Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([F:4])[F:3]>C(O)C.O=[Pt]=O>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: O=[N+]([O-])c1ccc(SC(F)(F)F)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc(SC(F)(F)F)cc1
Reaction time: 0.25 h

Procedure:
To p-nitrophenyl trifluoromethyl sulfide (3.0 g) in absolute ethanol (30 ml) is added Adams catalyst (Pt2O, 0.026 g). The mixture is hydrogenated in a Parr vessel at 50 lbs/sq. in. for about 15 min. The reaction is worked up by filtering through Celite and evaporating to yield p-aminophenyl trifluoromethyl sulfide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([CH3:23])([C@H:6]1[CH2:11][CH2:10][C@H:9](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:7]1)[CH3:5].[CH3:25][NH:26][CH3:27]>>[CH3:1][O:2][C:3](=[O:24])[C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:26]([CH3:27])[CH3:25])[CH2:8][CH2:7]1)([CH3:23])[CH3:5]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](OS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: CNC
Product: COC(=O)C(C)(C)[C@H]1CC[C@@H](N(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of 0.354 g of trans-2-methyl-2-[4-(toluene-4-sulfonyloxy)-cyclohexyl]-propionic acid methyl ester in 10 ml of 60% aqueous dimethylamine solution is heated to 110° C. for 48 hours. The reactions mixture is cooled to room temperature and extracted with dichloromethane (3×). The combined extracts are dried over sodium sulphate and concentrated. Flash chromatography (SiO2 60F) of the residue provides the title compound which is identified on the basis of its Rf-value.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[C:20]([CH3:36])=[C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1(C)C=CC=CC=1.Cl.O1CCOCC1.C1(C)C=CC=CC=1>O1CCOCC1.CCOC(C)=O.[Pd]>[CH2:28]([O:27][C:26]([NH:25][C:21]1[C:20]([CH3:36])=[C:19]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N:1][CH:2]=2)[CH:24]=[CH:23][CH:22]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(N3CCOCC3)ccc12
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a homogeneous solution of benzyl 3-(2-amino-1-(6-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (1.4934 g, 3.08 mmol) in dioxane (154 ml) were added 50% ethyl 2-oxoacetate/toluene (1.222 ml, 6.16 mmol) and 4N HCl/dioxane (1.541 ml, 6.16 mmol) under nitrogen. The reaction was stirred overnight. More 50% ethyl 2-oxoacetate/toluene (1.222 ml, 6.16 mmol) was added, and the reaction was stirred overnight. The reaction was concentrated in vacuo, dissolved in EtOAc (100 mL) and washed with water (25 mL) and brine (25 mL) successively, dried over MgSO4, and concentrated in vacuo to give a crude product, which was used in the subsequent step. To this crude were added 10% Pd/C (0.819 g, 0.770 mmol) and toluene (77 ml), and the mixture was refluxed overnight. The reaction was cooled to room temperature, diluted with EtOAc (200 mL), and filtered through a pad of CELITE®. The filtrate was washed with water (75 mL) and brine (75 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 120 g column eluting with 15-70% EtOAc/CH2Cl2 to give the desired product (0.354 g, 0.627 mmol, 20.4% yield) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]S(C3C=CC(C)=CC=3)(=O)=O)[C:13]=2[NH2:29])(=[O:10])=[O:9])=[CH:4][CH:3]=1>N([O-])=O.[Na+].O.Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=2[N:29]2[C:17]([CH3:16])=[CH:12][C:13]([CH3:14])=[N:29]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(OS(=O)(=O)c3ccc(C)cc3)c2N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2cccc(O)c2-n2nc(C)cc2C)cc1
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
To 278 mg of 2-amino-1,3-phenylene bis(4-methylbenzene sulfonate) was added 0.64 ml of 5N-hydrochloric acid, and to the mixture a solution in which 58 mg of sodium nitrite was dissolved in 0.4 ml of water was added dropwise at 0° C., and stirred for 30 minutes. Then, a solution in which 289 mg of stannous chloride was dissolved in 0.32 ml of 5N-hydrochloric acid was added dropwise at 0° C. and stirred for 1 hour. The solvent was distilled off under reduced pressure, and 1.3 ml of ethanol and 66 μl of acetyl acetone were added and heated at reflux for 2 hours. To the reaction mixture was added 50 ml of water, and neutralized with a saturated sodium bicarbonate solution and extracted with 50 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1) to yield 62.9 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1(/[CH:17]=[CH:18]/[C:19]2[O:20][C:21]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=3[N:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][C:21]3[O:20][C:19](/[CH:18]=[CH:17]/[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:28][C:22]=3[CH2:23][CH2:24]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C(=C/c1nc2c(o1)CCNCC2)\c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCc2nc(/C=C/c3ccccc3)oc2CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
4-Fluorobenzoyl chloride (0.016 mL, 0.14 mmol) was added dropwise to a stirred solution of 5,6,7,8-tetrahydro-2-[(E)-2-phenylethenyl]-4H-oxazolo[4,5-d]azepine (95 mg, 0.13 mmol) and TEA (0.026 mL, 0.19 mmol) in DCM (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes and then diluted with a saturated solution of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was triturated with DIPE to yield 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-2-[(E)-2-phenylethenyl]-4H-oxazolo[4,5-d]azepine (37 mg, 80% yield) as a white solid. C22H19FN2O2.
Reaction SMILES: Br.[Br:2][C:3]1[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:5][S:6][CH:7]=1.[Na].C(Cl)(Cl)Cl.[CH3:18][N:19]=[C:20]=[S:21]>C(O)C>[CH3:18][NH:19][C:20]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:4]1[C:3]([Br:2])=[CH:7][S:6][N:5]=1)=[S:21]
Reactant: CN=C=S
Reactant: NCCSCc1nscc1Br
Agent: Br
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CNC(=S)NCCSCc1nscc1Br
Yield: 108.8 %

Procedure:
The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g.) with cysteamine (from cysteamine hydrochloride (3.76 g) was performed under conditions similar to those described in Example 57, From the reaction there was obtained 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide, which, following recrystallisation from ethanol-ether and acetonitrile, gave needles (4.05 g.) m.p. 111°-112°. The amine base (2.73 g.) was isolated by basification with sodium bydroxide and extraction with chloroform and then dissolved in ethanol and treated with methyl isothiocyanate (0.78 g.) The solution was heated under reflux for 30 minutes, concentrated and the residue triturated with ether to yield the crystalline thiourea (2.9g.) m.p. 60°-61°. Recrystallisation from isopropyl acetate gave N-methylN'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]thiourea (2.3 g.) as needles, m.p. 62°-63°.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:4].[NH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[CH2:16]([N:12]1[C:13]2[C:8](=[C:7]([C:24]#[N:25])[N:6]=[C:5]([C:3]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2c1ccc(=O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.060 mmol), β-alanine (532 mg, 6.0 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The organic layer was dried over MgSO4 and concentrated. The residue was taken up in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 12 mg of the title compound as a pale pink solid. MS: (−) m/z 391.35 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([C:18](=[O:22])[C:19]([OH:21])=[O:20])=[C:9]1[CH2:23]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)=[CH:14][CH:15]=2)[C:10]2[C:18](=[O:22])[C:19](=[O:20])[O:21][CH2:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(O)C(=O)c1c(CO)n(Cc2ccccc2)c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: O
Product: O=C1OCc2c(c3cc(-c4ccc(Cl)cc4)ccc3n2Cc2ccccc2)C1=O
Temperature: 70 °C

Procedure:
A mixture of [1-benzyl-5-bromo-2-(hydroxymethyl)-1H-indol-3-yl](oxo)acetic acid, potassium salt (3.15 g, 7.4 mmol), 4-chlorophenylboronic acid (1.74 g, 2.6 mmol), potassium carbonate (2.55 g, 13.7 mmol), palladium(II) acetate (0.032 g) and tetrabutylammonium bromide (2.4 g, 7.4 mmol) in 15% dioxane in water (45 mL) was stirred at 70° C. The reaction was monitored by TLC. After no [1-benzyl-5-bromo-2-(hydroxymethyl)-1H-indol-3-yl](oxo)acetic acid, was detected by TLC, the reaction was cooled down and solvent was decanted. The dark gum-like oil was partitioned between ethyl acetate and 10% aqueous HCl. The upper organic layer was separated, washed with water, and filtered. This filtrate was evaporated to give a solid. This solid was triturated with ethyl ether with stirring and dried in vacuum at 60° C. for 8 hours to afford the title compound as an off-white solid (0.77 g), m.p. 263-264° C. Mass spectrum (ESI, [M+H]+) m/z 402. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.71-7.67 (m, 3H), 7.63 (dd, 1H, J=8.66 and 1.83 Hz),), 7.49 (dd, 2H, J=8.54 and 1.95 Hz), 7.34-7.25 (m, 3H), 7.22 (d, 2H, J=7.46 Hz), 5.88 (s, 2H), and 5.52 ppm (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:5]([N+:15]([O-])=O)=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.Cl.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[C:5]([NH2:15])=[C:4]([CH2:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH:3]=1
Reactant: CN1CCN(c2cc(Cl)cc(CS(=O)(=O)c3ccc(F)cc3)c2[N+](=O)[O-])CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(c2cc(Cl)cc(CS(=O)(=O)c3ccc(F)cc3)c2N)CC1
Temperature: 60 °C

Procedure:
A solution of 1-{5-chloro-2-nitro-3-{[(4-fluorophenyl)sulfonyl]methyl}phenyl}-4-methylpiperazine (1.0 mmol) in methanol is treated with Sn foil (593.3 mg), followed by 5.8 mL of 12 M HCl, heated at 60° C. for 4 h (until reaction is complete by thin layer chromatography), cooled to 0° C., treated with solid NaOH to pH>10 and extracted with CH2Cl2. The extracts are combined, washed with water and concentrated to dryness in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.[CH2:15]([N:17]=[C:18]=[S:19])[CH3:16]>CCOCC>[CH2:15]([NH:17][C:18]([N:12]1[CH2:13][CH2:14][N:9]([C:7]2[CH:6]=[N:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:10][CH2:11]1)=[S:19])[CH3:16]
Reactant: CCN=C=S
Reactant: COc1cncc(N2CCNCC2)n1
Solvent: CCOCC
Product: CCNC(=S)N1CCN(c2cncc(OC)n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 1.94 g. of 1-(6-methoxypyrazinyl)piperazine in 25 ml. of anhydrous ether is added dropwise a solution of 0.87 g. of ethylisothiocyanate in 25 ml. of anhydrous ether. The mixture is stirred 30 minutes and the solid collected and recrystallized from 80% ethanol, giving 2.27 g. of the desired product as white crystals, m.p. 120°-122° C.
Reaction SMILES: [CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:23])[CH2:4]2)[O:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O.[Cr]>[CH2:25]1[CH2:1][O:2][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:23])[CH2:4]2)[O:24]1
Reactant: C[C@H]1CC2(C[C@@H]3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Cr]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CC2(C[C@@H]3CC[C@@H]4[C@H](CC[C@]5(C)C(=O)CC[C@@H]45)[C@]31C)OCCO2
Yield: 100.6 %

Procedure:
35 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17β-ol is stirred in 350 ml of dimethylformamide with 70 g of pyridinium dichromate for 17 hours at room temperature. The reaction solution is stirred into ten times the amount of ethyl acetate, then the thus-separated chromium salts are left behind by decanting, and the organic phase is washed with water. After drying and evaporation, 35 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one is produced, mp 154° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccnc(F)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ccnc(F)c2)nc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-(2′-fluoro-2,4′-bipyridin-5-yl)acetate 208-2 (93 mg, 0.36 mmol) and NaOH (57 mg, 1.43 mmol) in THF (0.5 mL) and water (0.5 mL) was stirred at 65° C. for 3 hours. After cooled down to room temperature, the mixture was treated with 3N HCl aqueous solution to adjust the pH around 3, and then stirred for 15 minutes. The resulting solution was evaporated to dryness and the remaining solid was extracted with 20% methanol in ethyl acetate. The organic portion was concentrated to give 2-(2′-fluoro-2,4′-bipyridin-5-yl)acetic acid 208-3 as pale white solid. MS m/z 233.1 (M+1).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([N:17]([CH2:54][CH:55](OC)OC)[C:18](=[O:53])[CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][N:32]2[CH2:52][CH2:51][C:35]3([O:40][CH2:39][CH2:38][N:37]([C:41]([C:43]4[N:44]=[C:45]([CH:48]([CH3:50])[CH3:49])[S:46][CH:47]=4)=[O:42])[CH2:36]3)[CH2:34][CH2:33]2)[CH:25]=1)[CH2:14][CH2:15][CH3:16].Cl.[NH2:61][CH2:62][CH2:63][C:64]1[C:69]2[O:70][CH2:71][C:72](=[O:74])[NH:73][C:68]=2[C:67]([OH:75])=[CH:66][CH:65]=1.C(=O)(O)[O-].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN1C(=O)CCC1.O>[CH2:13]([N:17]([CH2:54][CH2:55][NH:61][CH2:62][CH2:63][C:64]1[C:69]2[O:70][CH2:71][C:72](=[O:74])[NH:73][C:68]=2[C:67]([OH:75])=[CH:66][CH:65]=1)[C:18](=[O:53])[CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][N:32]2[CH2:52][CH2:51][C:35]3([O:40][CH2:39][CH2:38][N:37]([C:41]([C:43]4[N:44]=[C:45]([CH:48]([CH3:49])[CH3:50])[S:46][CH:47]=4)=[O:42])[CH2:36]3)[CH2:34][CH2:33]2)[CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: NCCc1ccc(O)c2c1OCC(=O)N2
Reactant: CCCCN(CC(OC)OC)C(=O)CCOCCc1cccc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCN(CCNCCc1ccc(O)c2c1OCC(=O)N2)C(=O)CCOCCc1cccc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-Toluenesulphonic acid monohydrate (4 molar equivalents) was added to a solution of N-butyl-N-(2,2-dimethoxyethyl)-3-(3-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanamide (limiting reagent) in THF (10 volumes) and the resulting mixture stirred for 1 hour at room temperature. The solution was then added via a peristaltic pump to a suspension of 8-(2-aminoethyl)-5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one hydrochloride (1 molar equivalent) and sodium bicarbonate (6.5 molar equivalents) in a mixture of NMP (4 volumes) and water (0.45 volumes) which had been stirring at room temp for 1 hour. The resulting cloudy solution was stirred for 30 mins before sodium triacetoxyborohydride (3 molar equivalents) was added portionwise and the resulting mixture was stirred for 1 hour.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH2:10][OH:11])[CH2:8][O:9][C:4]=2[CH:3]=1.CN(C=O)C.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:11][CH2:10][CH:7]1[O:6][C:5]2[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=2[O:9][CH2:8]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: OCC1COc2cc(Br)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(c1)OCC(COCc1ccccc1)O2
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
A mixture of (6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)methanol (3.94 g, 16.1 mmol) and DMF (35 mL) at rt is treated with a 60% dispersion of NaH in mineral oil (0.706 g, 17.7 mmol). After 15 min, the mixture is treated with benzyl bromide (2.10 mL, 17.7 mmol). After 2 h, the mixture is poured into H2O and extracted with EtOAc (2×125 mL). The combined organics are washed with H2O (3×100 mL), brine, dried (MgSO4), filtered, and concentrated. The resulting oil is adsorbed onto SiO2 and chromatographed (Biotage 40M+SIM, 5% EtOAc/Hexane). The product fractions are pooled and concentrated to give an oil which solidified (upon standing) to give 3.91 g (73%) of 2-[(benzyloxy)methyl]-6-bromo-2,3-dihydro-1,4-benzodioxine: 1H NMR (400 MHz, CDCl3) δ 7.30-7.45, 7.06, 6.99, 6.81, 4.60-4.70, 4.30-4.40, 4.05-4.15, 3.65-3.85; MS (EI) m/z 244 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C@@H:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C@H:20]2[CH3:32])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.Cl>CO>[ClH:1].[Cl:1][C:2]1[C:3]([O:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[CH3:32])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Oc1cc(=O)n(-c2ccc(C#N)c(F)c2)cc1Cl
Agent: Cl
Solvent: CO
Product: CC1CNCCC1Oc1cc(=O)n(-c2ccc(C#N)c(F)c2)cc1Cl
Reaction time: 0.5 h
Yield: 229.6 %

Procedure:
To a solution of trans-tert-butyl 4-(5-chloro-1-(4-cyano-3-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)-3-methylpiperidine-1-carboxylate (200 mg, 0.433 mmol) in MeOH (1.0 mL) at room temperature was added hydrochloric acid (2.5 mL, 10.00 mmol, 4.0 M in dioxane). The reaction mixture was stirred for 30 min and then evaporated under reduced pressure. The residue was co-evaporated with ethanol (2×) to give 198 mg of the title compound as an orange solid. This material was used in the next step without further purification. MS (ESI) 362 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14]([OH:16])=[O:15])([CH3:10])([CH3:9])[CH3:8].[CH2:25]([N:27]([CH2:29][CH3:30])O)[CH3:26]>C(N(CC)CC)C>[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14]([O:16][N:27]([CH2:29][CH3:30])[CH2:25][CH3:26])=[O:15])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCN(O)CC
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)OC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 43.2 %

Procedure:
Following the procedure of Example II, the compound is prepared from 3.17 g of oxalyl chloride, 6.25 g of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 2.53 g of N,N-diethylhydroxylamine, and 2.53 g of triethylamine. The residue is recrystallized from petroleum ether to give 3.47 g of a white solid: mp 129°-137° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([NH:21][CH2:22][C:23]3[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=3[CH3:29])=[O:20])=[C:11]2[CH3:32])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:33][N:34](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:33]([C:2]1[CH:3]=[C:4]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([NH:21][CH2:22][C:23]3[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=3[CH3:29])=[O:20])=[C:11]2[CH3:32])[CH3:9])[CH:5]=[CH:6][CH:7]=1)#[N:34]
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3cccc(Br)c3)c3ccccc23)c(=O)[nH]1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3cccc(C#N)c3)c3ccccc23)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
1-(1-(3-bromophenyl)ethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (Compound 171; 100 mg, 0.2 mmol), Zn(CN)2 (36 mg, 0.3 mmol), Pd(PPh3)4 (47 mg, 0.04 mmol) were combined in 2 ml DMF, then stirred at 100° C. for 30 min under N2 in m.w. After the complete of the reaction, purified by pre-HPLC (A: CH3CN, B:water+0.1% HCl. A:B=32:62 ASB C18 150*25 mm) to afford the title compound (35 mg, yield: 40%), 1H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J=8 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.54 (m, 3H), 7.13 (m, 1H), 7.03 (d, J=4 Hz, 2H), 6.45 (s, 1H), 6.04 (m, 1H), 4.61 (s, 2H), 2.66 (s, 3H), 2.52 (s, 3H), 2.36 (s, 1H), 2.02 (d, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1cnoc1-c1ccc(F)cc1
Product: O=C(c1cnoc1-c1ccc(F)cc1)N1CCCC1

Procedure:
The title compound was prepared from 5-(4-fluorophenyl)isoxazole-4-carboxylic acid (10.4 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (9.6 mg). MS (pos) m/z 261.1 (M+H).