Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:18][O:19][C:20]1[CH:46]=[CH:45][C:23]([CH2:24][N:25]2[CH2:29][CH:28]([CH2:30][CH2:31]OS(C3C=CC(C)=CC=3)(=O)=O)[N:27]([CH3:43])[C:26]2=[O:44])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:15])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:31][CH2:30][CH:28]2[CH2:29][N:25]([CH2:24][C:23]3[CH:45]=[CH:46][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[C:26](=[O:44])[N:27]2[CH3:43])=[CH:8][CH:7]=1
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)OC(C)C
Temperature: 55 °C
Yield: 84.8 %

Procedure:
3-(4-Hydroxy-phenyl)-2-isopropoxy-propionic acid methyl ester (1.7 g, 7.3 mmol), Toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (3.4 g, 8.0 mmol), and Cs2CO3 (3.6 g, 11 mmol) were combined in 10 mL of DMF and heated at 55° C. for 18 h. After cooling, the mixture is diluted with 100 mL of water and extracted with 3×20 mL of ethyl acetate. The organics were dried, concentrated, and the residue is purified by flash chromatography using 7/3 ethyl actate/hexanes to give 3.0 g (86%) of the title compound as an oil. NMR
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N+:7](C)([CH3:13])[CH2:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C([O-])=O.CI>Cl.CC(C)=O.C(N(C(C)C)CC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[N+]1(C)Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Reaction time: 62 h

Procedure:
6,8-Dichloro-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium, trifluoroacetate; Intermediate 4 (100 mg) was dissolved in the form of its hydrochloride in acetone (1 ml) in the presence of diisopropylethylamine (58 μl). Methyl iodide (38 μl) was then added dropwise with stirring. The mixture was then stirred at room temperature for two hours and subsequently left to stand for 62 h. Since the reaction was still not complete, further methyl iodide (38 μl) was added and the mixture was heated to reflux. After two hours, the reaction mixture was cooled and then concentrated to dryness in a rotary evaporator. The residue was purified by preparative HPLC on RP-18 with acetonitrile/water (0.05% TFA), and the pure fractions were combined. The acetonitrile was stripped off and then the aqueous residue was freeze dried. 132 mg of the desired product were obtained as a solid. (Rt=4.22 min (method A); MS (Cl+): 306.0).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(CC)CC)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:28]#[C:29][C:30]3[CH:40]=[CH:39][C:33]([C:34]([O:36]CC)=[O:35])=[CH:32][CH:31]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:41])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:28]#[C:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:39][CH:40]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(CC)CC)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cccc(O)c2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 40.0 mg (0.076 mmol) in 3 ml of EtOH and 2 ml of THF was added 40.0 mg (1.00 mmol, 1.00 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 7.90 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.4 Hz), 7.35 (2H, s), 7.15-7.07 (2H, m), 6.77-6.69 (3H, m), 5.92 (1H, t, J=4.7 Hz), 2.25 (2H, d, J=4.7 Hz), 1.23 (6H, s).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:11][O:12][C:13]1[CH:41]=[CH:40][C:16]([C:17]([NH:19][C:20]2[C:21]([CH3:39])=[C:22]([CH3:38])[C:23]3[O:27][C:26]([CH3:29])([CH3:28])[CH:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]=3[C:36]=2[CH3:37])=O)=[CH:15][CH:14]=1.[OH-].[Na+]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:41]=[CH:40][C:16]([CH2:17][NH:19][C:20]2[C:21]([CH3:39])=[C:22]([CH3:38])[C:23]3[O:27][C:26]([CH3:29])([CH3:28])[CH:25]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]=3[C:36]=2[CH3:37])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccccc2)C(C)(C)O3)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccccc2)C(C)(C)O3)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
To a suspension of aluminum chloride (2.25 g, 16.9 mmol) in tetrahydrofuran (20 ml) was gradually added under ice cooling lithium aluminum hydride (640 mg, 16.9 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To this mixture was added 4-Methoxy-N-(2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)benzamide (1.40 g, 3.37 mmol) and the mixture was refluxed with heating for 3 hours. The reaction mixture was poured into ice water and neutralized with an 8 N aqueous solution of sodium hydroxide. The product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from methanol to obtain 0.80 g (59% yield) of the title compound. Melting point: 113-115° C.
Reaction SMILES: FC1C(C)=C(F)C(F)=C(F)C=1F.[OH-].[Na+].[CH:15]([O:18][C:19]1[C:35]([F:36])=[C:34]([F:37])[C:22]([CH2:23]OC2C=CC(C(=O)C)=CC=2)=[C:21]([F:38])[C:20]=1[F:39])([CH3:17])[CH3:16].[Br:40]N1C(=O)CCC1=O>O.C(O)(C)C>[CH:15]([O:18][C:19]1[C:35]([F:36])=[C:34]([F:37])[C:22]([CH2:23][Br:40])=[C:21]([F:38])[C:20]=1[F:39])([CH3:17])[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCc2c(F)c(F)c(OC(C)C)c(F)c2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1c(F)c(F)c(F)c(F)c1F
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1c(F)c(F)c(CBr)c(F)c1F

Procedure:
This compound can be prepared by reacting pentafluorotoluene with isopropanol and sodium hydroxide in water, as described for the preparation of compound 38, followed by bromination with N-bromosuccinimide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[NH2:55][CH:56]1[CH2:59][N:58]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:57]1>ClCCl>[C:63]([O:62][C:60]([N:58]1[CH2:57][CH:56]([NH:55][C:18]([C:17]2[CH:16]=[C:15]([CH:10]3[C:9]([CH3:25])([CH3:24])[CH2:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=4)[NH:11]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:59]1)=[O:61])([CH3:66])([CH3:65])[CH3:64]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CN(C(=O)OC(C)(C)C)C3)c1)N2
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol, 1.0 eq.) in dichloromethane (10.0 ml) was added N-hydroxy benzotriazole (89.2 mg, 0.66 mmol, 1.5 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (253.0 mg, 1.32 mmol, 3.0 eq.), followed by 4-methylmorpholine (133.5 mg, 1.32 mmol) and the resultant mixture was stirred at room temperature for 30 min. Then tert-butyl 3-aminoazetidine-1-carboxylate (90.9 mg, 0.53 mmol, 1.2 eq.) was added to the flask and the reaction mixture was stirred for an additional 30 min. LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 234 mg of methyl 2-(3-(1-(tert-butoxycarbonyl) azetidin-3-ylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[N:6][CH:7]=1.BrC1C(OC)=CC(NCC2C=CC3N=C(SC)SC=3C=2)=C([N+]([O-])=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(CNc3ncc(Cl)cc3[N+](=O)[O-])cc2s1
Agent: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Product: CSc1nc2ccc(CNc3ncc(Cl)cc3N)cc2s1
Yield: 65 %

Procedure:
Crude 5-chloro-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine was synthesized as a yellow solid using a procedure analogous to that describe in Step 2 of Example 41, substituting 5-chloro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine from Step 1 of this Example for 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline used in Example 41. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 5-chloro-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine (75 mg, 65%). LCMS (ESI) m/z 337 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[N:4][CH:3]=1.ClC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36]([C:43]1[CH:48]=[CH:47][C:46](Br)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[NH4+].O>CN1CCCC1=O>[CH2:36]([C:37]1[CH:42]=[CH:41][C:40]([N:4]2[CH:3]=[C:2]([CH3:1])[S:6]/[C:5]/2=[N:7]\[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:39][CH:38]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Brc1ccc(Cc2ccccc2)cc1
Reactant: Cc1cnc(NC(=O)N2CCCC2)s1
Agent: Clc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2ccc(Cc3ccccc3)cc2)/c(=N/C(=O)N2CCCC2)s1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial charged with a stir bar, N-(5-methyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxamide (58 mg, 0.27 mmol) was added, followed by copper(I) trifluoromethanesulfonate benzene complex (27 mg, 0.05 mmol), 5-chloro-1,10-phenanthroline (23 mg, 0.11 mmol) and cesium carbonate (97 mg, 0.3 mmol). A loose cap with septum was placed on the vial, and the vial was placed under vacuum in a vacuum oven for 30 minutes. The solid mixture was purged with nitrogen gas a couple of times. Then, 1-benzyl-4-bromobenzene (74 mg, 0.3 mmol) dissolved in 1-methyl-2-pyrrolidinone (1.0 mL) was added to the mixture. The vial was capped and placed on a heater/stirrer and heated to 120° C. overnight. Then 1 mL of a solution of concentrated ammonium hydroxide/water (1:2) was added. The reaction was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (C8, gradient 10-100% acetonitrile/water/0.1% trifluoroacetic acid).
Reaction SMILES: CO[C:3](=[O:13])[C@H:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])[NH2:5].[CH3:14][N:15]=[C:16]=[S:17]>>[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:16](=[S:17])[N:15]([CH3:14])[C:3]1=[O:13])(=[O:12])[CH3:11]
Reactant: CN=C=S
Reactant: COC(=O)[C@@H](N)CCCNC(C)=O
Product: CC(=O)NCCCC1NC(=S)N(C)C1=O

Procedure:
Using an analogous procedure to Example 1 Nδ-acetyl-L-ornithine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:23])C(=O)C1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:7]=1[Cl:23])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]nc(-c2cccs2)c1Cl

Procedure:
Following protocol L, 3-Thiophen-2-yl-1H-pyrazole-5-carboxylic acid ethyl ester was treated with NCS in DMF to yield the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[C:13]1([CH2:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC(=O)c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccccn1
Temperature: -78 °C
Reaction time: 5 h
Yield: 53.6 %

Procedure:
A solution of ethyl picolinate (1.0 g, 6.62 mmol) in anhydrous tetrahydrofuran (15 mL) was added benzylmagnesium chloride (3.64 mL, 7.28 mmol) at −78° C. The mixture was stirred at −78° C. for 5 h, and poured into saturated aqueous ammonium chloride solution (70 mL), and extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine (80 mL), and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give Intermediate 27 (700 mg, yield 53.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28]Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:31]1[C:36]2[CH2:37][CH2:38][N:39](C[B-](F)(F)F)[CH2:40][C:35]=2[CH:34]=[N:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:39]5[CH2:38][CH2:37][C:36]6[N:31]=[CH:32][N:33]=[CH:34][C:35]=6[CH2:40]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: F[B-](F)(F)CN1CCc2ncncc2C1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4ncncc4C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (7,8-dihydro-pyrido[4,3-d]pyrimidin-6-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=1.13 min; Mass spectrum (ESI+): m/z=540 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:33]=[N:32][CH:31]=1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 189.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC (Condition 4) tR=5.49 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=493.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.64 (m, 1H) 1.76-1.92 (m, 1H) 2.14-2.28 (m, 1H) 2.88-3.02 (m, 1H) 3.11-3.40 (m, 5H) 4.60 (t, J=1.00 Hz, 1H) 7.67 (d, J=8.60 Hz, 2H) 7.79-7.85 (m, 1H) 7.90 (d, J=8.60 Hz, 2H) 8.06 (d, J=1.96 Hz, 1H) 8.50 (s, 1H) 8.57 (d, J=2.74 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.26 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=[O:6].C(O)(C)C.[Cl-].[NH4+]>[Fe].O>[OH:1][CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1CO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(NNC(=O)c2ccccc2CO)cc1

Procedure:
Thereafter, the nitro compound was added to 300 ml of isopropyl alcohol with the addition of 30 ml of water and 3 g of ammonium chloride followed by reflux for 2 hours with the addition of 30 g of reducing iron and then the reflux liquid was filtered and the solid precipitated upon cooling the filtrate was filtered to obtain 4.2 g of 1-(2'-hydroxymethylbenzoyl)-2-(p-aminophenyl)hydrazine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cc(F)ccc1O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(F)ccc1O
Yield: 33.3 %

Procedure:
Using 5-fluorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]O>S(=O)(=O)(O)O>[C:1]1([CH:7]2[CH2:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CC(c2ccccc2)C1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CC(c2ccccc2)C1

Procedure:
A mixture of the cis and trans isomers of 3-phenylcyclobutane carboxylic acid (6.8g.) in methanol (100ml.) and concentrated sulphuric acid (0.5ml.) was refluxed overnight. The solution was concentrated to about 15ml., water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined and dried over anhydrous magnesium sulphate, the solvent was evaporated and the residue was distilled, to give methyl 3-phenylcyclobutanecarboxylate as a mixture of cis- and trans-isomers, b.p. 100°-120° C./0.2 mm. Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)([OH:16])[C:10]3[N:11]=[C:12]([CH3:14])[O:13][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1.[H-].[Na+].[CH3:28]I>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH3:28])[CH:22]=3)([OH:16])[C:10]3[N:11]=[C:12]([CH3:14])[O:13][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: Cc1nc2c(o1)CCc1cc(Cl)ccc1C2(O)c1c[nH]c(=O)[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2c(o1)CCc1cc(Cl)ccc1C2(O)c1cn(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of the product from step (vii) (2.0 g) in tetrahydrofuran (20 ml) at 0° C. was added sodium hydride (60% dispersion by wt, 0.22 g). The mixture was stirred at 0° C. for 40 min and treated with methyl iodide (0.35 ml). The mixture was further stirred at 0° C. for 2 hours and room temperature for 24 hours then partitioned between ethyl acetate and water. The organic phase was washed with water and saturated brine, dried (MgSO4) and solvent evaporated. Purification was by chromatography eluting with 10% ethanol in dichloromethane to give the product as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([CH:13]([SH:24])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([CH:13]([SH:24])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCC(S)C(Cc2ccc(N)nc2)C(=O)O)cc1
Agent: Cl
Product: Nc1ccc(CC(C(=O)O)C(S)CCc2ccc(O)cc2)cn1

Procedure:
2-[(6-Aminopyridin-3-yl)methyl]-5-(4-hydroxyphenyl)-3-mercaptopentanoic acid was synthesized from 2-[(6-aminopyridin-3-yl)methyl]-3-mercapto-5-(4-methoxyphenyl)pentanoic acid using standard conditions for the methoxy group hydrolysis (concentrated aqueous hydrochloric acid at reflux under argon for 24 h).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[C:5]2=[O:18].S(Cl)(Cl)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:24]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6](/[CH:13]=[CH:14]/[C:15]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)=[O:17])[C:5]2=[O:18]
Reactant: NCCCCc1cccnc1
Reactant: Cc1cc2ncn(/C=C/C(=O)O)c(=O)c2cc1C
Solvent: O=S(Cl)Cl
Product: Cc1cc2ncn(/C=C/C(=O)NCCCCc3cccnc3)c(=O)c2cc1C

Procedure:
The acid chloride is prepared from (E)-3-(6,7-dimethyl-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid and thionyl chloride as previously described. When this acid chloride is allowed to react with 3-pyridine butanamine under the usual conditions, (E)-3-(6,7-dimethyl-4-oxo-4H-quinazolin-3-yl)-N-[4-(3-pyridinyl)butyl]-2-propenamide is obtained.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)CC(C)C.[Na+].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27][CH2:28][CH2:29][CH:30]=[O:31]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:31][CH:30]([CH2:29][CH2:28][S:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:20])[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccccc1SCCC=O
Agent: CC(C)CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(O)CCSc1ccccc1C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
9.86 Grams of methyl acetoacetate were dissolved in 15 ml of water, and 12.67 g of a 30% aqueous sodium hydroxide solution was added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 1.07 g of sodium isovalerate and 2.42 g of tetrabutylammonium bromide were added thereto. Then a concentrated aqueous hydrochloric acid solution was added to the mixture so that the mixture had a pH of 6.8. Further, 26.2 g of a toluene solution containing 32.7% of 3-(2-methylphenylthio)propanal was added thereto and stirred at 45°-50° C. for 9 hours. The organic layer separated from the mixture was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Thereafter the layer was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 10.32 g of crude 4-hydroxy-6-(2-methylphenylthio)-2-hexanone (purity: 67.8%, yield: 62.1%). A purified product was obtained by column chromatography. The purified product had an nD21 of 1.5660.