Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18](Cl)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35]>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([F:31])[CH:33]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(F)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)ccn23)c1
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Nc3cccc(F)c3)c3c(-c4ccccc4)ccn23)c1
Yield: 38.7 %

Procedure:
A mixture of N-(tert-butyl)-5-(1-chloro-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.050 g, 0.11 mmol) and 3-fluoroaniline (0.151 g, 1.36 mmol) was heated in a s sealed tube at 100° C. for 12 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition B-6 described in general methods) to obtain N-(tert-butyl)-5-(1-((3-fluorophenyl)amino)-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.022 g, 38%) as a pale yellow solid. LCMS Method B-7: retention time 2.14 min, [M+1]=517.0, Purity 94.7%. LCMS Method B-8: retention time 1.74 min, [M+1]=517.0, Purity 95.4%. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.19 (s, 9H), 6.82 (td, J=2.0 Hz, J=8.4 Hz, 1H), 6.95 (dd, J=1.6 Hz, J=8.0 Hz, 1H), 7.12 (d, J=2.8 Hz, 1H), 7.27-7.31 (m, 1H), 7.50-7.64 (m, 6H), 7.70 (dt, J=2.4 Hz, J=12.0 Hz, 1H), 7.75 (d, J=2.8 Hz, 1H), 7.96 (s, 1H), 8.71 (t, J=2.0 Hz, 1H), 9.20 (d, J=2.0 Hz, 1H), 9.31 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:7]([CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:6]([CH3:28])=[CH:5]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:7]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:6]([CH3:28])=[CH:5]2
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(Cl)c(F)cc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1c(C)cc2cc(Cl)c(F)cc2c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (4.89 g, 10.99 mmol) in anhydrous dichloromethane (100 mL) at 0° C. was added Dess-Martin periodinane (5.59 g, 13.18 mmol) portion-wise over 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour and quenched with sodium thiosulfate solution and saturated sodium bicarbonate solution and stirred for 30 minutes. The mixture was diluted with ethyl ether and washed with saturated sodium bicarbonate solution (3×), brine and dried (MgSO4), filtered, concentrated to give a yellow oil with a white precipitate. The mixture was suspended in diethyl ether, washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give an off-white solid (4.60 g). 1H NMR (400 MHz, CDCl3) δ: 7.93 (d, J=7.0 Hz, 1H), 7.78 (d, J=9.6 Hz, 1H), 7.67 (s, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:11]1C=CC=C2[C:12]=1[CH2:13][CH2:14]C2=O)(O)=[O:9].Cl.CNC>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:8](=[O:9])[CH2:11][CH2:12][C:13]#[CH:14])=[CH:3][CH:4]=1
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: Nc1ccncc1
Agent: CNC
Agent: Cl
Product: C#CCCC(=O)Nc1ccncc1

Procedure:
The desired product was prepared by substituting 4-pentynoic acid and 4-aminopyridine for 4-carboxy-1-indanone and dimethylamine hydrochloride, respectively, in Example 40. MS (APCI(+)) m/e 175.1 (M+H)+.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][CH2:6][C:7]1[O:11][C:10]([C:12]2[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[S:19])[S:15][CH:16]=2)=[CH:9][CH:8]=1.Cl>O.CN(C)C=O>[NH:17]([C:14]1[S:15][CH:16]=[C:12]([C:10]2[O:11][C:7]([CH2:6][NH:5][C:2]([NH2:3])=[O:1])=[CH:8][CH:9]=2)[N:13]=1)[C:18]([NH2:20])=[S:19]
Reactant: N#C[O-]
Reactant: NCc1ccc(-c2csc(NC(N)=S)n2)o1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)NCc1ccc(-c2csc(NC(N)=S)n2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A solution of potassium cyanate (9.6 g) in water (50 ml) was added to a mixture of 4-(5-aminomethylfuran-2-yl)-2-thioureidothiazole (10.0 g) in N,N-dimethylformamide (80 ml) and 1N-hydrochloric acid (78.6 ml), and the mixture was stirred for 16 hours at ambient temperature. To the reaction mixture was added a water (100 ml) and isolated precipitate was collected by filtration to give 2-thioureido-4-(5-ureidomethylfuran-2-yl)thiazole (10.74 g).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>CN(C)C=O.O>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:16][C:15]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=2[F:7])=[CH:27][CH:26]=1
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: O=Cc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(F)c1
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
Potassium tert-butoxide (198 mg, 1.76 mmol) was added, at 0° C., to a solution of 3-Fluoro-4-hydroxy-benzaldehyde (235 mg, 1.68 mmol) in dry N,N-dimethylformamide (2 mL). The mixture was stirred for 10 minutes. 4-(3-Bromo-propoxy)-biphenyl (example 23, Step D) (539 mg, 1.84 mmol) was added and the reaction was stirred for 24 hours at room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (4×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under vacuum to produce a solid which was washed with hexanes to produce 4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-benzaldehyde as a pale brown solid (490 mg, 83%). 1H-NMR (CDCl3, 200.15 MHz): δ 9.83 (d, 1H, J=2.2), 7.64–7.23 (m, 9H), 7.09 (t, 1H, J=8.2), 6.96 (d, 2H, J=8.8), 4.32 (t, 2H, J=5.9), 4.21 (t, 2H, J=5.9), 2.35 (qn, 2H, J=5.9).
Reaction SMILES: [N:1]1[N:5]2[C:6](=O)[CH:7]=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O.C(N(C(C)C)CC)(C)C>>[Cl:13][C:6]1[N:5]2[N:1]=[CH:2][CH:3]=[C:4]2[N:9]=[CH:8][CH:7]=1
Reactant: O=c1cc[nH]c2ccnn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccnc2ccnn12
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
Pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.50 g, 3.70 mmols), phosphorus oxychloride (0.88 ml, 9.62 mmols) and diisopropylethylamine (DIEA, 0.13 ml, 0.74 mmols) were mixed and stirred at 90° C. overnight. It was poured onto water/ice, extracted with dichloromethane and washed with brine. It was dried, filtered and concentrated in vacuum. It was purified by chromatography (Silica gel, Hexane/Ethyl acetate 9:1) to afford the expected compound (83 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[N:6][C:5]([N+:11]([O-])=O)=[C:4]([NH2:14])[N:3]=1.[H][H]>[Pd].O>[NH2:1][C:2]1[C:7]([NH2:8])=[N:6][C:5]([NH2:11])=[C:4]([NH2:14])[N:3]=1
Reactant: Nc1nc(N)c([N+](=O)[O-])nc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: Nc1nc(N)c(N)nc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,6-Diamino 3,5-dinitro pyrazine (15.0 g, 75 mmol), 5% palladium on carbon (2.0 g) and deoxygenated water (200 mL) was added to a parr shaker and charged with 50 psi of hydrogen and allowed to shake at room temperature for 24 hours. The reaction mixture was added to deoxygenated boiling water (750 mL) and filtered hot. The filtrate was allowed to cool to room temperature and the resulting solid was recrystallized from concentrated HCl (16.1 g, 80.1%). Crystal exists as a trihydrogen chloride mono hydrate system.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:12]1([CH2:18][CH2:19][OH:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCOCC>C(Cl)Cl>[CH:12]1([CH2:18][CH:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OCCC1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCC1CCCCC1
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A suspension of 100 g (0.46 moles) of pyridinium chlorochromate and 100 g of celite in 800 ml of methylene chloride was stirred vigorously while 38 g (0.3 moles) of 2-cyclohexylethanol in 200 ml of methylene chloride was added all at once. The reaction turned dark immediately and became mildly exothermic. After 1 hour, 1000 ml of ether was added and the reaction mixture was filtered through a bed of silica gel (ca. 250 g) on a fritted glass disk. The pad was rinsed with an additional liter of ether. The combined filtrates were reduced in volume to approximately 200 ml and the solution was washed with 2×40 ml of 6N HCl, 1×50 ml of saturated sodium bicarbonate, and 1×50 ml of saturated NaCl solution. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a light green oil. The residue was distilled in vacuo to afford 21 g (56%) of a colorless oil (bp 74°-76° C. at 23 mm of Hg).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:13]=[CH:12][C:11]2=[O:24])=[CH:5][CH:4]=1)#[CH:2]>CO.[Pd]>[CH2:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH:13]=[CH:12][C:11]2=[O:24])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Cn2cc(-c3ccc(OC)cc3)ccc2=O)cn1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cn2cc(-c3ccc(OC)cc3)ccc2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
According to Scheme 33 Step 3: To a suspension of Pd/C 10% (0.05 eq) in MeOH (10 mL) under N2 atmosphere, a solution of 1-((6-ethynylpyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.15 mmol, 48 mg) was added at room temperature. The flask was evacuated and filled with hydrogen until the pressure reached 20 psi. The resulting suspension was shaken at room temperature for 1 hour. The catalyst was filtered off and the filtrate was evaporated under vacuum to give a residue. The residue was purified in a circular chromatography-TLC CH2Cl2/MeOH(NH3)sat. 2% yielding 1-((6-ethylpyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (30 mg, 61%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=[CH2:19])[CH:13](O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1C=CC(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=[CH2:19])[CH:13]([N:66]=[N+:67]=[N-:68])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C=CCC1CCN(C(=O)OCc2ccccc2)CC1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCC1CCN(C(=O)OCc2ccccc2)CC1N=[N+]=[N-]
Reaction time: 4 h

Procedure:
To a stirred solution of 4-Allyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (293 mg, 1.06 mmol) were added triphenyl phosphine(362 mg, 1.38 mmol), a solution of diethyl azodicarboxylate in toluene (0.6 ml, 1.38 immol; 40% solution) and DPPA (297 μL, 1.38 mmol). After stirring for 4 h, the mixture was evaporated and the residue was purified by column chromatography (15% AcOEt-hexane)to give 4-Allyl-3-azido-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [C:1]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[S:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.Cl>CCCCCC.O1CCCC1>[C:1]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[S:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[C:13]([B:32]([OH:35])[OH:33])[C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COB(OC)OC
Reactant: c1ccc2c(c1)sc1cccc(-c3cccc4sc5ccccc5c34)c12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc2c1sc1cccc(-c3cccc4sc5ccccc5c34)c12
Temperature: -80 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Into a 500-mL three-neck flask was put 5.0 g (13 mmol) of 4,4′-bidibenzothiophene, and the air in the flask was replaced with nitrogen. Into this flask was put 100 mL of tetrahydrofuran (THF), and this solution was cooled down to −80° C. To this solution, 8.7 mL (14 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped with a syringe. After the dripping, this solution was stirred for 2 hours while its temperature was returned to room temperature. After the stirring, this solution was cooled down to −80° C. To this solution, 1.9 mL (17 mmol) of trimethyl borate was added, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. After the stirring, approximately 50 mL of dilute hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. After the stirring, the aqueous layer of this mixture was extracted with ethyl acetate, and the extracted solution and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was dried with magnesium sulfate, and then this mixture was gravity-filtered. The resulting filtrate was concentrated to give a white solid. This solid was washed with 100 mL of hot toluene to give 2.6 g of white powder, which was an objective substance, in 50% yield. Synthesis Scheme (a-2) of Step 2 is shown below.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22]([C:24]3[NH:25][C:26]([CH2:30][CH3:31])=[C:27]([Cl:29])[N:28]=3)=[O:23])[C@H:17]([O:32][CH3:33])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].[OH-].[Li+]>CO.C1COCC1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22]([C:24]3[NH:25][C:26]([CH2:30][CH3:31])=[C:27]([Cl:29])[N:28]=3)=[O:23])[C@H:17]([O:32][CH3:33])[CH2:16]2)=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(NC(C)=O)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(NC(C)=O)c(C(=O)O)c3)C[C@H]2OC)nc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Methyl cis(±)-2-(acetylamino)-5-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (185e) (120 mg) was dissolved in methanol (4 ml) and THF (4 ml). A 2 N aqueous lithium hydroxide solution (2 ml) was added, and the mixture was stirred at 70° C. for one hour. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid and extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/methanol/hexane solvent to obtain 90 mg of the title compound as crystals.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)([C:11]3[N:7]([CH3:6])[N:8]=[N:9][CH:10]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.25 mL, 3.12 mmol) was added dropwise by syringe to a solution of 1-methyl-1H-1,2,3-triazole (268 mg, 3.22 mmol) in dry THF (32 mL) in a dry ice-methanol bath. The suspension was stirred for 30 minutes, slowly allowing the reaction mixture to warm to −10° C. (4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (0.500 g, 1.05 mmol, Intermediate 45: step f) in dry THF (5 mL) was added to the mixture via syringe and the resulting mixture was allowed to warm to ambient temperature overnight. The reaction was quenched with water. Brine was added and the aqueous mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-8% MeOH-DCM) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=1.7 Hz, 1H), 8.24 (d, J=1.9 Hz, 1H), 8.22 (s, 1H), 7.79-7.76 (m, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.7, 2.0 Hz, 1H), 6.97 (s, 1H), 5.95 (s, 1H), 4.30 (s, 2H), 4.08 (s, 3H), 3.88 (s, 3H), 3.33 (s, 3H), 2.12 (s, 3H); MS m/e 557.8 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]=[CH:6][C:7]1[C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:2].[H][H]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CCc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 78.4 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-acrylic acid ethyl ester (0.102 g, 0.21 mmol) in ethanol (20 mL) was added platinum oxide (0.010 g). The reaction mixture was shaken under positive pressure of hydrogen gas (20 psi) for 20 minutes. The resulting mixture was filtered through a pad of celite, the filter cake was washed with ethanol, and the combined filtrate was concentrated in vacuo to give the title compound (0.081 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26](O)[C:27]#[CH:28]>>[CH3:18][C:13]1([CH3:17])[S:14][CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:28][C:27]#[CH:26])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C@H:12]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: C#CCO
Product: C#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Yield: 95 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 0.30 g (0.775 mmoL) of tert-butyl(3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.054 mL (0.93 mmol) of propargyl alcohol gave 0.313 g of tert-butyl(3S)-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxylate as a white solid. Electrospray Mass Spec 426.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:22][PH:23]([O-])([O-:27])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@:10]([NH:9][C@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:23]([CH3:22])(=[O:27])[O:24][CH2:25][CH3:26])=[CH:3][CH:4]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccccc1)c1ccc(Br)cc1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@H](N[S@](=O)C(C)(C)C)c2ccccc2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To (R)—N—((R)-(4-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 23-a, (16 g, 43.83 mmol), ethyl methylphosphite (9.47 g, 87.67 mmol) and Et3N (13.3 g, 132 mmol) in THF (200 ml) was added PdCl2(dppf) (1.6 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1 l/1) to provide the crude product, 23-b, (9.5 g, 55%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([SH:8])=[N:5][N:4]=1.[H-].[Na+].Cl[C:12]1[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:7][C:6]([S:8][C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=2)=[N:5][N:4]=1
Reactant: N#Cc1nccnc1Cl
Reactant: CSc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CSc1nnc(Sc2nccnc2C#N)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(methylthio)-1,3,4-thiadiazole-2-thiol (821 mg, 5.0 mmol) in DMF and benzene (10 ml, 1/1) was added NaH (60% dispersion in mineral oil, 220 mg, 5.5 mmol) slowly at 0° C. under nitrogen atmosphere. The resulting suspension was stirred at 0° C. for 15 minutes and then to the mixture was added 3-chloropyrazine-2-carbonitrile (698 mg, 5.0 mmol). The reaction was stirred at 80° C. for 4 hr. The reaction was then cooled to room temperature and quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].C(N(CC)CC)C.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>C(Cl)(Cl)Cl>[CH:21]([NH:24][C:25]([O:1][CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13])=[O:26])([CH3:23])[CH3:22]
Reactant: O=C1C(O)SCN1c1ccccc1
Reactant: CC(C)N=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)OC1SCN(c2ccccc2)C1=O
Reaction time: 4 h

Procedure:
A stirred solution of 5-hydroxy-3-phenyl-4-thiazolidinone (prepared as in Preparative Example 17 above) (0.24 g) and triethylamine (0.01 ml) in chloroform (5 ml) was treated with iso-propyl isocyanate (0.116 g). The mixture was stirred for 4 hours, then evaporated under reduced pressure. Recrystallisation of the solid residue from diethyl ether/hexane afforded the title compound as colourless needles, yield 0.14 g, mp 130°-132° C.