Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH:10]=[CH:11][CH2:12][C@@H:13]([CH2:18][C@H:19]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[O:20][CH3:21])[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1.[H][H]>[Pd].CCO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:19]([O:20][CH3:21])[CH2:18][C@H:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:14]([O:16][CH3:17])=[O:15])=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@H](CC=CCOCc1ccccc1)C[C@@H](OC)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H](CCCCO)C[C@@H](OC)c1ccc(F)cc1

Procedure:
(S)-methyl 6-(benzyloxy)-2-((R)-2-(4-fluorophenyl)-2-methoxyethyl)hex-4-enoate (494 mg, 1.2 mmol) was dissolved into 5 mL EtOH and to it added 10% Pd/C (450 mg). The solution was saturated with H2 (stream of H2 bubbled through solution) and then stirred for 3 h at room temperature under one atmosphere of hydrogen (balloon). The mixture was filtered through a bed of Celite and rinsed with ethyl acetate. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18]C(=O)C)[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:18][CH:16]1[C:15](=[O:22])[NH:14][C:13](=[O:23])[CH:12]([N:5]2[C:4](=[O:24])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[C:6]2=[O:11])[CH2:17]1
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc(C)c3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1cccc2c1C(=O)N(C1CC(O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-(4-methyl-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1 g, 3.5 mmol) and p-toluenesulfonic acid (0.33 g, 1.8 mmol) in methanol (10 mL) is heated at reflux for 5 hours. The solvent is removed in vacuo to give 2-(5-hydroxy-2,6-dioxopiperid-3-yl)-4-methylisoindoline-1,3-dione. The product can be further purified by column chromatography.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][C:5]([CH2:15][CH3:16])([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH2:6][CH3:7].[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:6]([C:5]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)([CH2:15][CH3:16])[C:4]#[C:3][CH2:2][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH3:7]
Reactant: CCC(C#CCBr)(CC)OC1CCCCO1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC#CC(CC)(CC)OC1CCCCO1)OCC
Temperature: 130 °C

Procedure:
A mixture of Compound 403 (2.0 g) and triethyl phosphite (4.2 ml) was heated to 130° C. for 1.5 h. Excess triethyl phosphite was removed in vacuo (oil pump) for 2 h to give the title compound (2.2 g). 1H NMR: 0.96 (m, 6H), 1.35 (t, 6H), 1.45-1.95 (m, 10H), 2.81 (d, J=21.7 Hz, 2H), 3.50 (m, 1H), 3.93 (m, 1H), 4.18 (m, 4H), 5.05 (m, 1H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C@H:15]([N:22]([C:24](=[O:35])[CH2:25][C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][CH:27]=2)[CH3:23])[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)(C)(C)C.Cl>ClCCl>[O:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([CH2:25][C:24]([N:22]([CH3:23])[C@@H:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:36])=[O:5])[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:35])=[CH:27]1
Reactant: CN(C(=O)Cc1coc2ccccc12)[C@H](CN1CCCC1)c1cccc(OCC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Product: CN(C(=O)Cc1coc2ccccc12)[C@H](CN1CCCC1)c1cccc(OCC(=O)O)c1
Reaction time: 24 h

Procedure:
To a solution of Example 18 (1.272 g, 2.58 mmol) in dichloromethane (10 mL) was added HCl (2.5 mL of 4 M solution in dioxan). After stirring for 24 hours, all volatiles were removed in vacuo and the resulting solid washed with acetonitrile. After removing the solvent, the resulting solid was dried to give a beige solid, 0.50 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[P:7](C1C=CC=CN=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Li]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[PH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: c1ccc(P(c2ccccn2)c2ccccn2)nc1
Agent: [Li]
Solvent: C1CCOC1
Product: c1ccc(Pc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The tris(pyridin-2-yl)phosphine (22.4 g, 85 mmol) was suspended in THF (400 ml). To this were added lithium granules (5.0 g, 720 mmol). The mixture was then stirred at room temperature for four hours. This gave an intense red solution. The solution was then filtered into a clean Schlenk flask to remove any un-reacted lithium metal. The solvent was then removed under vacuum and water (100 ml, degassed with nitrogen gas for 20 minutes) added. Ether (400 ml) was then added and the biphasic solution stirred for 20 minutes. The upper (organic) phase was then cannula transferred into a clean Schlenk flask and then dried under vacuum. This gave dark orange/red oil. Yield=15.1 g, 94% 31P{1H}NMR (121 MHz, CDCl3) ä; −33.8 (s, PPy2).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCc2ccccc2)ccc1C=O
Reaction time: 4 h
Yield: 62.8 %

Procedure:
4-Hydroxy-2-methoxybenzaldehyde (2.0 g, 13.15 mmol), benzyl bromide (3.14 mL, 26.3 mmol) and potassium carbonate (3.63 g, 26.3 mmol) are combined in acetone (5 mL) and the mixture is stirred for 4 hours. The mixture is concentrated under vacuum, suspended in dichloromethane and washed with water. The organic phase is concentrated under vacuum and the residue purified by flash chromatography (10% ethyl acetate in cyclohexane) to give the title compound (yield 2.0 g).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1(C)C(C)=CC=CC=1>[C:15]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Product: CC(=O)N1c2ccccc2Sc2ccccc21
Yield: 93.7 %

Procedure:
The 10-acetylphenothiazine of formula (5) was synthesized by the following method. A 200-ml four-neck flask was loaded with 19.93 g (0.1 mole) of phenothiazine, 15.31 g (0.15 mole) of acetic anhydride, and 40 g of xylene, and the contents were subjected to heating under reflux conditions for 6 hours. The reaction liquid was cooled, the precipitate was separated by filtering, and the product washed with methanol. As a result, 22.6 g of 10-acetylphenothiazine having a molecular weight of 241.3 were obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]([C:11]1[S:12][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][N:15]=1)[NH2:10].O>CO>[C:16]([C:13]1[S:12][C:11]([NH:9][N:10]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:15][N:14]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)c1nnc(NN)s1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nnc(NN=Cc2ccccc2)s1
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A solution of benzaldehyde (5.3 g) in methanol (25 ml) was added to a solution of 2-hydrazino-5-t-butyl-1,3,4-thiadiazole (8.5 g) in methanol (40 ml). The mixture was stirred for 30 minutes, poured into water (100 ml) and filtered. The solid was crystallised from ethanol to give benzaldehyde 5-t-butyl-1,3,4-thiadiazolyl hydrazone (8.2 g, 63%) as a white powder, mp 195°-196° C.
Reaction SMILES: [C:1]([C@H:3]1[O:8][CH2:7][C@H:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)#[CH:2].[F:25][C:26]1[C:27](I)=[C:28]([NH2:32])[CH:29]=[N:30][CH:31]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:32][C:28]1[CH:29]=[N:30][CH:31]=[C:26]([F:25])[C:27]=1[C:2]#[C:1][C@H:3]1[O:8][CH2:7][C@@H:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1
Reactant: Nc1cncc(F)c1I
Reactant: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)CO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](C#Cc2c(N)cncc2F)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Yield: 166.9 %

Procedure:
tert-Butyl (2R,5R)-2-ethynyl-5-(tert-butyldimethylsilyloxy-methyl)morpholine-4-carboxylate (2.75 g, 7.73 mmol), 5-fluoro-4-iodopyridin-3-amine (1.84 g, 7.73 mmol), bis(triphenylphosphine)palladium(II) chloride (0.380 g, 0.541 mmol), triethylamine (32.3 mL, 232 mmol), and copper(I) iodide (0.147 g, 0.773 mmol) were heated at 70° C. for 2 hours. The reaction was quenched with saturated aqueous KH2PO4 and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification on silica gel (330 g) eluting with a gradient of 0-100% EtOAc/hexanes afforded the title compound (2.20 g, 12.9 mmol, 42% yield) as a viscous oil, MS (ESI): m/z=466.45 (MH+); 68% pure by LCMS, remainder is un-reacted 5-fluoro-4-iodopyridin-3-amine, taken onto next reaction as mixture.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:31][CH2:32][CH3:33]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:31][CH2:32][CH3:33])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
A solution of methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)acetate (2.5 g; 9.03 mmol) in dry DMF (45 mL) was cooled to −15° C. LHMDS (10.84 mL; 10.84 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (1.765 mL; 18.07 mmol). After stirring for 2 h at −15° C. the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 0.98 g (25%) of the title compound as a yellow oil. ESI/APCI(+): 319 (M+H).
Reaction SMILES: [CH:1]1[C:9]2[N:8]3[C:10]([C:13]45[CH2:20][CH2:19][C:16]([NH:21]C(=O)OCC6C=CC=CC=6)([CH2:17][CH2:18]4)[CH2:15][CH2:14]5)=[CH:11][N:12]=[C:7]3[CH:6]=[N:5][C:4]=2[NH:3][CH:2]=1.[BrH:32]>CCOC(C)=O>[BrH:32].[CH:1]1[C:9]2[N:8]3[C:10]([C:13]45[CH2:20][CH2:19][C:16]([NH2:21])([CH2:17][CH2:18]4)[CH2:15][CH2:14]5)=[CH:11][N:12]=[C:7]3[CH:6]=[N:5][C:4]=2[NH:3][CH:2]=1
Reactant: O=C(NC12CCC(c3cnc4cnc5[nH]ccc5n34)(CC1)CC2)OCc1ccccc1
Agent: Br
Solvent: CCOC(C)=O
Product: NC12CCC(c3cnc4cnc5[nH]ccc5n34)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Benzyl 4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-ylcarbamate (0.22 g, 0.529 mmol, prepared using Z from Preparation #N.1 and NaOH, R with diazomethane, S from Example #3, Step E, T with Lawesson's reagent and D with NaOH) was dissolved in HBr (33% in AcOH, 10 mL) and the mixture was stirred for about 10 min at ambient temperature. The reaction was then diluted with EtOAc (30 mL) and the precipitate was collected by filtration, extensively washed with MeCN and dried to yield 4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-amine hydrobromide (0.16 g, 83%) as a yellow solid: LC/MS (Table 1, Method a) Rt=1.67 min; MS m/z 282 (M+H)+.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:26])([CH3:25])[O:11]/[C:12](=[C:14]3/[C:15](=[O:24])[NH:16][C:17]4[C:22]/3=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)/[CH:13]=2)=[O:7])=[CH:4][N:3]=1.[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C=O)C.C(OCC)(=O)C>[F:23][C:19]1[CH:18]=[C:17]2[C:22](/[C:14](=[C:12]3/[CH:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:27]=[CH:28][C:2]([N:35]5[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][OH:29])[CH2:33][CH2:34]5)=[N:3][CH:4]=4)[C:10]([CH3:26])([CH3:25])[O:11]/3)/[C:15](=[O:24])[NH:16]2)=[CH:21][CH:20]=1
Reactant: OCCN1CCNCC1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1NC(=O)c1ccc(F)nc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1NC(=O)c1ccc(N2CCN(CCO)CC2)nc1
Temperature: 66 °C

Procedure:
To a stirred solution of 6-fluoro-N-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]nicotinamide (75 mg, 0.20 mmol) in DMF (3 mL) was added 1-(2-hydroxyethyl)piperazine (70 mg, 0.54 mmol). The reaction mixture was heated in 66° C. bath for 30 minutes, cooled to room temperature, and diluted with ethyl acetate (80 mL). The ethyl acetate solution was washed with brine (4×20 mL), dried over Na2SO4, and concentrated to give the crude product. Purification of the crude product by silica gel chromatography with a gradient of methanol in chloroform (5-20%) gave N-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-6-[4-(2-hydroxyethyl)piperazin-1-yl]nicotinamide as a yellow solid. Yield: 42 mg, 43%.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH3:24][C@@H:25]([OH:29])[CH2:26][CH2:27][CH3:28]>>[CH3:24][C@@H:25]([O:29][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCC[C@@H](C)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCC[C@@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C

Procedure:
Sodium t-butoxide (27.3 g, 284 mmol) was added portionwise to (R)-2-pentanol (140 ml) at room temperature, the mixture was stirred until homogeneous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (18.0 g, 71.0 mmol) was added and the reaction mixture heated at 50° C. for 160 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was washed with saturated sodium chloride solution (100 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with ether and the solid material filtered. The precipitate was re-washed with ether and the filtrates combined and evaporated. The crude material (ca. 10 g) was dissolved in DMSO:methanol (1:1) and purified on a reverse phase (C18) column (330 g) using a gradient of 25-65% acetonitrile (+0.1% TFA)-water (+0.1% TFA) over 8 column volumes, the fractions were immediately neutralised with saturated aqueous sodium carbonate solution. Appropriate fractions were combined and partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic phase was dried (MgSO4), filtered and evaporated to give the title compound as a pale cream foam (5.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]([C:27]([F:30])([F:29])[F:28])[C:22](OCC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:31][CH3:32])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH:21]([C:27]([F:28])([F:29])[F:30])[CH2:22][OH:23])=[CH:19][CH:20]=3)[CH:11]=[C:10]([CH2:31][CH3:32])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1ccc(Nc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1)C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CCc1cc(Nc2ccc(C(CO)C(F)(F)F)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
A solution of ethyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-3,3,3-trifluoropropanoate (0.070 g, 0.15 mmol) in dichloromethane (3 mL) at 0° C. was slowly treated with DIBAL (0.064 g, 0.45 mmol) dropwise and the resulting mixture was stirred for 2 h and then warmed to rt for 2 h. After this time, the reaction was quenched with methanol, 2M HCl, and water and then extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.035 g, 51%) as a white solid. MW=421.84. 1H NMR (DMSO-d6, 300 MHz) δ 9.71 (s, 1H), 8.38-8.27 (m, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.61-7.52 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 6.63 (s, 1H), 5.10 (t, J=5.4 Hz, 1H), 4.02-3.91 (m, 1H), 3.90-3.80 (m, 1H), 3.77-3.61 (m, 1H), 2.69 (q, J=7.6 Hz, 2H), 1.27 (t, J=7.6 Hz, 3H); APCI MS m/z 422 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:15][S:16]([CH2:19][CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)(=[O:18])=[O:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C=CS(C)(=O)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(CCS(C)(=O)=O)c2)OC1(C)C
Temperature: 90 °C
Yield: 63.4 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.3 g, 27.31 mmol), methylvinyl sulfone (4.349 g, 40.97 mmol) and DBU (2.042 mL, 13.66 mmol) were suspended in dry acetonitrile (54.63 mL) in a sealed glass bomb and heated in a sand bath at 90° C. overnight. The resulting reaction mixture was concentrated to a solid and the solids were washed with hexanes to yield 5.2 g (63.4%) of the title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]1[CH2:29][CH2:28][CH2:27][C@H:17]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])=[O:15])[CH3:13])=O)C1C=CC=CC=1.CCOCC.[BrH:35]>C(O)(=O)C>[BrH:35].[NH2:11][C@H:12]([C:14]([N:16]1[CH2:29][CH2:28][CH2:27][C@H:17]1[C:18]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
10 g (0.025 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline anilide were dissolved in 50 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. 300 ml of dry ether were then added. An oil precipitated out and was allowed to settle. The solution was decanted off and the oil was washed with two 150 ml portions of ether, dissolved in the minimum volume of methanol and treated with an excess of ethyl acetate. The product soon crystallised, there being obtained 7.2 g (83%) of L-alanyl-L-proline anilide hydrobromide of melting point 211°-214° C.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([CH3:16])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].O>C1C=CC=CC=1>[CH3:16][C:7]1[C:6]([N:5]=[S:1]=[O:2])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1cccc(N=S=O)c1C
Yield: 90 %

Procedure:
To a solution of thionyl chloride (6.63 mL, 91.0 mmol) in benzene (60 mL) was added a solution of methyl 3-amino-2-methylbenzoate (13.1 g, 91.0 mmol) in benzene (31 mL) at room temperature, and the mixture was heated under reflux for 18 hr. Water was added, and the mixture was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (17.3 g, yield 90%).
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.[CH4:13]>C1C=CC=CC=1.[Rh]>[CH:5]([C:6]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH2:13])=[O:4]
Reactant: CC(=O)OCC=CCOC(C)=O
Reactant: C
Agent: [Rh]
Solvent: c1ccccc1
Product: C=C(C=O)CCOC(C)=O
Reaction time: 6 h
Yield: 54 %

Procedure:
The procedure of Example 7 was repeated using 1,4-diacetoxy-2-butene (170 g.) and 5% by weight rhodium on 95% by weight charcoal (1.12 g.) in benzene (340 g.). The reaction took 6 hours to go to completion. Work-up in the manner of Example 7 gave a 54% yield of 2-formyl-4-acetoxybutene.
Reaction SMILES: C[C:2]1([C:12]([O-:14])=[O:13])[CH2:7][CH:6]=[CH:5][C:4](C)([C:8]([O-:10])=O)[NH:3]1.[CH3:15]O.[BH4-].[Na+]>ClCCl>[OH:10][CH2:8][C:4]1[N:3]=[C:2]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:6][CH:5]=1
Reactant: CO
Reactant: CC1(C(=O)[O-])C=CCC(C)(C(=O)[O-])N1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2,6-dimethylpyridine-2,6-dicarboxylate (950 mg, 4.87 mmol, 1.00 equiv) in a solvent mixture of methanol (33.2 mL) and dichloromethane (14.2 mL). NaBH4 (185 mg, 5.02 mmol, 1.00 equiv) was added to the reaction mixture in several batches at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 50 mL of NH4Cl (aq.). The resulting solution was extracted with 2×50 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1-2:1) as eluent to yield 750 mg (92%) of methyl 6-(hydroxymethyl)pyridine-2-carboxylate as a white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:6]=1)(=O)=O.[C-:25]#[N:26].[Na+]>CS(C)=O.C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][NH:11][C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:6]=[C:5]([C:25]#[N:26])[N:10]=1
Reactant: CS(=O)(=O)c1nc(NCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1nc(NCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.4 %

Procedure:
To a stirring solution of 2-[2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl-amino]-ethanol (493 mg) in dimethyl sulfoxide (15 ml) was added sodium cyanide (100 mg). The resulting solution was stirred at room temperature for 72 hrs. After diluting with ethyl acetate (100 ml) and washed with water (100 ml), brine (100 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a pale yellow solid (380 mg).