Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][Cl:15])(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:18]>>[C:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][Cl:15])[C:10]([NH2:11])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C#N)ccc1NC(=O)CCl
Reactant: O=S(=O)(O)O
Product: CC(=O)c1cc(C(N)=O)ccc1NC(=O)CCl
Reaction time: 8 h
Yield: 61.6 %

Procedure:
15.7 Parts of N-(2-acetyl-4-cyanophenyl)-2-chloroacetamide were added portionwise to 146.4 parts of concentrated sulfuric acid at room temperature. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was poured into 500 parts of crushed ice while stirring. The precipitated product was filtered off, washed with water and suspended in 20 parts of acetonitrile. The product was filtered off, boiled in 20 parts of acetonitrile and filtered off, after cooling, yielding 10.4 parts (61.6%) of 3-acetyl-4-[(2-chloroacetyl)amino]benzamide (int. 114).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)=O.CO.[BH4-].[Na+]>O>[CH2:1]([NH:8][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)c1ccc(Sc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(Sc2ccc(CNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
Combine benzylamine (17 mg, 0.16 mmol), 6-(4-formyl-phenylsulfanyl)-nicotinamide (40 mg, 0.16 mmol), 3 Å molecular sieves (0.1 g), and methanol (3 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (25 mg, 0.64 mmol) to the reaction and stirred at room temperature for 1 hour. Pour the reaction into water then extract with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (50 mg). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-[4-(benzylamino-methyl)-phenylsulfanyl]-nicotinamide, (24 mg): m/z=349.99 (M+1); 1H NMR (MeOD, 300.00 MHz): (8.84 (dd, 1H, J=2.3, 1.0 Hz), 8.02 (dd, 1H, J=8.6, 2.3 Hz), 7.66-7.49 (m, 4H), 7.66-7.49 (m, 4H), 7.42-7.34 (m, 5H), 6.99-6.92 (m, 1H), 3.88-3.77 (m, 4H). HPLC=99%@5.82 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. By the method of Example 7 the following compounds were prepared, isolated as the free base except where noted:
Reaction SMILES: [OH:1][C@H:2]([CH3:21])[C@@H:3]([CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].CO>C1COCC1.O>[OH:1][C@H:2]([CH3:21])[C@@H:3]([CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@H](CC1CCC(c2ccccc2)CC1)[C@@H](C)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of methyl (2R,3R)-3-hydroxy-2-(4-phenylcyclohexylmethyl)butanoate (4.17 g, 0.014 mol) and lithium hydroxide monohydrate (0.59 g, 0.014 mol) is stirred at 25° C. in a mixture of THF (30 mL), methanol (15 mL) and water (15 mL) for 72 h. The reaction is not complete and an additional 0.88 g (0.021 mol) of lithium hydroxide monohydrate in water (10 mL) is added. After 6 h an additional 0.59 g (0.014 mol) of solid lithium hydroxide monohydrate and the mixture is stirred at 25° C. for 18 h. The mixture is concentrated in vacuo and the residue is taken up in water, chilled in an ice-bath and the pH is adjusted to 2 with sodium bisulfate. The mixture is extracted with dichloromethane. The combined extracts were washed with saturated sodium chloride, dried over sodium sulfate and concentrated in vacuo to give 3.43 g (89%) of (2R,3R)-3-hydroxy-2-(4-phenylcyclohexylmethyl)butanoic acid as a yellow solid.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:14]([OH:20])(=[O:19])[CH2:15][CH2:16][C:17]#[CH:18]>>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:18]=[CH:17][CH2:16][CH2:15][C:14]([O:20][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:19])[CH2:11][CH2:12][CH3:13]
Reactant: C#CCCC(=O)O
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCC[Sn](C=CCCC(=O)O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Temperature: 60 °C

Procedure:
A mixture of tri-n-butyltinhydride (2.0 equiv.) (Aldrich) and 4-pentynoic acid (1.0 equiv.) (Aldrich) is warmed to 60° C. for six hours. Kugelrohr distillation of the crude product gives tri-n-butylstannyl 5-(tri-n-butylstannyl)-4-pentenoate acid.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:13]([O:15][N:16]=[C:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:18]#[N:19])=[O:14]>C1(C)C=CC=CC=1>[C:1]([O:5][C:13]([O:15][N:16]=[C:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:18]#[N:19])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: N#CC(=NOC(=O)Cl)c1cccc2ccccc12
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)ON=C(C#N)c1cccc2ccccc12
Reaction time: 3 h

Procedure:
The mixture was stirred for 3 hours at the same temperature and allowed to stand overnight. A solution of tert-butyl alcohol (11.1 g.) and pyridine (12 ml.) in toluene (20 ml.) was added dropwise, under ice-cooling, to the resultant mixture containing 2-chlorocarbonyloxyimino-2-(1-naphthyl)-acetonitrile. The mixture was stirred for 6 hours at the same temperature and allowed to stand overnight. The reaction mixture was then washed with water, 1N hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solution was concentrated under reduced pressure and n-hexane and methanol were added to the residue. The mixture was allowed to stand in a refrigerator and the precipitated crystals were collected by filtration and recrystallized twice from methanol to give 2-tert-butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile (3.3 g.), mp 90° to 92° C.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:18][CH2:17]1.C(OCC)(=O)C.ClCCl>CS(C)=O>[Cl:29][C:24]1[CH:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:1]3[C:9]4[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=4[CH:3]=[CH:2]3)[CH2:21][CH2:20]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: O=C1CCCc2[nH]ccc21
Reactant: ClCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CCCc2c1ccn2CCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 1,5,6,7-tetrahyroindol-4-one (107 mg) in DMSO (2 mL) was added powdered sodium hydroxide (33 mg) and the mixture was stirred at ambient temperature for 0.5 hours. 1-(2-Chloroethyl)-4-(3,4-dichlorophenyl)piperazine (220 mg) from step 1 was then added as a solution in DMSO (2 mL) and the resulting mixture stirred at ambient temperature for 24 hours then heated to approximately 60° C. for 2 hours, after which time thin layer chromatography (TLC) (ethyl acetate:dichloromethane 1:1) showed complete reaction. The reaction was poured into ice cold water (15 mL) and stirred for 0.5 hours. A solid mass formed and was separated by decanting the water. The aqueous layer was extracted with dichloromethane (10 mL). The solid mass was dissolved with dichloromethane (5 mL) and the combined organics were dried with sodium sulfate and the solvent removed under vacuum to obtain an oil (250 mg) as the titled compound.
Reaction SMILES: [I-].[Na+].C[Si](C)(C)Cl.C(#N)C.[F:11][C:12]1[CH:13]=[CH:14][C:15]2=[C:16]([CH:44]=1)[O:17][CH2:18][C:19]1[CH:29]=[C:28]([CH:30](O)[C:31]3[N:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]4=[N:33][C:32]=3[CH2:40][O:41][CH3:42])[CH:27]=[CH:26][C:20]=1/[C:21]/2=[C:22](/[CH3:25])\[C:23]#[N:24]>O.CCCCCC>[F:11][C:12]1[CH:13]=[CH:14][C:15]2=[C:16]([CH:44]=1)[O:17][CH2:18][C:19]1[CH:29]=[C:28]([CH2:30][C:31]3[N:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]4=[N:33][C:32]=3[CH2:40][O:41][CH3:42])[CH:27]=[CH:26][C:20]=1/[C:21]/2=[C:22](/[CH3:25])\[C:23]#[N:24]
Reactant: COCc1nc2ccccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCCCCC
Product: COCc1nc2ccccn2c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
[step 5] To sodium iodide (197 mg, 1.32 mmol) were added trimethylchlorosilane (165 mL, 1.32 mmol) and acetonitrile (69 mL, 1.3 mmol), and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added hexane (0.22 mL). Furthermore, (E)-2-(3-fluoro8-{hydroxy[2-(methoxymethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (100 mg, 0.22 mmol) obtained in step 4 was added, and the mixture was stirred for 1 hr. The reaction was discontinued with water, and the mixture was extracted with chloroform, the extract was washed with saturated sodium thiosulfate aqueous solution, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained reaction residue was purified by silica gel column chromatography (chloroform/methanol=10/1 v/v) to give the title compound (60 mg, 62%).
Reaction SMILES: Br.[CH2:2]([N:20]([CH2:22][CH:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])C>>[CH2:2]([NH:20][CH2:22][CH:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:10][CH:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC(O)CN(C)CCCCCCN(C)CC(O)CCCCCCC
Agent: Br
Product: CCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCC

Procedure:
In a manner similar to that of Example 22, methylation of N,N'-(1,6-hexylene)-bis[2-hydroxynonylamine] (36 g.) and treatment of the resulting product (25 g., b.p. 172°-176° C./0.05 mm.) with hydrogen bromide gave N,N'-(1.6-hexylene)-bis[N-methyl-2-hydroxynonylamine] (I: R= CH3 (CH2)6, R' = CH3, X= (CH2)6, Z= H) dihydrobromide (26.3 g., m.p. 176.0° -177.0° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:10])=[CH:4][CH:3]=1.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>O.C(COC)OC>[Na+:15].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:11]([O-:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[Br-:10].[Na+:15]
Reactant: Fc1ccc(CCBr)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=S(=O)([O-])CCc1ccc(F)cc1
Product: [Br-]
Reaction time: 72 h
Yield: 626.8 %

Procedure:
A mixture of 2-(4-fluorophenyl)ethyl bromide (1.8 g, 8.9 mmol) (Ref. Chim. Ther., 1969, 4(3),185) and sodium sulfite (2.24 g, 8.9 mmol) in water (5 ml) and dimethoxyethane (5 ml) was heated under reflux for 21 hours. The mixture was then left for 72 hours at room temperature. The mixture was concentrated under vacuum to leave the title compound as a crytalline mixture with sodium bromide (2.87 g).
Reaction SMILES: [K+].[CH2:2]([N:9]([CH3:14])[CH2:10][C:11]([O-:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][CH2:16][CH2:17]O.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1>ClCCl>[Br:15][CH2:16][CH2:17][O:12][C:11](=[O:13])[CH2:10][N:9]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:14]
Reactant: OCCBr
Reactant: CN(CC(=O)[O-])Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CC(=O)OCCBr)Cc1ccccc1
Temperature: 25 °C

Procedure:
N-Benzyl-N-methyl glycine potassium salt (2.00 g. 11.16 mmol) and 2-Bromo ethanol (2.48 g. 17.86 mmol) was suspended in 20 mL of dichloromethane. To this solution was added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.40 g. 33.5 mmol) and 4-dimethylamino)pyridine. (1.00 g.) and the reaction was stirred at 25° C. The mixture was diluted with 40 mL of dichloromethane, and was washed with water (1×60 mL), saturated sodium bicarbonate solution (2×60 and brine (1×60 mL). The organic phase was then dried over magnesium sulfate, and filtered through a pad of Celite. Evaporation of the solvent in vacuo affordedd an oil, which was purified on silica gel eluting with ethyl acetate to afford N-Benzyl-N-methyl glycine 2-bromoethyl ester as an oil (0.70 g. 27% yeild).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)=[CH:14][N:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:31].O1CCOCC1>C(Cl)Cl>[ClH:31].[ClH:31].[NH:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[N:13][CH:14]=2)[CH:22]=[N:21]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3cn[nH]c3)cn2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3cn[nH]c3)cn2)CCC1
Reaction time: 15 h

Procedure:
To a solution of {1-[5-(1H-pyrazol-4-yl)-pyridin-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester (300 mg, 0.96 mmol) in CH2Cl2 (5 mL) was added TFA (0.37 mL, 4.8 mmol). After 15 h, 4M HCl in dioxane (1.2 mL, 4.8 mmol) was added. After 1 h, the reaction was concentrated in-vacuo to yield 303 mg of the title compound, m/z 215.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[CH2:33][C:34]#[N:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][C:12]=3[F:25])[C:3]=12.[CH3:37][C:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:41])[CH:39]=O.N1CCCCC1>O1CCOCC1.CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[C:33]([C:34]#[N:35])=[CH:41][C:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:37])[CH3:39])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][C:12]=3[F:25])[C:3]=12
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2F)c2c(N)ncnc21
Solvent: C1COCCO1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 6 h
Yield: 18.2 %

Procedure:
To a solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (245 mg, 0.5 mmol, 1 equiv) and tert-butyl 2-methyl-1-oxopropan-2-ylcarbamate (935 mg, 5 mmol, 10 equiv) in dioxane (30 mL) was added 0.5 mL piperidine, 1 drop AcOH and 2 g of 4 A molecular sieves. The resulting mixture was stirred for 6 h at 110° C. The solids was filtered out, the filtrate was diluted with 200 mL of ethyl acetate, washed with brine, dried over Na2SO4, concentrated and purified with silica gel column (ethyl acetate/MeOH 10/1) to give 60 mg of tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-ylcarbamate as white solid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: COc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(OC)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (200 mg, 0.58 mmol, 1.00 equiv), 1-(4-methoxyphenyl)piperazine (230.4 mg, 1.20 mmol, 2.00 equiv) and DIEA (232.3 mg, 1.80 mmol, 3.00 equiv) in DMF (6 mL) was placed in a 20-mL sealed tube and stirred overnight at 100° C. in an oil bath, then concentrated under vacuum. Purification via prep-HPLC yielded 117.1 mg (42%) of methyl 3-(4-(4-methoxyphenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH:12]([S:14][CH2:15][CH3:16])[CH3:13])[CH2:6][C:5]1=[O:17])(=O)[CH3:2].C(O)(=O)C.[Cl:22]/[CH:23]=[CH:24]/[CH2:25][O:26][NH2:27].[OH-].[Na+]>O.CCCCCC>[Cl:22]/[CH:23]=[CH:24]/[CH2:25][O:26][NH:27][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH:12]([S:14][CH2:15][CH3:16])[CH3:13])[CH2:6][C:5]1=[O:17])[CH3:2]
Reactant: NOC/C=C/Cl
Reactant: CCSC(C)CC1CC(=O)C(C(C)=O)C(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: CCSC(C)CC1CC(=O)C(=C(C)NOC/C=C/Cl)C(=O)C1

Procedure:
In this example, 29.5 g (0.1151 mol) of 2-acetyl-5-(2-ethylthiopropyl)cyclohexane-1,3-dione; 1.7 g (0.0277 mol) of acetic acid, and 19.7 g (0.1369 mol) of 3-trans-chloroallyloxyamine in 62 ml of water were admixed to 37 ml of hexane. Aqueous 5 wt. % sodium hydroxide was slowly added dropwise over about 15 minutes until 5.5 g (0.1369 m+small excess) of sodium hydroxide had been added yielding a reaction mixture pH of about 6. The mixture was heated to and maintained at 40° C. for 21/2 hours and then cooled to room temperature. The organic (i.e., hexane) phase was separated and washed with 16 ml of aqueous 5 wt. % hydrochloric acid and then aqueous 6.25 wt. % sodium hydroxide added until pH12. The aqueous phase was separated and admixed with 35 ml of hexane at about 0° C. (ice bath) and the pH adjusted to 5 by the dropwise addition of aqueous 36 wt. % hydrochloric acid over an ice bath. A few mls of methylene chloride was then added. The organic phase was separated, dried over magnesium sulfate and then concentrated by evaporation affording 35.2 g of a crude product as an oil. The crude product was purified by column chromatography over silica gel eluting with hexane:methylene chloride mixtures affording 17.4 g of the purified title compound also as an oil. Elemental analysis carbon calculated 55.56%, found 54.43%; Hydrogen calculated 6.99%, found 6.53%; Nitrogen 4.05%, found 4.31%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].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.[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1>CN(C=O)C.CCOC(C)=O>[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:18](=[O:20])[CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=3)=[CH:15][CH:14]=2)=[CH:57][CH:56]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: N#Cc1cc(Oc2ccc(CCC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)cc3)cc2)ccn1

Procedure:
A solution of 3-{4-[(2-cyanopyridin-4-yl)oxy]phenyl}propanoic acid (400 mg, 1.49 mmol), HATU (681 mg, 1.79 mmol), DIPEA (0.5 mL, 2.98 mmol), and 4-chloroaniline (209 mg, 1.63 mmol) in DMF (5 mL) was stirred overnight at rt. The reaction mixture was diluted with EtOAc and washed with 1N HCl, 1N NaOH and brine, dried over Na2SO4 and concentrated. The resulting solid was triturated with DCM and filtered to give A-21 (187 mg, 33%). 1H NMR (300 MHz, d6-DMSO): δ 10.02 (s, 1H), 8.56 (dd, J1=0.50 Hz, J2=5.8 Hz, 1H), 7.57-7.63 (m, 3H), 7.31-7.40 (m, 4H), 7.10-7.17 (m, 3H), 2.95 (t, J=7.5 Hz, 2H), and 2.65 (t, J=7.8 Hz, 2H).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][CH2:7][CH2:8][CH:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[N:10]1[CH2:15][CH2:14][C:13]2[S:16][CH:17]=[CH:18][C:12]=2[CH2:11]1)C.C(O)C.[OH-].[Na+]>O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:9]([N:10]1[CH2:15][CH2:14][C:13]2[S:16][CH:17]=[CH:18][C:12]=2[CH2:11]1)[CH2:8][CH2:7][CH2:6][C:5]([CH3:26])([CH3:27])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCC(c1ccccc1Cl)N1CCc2sccc2C1)C(=O)O
Yield: 55.7 %

Procedure:
6-(2-Chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylhexanoic acid ethyl ester (2.5 g, 7.33 mmol) was added to a solution of ethanol (100 mL) and sodium hydroxide (1.8 g, 43.8 mmol) in water (32 mL). The mixture was heated to reflux for 6.5 hours. The solution was evaporated under reduced pressure and water (100 mL) was added to the residue. The water solution was extracted with ethyl acetate/heptane=1/10 (100 mL). The organic layers were discarded and the aqueous solution was adjusted with 10 N hydrochloric acid solution to pH=6. The product was extracted with dichloromethane (3×100 mL), which was dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6-(2-chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylhexanoic acid (1.6 g, 68.7%) as a yellow oil. 6-(2-Chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylhexanoic acid (3.97 g, 10.2 mmol) was dissolved in 36% HCl (0.95 mL) and water (59 mL). After stirring for 10 minutes, the aqueous solution was extracted with ethyl acetate/heptane (20/80, 110 mL). The organic extract was discarded and the aqueous fraction was freeze-dried to provide 6-(2-chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylhexanoic acid, hydrochloride salt (Compound Ic hydrochloride, 3.48 g, 79.8% yield, 99.7% purity by HPLC) as a white solid melting at 136-138° C. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.69 (s, 1H), 7.47-7.38 (m, 3H), 7.21 (d, 1H, J=3.9 Hz), 6.71 (d, 1H, J=3.9 Hz), 4.92 (m, 1H), 4.31-4.15 (m, 2H), 3.15-3.05 (m, 4H), 2.24-2.14 (m, 2H), 1.47-1.36 (m, 2H), 1.08-1.06 (m, 2H), 0.99 (s, 6H). (mixture of rotation isomers in NMR). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 181.10, 137.13, 132.80, 132.77, 132.04, 131.79, 130.48, 129.73, 128.73, 126.62, 126.14, 66.14, 51.52, 42.87, 40.92, 32.04, 25.88, 25.47, 23.45, 22.50. MS (FIA-ESI-TOF): Calculated for C21H26ClNO2S (MH)+: 392.1446. found 392.1453. CHN analysis: Calculated; 58.87; C, 6.35; H, 3.27; N, 16.55; Cl, 7.48; S. found; 57.80; C, 6.44; H, 3.15; N, 16.14; Cl, 7.15; S, Best fit for CHN Data: C21H27Cl2NO2S+0.55H2O