Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Yield: 67.9 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (460 mg, 1.2 mmol) and 4-chlorophenylboronic acid (225 mg, 1.44 mmol) in toluene (10 mL) was added Pd(0) (40 mg) and Na2CO3 (1.2 mL of a 2 M solution), and the mixture was heated at reflux for 1.5 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on a silica gel column, eluting with hexane:Et2O 100:10-100:30 to afford of the title compound (345 mg, 68% yield). MS (CI/NH3) m/z 423 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.45 (s, 9H), 1.89 (m, 2H), 2.03 (m, 2H), 3.37 (m, 2H), 4.00 (m, 1H), 4.15 (m, 2H), 7.42 (m, 6H), 8.10 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:15][C:3]=1[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:5].[BH4-].[Na+]>C(O)C.O>[CH3:12][C:11]1[CH:10]=[C:9]([CH3:13])[CH:8]=[C:7]([CH3:14])[C:6]=1[CH:4]([C:3]1[CH:15]=[C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:17]=[CH:18][C:2]=1[CH3:1])[OH:5]
Reactant: Cc1cc(C)c(C(=O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Temperature: 50 °C
Reaction time: 10 h
Yield: 78.9 %

Procedure:
To a suspension of 7.3 g of 2-methyl-5-(1-imidazolyl)-2',4',6'-trimethylbenzophenone in 50 ml of ethanol is added a solution of 1 g of sodium borohydride in 10 ml of water. After the mixture is stirred at 50° C. for 10 hours, the reaction mixture is poured into ice-cold water. The crystals precipitated are filtered off and recrystallized from ethanol to give 5.8 g of α-(2,4,6-trimethylphenyl)-2-methyl-5-(1-imidazolyl)benzenemethanol as white crystals, melting at 190°-191° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].Br[CH2:15][CH2:16][C:17]([F:21])=[C:18]([F:20])[F:19]>C(OCC)C.[Ag]>[F:1][C:2]([F:12])([F:13])[C:3]([F:10])([F:11])[C:4]([F:8])([F:9])[C:5]([O:7][CH2:15][CH2:16][C:17]([F:21])=[C:18]([F:20])[F:19])=[O:6]
Reactant: FC(F)=C(F)CCBr
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Ag]
Solvent: CCOCC
Product: O=C(OCCC(F)=C(F)F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 3.2 grams (0.01 mole) of the silver salt of heptafluorobutyric acid in 40 ml of diethyl ether was added dropwise 1.9 grams (0.01 mole) of 4-bromo-1,1,2-trifluoro-1-butene in 10 ml of diethyl ether. Upon completion of addition the reaction mixture was stirred for two hours at ambient temperature, then was heated under reflux for one hour. The ether solvent was removed by distillation and the residual oil distilled under reduced pressure to give 1.0 gram of (3,4,4-trifluoro-3-butenyl) heptafluorobutyrate; b.p. 25° C./4.0 mm Hg. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][NH:19][C:18](=[O:21])[CH2:17][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>C1COCC1>[C:29]([O:28][C:24](=[O:27])[CH2:25][CH2:26][N:19]1[C:18](=[O:21])[CH2:17][O:16][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[CH2:20]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1COC(c2ccc(OCc3ccccc3)cc2)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCN1CC(c2ccc(OCc3ccccc3)cc2)OCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a mixture of 6-(4-benzyloxy-phenyl)-morpholin-3-one (13.40 g; 47.3 mmol) and powdered NaOH (3.78 g; 94.6 mmol) in THF (250 mL) was added tert-butyl acrylate (13.7 mL; 94.6 mmol). The resulting mixture was stirred at RT for 2 hours and subsequently concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 3-[2-(4-benzyloxy-phenyl)-5-oxo-morpholin-4-yl]-propionic acid tert-butyl ester (14.20 g).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:35][S:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)(=[O:38])=[O:37]>C(#N)C.O.Cl>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:43][C:42]3[CH:41]=[CH:40][C:39]([S:36]([CH3:35])(=[O:38])=[O:37])=[CH:46][CH:45]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(S(C)(=O)=O)cc3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A suspension of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (17 mg, 0.044 mmol) in Acetonitrile (0.4 mL) was treated with Cs2CO3 (57.9 mg, 0.178 mmol), 4-methylsulfonylbenzyl bromide (44.3 mg, 0.089 mmol), and stirred at 70° C. for 1.5 hours. The reaction was cooled to rt, diluted with water and 1N HCl, extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(6-methyl-1-(4-(methylsulfonyl)benzyl)-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (22 mg, 0.040 mmol, 90% yield) as yellow oil. The ester intermediate was dissolved in Methanol (0.5 mL) and Tetrahydrofuran (THF) (0.5 mL), treated with 2M LiOH (0.120 mL, 0.24 mmol), and stirred at 60° C. for 2 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to give title compound (9.3 mg, 0.017 mmol, 37.6 yield) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.00 (s, 9H), 2.44 (s, 3H), 3.02 (s, 3H), 3.64 (s, 3H), 5.47 (s, 1H), 5.81 (d, J=15.7 Hz, 1H), 6.02 (d, J=15.6 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 7.05 (d, J=2.9 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.32-7.43 (m, 3H), 7.47-7.58 (m, 1H), 7.89 (d, J=8.4 Hz, 2H). LCMS (m/z) ES+=537 (M+1).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[S-:12][C:13]#[N:14].[Na+].[Br-].[Na+].BrBr>CO.[Cl-].[Na+].O>[S:12]([C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]([OH:11])=[CH:2][CH:3]=1)[C:13]#[N:14]
Reactant: N#C[S-]
Reactant: Oc1cccc2c1CCCC2
Agent: BrBr
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: N#CSc1ccc(O)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5,6,7,8-Tetrahydro-naphthalen-1-ol (1 g, 6.8 mmol) was dissolved in 25 ml MeOH. Sodium thiocyanate (1.76 g, 22 mmol) and sodium bromide (0.7 g, 6.8 mmol) were added and stirred for 5 minutes at ambient temperature. Bromine (1.2 g, 7.48 mmol) was added drop wise over 5 minutes. The orange solution was allowed to stir two hours. Brine was added and the crude product was extracted twice into ethyl acetate. The combined organic extracts were washed once with brine, dried over anhydrous sodium sulfate, decanted and concentrated. Normal phase chromatography afforded the title product, 1.28 g, 92%. 400 MHz 1H NMR (DMSO-d6) δ 11.1 (s, 1H), 7.40 (d, 1H, J=8.8 Hz), 6.61 (d, 1H, 8.8 Hz), 2.78 (m, 2H), 2.59 (m, 2H), 1.70 (m, 4H). MS m/z 278 (m+1)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: COC(=O)c1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)c2ccc(C(=O)O)cc2)n2c1ccc1ccccc12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
3-Cyano-1-(4-methoxycarbonyl-benzoyl)-pyrrolo[1,2-a]quinoline (10 mg, 0.028 mmol) was disolved in a mixture of 5 mL of THF and 0.5 mL of ethyl alcohol and 1 mL of 2M NaOH was added and the mixture was stirred for 4 h at 50° C. The mixture was cooled to 0° C., acidified using 2N HCl and the resulting precipitate was collected, washed with cold ethyl alcohol and dried under vacuum (9.6 mg, 99%). 1H NMR (DMSO): 8.11–7.99 (m, 5H), 7.80–7.83 (m, 2H), 7.61–7.72 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:9]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:10][CH2:11][C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>CCOCC.O>[C:29]([O:28][C:26]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:10][CH2:11][CH:12]=[O:13])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)CC[C@H](C(=O)OCc1ccccc1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CCC=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To a −78° C. of 1-benzyl 5-methyl N,N-bis(tert-butoxycarbonyl)-D-glutamate (48.2 g, 106.8 mmol) in Et2O (400 mL), was added DIBAL (133.4 mL of 1.0 M solution in toluene, 133.4 mmol) slowly so as not to let the internal temperature exceed −65° C. After 15 min, 20 mL more of DIBAL was added. After stirring for additional 20 min, water (300 mL) was added and the reaction was warmed to room temperature and stirred for 30 min. This mixture was further diluted with Et2O and H2O, the layers separated and the aqueous phase extracted with more Et2O. The combined organics extracts were washed with a saturated aqueous solution of sodium potassium tartrate (2×), brine, dried over magnesium sulfate, filtered and concentrated to give benzyl N,N-bis(tert-butoxycarbonyl)-5-oxo-D-norvalinate (44.4 g) which was carried directly into the next step. MS 444.1 (M+Na). This material was dissolved in toluene (310 mL) and nitromethane (57.1 mL, 1.05 mol) and 1,1,3,3-tetramethylguanidine (1.3 mL, 10.5 mmol) were added at 0° C. After stirring for 30 min the nitroaldol reaction was complete, so methanesulfonyl chloride (12.2 mL, 158 mmol) was added followed triethylamine (22.0 mL, 158 mmol) at 0° C. and the reaction was allowed to warm to RT. After 1 h, 4 mL MsCl and 5.5 mL triethylamine were added. After stirring for an additional 30 min the mixture was diluted with Et2O and NaHCO3, the phases separated and the aqueous layer backwashed with another portion of Et2O. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (5%→50% ethyl acetate/hexanes) to give the title compound (34.3 g, 70%). MS 487.1 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.ClC(Cl)C.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:32][CH:29]3[CH2:31][CH2:30]3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=CC1CC1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCN(CC2CC2)CC1
Reaction time: 8 h

Procedure:
To a small sample of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034 g, 0.1 mmol) weighed out in a 1 mL sealable vial, dichloroethane was added (300 μL), followed by excess of cyclopropanecarboxaldehyde (20 μL, >0.15 mmol) and sodium triacetoxyborohydride (200 μL of a 1.5 M solution in N-methylpyrrolidinone). The vial was capped and placed in a shaker at 70° C. overnight. After an additional 24 h at room temperature, methanol was added (400 μL) and the vial was shaken for a few minutes. The reaction mixture was then applied to a 2 g SCX column, washed with methanol (30 mL) and gravity-eluted with 1 N ammonia in methanol (20 mL). The yellow fractions were combined and concentrated in vacuo to a dry residue (0.040 g, >100%), which was identified as the title compound by LC-MS (Method A).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCCCOc1ccc(C2=CCCCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCOc1ccc(C2CCCCCCC2)cc1

Procedure:
2 g of palladium on charcoal (5% strength) are added to a solution of 20 g of 5-[p-(1-cyclooctenyl)-phenoxy]-pentanoic acid ethyl ester in 100 ml of ethanol and hydrogenation is carried out at room temperature and normal pressure until one equivalent of hydrogen has been absorbed. The catalyst is then filtered off and the filtrate is evaporated to dryness in vacuo. Distillation of the evaporation residue in a high vacuum gives 5-(p-cyclooctyl-phenoxy)-pentanoic acid ethyl ester of boiling point 170° -175° C at 0.05 mm Hg.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1.IC1C=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[C:15]([CH2:22][CH2:23][CH3:24])C=1.NC1(CO)CCCC1.[N-]=C=S>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:20]2[S:21][CH2:17][C:16]3([CH2:15][CH2:22][CH2:23][CH2:24]3)[NH:19]2)=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCCc1cc(I)ccc1N
Reactant: CCCc1cc(I)ccc1N=C=S
Agent: NC1(CO)CCCC1
Agent: [N-]=C=S
Product: CCCc1cc(I)ccc1N=C1NC2(CCCC2)CS1

Procedure:
4-Iodo-2-n-propylaniline was converted into 4-iodo-2-n-propylphenyl isothiocyanate in a manner analogous to Method A2b. Concurrently, 1-amino-1-(hydroxymethyl)cyclopentane was converted to the chloromethyl analogue, then reacted with the isothiocyanate in a manner analogous to Method C2a to give 2-(4-iodo-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane. A slurry of 2-(4-iodo-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane (0.54 g, 1.35 mmol) and CuCN (0.24 g, 2.70 mmol) in DMF (4 mL) was heated at 140° C. overnight. The resulting mixture was cooled to room temp, concentrated under reduced pressure and purified by flash chromatography (10% EtOAc/hex) to give 2-(4-cyano-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane as a white solid (0.26 g, 65%): TLC (30% EtOAc/hex) Rf0.37.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:23][CH:22]=1>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:29][CH:26]([O:25][C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:31][CH:30]=3)[CH2:27]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc(OC2CN(c3nc(Cl)ncc3F)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution 2,4-dichloro-5-fluoropyrimidine (150.0 mg, 0.898 mmol) in 2-propanol (4.00 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (0.469 mL, 2.70 mmol) followed by 3-(4-fluorophenoxy)azetidine hydrochloride (183 mg, 0.898 mmol). The resulting reaction mixture was stirred at RT for 1 h and concentrated. Purification of the crude using MPLC (25 g cartridge, 40 g column, 0 to 60% EtOAc-hexanes) gave 2-chloro-5-fluoro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (240.6 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21].[K].I([O-])(=O)(=O)=[O:26].[Na+].Cl>O.ClCCl>[CH3:1][C:2]1([CH3:23])[S:6](=[O:26])[C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 3 h

Procedure:
Penicillin G, potassium salt (349.9 g) was dissolved in 3 liters of water. Sodium periodate (194 g) was added and the mixture was stirred for three hours. Dichloromethane (500 ml) was added and the pH of the water layer was adjusted to 2.3 with 6 N hydrochloric acid with vigorous stirring. The aqueous layer was separated and extracted with four 400 ml portions of dichloromethane. The combined extract was washed with aqueous sodium bisulfite to remove any iodine color, dried over sodium sulfate, filtered, and evaporated. The solid residue was empasted with 400 ml of ethyl acetate and allowed to stand at 0° C. overnight. The solid was isolated by filtration and dried in vacuo to afford 322 g of penicillin G sulfoxide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.Br[C:25]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:33]2[C:28](=[CH:29][C:30]([CH3:35])=[C:31]([Cl:34])[CH:32]=2)[NH:27][C:26]1=[O:36]>C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:25]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[C:33]3[C:28](=[CH:29][C:30]([CH3:35])=[C:31]([Cl:34])[CH:32]=3)[NH:27][C:26]2=[O:36])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc2c(cc1Cl)C(Br)(c1ccccc1Cl)C(=O)N2
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cl)C(NCCC1CCN(C(=O)OC(C)(C)C)CC1)(c1ccccc1Cl)C(=O)N2
Yield: 56.2 %

Procedure:
A solution of 1.35 g of 4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperidine and 1.75 g of triethylamine in 20 ml of THF is added dropwise at RT to a solution of 2.1 g of 3-bromo-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one, obtained in step B' of Preparation 71, in 20 ml of THF and the reaction mixture is stirred for 1 hour at RT. It is concentrated under vacuum, the residue is taken up with 400 ml of AcOEt and 50 ml of THF, the resulting suspension is washed twice with a 5% solution of sodium carbonate, with water and with a saturated solution of NaCl and, after decantation, the solid in suspension is filtered off. The solid is dissolved in 400 ml of boiling THF and dried over sodium sulfate and the solvent is partially evaporated off under vacuum. The crystalline product formed is filtered off to give 1.65 g of the expected product. M.p.=245°-248° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[N:19][CH:20]=3)[C:15]3=[N:22][O:23][C:24]([CH3:25])=[C:14]3[C:13]2=[O:26])[CH2:7]1)=[O:5])C.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:25][C:24]1[O:23][N:22]=[C:15]2[C:16]3[C:21](=[CH:20][N:19]=[CH:18][CH:17]=3)[N:12]([CH:8]3[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:13](=[O:26])[C:14]=12
Reactant: CCOC(=O)C1CCCC(n2c(=O)c3c(C)onc3c3ccncc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1onc2c1c(=O)n(C1CCCC(C(=O)O)C1)c1cnccc21
Yield: 87.3 %

Procedure:
Combine 3-(3-methyl-4-oxo-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexane-carboxylic acid ethyl ester (620 mg, 1.75 mmol) with aqueous sodium hydroxide (2N, 5.0 mL, 10.0 mmol), ethanol (2 mL), and tetrahydrofuran (2 mL) and stir at ambient temperature until hydrolysis is complete. Add water and adjust to approx. pH 3.0 with aqueous hydrochloric acid. Extract with dichloromethane and dry over sodium sulfate and concentrate in vacuo to give the desired acid as a tan solid (500 mg, 88%).
Reaction SMILES: [CH3:1][C:2]1([CH:10]=[O:11])[CH:7]([CH3:8])[CH2:6][C:5]([CH3:9])=[CH:4][CH2:3]1.[CH2:12]=[CH:13][C:14](=C)C>>[CH3:1][C:2]1([C:10](=[O:11])[CH2:12][CH2:13][CH3:14])[CH:7]([CH3:8])[CH2:6][C:5]([CH3:9])=[CH:4][CH2:3]1
Reactant: C=CC(=C)C
Reactant: CC1=CCC(C)(C=O)C(C)C1
Product: CCCC(=O)C1(C)CC=C(C)CC1C

Procedure:
The 1,4,6-trimethylcyclohex-3-ene-1-carbaldehyde according to the invention and the analogous ketones according to the invention are directly accessible by means of 1,4-cycloaddition of isoprene with tiglic aldehyde or with the corresponding 2-propenylalkyl ketones. The carbaldehyde according to the invention and the analogous ketones are directly accessible by 1,4-cycloaddition of tiglic aldehyde or the corresponding 2-propenylalkyl ketones with isoprene.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH2:34][CH2:33][N:32]([C:35](OC(C)(C)C)=O)[CH2:31][CH:30]=6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[OH-].[Na+]>C=O.C(O)=O>[CH3:35][N:32]1[CH2:31][CH:30]=[C:29]([C:26]2[CH:27]=[N:28][C:23]([N:19]3[CH2:20][CH2:21][CH2:22][CH:17]([CH2:16][N:13]4[C:11]5=[N:12][C:7]([C:5]6[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=6)=[CH:8][N:9]=[C:10]5[N:15]=[N:14]4)[CH2:18]3)=[N:24][CH:25]=2)[CH2:34][CH2:33]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(C6=CCN(C(=O)OC(C)(C)C)CC6)cn5)C4)c3n2)cn1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CC=C(c2cnc(N3CCCC(Cn4nnc5ncc(-c6cnn(C)c6)nc54)C3)nc2)CC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
tert-butyl 4-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (71 mg, 0.13 mmol) was dissolved in 35% HCHO (0.2 ml)+HCO2H (1 ml), followed by stirring at 95° C. overnight. After the completion of the reaction, the reaction mixture was adjusted to pH 11-12 with NaOH (aq.), and extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give (1-((1-(5-(1-methyl-1,2,3,6-tetrahydro pyridin-4-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (10 mg, 16%).
Reaction SMILES: O[CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([CH2:2][C@@H:3]2[NH:7][C:6](=[O:8])[CH2:5][CH2:4]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC[C@H](CO)N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)C[C@H]2CCC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of (5R)-5-hydroxymethyl-2-pyrrolidinone (5.0 g, 43 mmol) in methylene chloride (100 ml) was added 4-dimethylaminopyridine (15.7 g, 129 mmol) and p-toluenesulphonyl chloride (9.0 g, 47 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction was then washed with 1M hydrochloric acid and the organic layer separated. This was then dried over MgSO4, filtered and evaporated to give (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (10.3 g, 89%) as a white solid.