), and water (0.16 mL) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 71 mg of tert-butyl 4-(1-methyl-1H-pyrrol-2-yl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a light yellow solid.
Reaction SMILES: [SH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:10])[S:6][C:7]=1[CH:8]=O.C(O)(=O)C>C(O)C>[CH3:10][C:5]1[S:6][C:7]2[C:3](=[CH:2][S:1][CH:8]=2)[N:4]=1
Reactant: Cc1nc(CS)c(C=O)s1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2cscc2s1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5 mmol of 4-(mercaptomethyl)-2-methyl-1,3-thiazole-5-carbaldehyde was dissolved in 50 ml of ethanol, then 50 mmol of acetic acid was added, and stirring was continued for 1 hour at a room temperature. Then the temperature was heated up to 80° C. to carry out the reaction for 4 hours. The reacted liquid was cooled down to a room temperature. The solvent was evaporated out and then purification was carried out using column separation with solvents of ethylacetate and hexane, obtaining 2-methylthieno[3,4-d][1,3]thiazole.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:17]1([CH2:23][CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:17]1([CH2:23][CH2:24][NH:25][CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: NCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)CCCC2NCCc1ccccc1

Procedure:
A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.82 g), phenylethylamine (15.6 ml) and p-toluensulfonic acid (8.7 g) in 250 ml of toluene was refluxed with removal of water for twenty hours. The mixture was then treated with a dilute NaOH solution, and extracted with ethyl acetate (3x). The combined organics were washed with water and dried (saturated NaCl solution, MgSO4).
Reaction SMILES: [CH:1]1([C:7]([S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:21](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+].C(P(CCCC)CCCC)CCC>CC(C)=O.O.C1(C)C=CC=CC=1>[C:1]1(=[C:7]2[NH:21][C:12](=[O:13])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccccc1SC(=O)C1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC(=C2CCCCC2)Sc2ccccc21
Temperature: -15 °C
Yield: 9.5 %

Procedure:
2-[(Cyclohexylcarbonyl)thio]benzoic acid (14.77 g, 56 mmol) was suspended in acetone (150 ml). While stirring under ice cooling, triethylamine (5.10 g, 50 mmol) and then ethyl chloroformate (6.70 g, 62 mmol) were dropwise added to the suspension. After stirring at the same temperature for 40 minutes, an aqueous solution (20 ml) of sodium azide (5.00 g, 77 mmol) was dropwise added to the reaction mixture, followed by further stirring for an hour. The reaction mixture was diluted with water and the dilution was extracted with toluene (100 ml×3). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then filtered. The toluene solution was cooled to about −15° C. and a solution (10 ml) of tributylphosphine (10.37 g, 51 mmol) in toluene was dropwise added to the solution. After completion of the dropwise addition, the reaction temperature was reverted to room temperature and the mixture was heated under reflux for 15 minutes. The reaction solution was concentrated under reduced pressure. The residue was applied to column chromatography using silica gel (150 g) to elute with hexane-ethyl acetate (2:1, v/v). The eluate was crystallized from acetone-ethyl acetate to give the title compound (1.16 g, 10%) as crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:18]([NH:20][C:21](=[O:36])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][C:23]=1[F:35])[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.ClCCl.CO>[CH2:18]([NH:20][C:21](=[O:36])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:31][CH2:30]2)=[CH:24][C:23]=1[F:35])[CH3:19]
Reactant: CCNC(=O)c1cc(F)c(N2CCNCC2)cc1F
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc(F)c(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1F
Temperature: 90 °C
Yield: 36.7 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (10.76 mg, 0.049 mmol), N-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamide hydrochloride (15 mg, 0.049 mmol), (cyanomethyl)trimethylphosphonium iodide (17.88 mg, 0.074 mmol) and N,N-diisopropylethylamine (0.043 mL, 0.245 mmol) were suspended in propiononitrile (Volume: 0.2 mL) and heated in a closed vial at 90° C. for 2 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, diluted with dichloromethane (2 mL) and methanol (0.3 mL), and purified using flash column chromatography on silica gel (12 g SiO2, dichloromethane-methanol 100:0-90:10). The resulting solid was suspended in ether (1 mL), stirred until a fine suspension resulted, filtered and the solid was recrystallized from MeOH-water (1:7, 4 mL) and dried in vacuum to afford (S)—N-ethyl-2,5-difluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (8.5 mg, 0.018 mmol, 36.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.20 Hz, 3 H) 1.76-1.97 (m, 3 H) 2.11 (m, J=6.44, 4.17 Hz, 1 H) 2.36-2.42 (m, 4 H) 3.03 (br. s., 4 H) 3.12-3.22 (m, 2 H) 3.28-3.37 (m, 3 H) 3.46-3.59 (m, 1 H) 3.86-3.97 (m, 1 H) 6.81 (dd, J=12.63, 7.07 Hz, 1 H) 6.91 (d, J=1.77 Hz, 1 H) 7.30 (dd, J=13.64, 6.82 Hz, 1 H) 7.55 (d, J=1.52 Hz, 1 H) 7.95-8.04 (m, 1 H) 10.38 (s, 1 H). [M+H] calc'd for C24H28F2N6O2, 471; found, 471.