Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][CH2:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[N:5]=[CH:4][N:3]=1.N>C(OC(OCC)OCC)(=O)C.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][CH2:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOP(=O)(CCCONc1ncnc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Agent: N
Solvent: CO
Product: CCOP(=O)(CCCOn1cnc2c(Cl)ncnc21)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
A solution of 4-chloro-6-[[3-(diethoxyphosphoryl)-propoxy]amino]-5-formamidopyrimidine (0.86 g, 2.3 mmol) in diethoxymethyl acetate (5 ml) was heated at 120° C. for 2 hours. After cooling to ambient temperature, excess solvent was removed under reduced pressure to leave an oil. The oil was dissolved in methanol (20 ml) and 880 ammonia (0.5 ml) was added. After 20 minutes at ambient temperature, the solvent was evaporated to leave an oil. Purification by column chromatography on silica gel (dichloromethane:methanol, 96:4 as eluant) gave the title compound as a yellow oil (0.7 g, 85%). IR: υmax 3065, 3000, 1595, 1560, 1330, 1240, 1215, 1160, 1050, 1025, 960 and 930 cm-1. 1H NMR: δH [(CD3)2SO] 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.6-2.1 (4H, m, OCH2CH2CH2P), 4.00 (4H, m, (OCH2CH3)2), 4.50 (2H, t, J=6Hz, OCH2), 8.8 (1H, s), 9.05 (1H, s).
Reaction SMILES: Br[C:2]1[C:3]([C:31]#[N:32])=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([CH3:16])([CH3:15])[C:10]3[CH:17]=[C:18]([O:21][CH2:22][C@H:23]4[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]4)[CH:19]=[CH:20][C:9]=3[C:8](=[O:30])[C:7]2=1.[Cl-].[Li+].[CH3:35][Sn](C)(C)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.Cl>CN(C=O)C>[CH3:29][C:25]1([CH3:28])[O:24][C@@H:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[C:2]([CH3:35])[C:3]([C:31]#[N:32])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:15])[C:10]=3[CH:17]=2)[CH2:27][O:26]1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4c(Br)c(C#N)ccc4c2C3=O)O1
Reactant: C[Sn](C)(C)C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1c(C#N)ccc2c3c([nH]c12)C(C)(C)c1cc(OC[C@H]2COC(C)(C)O2)ccc1C3=O
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Under nitrogen atmosphere, 4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound U8-1, 30.0 mg, 60.56 μmol) and lithium chloride (7.70 mg, 181.7 μmol) were dissolved in DMF (1.00 mL), added with tetramethyl tin (12.5 μL, 90.84 μmol), tetrakistriphenylphosphine palladium (3.50 mg, 6.056 μmol) and tricyclohexylphosphine (toluene solution, 20 wt %, 17.0 mg, 3.028 μmol), and the mixture was stirred at 100° C. for 24 hr. The reaction solution was poured into hydrochloric acid (1 M), extracted with ethyl acetate, washed with water, saturated aqueous solution of sodium bicarbonate and saturated brine, dried over sodium sulfate, and then filtered. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain 8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-4,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile as a crude product (20.9 mg, 80%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Fc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3c(F)cccc32)nc(N2CCOCC2)cc1=O
Yield: 27.4 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 274 mg of 4-fluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 102 mg of 2-[2-(4-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale pink powder, the characteristics of which are the following:
Reaction SMILES: C([O:8][C:9]([CH:11]([CH2:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH2:12][P:13]([CH3:23])(=[O:22])[O:14]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>O.[Pd]>[CH3:23][P:13]([CH2:12][CH:11]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:9]([OH:10])=[O:8])([OH:22])=[O:14]
Reactant: CP(=O)(CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: CP(=O)(O)CC(CCC(=O)O)C(=O)O

Procedure:
2,4-di(benzyloxycarbonyl)buty(methyl)-O-benzylphosphinic acid (0.8 g, 1.6 mmol) in 20 mL of water containing 100 mg of 10% Pd/C was hydrogenated at 40 psi for 4 hours. The mixture was filtered over a pad of Celite and evaporated at high vacuum to give 2-[(methylhydroxyphosphinyl),methyl]pentanedioic acid (4, R=CH3, 0.28 g, 78% as a clear and colorless viscous oil.
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH:9]([CH3:12])[CH2:10][CH3:11])=[N:7][C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][N:4]=1)[NH2:2].[CH3:19][CH:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:19][CH:20]([C:26]1[N:4]2[CH:5]=[C:6]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:7]=[C:8]([CH:9]([CH3:12])[CH2:10][CH3:11])[C:3]2=[N:1][N:2]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCC(C)c1nc(-c2cccnc2)cnc1NN
Reactant: CCOC(=O)C(C)C(=O)OCC
Product: CCOC(=O)C(C)c1nnc2c(C(C)CC)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to that described in Example 1, by condensing 2-hydrazino-3-[(RS)-1-methylpropyl]-5-(3-pyridyl)pyrazine with diethyl methylmalonate there is obtained ethyl rac-α-methyl-8-[(RS)-1-methylpropyl]-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 353 (M)+, which by saponification analogously to Example 1 is converted into the above acid which is used directly in the next step.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:13].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O>[CH3:11][Si:2]([CH3:1])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:13])=[O:9]
Reactant: C[Si](C)(C)C#CCCCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#CCCCC(=O)O
Reaction time: 24 h

Procedure:
To a solution of 10 gm of 6-trimethylsilylhex-5-ynol in 400 ml of dry dimethylformamide, was added 98 gm of pyridinium dichromate. The solution was stirred in the dark for 24 hours and then partitioned between ether and water. The ether extract was dried over magnesium sulphate and evaporated to an oil. Distillation gave the title compound, b.p. 121°-124° C. (1 mm Hg), IR: 3290, 2162, 1720 cm-1.
Reaction SMILES: O[CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1.C(Cl)Cl.COCCN(CCOC)S(F)(F)[F:19].C(O)C>>[F:19][CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1
Reactant: C=C1CC(C#N)(CO)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: C=C1CC(C#N)(CF)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(hydroxymethyl)-3-methylenecyclobutanecarbonitrile (0.252 g, 0.00205 mol) in methylene chloride (20 mL, 0.3 mol) in a plastic bottle was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (1. 13 mL, 0.00614 mol) followed by ethanol (20 μL, 0.0004 mol). The reaction was stirred at rt overnight, then quenched with aq. sodium bicarbonate, and extracted with dichloromethane. The extracts were combined and washed with water, brine, and dried over magnesium sulfate, and evaporated to dryness. The residue was used directly in next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5](I)=[CH:4][N:3]=1.[C-:35]#[N:36].[Na+].O>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5]([C:35]#[N:36])=[CH:4][N:3]=1
Reactant: C[C@H](Nc1nc(N)ncc1I)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Reactant: [C-]#N
Agent: I[Cu]I
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To a solution of (S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (65) (240 mg, 0.43 mmol) in anhydrous acetonitrile (12 mL) in a sealed tube, sodium cyanide (209 mg, 4.26 mmol), tetrakis(triphenylphosphine) palladium(0) (246 mg, 0.21 mmol), and copper iodide (57 mg, 0.30 mmol) were added and the resulting mixture was stirred at 80° C. for 16 h. The mixture was allowed to cool to RT, quenced with water and extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-2-amino-4-((1-(8-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile (69) (60 mg, 30% yield). ESI-MS m/z: 463.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:11][C:12]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[Cl:19])[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.[CH3:28][C:29]1(C)C(C)(C)OB(C=C)O1>COCCOC.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:1]([O:5][C:6](=[O:20])[N:7]([CH2:11][C:12]1[CH:17]=[C:16]([CH:28]=[CH2:29])[CH:15]=[CH:14][C:13]=1[Cl:19])[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)ccc1Cl)C1CC1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a sol. of (5-bromo-2-chloro-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (105 g, 0.292 mol) in DME (800 mL) under N2 at rt was added Pd(PPh3)4 (16.9 g, 14.6 mmol). The mixture was stirred at rt for 30 min, and K2CO3 (40.7 g, 292 mmol), water (350 mL) and 4,4,5,5-tetramethyl-2-vinyl-[1,3,2]dioxaborolane (52.0 mL, 292 mmol) were added. The mixture was heated to reflux for 3 h. The mixture was allowed to cool to rt, and water (500 mL) was added. The mixture was extracted with Et2O (4×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 9:1) yielded the title compound (70.9 g, 79%). LC-MS: tR=1.10 min; ES+: 293.38.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:56]([NH:60][C:61]([C:63]1([CH:69]2[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]2)[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>ClCCl.CN(C)C=O>[C:56]([NH:60][C:61]([C:63]1([CH:69]2[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]2)[CH2:64][CH2:65][N:66]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:67][CH2:68]1)=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Reactant: CC(C)(C)NC(=O)C1(C2CCCCC2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)N2CCC(C(=O)NC(C)(C)C)(C3CCCCC3)CC2)cc1
Reaction time: 3 h
Yield: 11.1 %

Procedure:
To 150 mg (0.45 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxy-phenyl)propanoic acid dissolved in 3 ml of dichloromethane and 0.5 ml of dimethylformamide are added 0.16 ml (0.90 mmol) of diisopropylethylamine, 161 mg (0.50 mmol) of TBTU and 133 mg (0.50 mmol) of 4-tert-butylcarbamoyl-4-cyclohexylpiperidine. After 3 hours, the solution is washed with 1N sodium hydroxide solution and the organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product obtained is purified by preparative TLC (eluent: dichloromethane/methanol 85/15). 29 mg of 4-tert-butylcarbamoyl 4-cyclohexyl-1-[2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]-piperidine in the form of a white powder are obtained in a yield of 11%.
Reaction SMILES: C[C:2]1([C:14]([O:16]C)=O)[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:33]COCC>C1COCC1>[CH3:33][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH2:14][OH:16])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: CCOCC
Reactant: COC(=O)C1(C)C=CC(c2ccccc2)=CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methyl-(1,1'-biphenyl)-4-carboxylic acid, methyl ester (1.43 g) in ether (25 ml) and THF (25 ml) was added over 5 min to LiAlH4 (420 mg) in ether (25 ml). The mixture was stirred at room temperature for 1 h and then cooled in ice. Aqueous NaOH (1 M, 2.1 ml) was added and after stirring (15 min) excess anhydrous Na2SO4 was added. The mixture was filtered and the filtrate evaporated to give a solid. Crystallisation from cyclohexane-methanol gave the title compound (1.04 g) m.p. 128°-31°.
Reaction SMILES: [C:1]1([C:7]2([C:19]#[N:20])[CH2:12][CH2:11][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:34]([O-])([O-:36])=[O:35].[K+].O>C(#N)C>[N+:34]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2([C:19]#[N:20])[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:11][CH2:12]2)=[CH:6][CH:5]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])[O-]
Reactant: N#CC1(c2ccccc2)CCN(C(=O)C(F)(F)F)CC1
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCN(C(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
4-Phenyl-1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonitrile was dissolved in Acetonitrile (12.0 mL), Trifluoroacetic anhydride (4.00 mL, 28.3 mmol) was added and the mixture was cooled in an ice bath. Potassium nitrate (1.58 g, 15.6 mmol) was then added and the reaction was stirred at 0° C. for 2 h, then water (100 mL) was added at 0° C. The mixture was extracted with EtOAc (2×50 mL), the organics were washed with 1:1 brine:satd. NaHCO3 (2×50 mL), dried over sodium sulfate and then filtered through 8 mL silica gel, washing with 100 mL EtOAc. The filtrate was conc. in vacuo. 1H-NMR indicated a mixture of nitration products and starting material. Resubjection to the nitration conditions (12 mL MeCN, 4 mL TFAA, 1.59 g KNO3, rt, overnight). Work up as before, conc. in vacuo to afford an oil, 1H-NMR showing -2.6:1 ratio of nitration products. The crude oil was dried in vacuo and then dissolved in DCM, loaded onto a 25 g ISCO cartridge and purified (120 g column, 0%, then 5-30% EtOAc:Hex) to afford partial separation of the nitro products, the major eluting first. Clean fractions were conc. in vacuo to afford 4-(4-Nitro-phenyl)-1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonitrile (1.29 g; Yield=31.4%) as a white solid. 1H-NMR (DMSO-d6): 8.31 (d, 2H, J=8.8 Hz), 7.91 (d, 2H, J=8.8 Hz), 4.52 (m, 1H), 4.07 (m, 1H), 3.55 (m, 1H), 3.17 (m, 1H), 2.27 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=4[Cl:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(Cl)ccc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,5-dichloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=630.5)=60%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[CH:9][CH:8]=[C:7]2[O:14][CH3:15].CC(=CC)C.[O-:21]Cl=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([OH:21])=[O:13])=[CH:9][CH:8]=[C:7]2[O:14][CH3:15]
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(C=O)c2c(Cl)cccc12
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
To a mixture of 8-chloro-4-methoxy-1-naphthaldehyde (step-3 intermediate) (2.0 g, 9.06 mmol) in tBuOH (20 mL) and 2-methyl-2-butene (14.4 mL, 136.0 mmol) at 0° C. was added a solution of NaClO2 (4.1 g, 45.3 mmol) and NaH2PO4.H2O (6.3 g, 45.3 mmol) in H2O (16 mL) dropwise. The resulting solution was stirred at RT for 24 h. The solvent was evaporated and the crude mixture was basified with 10% NaOH solution and then washed with EtOAc. The aqueous layer was acidified with 1 N HCl and again extracted with EtOAc. The combined organic layer was washed with water, brine, dried (Na2SO4) and filtered. The solvent was evaporated to provide the desired acid as pale yellow solid (1.7 g, 80%).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41]C(=O)OC(C)(C)C)[CH2:36]1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH2:41])[CH2:36]1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccccc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccccc2c1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
To a solution of tert-butyl {(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)quinolin-4-yl]piperidin-3-yl}carbamate (115.8 mg, 0.17 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (20.5 mg, 25%). LCMS calc. for C24H23F2N6OS (M+H)+: m/z=481.2. found 481.2.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1)[C:5](=[O:7])[CH3:6].O1[CH2:23][CH2:22][CH2:21][CH2:20]1.C([Li])CCC.Cl>CCCCCC>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:4](=[CH:3][CH2:20][CH2:21][CH2:22][CH3:23])[C:5](=[O:7])[CH3:6])[CH:9]=1
Reactant: CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCCC=C(C(C)=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture was prepared of 5.14 g. (0.02 mole) of 4-(dimethylamino)-3-(α,α,α-trifluoro-m-tolyl)-3-buten-2-one and 75 ml. of dry tetrahydrofuran and there was added dropwise thereto an equivalent amount of n-butyllithium in hexane while maintaining the temperature of the reaction mixture at about -20° C. After the addition was complete the mixture was stirred for about 1 hour at a temperature of about -20° to -30° C. The reaction mixture was then allowed to warm to room temperature and 25 ml. of 1 N HCl was added and the mixture was concentrated in vacuo. The residual dark oil was taken up in 100 ml. of ether and washed with 2×50 ml. of water and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated in vacuo to give a dark oil. This oil was chromatographed over silica gel using ether as a solvent and eluent and the product was finally purified by molecular distillation. The product was identified by elemental analyses as 3-(α,α,α-trifluoro-m-tolyl)-3-octen-2-one. It weighed 4.5 g. (83% yield).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:9]2[CH2:8][C@@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)=[CH:19][CH:20]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(OC(F)(F)F)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccc(OC(F)(F)F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
(2R,4S)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethoxy)benzyl)-piperidine-1-carboxylate (0.690 g, 1.72 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 13.58 mL, 77.56 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(4-(trifluoromethoxy)benzyl)-piperidin-4-yl)isoxazol-3(2H)-one (55 mg, 9.4%). 1H NMR (600 MHz, dmso) δ 1.07 (q, 1H), 1.34 (dq, 1H), 1.69-1.78 (m, 2H), 2.45-2.74 (m, 5H), 2.93-2.99 (m, 1H), 5.64 (s, 1H), 7.20-7.25 (m, 2H), 7.26-7.32 (m, 2H). HRMS Calculated for [C16H17F3N2O3+H]+: 343.1270. Found: 343.1241