Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:31]3[CH2:34][N:33]([C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)[CH2:32]3)=[O:30])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.[CH:41]1([CH:44]=O)[CH2:43][CH2:42]1.C(O)(=O)C.C([BH3-])#N>CO>[CH:41]1([CH2:44][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([CH:31]4[CH2:34][N:33]([C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)[CH2:32]4)=[O:30])=[CH:26][CH:27]=3)[CH2:17][CH2:16]2)[CH2:43][CH2:42]1
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)C1CN(c2cccnc2)C1
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1ccc(OC2CCN(CC3CC3)CC2)cc1)C1CN(c2cccnc2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
In a 20 mL vial was added N-(4-(piperidin-4-yloxy)phenyl)-1-(pyridin-3-yl)azetidine-3-carboxamide bis(2,2,2-trifluoroacetate) (67 mg, 0.12 mmol) dissolved in methanol (2.0 mL) followed by the addition of cyclopropanecarbaldehyde (10 mg, 0.14 mmol) dissolved in methanol (0.45 mL), followed by the addition of neat acetic acid (66 μL, 1.2 mmol). The mixture was shaken for 1 hour at 70° C. After that, 265 mg of MP-cyanoborohydride resin (2-3 mmol/g) was added and the resulting mixture was shaken at 70° C. overnight. The reaction mixture was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 DMSO/CH3OH and purified by reverse phase HPLC. 1H NMR (500 MHz, pyridine-d5/D2O) δ ppm 8.20-8.25 (m, 1 H) 8.13 (d, J=2.75 Hz, 1 H) 7.98-8.03 (m, 2 H) 7.11 (dd, J=8.24, 4.58 Hz, 1 H) 7.02-7.07 (m, 2 H) 6.72-6.78 (m, 1 H) 4.58 (d, J=2.75 Hz, 1H) 4.34 (t, J=6.71 Hz, 2 H) 4.05 (t, J=7.63 Hz, 2 H) 3.80-3.92 (m, 1 H) 3.34 (s, 4 H) 2.92 (d, J=7.32 Hz, 2 H) 2.32-2.44 (m, 2 H) 2.12 (s, 2 H) 1.09-1.22 (m, 1 H) 0.51-0.58 (m, 2 H) 0.28-0.34 (m, 2 H); MS (ESI(+)) m/e 407 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C([N:25]([CH2:28][CH3:29])CC)C.Cl.N[C@H:32]1CC[O:34][CH2:33]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:25][CH:28]3[CH2:29][CH2:32][CH2:33][O:34]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: CCN(CC)CC
Reactant: N[C@H]1CCOC1
Agent: Cl
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NC3CCCO3)n2)cc1
Yield: 59 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and (s)-3-aminotetrahydrofuran hydrochloride salt (14 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (27 mg, 59% yield.) MS/ES+: m/z=401.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:5]1[C:6]2[C:11](=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[NH:3][CH:4]=1
Reactant: Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(-c2ccc3c(Br)c[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
A mixture solution of bromine (25 μL, 0.48 mmol) in DMF (1 mL) was added to a mixture solution of 4-(1H-indol-6-yl)phenol (100 mg, 0.48 mmol) in DMF (1 mL) at room temperature. After stirring for 1.5 hours at room temperature, followed by addition of icy water and addition of sodium thiosulfate, the mixture was stirred for 1 hour. Thus produced solid was filtered, washed with water and dried at room temperature. The target compound (136 mg) was obtained as white solid.
Reaction SMILES: N.[C:2]([NH:6][S:7]([C:10]1[CH:19]=[C:18]([C:20](=[O:22])[NH2:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=O)(=[O:9])=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH3:23][NH:24][CH3:25]>CO>[CH3:23][N:24]([CH3:25])[C:12](=[O:14])[C:11]1[CH:16]=[CH:17][C:18]([C:20](=[O:22])[NH2:21])=[CH:19][C:10]=1[S:7](=[O:8])(=[O:9])[NH:6][C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CNC
Reactant: COC(=O)c1ccc(C(N)=O)cc1S(=O)(=O)NC(C)(C)C
Agent: N
Solvent: CO
Product: CN(C)C(=O)c1ccc(C(N)=O)cc1S(=O)(=O)NC(C)(C)C
Reaction time: 7 h

Procedure:
Similarly to Examples A5 to A6, and using ammonia as basic reagent in Example A5, methyl 2-tert-butylsulfamoyl-4-carbamoylbenzoate was prepared first. At room temperature, 3.0 g (0.01 mol) of this compound were subsequently added to a solution of 45 g (1.0 mol) of dimethylamine in 60 ml of methanol, and the reaction mixture was left standing at room temperature for 7 h. The mixture was concentrated and the desired product was isolated by silica gel column chromatography (mobile phase: ethyl acetate; Rf≈0.2). This gave 1.0 g (31% of theory) of N,N-dimethyl-2-tert-butylsulfamoyl-4-carbamoylbenzamide of a glass-like consistency.
Reaction SMILES: C[Li].CN(C)P(N(C)C)(N(C)C)=O.[CH3:14][C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[C:16]=1[CH:22]=[CH:23][C:24]#[C:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1.Cl[Si](C)(C)[CH3:39]>CSC.[Cu]Br.C1COCC1>[CH3:14][C:15]1([CH3:39])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]1/[CH:22]=[CH:23]/[C:24]#[C:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc(C#CC=CC2=C(C)CCCC2=O)cc1
Agent: [Cu]Br
Agent: [Li]C
Solvent: CSC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#C/C=C/C2C(=O)CCCC2(C)C)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A 1.3M solution of methyllithium (2.2 mL, 2.85 mmol) was added to a stirring suspension of copper (I) bromide-dimethyl sulfide (293 mg, 1.43 mmol) and 6 mL of THF at -78° C. The solution was warmed to -40° C. over 30 minutes and then recooled to -78° C. Freshly distilled hexamethylphosphoramide (0.37 mL, 2.14 mmol) was added, and the solution was stirred at -78° C. for 30 min. A solution of ethyl 4-(4-(3-methyl-2-cyclohexen-1-on-2-yl)but-3-ene-1-yn-1-yl)benzoate (Compound 5, 220 mg, 0.713 mmol), chlorotrimethylsilane (0.271 mL, 2.14 mmol) and 1.5 mL of THF was added. The solution was stirred at -78° C. for 1 hour, and warmed slowly to -30 ° C. The reaction was then quenched by the addition of saturated aqueous NH4Cl and ethyl acetate. The layers were separated and the aqueous layer extracted 3× with ethyl acetate. The combined organic layers were washed with 10% aqueous HCl until all of the enol ether was hydrolyzed. The layers were separated and the organic layer was washed with water, and brine, and dried (MgSO4). The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (10:1, hexane:ethyl acetate) to give the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2cccnc2)nc2ccc(F)cc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)nc2ccc(F)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (140 mg, 0.51 mmol), 2,5-dimorpholinoaniline (135 mg, 0.51 mmol) and a 4.0M solution of HCl in dioxane (0.13 mL, 0.51 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-6-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.88 (1H, d, J=2.3 Hz), 8.72 (1H, dd, J=5.1, 2.0 Hz), 8.16 (1H, dd, J=9.0, 5.5 Hz), 7.99 (1H, dt, J=7.8, 2.2 Hz), 7.43-7.57 (3H, m), 7.16-7.20 (1H, m), 7.13 (1H, d, J=8.6 Hz), 6.46 (1H, dd, J=8.6, 2.7 Hz), 5.97 (1H, d, J=2.7 Hz), 3.87-3.99 (4H, m), 3.67-3.80 (4H, m), 3.01-3.13 (4H, m), 2.83-2.98 (4H, m), 2.33 (3H, s). Mass Spectrum (ESI) m/e=500.0 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([S:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([C:35]#[N:36])=[CH:27][CH:26]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:35]([C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([C:2]2[C:3]([S:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:27]=1)#[N:36]
Reactant: CC1(C)OB(c2ccc(C#N)c3ccccc23)OC1(C)C
Reactant: CCOC(=O)C(C)(C)Sc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Sc1ncccc1-c1ccc(C#N)c2ccccc12
Temperature: 80 °C
Yield: 36.1 %

Procedure:
A mixture of ethyl 2-(3-bromopyridin-2-ylthio)-2-methylpropanoate (271 mg, 0.89 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (248 mg, 0.89 mmol), palladium tetrakis triphenylphoshine (51 mg, 0.044 mmol) and aqueous sodium carbonate solution (2M, 1.5 mL, 3 mmol) in dioxane (3 mL) was degassed and heated to 80° C. for 5 hours. The mixture was washed with water and extracted with ethyl acetate. The organic layer was dried with Mg2SO4, concentrated and purified by chromatography to yield ethyl 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoate (0.121 g, 36%).
Reaction SMILES: CO[C:3]([C:5]1([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([C:25]3[S:26][C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=3)[O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6]1)=O.[Li].[C:35](OCC)(=[O:37])C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[CH:16]([O:17][CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:12]1[CH:11]=[C:10]([S:9][CH2:8][C:5]2([CH2:3][CH2:35][OH:37])[CH2:6][CH2:7]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)C1(CSc2cccc(C(OC3CCN(C)CC3)c3nc4ccccc4s3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(OC(c2cccc(SCC3(CCO)CC3)c2)c2nc3ccccc3s2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropanecarboxylic acid methyl ester (56 mg) in tetrahydrofuran (5 mL) is added lithium aluminumhydride (25 mg) at 0° C. The reaction mixture is allowed to reach room temperature and ethyl acetate (2 mL) is added. After stirring for 5 minutes, a half-saturated aqueous solution of sodium carbonate (6 mL) is added. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 95/5/0.5) to afford 2-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropyl)ethanol.
Reaction SMILES: [C:1]([O:5][CH:6]([CH3:17])[CH2:7][CH2:8][CH2:9][CH:10]1[O:15][CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([Mg]Cl)=[CH2:19].[Mg].C(Cl)=C>O1CCCC1>[OH:16][CH:14]([CH2:13][CH2:12][CH2:11][CH:10]([OH:15])[CH2:9][CH2:8][CH2:7][CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17])[CH:18]=[CH2:19]
Reactant: C=C[Mg]Cl
Reactant: CC(CCCC1CCCC(O)O1)OC(C)(C)C
Agent: C=CCl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(O)CCCC(O)CCCC(C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-[4-(t-butoxy)pentyl]-tetrahydropyran-2-ol (5 g.) in tetrahydrofuran (50 ml.) was added within 30 minutes at 5° to a solution of vinyl magnesium chloride in tetrahydrofuran, prepared from magnesium (2.0 g.) and 4 g. of vinyl chloride, dissolved in tetrahydrofuran (50 ml.). After stirring overnight at room temperature, the reaction solution was treated with ammonium chloride-ice and then extracted with chloroform (3 times, each time 100 ml.). The organic phase was washed with water, dried and evaporated in vacuo giving crude 3,7-dihydroxy-11-(t-butoxy)-dodec-1-ene.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][C:14]1([C:24]([OH:26])=O)[S:21](=[O:23])(=[O:22])[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH2:15]1.ClC(Cl)C>>[CH3:13][C:14]1([C:24]([NH2:3])=[O:26])[S:21](=[O:23])(=[O:22])[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH2:15]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C(=O)O)Cc2ccsc2S1(=O)=O
Solvent: CC(Cl)Cl
Product: CC1(C(N)=O)Cc2ccsc2S1(=O)=O
Yield: 52.9 %

Procedure:
Carbonyldiimidazole (13.3 g, 82.0 mmol) was added to a solution of 2,3-dihydro-2-methylthieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide (12.7 g, 54.7 mmol) in dry, degassed DMF (200 mL). The reaction was stirred under N2 until an aliquot quenched with methanol showed no more starting material by tlc (about 1 h). An excess of a saturated solution of NH3 (g) in CHCl3 was added and the reaction stirred 1.5 h. The reaction was diluted with water and extracted with ethyl acetate 3X. The combined organic extracts were washed with brine and dried over MgSO4, filtered, and the solvent removed in vacuo to give a semi-solid. This semi-solid was treated with dichloroethane, cooled in the freezer, and filtered to give the title compound (6.69 g, 53%). 1H NMR (300 MHz,DMSO-d6) 1.70(s,3H), 3.00(d, 1H), 3.85(d,1H), 7.10(d,1H), 7.63(bs,1H exch.), 7.69(bs,1 H, exch.), 8.05(d,1H).
Reaction SMILES: [CH:1]1([C:4]2([CH:10]3[CH2:12][CH2:11]3)[CH2:8][C:7](=[O:9])[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.Cl>C(OCC)C>[CH:10]1([C:4]2([CH:1]3[CH2:3][CH2:2]3)[CH2:8][CH:7]([OH:9])[CH:6]=[CH:5]2)[CH2:12][CH2:11]1
Reactant: O=C1C=CC(C2CC2)(C2CC2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OC1C=CC(C2CC2)(C2CC2)C1
Reaction time: 0.33 h
Yield: 27.8 %

Procedure:
To a solution of 4,4-dicyclopropyl-2-cyclopenten-1-one (1.88 g) in diethyl ether (20 ml) was added diisobutylaluminum hydride (0.94N in n-hexane, 14 ml) at -70° C. to -64° C. under nitrogen atmosphere. After being stirred for 20 minutes, ethyl acetate (6 ml) was added thereto and the solution was acidified with dil. hydrochloric acid and extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo to give 4,4-dicyclopropyl-2-cyclopenten-1-ol (0.53 g). Since this compound was not so stable, it was used in the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.CCN(C(C)C)C(C)C.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:31]([O:15][CH2:14][C:13]1[CH:12]=[C:11]2[C:6](=[N:5][C:4]=1[CH:3]([O:2][CH3:1])[O:16][CH3:17])[NH:7][CH2:8][CH2:9][CH2:10]2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(OC)c1nc2c(cc1CO)CCCN2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methanol (intermediate 40, 6.5 g, 27.3 mmol) in DCM (100 ml) and DMF (25 ml) at 0° C. were added DIPEA (7.15 ml, 40.9 mmol), tert-butylchlorodimethylsilane (4.93 g, 32.7 mmol) and DMAP (0.067 g, 0.546 mmol). The reaction mixture was then stirred for 1 h at room temperature, then poured into sat. aq. NaHCO3 and extracted twice with DCM. The combined organic phases were dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (120 g silica gel cartridge, heptanes/EtOAc 95:5 to 0:100) to give the title compound as a light yellow oil which solidified upon standing to give an off-white powder. (UPLC-MS 3) tR 1.10 min; ESI-MS 353.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C([Li])(C)(C)C.CCCCC.[Sn:35](Cl)([CH3:38])([CH3:37])[CH3:36].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:36][Sn:35]([CH3:38])([CH3:37])[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][OH:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2ccc(Br)cc2c2ccccc12
Reactant: C[Sn](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: C[Sn](C)(C)c1ccc2cc(CO)c3ccccc3c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Bromophenanthrene 5 (1.02 g, 2.5 mmol) was dissolved in anhydrous THF (15 mL) and cooled to -78° C. under nitrogen. To this stirred solution was added a solution of t-Butyllithium in pentane (2.2 equiv.; 5.5 mmol; 3.0 mL). After 30 minutes at -78° C., the reaction was warmed to -50° C. for 20 minutes, after which time Me3SnCl (1.1 equiv.; 2.75 mmol; 548 mg) was added as a solid. The cold q bath was removed and the reaction allowed to reach ambient temperature. After 75 minutes, the reaction was quenched with water. The solvent was removed in vacuo and the residual dissolved in Et2O. Washing with water and brine was followed by drying over MgSO4, filtering and removal of solvent. The residual was dissolved in anhydrous THF and treated with a 1.0M solution of n-Bu4NF in THF (1.1 equiv.; 2.75 mmol; 2.75 mL) at ambient temperature for 5 minutes. Quenching the reaction with saturated NH4Cl was followed by removal of the solvent in vacuo. The residual was dissolved in EtOAc and washed with water and brine, dried (MgSO4), filtered and the solvent removed in vacuo. Purification by flash chromatography (25% EtOAc/hexanes) provided 733 mg (78%) of stannyl alcohol 5A as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([OH:13])=O)[CH:7]=1)#[N:2].CN1CCOCC1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].O>CC1CCCO1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([NH:33][O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[O:13])[CH:7]=1)#[N:2]
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(C#N)cn1)(C(=O)O)S(C)(=O)=O
Solvent: O
Solvent: CN1CCOCC1
Solvent: CC1CCCO1
Product: C[C@@](CCn1cc(C#N)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of the crude (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid in 2-methyltetrahydrofuran (20 mL) was added N-methyl morpholine (0.494 g, 4.83 mmol, 3 eq) and CDMT (0.424 g, 2.42 mmol, 1.5 eq). The solution was allowed to stir at room temperature for one hour. O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.283 g, 2.42 mmol, 1.5 eq) was added to the solution, and the reaction mixture was allowed to stir for an additional hour at room temperature. Water (20 mL) was added, and the solution was extracted with 2-methyltetrahydrofuran (100 mL). The aqueous layer was re-extracted with 2-methyltetrahydrofuran (150 mL) and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product mixture was purified by flash chromatography on a 40 g silica column eluting with 70-100% EtOAc/Heptane to give (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (165 mg, 28% yield over two steps) as a white solid. LC-MS M−H 369.4.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@:15]([OH:27])([C@@H:22]([CH3:26])[C@@H:23]1[O:25][CH2:24]1)[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.O>C(OCC)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@:15]([OH:27])([C@@H:22]([CH3:26])[C@@H:23]([OH:25])[CH3:24])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: C[C@@H]([C@H]1CO1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C[C@H](O)[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 74.7 %

Procedure:
84 mg (2.16 mmole) of lithium aluminum hydride were added, under an atmosphere of nitrogen, to a solution of 320 mg (1.08 mmole) of (2R*,3S*,4S*)-2-(2,4-difluoro-phenyl)-4,5-epoxy-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-pentanol (stereoisomer A) [prepared as described in step (a) above] in 20 ml of diethyl ether, whilst ice-cooling and stirring. Ten minutes later the reaction mixture was heated under reflux, and this was continued for hour. At the end of this time, the mixture was cooled, and 2 ml of water were slowly added; the mixture was then stirred for 10 minutes. The insoluble materials in the reaction mixture were removed by filtration using a Celite filter aid, and then the residue was washed with ethyl acetate. The combined filtrate and washings were dried and freed from the solvent by distillation under reduced pressure. The resulting oily residue was subjected to column chromatography through silica gel, using a 5:5:1 by volume mixture of ethyl acetate, chloroform and hexane as the eluent, to afford 240 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:25][NH2:26]>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:25][NH2:26])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: NN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NNC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrophenylacetic acid (2.81 mmol) in dry dichloromethane (10 ML) was treated with a 2N solution of oxalyl chloride (3.0 mL) and DMF (0.02 mL) via syringe, and the reaction stirred at ambient temperature for 1 h. The reaction was concentrated to dryness in vacuo and the crude product was dissolved in dry dichloro-methane (20 mL), treated with anhydrous hydrazine (11.1 mmol) via syringe, and stirred at ambient temperature for 18 h. The resulting suspension was filtered, solids rinsed with dichloromethane, dissolved in MeOH/CH2Cl2, filtered, and filtrate concentrated in vacuo giving the title compound as an orange solid. 1H NMR (DMSO-d6) δ 8.17 (2H, d, J=8.8 Hz,), 7.54 (2H, d, J=8.8 Hz), 3.54 (2H, s).