Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].B1C2CCCC1CCC2.[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15].[OH-].[Na+]>O1CCCC1>[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]/[CH:3]=[CH:2]/[CH2:1][OH:4])=[CH:18][CH:17]=1)#[N:15]
Reactant: C#CCO
Reactant: N#Cc1ccc(CBr)cc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C/C=C/CO)cc1
Temperature: 25 °C

Procedure:
To a solution of propargyl alcohol (67, Aldrich, 1.46 mL, 25 mmol) in anhydrous tetrahydrofuran (10 mL), was added 0.5M 9-BBN in THF (Aldrich, 100 mL, 50 mmol) through an addition funnel at 0° C. under nitrogen over a period of 1 hour. After the addition was complete, the flask with the reaction mixture was stored in a 5° C. refrigerator under nitrogen for 18 hours. The reaction mixture was warmed to room temperature under nitrogen. To the reaction mixture was added 4-bromotolunitrile (compound 61, Aldrich, 5.88 g, 30 mmol), tetrakis(triphenyl-phosphine)palladium (0) (Aldrich, 1.00 g, 0.86 mmol), and 2M sodium hydroxide solution (25 mL, 50 mmol). The reaction mixture was degassed with nitrogen three times, and then refluxed at 65° C. for 2 hours. The reaction mixture was cooled to room temperature. To that solution was added slowly 30% hydrogen peroxide in water (30 mL) and 2M sodium hydroxide solution (10 mL). A lot of gas was released during addition of hydrogen peroxide. The resulting solution was stirred at room temperature for an additional hour. The reaction mixture was extracted with ethyl acetate. The combined extracts were washed with brine and then dried over Na2SO4. After filtration and evaporation, the crude product was purified on a silica gel column, eluting with hexane-ethyl acetate (4:1 and 3:1). The product 68 was obtained as colorless oil (1.05 g, 24% yield). TLC Rf 0.30 (Hexane:EtOAc 1:1); 1H-NMR (400 MHz, CDCl3): δ 7.58 (d, 2H, J 8.1 Hz), 7.29 (d, 2H, J 8.1 Hz), 5.82 (dt, 1H, J 15.6 Hz, J 6.4 Hz), 5.71 (dt, 1H, J 15.6 Hz, J 5.4 Hz), 4.14 (d, 2H, J 5.4 Hz), 3.44 (d, 2H, J 6.4 Hz), 1.62 (s, 1H).
Reaction SMILES: C#C.[CH2:3]([Mg]Br)[CH3:4].[CH3:7][C:8]([CH3:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]=[O:10].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:8]([CH3:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]([OH:10])[C:3]#[CH:4]
Reactant: CCCCC(C)(C)C=O
Reactant: CC[Mg]Br
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)C(C)(C)CCCC
Reaction time: 0.75 h

Procedure:
To a solution containing 90 parts of acetylene dissolved in 600 parts by volume of tetrahydrofuran is added, over a period of about 50 minutes at -70°, 600 parts by volume of tetrahydrofuran containing 133 parts of ethyl magnesium bromide. Acetylene gas is continuously passed through the mixture during the addition period. Following that addition, the mixture is stirred at approximately -40° for about 45 minutes. To that mixture is then added, with stirring under nitrogen over a period of about 1 hour, 80 parts by volume of 2,2-dimethyl-n-hexaldehyde dissolved in 350 parts by volume of tetra=hydrofuran. Stirring at room temperature is continued for about 16 hours, at the end of which time approximately 125 parts by volume of saturated aqueous ammonium chloride is added slowly with stirring. The precipitate which forms is removed by filtration and the filtrate is partially concentrated, then diluted with ether and again filtered. The filtrate is stripped of solvent, then is distilled under reduced pressure to afford 4,4-dimethyl-1-octyn-3-ol, boiling at about 55°-65° at a pressure of about 3 mm.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[S:10](=O)(=[O:13])([OH:12])[OH:11]>>[S:10]([C:7]1[CH:8]=[C:2]([CH:1]=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1)([OH:13])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: O=Cc1ccccc1O
Product: O=Cc1cc(S(=O)(=O)O)ccc1O

Procedure:
reacting salicylaldehyde with fuming sulfuric acid to yield 5-sulfosalicylaldehyde;
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:24][C:15]1[C:14]([CH2:25][NH:26][CH3:27])=[CH:13][N:12]([S:9]([C:7]2[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)(=[O:11])=[O:10])[C:16]=1[C:17]1[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(C(C)=O)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of tert-butyl {[1-[(5-acetyl-2-furyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (180 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 82.8 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:13][CH3:14])=[CH:5][C:6]2[Te:10][C:9]([CH3:11])=[N:8][C:7]=2[CH:12]=1.[F:15][C:16]([F:23])([F:22])[S:17]([O:20]C)(=[O:19])=[O:18]>ClCCl>[F:15][C:16]([F:23])([F:22])[S:17]([O-:20])(=[O:19])=[O:18].[CH3:1][O:2][C:3]1[C:4]([O:13][CH3:14])=[CH:5][C:6]2[Te:10][C:9]([CH3:11])=[N+:8]([CH3:16])[C:7]=2[CH:12]=1
Reactant: COc1cc2nc(C)[te]c2cc1OC
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2[te]c(C)[n+](C)c2cc1OC
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
5,6-Dimethoxy-2-methylbenzotellurazole (Example 19) (4.8 g=0.013 mole) was dissolved in dichloromethane (75 ml), and methyl trifluoromethanesulfonate (2.48 g=1.66 ml=0.013 mole) was added. The solution turned cloudy and crystals started to deposit within a few minutes. Precipitation was completed by addition of diethyl ether. The product was collected by filtration to give 5.5 g, 86.5% of theory, m.p. 210°-234° C. The product was recrystallized from boiling acetone (≃130 ml required) m.p. 242°-243° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([CH2:8][CH3:9])[CH2:6][OH:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([CH2:8][CH3:9])[CH2:6][O:7][S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CC[C@H](CO)Cc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](COS(C)(=O)=O)Cc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
A flask was charged with 7.2 g (36 mmol) of (S)-2-(2,4-difluoro-benzyl)-butan-1-ol and 30 mL of dichloromethane, and the solution was cooled to 0° C. To this solution was added 7.53 mL (54 mmol) of triethylamine, and the mixture was stirred cold for 5 minutes. Then 3.1 mL (39.6 mmol) of methane sulfonyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The dichloromethane was removed under reduced pressure, and the residue was partitioned between 1 N HCl aq. and diethyl ether. The ether layer was collected and washed with sat. aq. sodium bicarbonate, water, and brine. The ether layer was dried over sodium sulfate, filtered, and the ether was removed under reduced pressure. This procedure gave 9.54 g (95% yield) of the titled compound as an orange oil. This material was used without further purification.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[CH3:11].S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C#N)nc1CO
Solvent: ClCCl
Product: Cc1ccc(C#N)nc1CCl
Yield: 99 %

Procedure:
A solution of 6-(hydroxymethyl)-5-methyl-2-pyridinecarbonitrile (184 mg) and thionyl chloride (0.16 ml) in dichloromethane (3.5 ml) was stirred at ambient temperature for 7 hours. Solvent was removed in vacuo and toluene (2 ml) added then removed in vacuo to afford the title compound (205 mg, 99%) as a pale buff solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)C)[CH2:21]4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1.Cl.N[C@H]1CCN(C2C=CC(N3C[C@H](CN(C4C=CON=4)C(OCC(Cl)(Cl)Cl)=O)OC3=O)=CC=2F)C1.[CH3:65][S:66](Cl)(=[O:68])=[O:67]>>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@H:22]([NH:25][S:66]([CH3:65])(=[O:68])=[O:67])[CH2:21]4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Agent: Cl
Agent: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Product: CS(=O)(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4-(3(S)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (400 mg, 0.74 mM) and methanesulfonyl chloride gave the desired product (361 mg ). NMR (DMSO-d6) δ: 1.87 (hextet, 1H); 2.19 (hextet, 1H); 2.97 (s, 3H); 3.20 (m, 1H); 3.30 (m, 1H); 3.37 (m, 1H); 3.54 (m overlapped by H2O, ˜1H); 3.83 (dd, 1H); 3.97 (dd, 1H); 4.13 (dd overlapping m, 2H); 4.36 (dd, 1H); 4.97 (d, 1H); 5.02 (m, 1H); 5.07 (d, 1H); 6.74 (t, 1H); 6.88 (d, 1H); 7.09 (dd, 1H); 7.36 (dd overlapping br, 2H); 8.89 (d, 1H). MS (ESP): 578 (MH+) for C21H23Cl3FN5O7S
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].C[O-].[Na+]>C(OC)(C)(C)C>[F:16][C:17]([F:24])([F:23])[C:18](=[O:19])[CH2:14][C:13]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)=[CH:7][C:2]=1[F:1])=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-c2cscn2)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)cc1F
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a stirred solution of 1-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (2.03 g, 9.18 mmol) in t-butylmethylether (60 ml) was added ethyl trifluoroacetate (1.56 g, 11.01 mmol), sodium methoxide (28 wt. % solution in methanol; 2.49 ml, 11.01 mmol) at 0° c., and the mixture was stirred for 3 hours. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give title compound (2.92 g, 99% yield). The compound was used for next reaction without purification.
Reaction SMILES: [H][H].[F:3][C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(OCC)(=O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:3])[CH:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAc was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 h to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The PH of the solution was adjusted to 4 with NaOH (aq.). The mixture was extracted with more ethyl acetate. The organic layer was washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80 ° C. for 1 h. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 h and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation with a hydrogen balloon converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH:21]=O)=[N:15][NH:16]2>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:21]([C:14]3[C:13]4[C:17](=[CH:18][CH:19]=[CH:20][C:12]=4[F:11])[NH:16][N:15]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=Cc1n[nH]c2cccc(F)c12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3n[nH]c4cccc(F)c34)[nH]c2cc1C
Temperature: 120 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A mixture of 4,5-dimethylbenzene-1,2-diamine (70 mg) and 4-fluoro-1H-indazole-3-carbaldehyde [80 mg, Reference Example 20(b)] in dimethylformamide (8 ml) was heated to 120° C. for 30 minutes and then at 100° C. for 16 hours. The reaction mixture was cooled, then diluted with ethyl acetate and then washed five times with brine. The organic phase was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluding with a mixture of 40/60 petrol and ethyl acetate (1:5, v/v) to give 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4-fluoro-1H-indazole (104 mg) as a light brown solid. MS: 281 (M+H)+. HPLC (METHOD B1): RT=10.08 minutes. (b) 4-Chloro-3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C(C3C(C)=NC(C)=CC=3)O)[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.N1(C2C=CC(CC3C(Cl)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=C[CH:37]=N1.[CH3:61][N:62]1[C:66]([C:67]([C:69]2[CH:74]=[CH:73][N:72]=[C:71]([C:75](F)(F)F)[CH:70]=2)=[O:68])=[CH:65][N:64]=[N:63]1.S1C(CC2C(OC)=NC3C(C=2Cl)=CC(C(C2N(C)C=NC=2)(C2C=NC(C(F)(F)F)=CC=2)O)=CC=3)=CC2C=CC=CC1=2>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:67]([C:69]3[CH:70]=[C:71]([CH3:75])[N:72]=[C:73]([CH3:37])[CH:74]=3)([C:66]3[N:62]([CH3:61])[N:63]=[N:64][CH:65]=3)[OH:68])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=1
Reactant: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Reactant: Cn1nncc1C(=O)c1ccnc(C(F)(F)F)c1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Product: COc1nc2ccc(C(O)(c3cc(C)nc(C)c3)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared analogously to the method described in Example 78 using 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (Intermediate 12: step d) in place of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline (Intermediate 57) and (1-methyl-1H-1,2,3-triazol-5-yl)(2-(trifluoromethyl)pyridin-4-yl)methanone (Intermediate 29: step b) in place of 1-(4-(6-(trifluoromethyl)nicotinoyl)piperidin-1-yl)ethanone (Intermediate 56: step d). MS m/e 568.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[C:15]1(O)[CH:22]2[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:24][CH:16]1[CH2:17]3)[CH2:21]2)[C:5]([O:7]C(C)(C)C)=[O:6].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:16]12[CH2:24][CH:20]3[CH2:19][CH:18]([CH2:23][CH:22]([CH2:21]3)[CH:15]1[C:14]1[CH:13]=[CH:12][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[Cl:1])[CH2:17]2
Reactant: CC(C)(C)OC(=O)c1ccc(C2(O)C3CC4CC(C3)CC2C4)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C2C3CC4CC(C3)CC2C4)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
To a solution of tert-butyl 3-chloro-4-(2-hydroxyadamantan-2-yl)benzoate (0.581 g, 1.60 mmol) in dichloromethane (50 mL) was added triethylsilane (5 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at ambient temperature for 20 hours and the reaction solution was concentrated in vacuo to dryness. The residue was triturated with hexanes (15 mL) to afford the title compound (0.27 g, 57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=1.6 Hz, 1H), 7.94 (dd, J=1.6, 8.2 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 3.33 (s, 1H), 2.33 (br s, 2H), 1.98-1.92 (m, 8H), 1.78 (s, 2H), 1.70-1.66 (m, 2H) (OH not observed); MS (ES−) m/z 289.3, 291.3 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:13][NH:12][C:11](=[O:14])[C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:34][CH:35]([CH3:37])[CH3:36]>O1CCCC1.CN1CCCC1=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:13][N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:14])[C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:9]1
Reactant: CC(C)CI
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN1C[C@H](c2ccccc2F)C[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a pre-cooled 0° C. solution of tert-butyl [(3S,5S)-5-(2-fluorophenyl)-2-oxopiperidin-3-yl]carbamate (0.85 g, 2.76 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 18 mL) was added lithium bis(trimethylsilyl)amide (3.58 mL, 3.58 mmol, 1 M in THF) and the mixture was stirred at 0° C. for 30 min. 1-Iodo-2-methylpropane (0.48 mL, 4.13 mmol) was added and the resulting mixture was stirred at 0° C. for 2 h and then warmed to 23° C. and stirred for an additional 18 h. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→70% ethyl acetate/hexane) was followed by separation of the cis/trans diastereomers using supercritical fluid chromatography with a ChiralPak® AD column and eluting with 20% ethanol in carbon dioxide to afford the title compound as the second diastereomer to elute. MS: m/z=387.2 (M+Na).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[Na+].[CH3:33][S:34]([O-:36])=[O:35].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CS(=O)[O-]
Reactant: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Cc1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-Cyclopropyl-1-[3-(4-bromomethylphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxaride from Step 1 in N,N-dimethylformamide (20 ml/mmol) was added methanesulfinic acid sodium salt (1.3 eq) and the resulting mixture was stirred at room temperature for 18 hours. To the mixture was added saturated aqueous ammonium chloride solution and ethyl acetate, and the insoluble solid was filtered and washed well with water, hexane, ether and ethyl acetate to afford the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:24](O)=[O:25])[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:36][CH:37]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[CH2:38][CH2:39][NH:40][C:41]([NH2:43])=[O:42]>CN1C(=O)CCC1.CCOC(C)=O>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([CH:37]([NH:36][C:24]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:14][CH2:13][N:12]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH2:11][CH2:10]2)=[O:25])[CH2:38][CH2:39][NH:40][C:41]([NH2:43])=[O:42])=[CH:45][CH:46]=1
Reactant: NC(=O)NCCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCNC(N)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluoro-phosphate (378 mg, 0.99 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (240 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.329 mL, 1.99 mmol) in NMP (2 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. 1-(3-amino-3-(4-chlorophenyl)propyl)urea (Intermediate 111) (151 mg, 0.66 mmol) in NMP (2 mL) was then added to the reaction and stirred for 18 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(1-(4-chlorophenyl)-3-ureidopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (379 mg, 100%) as a white solid. m/z (ESI+) (M+H)+=571; HPLC tR=1.88 min.
Reaction SMILES: [CH2:1]([O:17][C@H:18]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:19][OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[O:45](S(C(F)(F)F)(=O)=O)[S:46]([C:49]([F:52])([F:51])[F:50])(=O)=[O:47]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[S:46]([O:20][CH2:19][C@H:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:47])=[O:45]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)OCCCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2,3-bis(hexadecyloxy)propan-1-ol (1 eq) and pyridine (4 eq) in DCM (0.1 M) at 0° C., was added Tf2O (2 eq). The reaction was stirred at 0° C. for 1 hour and quenched by H2O. The aqueous phase was extracted with DCM. The combined organic phases were washed with H2O, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give (R)-2,3-bis(hexadecyloxy)propyl trifluoromethanesulfonate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([C:11]#[N:12])[CH2:6]1)=[O:4].[CH3:13]I>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][CH3:13])[CH:7]([C:11]#[N:12])[CH2:6]1)=[O:4]
Reactant: CI
Reactant: COC(=O)C1CC(O)C(C#N)C1
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)C(OC)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of (1SR,3RS,4SR)-3-cyano-4-hydroxy-cyclopentanecarboxylic acid methyl ester (878 mg; example 15A) in THF (15 ml) was transferred to a sealed tube and treated with Ag2O (3.6 g) and methyl iodide (3.23 ml) and stirred at 60° C. overnight. The reaction mixture was filtered, and the cake was rinsed with plenty of THF. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give (1SR,3RS,4SR)-3-cyano-4-methoxy-cyclopentanecarboxylic acid methyl ester (600 mg) as light yellow oil.