Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[C:33](=O)([O:37]CC)[O:34][CH2:35][CH3:36]>O>[CH2:35]([O:34][C:33]([CH2:2][C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1)=[O:3])=[O:37])[CH3:36]
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OC(C)=O)cc1
Reactant: CCOC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)CC(=O)OCC)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
The product from (b) (42 g, 0.12 mol) was added portionwise to a suspension of potassium t-butoxide (21.3 g, 0.19 mol) in diethyl carbonate (56.6 g, 0.48 mol) at 75° C. over 10 minutes. Heating was continued at 95° C. for 1 h. After cooling to 50° C., the suspension was poured into cold water (1 liter) and extracted with ethyl acetate (3×400 ml). The organic solution was dried and evaporated under reduced pressure to give the product (47 g, 93%) as a yellow waxy solid which was used in the next reaction without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1.C(O)C.Cl[Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27].N1C=CN=C1>[Pd].C(OCC)C>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:9]([O:8][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CCO
Product: CC(C)[Si](Oc1ccc(C(F)(F)F)cc1C#N)(C(C)C)C(C)C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
Intermediate B, Step 2: A 250-mL round bottom flask containing a magnetic stir bar was charged successively with 2-(benzyloxy)-5-(trifluoromethyl)benzonitrile (7.30 g, 26.3 mmol), ethanol (76 mL) and 10 wt % palladium on carbon (560 mg, 5.27 mmol). The resulting solution was put under a hydrogen atmosphere and stirred for 3 h. The solution was then filtered and evaporated until all ethanol was removed. The residue was redissolved in DMF (38 mL), and chlorotriisopropylsilane (9.02 mL, 42.1 mmol) and imidazole (2.87 g, 42.1 mmol) were added and stirred for 4 h. At this time the solution was diluted with diethyl ether (300 mL) and washed with brine (5×100 mL). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified using a 120 g silica gel cartridge and 20:1 Hex/EtOAc to 4:1 Hex/EtOAc to elute 5-(trifluoromethyl)-2-(triisopropylsilyloxy)benzonitrile (8.80 g, 25.6 mmol, 97% yield) as a colorless oil. LC/MS [M+H]-=344.19. 1H-NMR (400 MHz, CDCl3) δ=7.83 (s, 1H), 7.70 (dd, J=8.0, 3.6 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 1.15-1.0 (m, 21H).
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:26])[C:12](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[C:13]([CH3:15])=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:27][O:28][C:29](=[O:34])/[CH:30]=[C:31](\[NH2:33])/[CH3:32]>>[N+:23]([C:19]1[CH:18]=[C:17]([CH:16]2[C:30]([C:29]([O:28][CH3:27])=[O:34])=[C:31]([CH3:32])[NH:33][C:13]([CH3:15])=[C:12]2[C:11]([O:10][CH2:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:26])[CH:22]=[CH:21][CH:20]=1)([O-:25])=[O:24]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCC=Cc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC=Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 67 %

Procedure:
3.51 g (10 mM) of 2-(3-nitrobenzylidene)acetoacetic acid cinnamyl ester was mixed with 1.38 g (12 mM) of 3-aminocrotonic acid methyl ester, and heated at 120° for 3 hours. The reaction mixture was separated by silica gel column chromatography, and 3.00 g of cinnamyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (trans) was obtained (yield 67%). This derivative was recrystallized once with methanol.
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([O:6]CC)=[O:5])C.C[Si](Br)(C)C>ClCCl>[P:4]([CH2:9][O:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([OH:6])([OH:5])=[O:3]
Reactant: CCOP(=O)(COCCOn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2OCCOCP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 9-[2-(diethoxyphosphorylmethoxy)ethoxy]adenine (0.63 g, 1.83 mmol) in dry dichloromethane (10 ml) was added trimethylsilyl bromide (1.45 ml, 11 mmol) and the solution stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in methanol (10 ml). The solvent was evaporated and the residue again dissolved in methanol and solvent evaporated to give a solid residue. Crystallisation from methanol: acetone gave the title compound which was recrystallised from methanol: water (0.24 g, 45%), m.p. 241°-244° C. UV: λmax (EtOH) 259 nm (ε 13,500); IR: νmax (KBr) 3428, 3312, 3084, 1685, 1644, 1612, 1484, 1462, 1455, 1336, 1294, 1278, 1255, 1215, 1195, 1104, 1060, 1046, 1033, 955, 934, 892 cm-1. 1H NMR: δH [(CD3)2SO]3.64 (2H,d,J=8.2 Hz, OCH2P), 3.82 (2H,m,N-OCH2CH2O), 4.50 (2H,m, N-OCH2CH2), 7.42 (2H, br.s, D2O exchangeable NH2), 8.15 (1H,s,H-8), 8.38 (1H,s,H-2) 10.0-4.5 (2H,broad, D2O exchangeable PO(OH )2). Found: C,32.84; H,4.41; N: 23.74%. C8H12N5O5P. H2O requires: C,33.01; H,4.19; N:24.06%.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:18]N(C=O)C.IC.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:15])([F:16])[F:17])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred solution of 2-methyl-3-nitro-5-(trifluoromethyl)benzoic acid (1 equiv.) in DMF (3 ml per 1 mmol), iodomethane (4 equiv.) and sodium carbonate (4 equiv.) were added. The resulting reaction mixture was stirred at 60° C. for 8 h. On completion, reaction mixture was filtered and the inorganic solid residue washed with ethyl acetate. The combined filtrate was concentrated under vacuum till dryness and the residue re-dissolved in ethyl acetate before washing with 5% sodium bicarbonate solution followed by 5M HCl solution. the organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford pure methyl 2-methyl-3-nitro-5-(trifluoromethyl)benzoate (yield 90-95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:12].[CH2:13]=[O:14]>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:13][OH:14])=[C:5]2[OH:12]
Reactant: Oc1ccnc2ccc(Cl)cc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: OCc1cnc2ccc(Cl)cc2c1O

Procedure:
6-Chloro-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide at 55° for 24 hours to give the novel compound 6-chloro-4-hydroxy-3-hydroxymethylquinoline, m.p. >300°.
Reaction SMILES: COC1C=CC(C([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=O)=CC=1.[OH-].[Na+]>CO>[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:26])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2OC(=O)c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccccc2O)cc1
Reaction time: 16 h
Yield: 89.9 %

Procedure:
A solution of N-[2-(4-methoxybenzoyloxy)phenyl]-4-methoxybenzamide (3.0 g, 8.0 mmol) in methanol (50 mL) was treated with 5 N aqueous sodium hydroxide (4.78 mL) at room temperature for 16 h. The solution was concentrated to one-half volume in vacuo, 5 N aqueous sodium hydroxide was added, and the resulting mixture stirred for an additional 16 h. The mixture was concentrated in vacuo and acidified with dilute hydrochloric acid. The resulting precipitate was collected by filtration, dissolved in ethyl acetate, and extracted with saturated aqueous potassium carbonate solution. The aquous layer was acidified with dilute hydrochloric acid and extrated with ethyl acetate. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo to provide 1.75 g (90%) the title product as a crystalline solid.
Reaction SMILES: [C:1]([C:3]([C:17]#[N:18])=[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)#[N:2].Cl.[CH3:20][NH:21][CH3:22].NC1C=CC=CC=1>>[C:17]([C:3]([C:1]#[N:2])=[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][C:8]([N:21]([CH3:22])[CH3:20])=[O:10])#[N:18]
Reactant: N#CC(C#N)=C(CCCC(=O)O)c1ccccc1
Reactant: CNC
Agent: Cl
Solvent: Nc1ccccc1
Product: CN(C)C(=O)CCCC(=C(C#N)C#N)c1ccccc1

Procedure:
The desired product was prepared by substituting 6,6-dicyano-5-phenyl-5-hexenoic acid (prepared by substituting 5-oxo-5-phenylpentanoic acid for Example 1A in Example 1B) and dimethylamine hydrochloride for Example 66B and aniline, respectively, in Example 66C. MS (ESI(−)) m/e 266 (M−H)−.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([C:15]([F:18])([F:17])[F:16])[C:9]([C:19]([O:21]CC)=[O:20])=[CH:8]2)([F:4])[CH3:3].C1COCC1.CCO.O.[OH-].[Na+]>O>[F:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([C:15]([F:16])([F:17])[F:18])[C:9]([C:19]([OH:21])=[O:20])=[CH:8]2)([F:4])[CH3:3]
Reactant: CCOC(=O)C1=Cc2cc(C(C)(F)F)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.1 %

Procedure:
A 500 mL round bottom flask was charged with ethyl 6-(1,1-difluoroethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Step 1 (0.385 g, 1.145 mmole), THF: EtOH: H2O (7:2:1 volume ratio, 3 ml), and aqueous NaOH (0.55 mL, 1.374 mmole) and stirred at r.t. for two days. The reaction was concentrated in vacuo yielding a semi-solid. The semi-solid was dissolved in water washed with diethyl ether, and the resulting aqueous phase sparged with nitrogen with warming. The resulting organic solvent-free aqueous phase was acidified with concentrated HCl solution (to pH 1) yielding a gummy solid. This mixture was extracted with ethyl acetate. The combined organics were dried over MgSO4, filtered, diluted with isooctane, and concentrated in vacuo yielding an oil. Upon standing, the oil formed a white crystalline powder (0.159 g, 45%): mp 156-158° C. (w/decomp). LCMS m/z 309 (M+H). HRMS m/z 307.0408 (M−H, C13H8F5O3, Calc'd 307.0388). 1H NMR (acetone-d6/300 MHz) 12.2-11.2 (br s, ˜0.5H (1H exch), 7.97 (s, 1H), 7.72 (s, 1H), 7.61(d d, 1H, J=8.5, 2.2 Hz), 7.13 (d, 1H, J=8.7 Hz), 5.89 (q, 1H, J=7.0 Hz), 1.97 (t, 3H, J=18.3 Hz).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:11])[CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([OH:9])[CH3:8].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:9][C:7]([CH3:10])([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]([NH:2][S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19])[CH3:11]
Reactant: CC(N)CCCC(C)(C)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: CC(CCCC(C)(C)O)NS(=O)(=O)c1ccccc1

Procedure:
In this case, 6-amino-2-methyl-2-heptanol hydrochloride (381.6 g, i.e. 2.1 mol) is neutralized and reacted with 353 g of benzenesulphonyl chloride (2 mol) according to Example 1(a).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[N:36][CH:35]=[N:34]3)=[CH:29][CH:28]=2)[CH2:16][C:17]([NH:19][O:20]C(OC)(C)C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[ClH:38]>CCOC(C)=O>[ClH:38].[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH:37]=[N:36][CH:35]=[N:34]3)=[CH:31][CH:32]=2)[CH2:16][C:17]([NH:19][OH:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)OC)Cc2ccc(-n3cncn3)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)NO)Cc2ccc(-n3cncn3)cc2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 4.2 g (7.93 mmol) of 2-[(4-but-3-enyloxy-benzenesulfonyl)-(4-[1,2,4]triazol-1-yl-benzyl)-amino]-N-(1-methoxy-1-methyl-ethoxy)-acetamide (stage 79.6) in 100 ml of AcOEt, 28 ml of 5 N aqueous hydrochloride are added at r.t. After stirring for 5 min, precipitates are filtered off and dried in vacuo to give 2-[(4-but-3-enyloxy-benzenesulfonyl)-(4-[1,2,4]triazol-1-yl-benzyl)-amino]-N-hydroxy-acetamide-hydrochloride salt as colorless powder. 1H-NMR (400 MHz, DMSO-d6): 2.45–2.55 (m, 2H), 3.67 (s, 2H), 4.13 (t, 2H, J=6.56 Hz), 4.41 (s, 2H), 5.09–5.22 (m, 2H), 5.90 (m, 1H), 7.10 (d, 2H, J=9.04 Hz), 7.45 (d, 2H, J=8.56 Hz), 7.75–7.85 (m, 4H), 8.25 (s, 1H), 9.32 (s, 1H), 10.55 (brs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.Cl.[NH2:29][OH:30]>CC(O)=O.C(O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[N:29][OH:30])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: NO
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=NO)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) (1 eq), hydroxylamine hydrochloride (2 eq) and 1 drop of HOAc, dissolved in absolute ethanol (0.028M) was stirred at room temperature for 1.5 hours. The mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo . The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-80% ethyl acetate in hexane to give 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone oxime as a white solid. 1H NMR (Methanol-d4): δ 8.56 (s, 1H), 8.52 (s, 1H), 8.12 (d, 1H), 7.45 (d, 2H), 7.31 (s, 1H), 7.12 (m, 3H), 4.51 (s, OH), 3.15 (t, 2H), 3.01 (t, 2H), 2.39 (s, 3H), 2.09 (s, 3H). LRMS [M+H]=371.2
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21]Br)[CH:11]=3)=[CH:9][C:2]=12.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC)=O>[N:23]1([CH2:21][CH2:20][CH2:19][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:8]3[NH:7][C:3]4=[N:4][CH:5]=[CH:6][N:1]=[C:2]4[CH:9]=3)=[CH:11]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: C1COCCN1
Reactant: BrCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2CCCN1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propylbromide [250 mg, Reference Example 4], morpholine (0.5 mL), potassium carbonate (100 mg) and potassium iodide (2 crystals) in ethyl methyl ketone was heated at reflux for 2 hours. The mixture was then allowed to cool to ambient temperature over 16 hours then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give a yellow glass which was triturated with ethyl acetate and pentane to give the title compound (40 mg) as a yellow solid, m.p. 180–185° C. MS: 362 (MH+).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[CH3:14][NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18]([CH2:17][CH2:16][N:15]([CH3:14])[CH2:3][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:1]([O:11][CH2:12][CH3:13])=[O:10])=[O:19])[CH3:22]
Reactant: CCOC(=O)CCNC
Reactant: C=C(C(=O)OCC)c1ccccc1
Product: CCOC(=O)CCN(C)CC(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
184.47 g of ethyl atropate (of Example 1c) are added dropwise, over a 20 minute period, to 132.16 g of ethyl β-methylaminopropionate (of Example 1a). The mixture is stirred for 18 hours at room temperature under a nitrogen atmosphere. The mixture is combined with 1.8 l. of ether and then the resultant mixture is extracted with two 800 ml portions of 2 N hydrochloric acid. The acid solution is extracted with two 150 ml portions of ether. The aqueous extracts are basified with 50 weight percent aqueous NaOH solution and then extracted with three 900 ml portions of ether. The ether extracts are combined and dried for 18 hours over MgSO4. The combined ether portions are filtered and concentrated in vacuo to yield ethyl N-(2-ethoxycarbonylethyl)-3-methylamino-2-phenylpropionate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]2[N:10]([C:14]([CH2:18][C:19]#[CH:20])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[CH3:29].O>CN(C)C=O>[CH3:17][C:15]1[N:16]=[C:9]2[C:8]([O:7][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[CH3:29])=[CH:13][CH:12]=[CH:11][N:10]2[C:14]=1[CH2:18][C:19]#[CH:20]
Reactant: Cc1cnccc1CCl
Reactant: C#CCc1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCc1c(C)nc2c(OCc3ccncc3C)cccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
Potassium carbonate (0.52 g) was added to a solution of 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.5 g) and 4-chloromethyl-3-methylpyridine (0.53 g) in N,N-dimethylformamide (10 ml). The mixture was stirred under a nitrogen atmosphere for 5 hours at room temperature and then poured into water. The resulting precipitates were collected by filtration and recrystallized from ethyl acetate to give 2-methyl-8-(3-methyl-4-pyridylmethoxy)-3-(2-propynyl)imidazo[1,2-a]pyridine (0.58 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.OC(C(F)(F)F)=O.[C:29]1([C:35]2[CH2:39][C:38]3([CH2:44][CH2:43][CH2:42][NH:41][CH2:40]3)[O:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[N:3]=[C:2]([N:41]3[CH2:42][CH2:43][CH2:44][C:38]4([O:37][N:36]=[C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:39]4)[CH2:40]3)[CH:10]=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: c1ccc(C2=NOC3(CCCNC3)C2)cc1
Reactant: CS(=O)(=O)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(Nc2nc(N3CCCC4(CC(c5ccccc5)=NO4)C3)ccc2C(N)=O)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 25.8 %

Procedure:
A mixture of 6-chloro-2-(4-(methylsulfonyl)phenylamino)nicotinamide (30 mg, 0.092 mmol), 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-ene TFA salt (30.4 mg, 0.092 mmol) and N,N-diisopropylethylamine (0.064 mL, 0.368 mmol) in DMF (1 mL) was stirred at 120° C. for 20 h. The mixture was cooled to room temperature and purified by reverse phase HPLC, using Sunfire S10 30×250 mm column and eluting with 40% to 100% solvent B (10% MeOH-90% H2O-0.1% TFA) in solvent A (90% MeOH-10% H2O-0.1% TFA), to give a brown solid (12 mg, 21%). LCMS: (M+H)+=506.10. 1H NMR (400 MHz, acetonitrile-d3) δ ppm 7.69-7.80 (3H, m), 7.62-7.69 (2H, m), 7.55 (2H, d, J=9.03 Hz), 7.36-7.44 (3H, m), 6.28 (1H, d, J=9.04 Hz), 3.50-3.95 (4H, m), 3.08-3.38 (2H, m), 2.85 (3H, s), 2.01-2.13 (2H, m), 1.65-1.83 (2H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)=[CH:11][C:10]([N+:18]([O-])=O)=[CH:9][N:8]=2)[CH2:3][CH2:2]1>[Pd].CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:18])=[CH:11][C:12]=2[N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc(N2CCOCC2)c(-n2cccn2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(N2CCOCC2)c(-n2cccn2)c1
Yield: 94 %

Procedure:
A methanol (5 ml) solution containing 2-morpholino-5-nitro-3-(1H-pyrazol-1-yl)pyridine (37 mg) was prepared and was subjected to a hydrogenation reaction (room temperature; 1 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and a white solid of 6-morpholino-5-(1H-pyrazol-1-yl)pyridin-3-amine (31 mg) was thus obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[S:47][C:46]([S:48](Cl)(=[O:50])=[O:49])=[CH:45][CH:44]=1.N1C=CC=CC=1C1C=CSC=1S(Cl)(=O)=O>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:48]([C:46]2[S:47][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=3)=[CH:44][CH:45]=2)(=[O:49])=[O:50])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: O=S(=O)(Cl)c1sccc1-c1ccccn1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of {3-[(4-thiazol-2-yl-benzylamino)-methyl-]-phenoxy}-acetic acid tert butyl ester (111 mg, 0.270 mmol), prepared in Step A of Example 13i, triethylamine (120 mg, 1.19 mmol) and dichloroethane (10 mL) was added 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (77.2 mg, 0.297 mmol). The reaction was stirred for 72 h and additional 5 pyridin-2-yl-thiophene-2-sulphonyl chloride (38.5 mg) was added. The reaction was stirred for an additional 48 h. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (58 mg). MS 633 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O1CCCC1.B.ClCCCl>O1CCCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[CH:7]=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1I
Agent: O=[Mn]=O
Agent: B
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 121.4 %

Procedure:
To a solution of 5-chloro-2-iodo benzoic acid (4.92 g, 17 mmol) (TRANS) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added borane tetrahydrofuran (1 M, 34 mL, 34 mmol) dropwise. The reaction mixture was then stirred at room temperature for 18 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give a colorless oil. The oil was dissolved into 1,2-dichloroethane (50 mL), and activated MnO2 (15 g) was added. The mixture was then heated at reflux for 2 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated and purified by chromatography (EtOAc:hexanes=1;8) to give 5-chloro-2-Iodo-benzaldehyde as a white solid (Yield 5.5 g, 25%).