Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[S:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([S:9]([NH2:8])(=[O:11])=[O:10])[CH:13]=2)[CH:3]=1)(=[O:11])=[O:10]
Reactant: CC(C)CN(Cc1cc(Br)cs1)S(=O)(=O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1cc(-c2cccc(S(N)(=O)=O)c2)cs1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(4-bromo-thiophen-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide (example 14, step 2) was reacted with (3-aminosulfonyl)-benzeneboronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-[4-(3-aminosulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as an off-white solid. MS: 497.1 ([M−H]−)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:15][O:16][C:17]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26](OC2C=CC([N+]([O-])=O)=CC=2)=[O:27])[CH2:22][CH2:21]1)=[O:18]>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:26]([N:23]3[CH2:24][CH2:25][CH:20]([CH2:19][C:17]([O:16][CH3:15])=[O:18])[CH2:21][CH2:22]3)=[O:27])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCN(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)CC1

Procedure:
1.3 g of 4-(4-cyanophenyl)-piperidine and 2.9 g of 4-(methoxycarbonylmethyl)-1-[(4-nitrophenyl)-oxycarbonyl]-piperidine are stirred at 140° C. for 2.5 hours. The mixture is left to cool and the residue is dissolved in ethyl acetate. The organic phase is washed twice with 0.5N sodium hydroxide solution and once with water. The ethyl acetate phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue remaining is chromatographed over silica gel. Yield: 1.5 g (58% of theory), Melting point: 115°-118° C. Rf value: 0.32 (silica gel; ethyl acetate/cyclohexane=1:1)
Reaction SMILES: ClC1C=C([N:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)C2N(C(C#N)=CN=2)N=1.NC1C=CC(C)=C(NC(=O)C)C=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(N(C)C)=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][CH:23]2[CH2:25][CH2:24]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: CC(=O)Nc1cc(N)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1ccc(CNC2CC2)cc1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
DMA (1.5 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was degassed by bubbling argon through it for 10 minutes. 1G (0.15 g, 0.42 mmol), N-(5-amino-2-methylphenyl)acetamide (0.104 g, 0.636 mmol), copper(I) iodide (0.040 g, 0.212 mmol), xantphos (0.049 g, 0.085 mmol), and Pd2(dba)3 (0.039 g, 0.042 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE®, washing with THF. The filtrate was then diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted EtOAc (3×10 mL). The organics were combined, washed with water and brine, and dried over anhydrous sodium sulfate. Filtration and concentration afforded a tan solid, which was triturated in DCM and cooled to 0° C. The resulting precipitate was filtered and washed with cold DCM. The filtrate was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm). The appropriate fractions were pooled and concentrated under reduced pressure. The material isolated from chromatography, and the solid were combined, suspended in DCM (3 mL) and treated with triethylsilane (0.68 mL, 4.24 mmol) and TFA (0.3 mL). After 30 minutes, the suspension was cooled in an ice bath and filtered. The solid was suspended in EtOAc (20 mL) and stirred with saturated aqueous sodium bicarbonate (15 mL). After 30 minutes, the solid was isolated via filtration, washed with water and EtOAc, and dried overnight in vacuo to afford Example 1 (0.154 g, 0.422 mmol, 100%) as a white solid. HPLC: Rt=3.496 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=362.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (1H, s), 9.21 (1H, s), 8.10 (1H, s), 7.81 (1H, s), 7.64 (2H, s), 7.11 (1H, d, J=8.03 Hz), 6.25 (1H, s), 2.52-2.55 (1H, m), 2.15 (3H, s), 2.06 (3H, s), 0.75-0.82 (2H, m), 0.61-0.68 (2H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:29])[CH2:9][CH2:8]1.[H-].[Na+].[Si:35]([O:42][CH2:43][CH2:44]Br)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:35]([O:42][CH2:43][CH2:44][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:13]([CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:30]=[CH:31][CH:32]=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH2:8][CH2:9]2)[C:14]1=[O:29])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2cccc(CO)c2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)N(C2CCN(Cc3cccc(CO)c3)CC2)C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To a solution of 200 mg (0.468 mmol) of 3-[1-(3-hydroxymethylbenzyl) piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 3 ml of DMF, 22 mg (0.55 mmol) of sodium hydride (60%) were added under ice-cooling and stirred at the same temperature for 5 minutes and at room temperature for 10 minutes. After ice-cooling again, 224 mg (0.55 mmol) of 2-tert-butyldimethylsilyloxyethylbromide and 2 mg of tetrabutylammonium iodide were added thereto and stirred under ice-cooling for 4 hours. It was poured into aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with water, aqueous saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform—3% methanol/chloroform) to give 92 mg (0.16 mmol) of the title compound as colorless oil.
Reaction SMILES: C1(N)C=CC(N)=CC=1.Cl.N([O-])=O.[Na+].C.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]#[N:32])=[CH:27][CH:26]=1>O>[OH:21][C:15]1[CH:20]=[CH:19][C:18]([N:32]=[N:31][C:28]2[CH:29]=[CH:30][C:25]([NH2:24])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: N#[N+]c1ccc(N)cc1
Reactant: Oc1ccccc1
Agent: Cl
Agent: Nc1ccc(N)cc1
Agent: O=N[O-]
Solvent: O
Product: Nc1ccc(N=Nc2ccc(O)cc2)cc1

Procedure:
108 Parts by weight of p-phenylene-diamine which are placed into 300 parts by volume of water and 1000 parts by weight of ice are diazotized at a pH of from 1.5 to 3.5 by adding a total of about 200 parts by volume of 31% by weight hydrochloric acid and about 69 parts by weight of sodium nitrite in an aqueous solution. Upon clarification with active charcoal/guhr, 180 parts by weight of phenol are added, and a pH in the range of from 8 to 11 is established with 90 parts by volume of a 33% by weight sodium hydroxide solution. Within 30 minutes the 4-amino-benzene-diazonium salt is coupled to give the 4-hydroxy-4'-aminoazobenzene. Subsequently 170 parts by volume of 33% by weight of sodium hydroxide solution and 65 parts by weight of sodium nitrite are added.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH2:4][CH2:3]1>[Ni]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(COc2cccc(C#N)c2)CC1
Agent: [Ni]
Product: CN1CCC(COc2cccc(CN)c2)CC1

Procedure:
3-[(1-Methylpiperidin-4-yl)methoxy]benzonitrile (0.417 g, 1.81 mmol) was dissolved in MeOH/NH3(sat) (0.05M) and hydrogenated over a Raney Nickel CatCart (30×4 mm) using the H-Cube system (50 bar, 50° C., 1 mL/min). The product was concentrated and dried in vacuo, to give the title compound as an oil. Yield: 0.371 g (87%). 1H NMR (400 MHz, CD3OD) δ 7.18 (t, 1H, J=8.1 Hz), 6.83-6.89 (m, 2H), 6.75 (dd, 1H, J=8.1 Hz, J=2.1 Hz), 4.82 (s, 2H), 3.80 (d, 2H, J=6.1 Hz), 3.71 (s, 2H), 2.84-2.91 (m, 2H), 2.46 (s, 3H), 1.97-2.06 (m, 2H), 1.79-1.87 (m, 2H), 1.70-1.79 (m, 1H), 1.33-1.46 (m, 2H).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C(NC(C)C)(C)C.[CH2:13]([CH:15]1[CH:20]([C:21](=[O:23])[CH3:22])[CH:19]([CH3:24])[CH:18]=[CH:17][CH2:16]1)[CH3:14].C(=O)C.Cl.[Na+].[Cl-].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH2:13]([C@@H:15]1[C@H:20]([C:21](=[O:23])/[CH:22]=[CH:1]/[CH3:2])[C@@H:19]([CH3:24])[CH:18]=[CH:17][CH2:16]1)[CH3:14]
Reactant: [Li]CCCC
Reactant: CCC1CC=CC(C)C1C(C)=O
Agent: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: C/C=C/C(=O)[C@H]1[C@@H](CC)CC=C[C@@H]1C
Temperature: -20 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
At −78° C., a solution of n-butyl lithium (37.3 ml, 1.6M in hexane, 59 mmol) was treated with a solution of diisopropylamine (5.8 g, 57 mmol) in tetrahydrofuran (35 ml). The resulting solution was warmed to −20° C., cooled to −78° C., and treated with a solution of the crude 1-(6-ethyl-2-methylcyclohex-3-enyl)ethan-1-one mixture (8.1 g) in tetrahydrofuran (40 ml). The resulting solution was stirred 1 h at −70° C., warmed to 0° C., cooled at −70° C. and treated with a solution of acetaldehyde (10.5 g, 239 mmol) in tetrahydrofuran (40 ml). After 1 h stirring, a mixture of aqueous 2N HCl (50 ml) and saturated aqueous NaCl solution (50 ml) was added and the reaction mixture warmed to 0° C. The aq. phase was extracted with diethyl ether (2×100 ml) and the combined org. phases washed with saturated aqueous NaHCO3 solution and water, dried (MgSO4), and concentrated. The residue (13.4 g) dissolved in toluene (50 ml) was treated with para-toluene sulfonic acid monohydrate (0.5 g, 2.6 mmol) and refluxed during 1 h. The reaction mixture was cooled, treated with a saturated aqueous solution of Na2CO3 and the aqueous phase was extracted with cyclohexane (90 ml). The combined organic phases were washed with saturated aqueous NaCl solution, dried (MgSO4) and concentrated. FC (SiO2, hexane/methyl tert.-butyl ether 20:1) of the crude product gave (2E)-1-(rel-(1S,2S,6S)-6-ethyl-2-methylcyclohex-3-enyl)but-2-en-1-one (0.7 g, 3 steps: 7%) and a 67:27:6 mixture of (2E)-1-(rel-(1S,2S,6S)-/(2E)-1-(rel-(1R,2S,6S)-6-ethyl-2-methylcyclohex-3-enyl)but-2-en-1-one/unassigned stereoisomer (5.7 g, 3 steps: 58%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCc1ccccn1
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 2-(2-aminoethyl)pyridine in DME. EI-MS m/e (%): 306 (M+, 80), 93 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].CC(O)=O.[O:29]1[CH2:32][C:31](=O)[CH2:30]1.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:31]2[CH2:32][O:29][CH2:30]2)[CH:3]=1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2COC2)c1
Temperature: 22 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (100 mg, 0.31 mmol) in MeOH (5 mL) was added AcOH (0.05 mL) and oxetan-3-one (22 mg, 0.31 mmol). The mixture was stirred at 22° C. for 2 h. NaBH3CN (98 mg, 1.55 mmol) was added, and the resulting mixture was stirred at 22° C. for 2 h. The reaction solution was concentrated, the residue was washed with water, extracted with EA, the organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (17 mg, Yield 14.4%). 1H NMR (CD3OD, 400 MHz): δ 7.17-6.97 (m, 6H), 6.96-6.88 (m, 1H), 6.72-6.62 (m, 1H), 5.03-4.95 (m, 2H), 4.67-4.59 (m, 1H), 4.59-4.49 (m, 2H), 4.15-4.04 (m, 1H), 3.80-3.69 (m, 2H), 3.56-3.40 (m, 2H), 2.96-2.79 (m, 4H), 2.73-2.58 (m, 2H). LCMS (m/z): 382.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Cl:10]C1C=CC=CC=1O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:10])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: Oc1ccccc1Cl
Product: Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
The selectivity was 0.62 mol of 2,6-dichlorophenol per 1 mol of ortho-chlorophenol introduced.
Reaction SMILES: CC1NC2C(C=1C1C=C(C3C4C(=CC(C)=C(C)C=4)NC=3C)OC1=O)=CC(C)=C(C)C=2.[CH2:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH:42]2[CH:46]=[C:45]([C:47]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:49]([CH2:56][CH3:57])[C:48]=3[CH3:58])[O:44][C:43]2=[O:59])=[C:34]1[CH3:60])[CH3:32]>>[CH2:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]2[C:43](=[O:59])[O:44][CH:45]([C:47]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:49]([CH2:56][CH3:57])[C:48]=3[CH3:58])[CH:46]=2)=[C:34]1[CH3:60])[CH3:32]
Reactant: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)C(=O)O2)c2ccccc21
Agent: Cc1cc2[nH]c(C)c(C3=CC(c4c(C)[nH]c5cc(C)c(C)cc45)C(=O)O3)c2cc1C
Product: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)OC2=O)c2ccccc21

Procedure:
When 3,5-bis(2,5,6-trimethyl-3-indolyl)-2(3H)-furanone is substituted for 3,5-bis(1-ethyl-2-methyl-3-indolyl)-2(3H)-furanone in part B of this example, there is obtained 3,5-bis(2,5,6-trimethyl-3-indolyl)-2(5H)-furanone (Formula IV: R=H; R1 =CH3 ; Y=5,6-(CH3)2).
Reaction SMILES: [CH2:1]([OH:14])[C@@H:2]([OH:13])[CH2:3][CH2:4][CH:5]([OH:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>CCOCC.[Os](=O)(=O)(=O)=O>[OH:13][C@H:2]1[CH2:3][CH2:4][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:12][C:1]1=[O:14]
Reactant: CCCCCCC(O)CC[C@H](O)CO
Agent: O=[Os](=O)(=O)=O
Solvent: CCOCC
Product: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1

Procedure:
When (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone was prepared from (2R)-octane-1,2-epoxide as the starting compound, a tetrahydrofuran solution of an aryl Grignard reagent was synthesized from an aryl bromide by the process disclosed in Organic Synthesis, V, 608 (1973), a tetrahydrofuran solution of (2R)-octane-1,2-epoxide was added thereto, and the mixture was refluxed and reacted in an argon atmosphere. A saturated aqueous solution of ammonium chloride was added to the reacted mixture, and the mixture was extracted with chloroform. The chloroform solution was separated, washed with a saturated aqueous solution of sodium chloride, and dried on magnesium sulfate and concentrated under reduced pressure to obtain a crude product. Osmium tetroxide was added to a solution of the crude product in anhydrous ether to effect reaction, and the precipitated osmic ester was recovered by filtration and shaken with mannitol, an aqueous solution of potassium hydroxide and chloroform. Crude (2RS,5R)-1,2,5-undecanetriol was obtained from the chloroform phase, and in the same manner as described above with respect to (2S,5RS)-1,2,5-undecanetriol, protecting reaction, oxidation, removal of the protecting group, cyclization and optical resolution were carried out to obtain (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone.
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C@@H:23]3[CH2:27][C@H:26]([S:28][C:29]4[C@H:30]([CH3:53])[C@@H:31]5[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]5[C:33]=4[C:34]([O:36]CC4C=CC([N+]([O-])=O)=CC=4)=[O:35])[CH2:25][N:24]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:22])[CH2:17][C@@H:16]2[CH3:67])[CH3:14])=O)=CC=1)([O-])=O>O1CCCC1.O>[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:17][C@@H:16]1[CH3:67])(=[NH:12])[CH3:14]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1C
Solvent: C1CCOC1
Solvent: O
Product: CC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)C[C@@H]1C
Yield: 33.4 %

Procedure:
85 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-[(3S)-4-(N-4- nitrobenzyloxycarbonylacetimidoyl)-3-methylpiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 4.1 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and were hydrogenated by bubbling hydrogen through the solution at room temperature for 2 hours in the presence of 210 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 1(b), to give 14 mg of the title compound as a powder.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([CH:23]=[CH2:24])[C:20]3[CH:19]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[CH:10][CH:9]=4)[CH:22]=[C:21]([CH:23]=[CH2:24])[C:20]2=3)[CH2:28][CH2:29]1
Reactant: C=Cc1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acetic acid methyl ester (Intermediate 71, 0.14 g, 0.327 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of lithium hydroxide (1.5 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated aqueous ammonium chloride solution and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (0.135 g, 96%).
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:14]>CO>[NH2:14]/[C:2](/[CH2:8][CH3:9])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5]
Reactant: [NH4+]
Reactant: CCC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Solvent: CO
Product: CC/C(N)=C/C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 18415.4 %

Procedure:
A mixture of methyl 3-oxovalerate (75.0 g, 576 mmol), ammonium acetate (222 g, 2.88 mmol) and methanol (750 mL) was stirred at room temperature for 3 days. After concentration under reduced pressure, and water (500 mL) was added to the residue and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give the title compound (68.5 g, 92%) as a pale-yellow oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][CH2:22][CH:23]([F:25])[F:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[C:26](=O)[C:27]([N:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:45]=[C:46]=[N:47][Si](C)(C)C)(C)C.Cl.C(=O)(O)[O-]>C(#N)C>[NH2:45][C:46]1[N:47]=[C:26]([C:27]([N:29]2[CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:37]2)=[O:28])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([CH:15]([CH2:21][CH2:22][CH:23]([F:25])[F:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=2)[N:8]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CCOC(=O)C(CCC(F)F)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(CCC(F)F)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.7 g of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-5,5-difluoropentanoate are dissolved in 50 ml of acetonitrile under argon. 486 mg of caesium fluoride and 869 μl of bis(trimethylsilyl)carbodiimide are added to the solution. The mixture is stirred at room temperature for 15 min, and 6 ml of hydrochloric acid (1N) are then added, and the mixture is neutralised using bicarbonate. The aqueous phase is washed three times with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo. Yield: 1.4 g (96%) of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoate (oil); LC-MS retention time: 1.71 min (“nonpolar” gradient).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C@@H:9]([CH2:12][OH:13])[CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1C(=NO)C.P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+].C[N:29](C)[C:30](=O)[CH3:31].C(#N)C>>[CH3:31][C:30]1[O:1][C:2]2[C:11]3[O:10][CH:9]([CH2:12][OH:13])[CH2:8][O:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:29]=1
Reactant: CC(=O)N(C)C
Reactant: CC(=NO)c1ccc2c(c1O)O[C@@H](CO)CO2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nc2ccc3c(c2o1)OC(CO)CO3
Temperature: 0 °C
Reaction time: 48 h

Procedure:
3.03 g (12.6 mmole) of 1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone oxime was dissolved in- a mixture of 1:3 N,N-dimethylacetamide/acetonitrile (100 mL). The solution was cooled in an ice/water bath and a solution of phosphorus oxychloride (1.26 mL, 35 mmole) in 1:3 N,N-dimethylacetamide/acetonitrile (30 mL) was added. The reaction mixture was stirred under nitrogen over a period of 48 hours. It was then added to an ice cold, saturated solution of sodium acetate, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated in vacuum. The resulting crude oil was column chromatographed on silica gel with 60% hexane/ethyl acetate to remove impurities and the product eluted with 40% hexane/ethyl acetate. After evaporation of the solvent in vacuum, 2.08 g (75%) of the (S)-enantiomer of the title compound was obtained as a white solid, m.p. 120° C. MS (ESI) m/z 222 (M+H)+.