Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.Cl[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:23](=[O:24])[C:22]3[N:14]([C:15]4[C@@H:16]5[CH2:25][C@H:19]([C:20]=4[CH:21]=3)[CH2:18][CH2:17]5)[CH2:13][CH2:12]2)[C:6]=1[CH:26]=[O:27].[CH3:28][N:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][C@@H:52]3[CH3:61])=[CH:47][N:46]=2)[C:30]1=[O:62].C([O-])(=O)C.[K+]>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].O>[CH3:28][N:29]1[C:30](=[O:62])[C:31]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:58][O:59][CH2:60]4)[CH2:53][C@@H:52]3[CH3:61])=[CH:47][N:46]=2)=[CH:32][C:33]([C:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[C:23](=[O:24])[C:22]4[N:14]([C:15]5[C@@H:16]6[CH2:25][C@H:19]([C:20]=5[CH:21]=4)[CH2:18][CH2:17]6)[CH2:13][CH2:12]3)[C:6]=2[CH:26]=[O:27])=[CH:34]1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2[C@H]2CC[C@@H]3C2)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5[C@H]5CC[C@@H]6C5)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 80 °C
Yield: 28.8 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (30 mL), 4-chloro-2-[(1S,11R)-7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl]pyridine-3-carbaldehyde 167g (170 mg, 0.50 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 130f (336 mg, 0.70 mmol), water (3 mL), and potassium acetate (147 mg, 1.5 mmol). After bubbling argon through the suspension for 30 minutes, 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (408 mg, 0.05 mmol) was added. The system was subjected to three cycles of vacuum/argon flush and heated at 80° C. for 3 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×100 ml). The combined filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 171a (95 mg, 29%) as a light yellow solid. MS-ESI: [M+H]+ 661.3
Reaction SMILES: [C:1]([S:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O.C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:1]([S:5](/[N:7]=[CH:8]\[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C=O
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1/C=N\S(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
tert-Butylsulphinamide (1.21 g, 10 mmol) was added to a stirred mixture of tert-butyl 2-formylpiperidine-1-carboxylate (1.64 g, 7.7 mmol) and titanium ethoxide (3.2 mL, 15.4 mmol) in THF (20 mL). The reaction mixture was stirred for 12 h at ambient temperature, poured into a bi-phasic mixture of brine (100 mL) and ethyl acetate (100 mL) and stirred for a further 30 min. The mixture was filtered through a pad of Celite and the phases were separated. The organic phase was dried (MgSO4) and concentrated to give the title product which was used without purification (2.77 g). 1H NMR (400 MHz, CDCl3): δ 7.93 (1H, dd, J=6.8, 2.1 Hz), 5.03 (1H, br), 4.00 (1H, br s), 2.76-3.03 (1H, br), 2.1 (1H, d, J=13 Hz), 1.87-1.55 (3H, m), 1.50-1.40 (9H, br), 1.36-1.13 (11H, m),
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[C:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])=[N:5]2.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[C:21]([C:25](O)=[O:26])[CH:20]=1.Cl.CN(C)CCCN=C=NCC.CO.C(Cl)Cl>ClC(Cl)C.CN(C)C1C=CN=CC=1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[C:11][C:12]1[CH:13]=[C:14]([NH:15][C:25](=[O:26])[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH3:28])[CH:20]=3)[CH:16]=[CH:17][CH:18]=1)=[N:5]2
Reactant: Nc1cccc(C#Cc2ccc3nccn3n2)c1
Reactant: Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2cccc(C#Cc3ccc4nccn4n3)c2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-(imidazo[1,2-b]pyridazin-6-ylethynyl)aniline (93.6 mg, 0.4 mmol, 1 eq) and m-toluic acid (55 mg, 1 eq) in anhydrous dichloroethane (4 mL) under nitrogen atmosphere was added 4-(dimethylamino)pyridine (10 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (92.2 mg, 1.2 eq). After the reaction was stirred at 60° C. for four hours and was cooled to room temperature, white precipitates were observed. It was filtered directly to give a white solid. This solid was further subject to a gradient column chromatography (MeOH-DCM 1:50 to 1:20) to yield N-[3-(imidazo[1,2-b]pyridazin-6-ylethynyl)phenyl]-3-methylbenzamide as a white solid in amount of 85 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9](=O)[C@@H:8]([F:13])[CH2:7]1)=[O:5])[CH3:2].[CH3:14][C@@H:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClC(Cl)C.C(O)(=O)C.CO.ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:22][C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])[C@@H:8]([F:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCC(=O)[C@@H](F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCOC(=O)[C@@H]1CC[C@@H](N[C@H](C)c2ccccc2)[C@@H](F)C1
Reaction time: 4.5 h

Procedure:
Ketone (b) (1.02 g, 5.4 mmol) in dichloroethane (24 mL) and acetic acid (1 mL) was treated with (R)-α-methyl benzylamine (0.88 mL) and sodium triacetoxyborohydride (2.2 g). After 4.5 hours, the reaction mixture was loaded onto a silica gel column packed in 0.5% (2M ammonia in methanol) in dichloromethane and eluted with 0.5-10% (2M ammonia in methanol) in dichloromethane to give an oil (1.2 g).
Reaction SMILES: [C:1]([O-:17])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O-:15])=[O:14].[K+].[K+].[C:20]([O-])(=O)[CH2:21]CCCCCCCCCCCCCCCC.[Al+3].C([O-])(=O)CCCCCCCCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCCCCCCCC>>[C:1]1(=[O:17])[O:16][CH2:21][CH2:20][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])CCCCCCCCCCCC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Al+3]
Agent: [K+]
Product: O=C1CCCCCCCCCCCC(=O)OCCO1
Yield: 81.6 %

Procedure:
A mixed metal catalyst comprised of potassium brassylate and aluminum stearate (1:1 molar ratio of K:Al) was employed for the depolymerization of poly(ethylene brassylate) at a 1.8 wt. percent level. An 81.6 percent yield of ethylene brassylate was obtained. Comparable yields are obtained when this mixed metal catalyst is used for the depolymerization of poly(ethylene sebacate) and poly(3-oxa-pentamethylene azelate).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[C:16]([CH3:32])[CH:15]=2)=[CH:9][C:8]=1[CH2:33][CH2:34][CH3:35])C.[Li+].[OH-].O.Cl>C1COCC1>[CH3:32][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH2:33][CH2:34][CH3:35])[CH:9]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=1
Reactant: CCCc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Compound 4.5 (32.7 g, 63.0 mmol) was dissolved in THF (250 mL). To the solution was added 4N LiOH (31.5 mL, 126 mmol) and the reaction was stirred at room temperature for 1 h, after which time water (31.5mL) was added, and the reaction mixture was stirred for 30 min. 2N HCl (70 mL) was then added to the reaction and the THF was removed in vacuo. The residue was diluted with hexane (250 mL) with stirring, and the deposited crystals were collected by filtration and recrystallized from EtOAc—hexane to provide 4 (24.12 g). MS APSI m/e: 489 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 12.90 (1H, brs); 7.76 (2H, d, J=8.2 Hz); 7.67 (2H, d, J=8.2 Hz); 7.20-7.05 (4H, m); 6.99 (1H, d, J=8.6 Hz); 6.81 (1H, d, J=8.4 Hz); 5.23 (2H, s); 4.68 (2H, s); 2.56-2.47 (2H, m); 2.18 (3H, s); 1.60-1.47 (2H, m); 0.85 (3H, t, J=7.4 Hz).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])=[CH:48][CH:47]=2)=[CH:26][CH:25]=1.CN1CCOCC1.[NH2:68][C@@H:69]([C:80]([OH:82])=[O:81])[CH2:70][C:71]1[C:79]2[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=2)[NH:73][CH:72]=1.[BH4-].[Na+]>CN(C=O)C.CO.CS(C)=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][CH:37]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[OH:38])[C@H:31]2[C:46]2[CH:47]=[CH:48][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:68][C@@H:69]([C:80]([OH:82])=[O:81])[CH2:70][C:71]3[C:79]4[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=4)[NH:73][CH:72]=3)=[O:57])=[O:53])=[CH:59][CH:60]=2)=[CH:28][CH:29]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 1 h

Procedure:
TBTU (0.016 g, 0.051 mmol) was added to a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.025 g, 0.046 mmol) and N-methylmorpholine (0.014 g, 0.139 mmol) in DMF (2 ml) at 30° C. After 1 h, DMSO (1 ml) and D-tryptophan (0.019 g, 0.092 mmol) were added. After 10 minutes, the reaction was quenched by the addition of water (1 ml). The mixture was stirred for 10 minutes and MeOH (1 ml) and NaBH4 (0.035 g, 0.925 mmol) were added. After 5 minutes, full conversion to the corresponding alcohol was obtained. The reaction was quenched by the addition of 0.1M NH4OAc buffer (1 ml). The reaction mixture was concentrated and the residue was purified by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M NH4OAc buffer. This gave the title compound (0.028 g, 83%) as a colurless solid. M/z: 727.0 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 2.79-3.18 (m, 4H), 3.61-3.80 (m, 2H), 4.26-4.34 (m, 2H), 4.43-4.54 (m, 2H), 4.68-4.78 (m, 1H), 4.97-5.04 (m, 1H), 6.84-7.55 (m, 1H), 7.65-7.82 (m, 1H), 8.22-8.25 (m, 1H), 10.73 (s, 1H).
Reaction SMILES: N(OCCC(C)C)=O.[Cl-:9].[Li+].N[C:12]1[C:13]([O:24][CH3:25])=[CH:14][C:15]([Cl:23])=[C:16]2[C:21]=1[C:20](=[O:22])[NH:19][CH2:18][CH2:17]2>C(#N)C.[Cu](Cl)Cl>[Cl:23][C:15]1[CH:14]=[C:13]([O:24][CH3:25])[C:12]([Cl:9])=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][C:20]2=[O:22]
Reactant: [Cl-]
Reactant: COc1cc(Cl)c2c(c1N)C(=O)NCC2
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: [Li+]
Solvent: CC#N
Product: COc1cc(Cl)c2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
Isopentyl nitrite (20 mL, 0.149 mol) was added dropwise to a heated (55° C.) suspension of copper (II) chloride (40 g, 0.298 mol) and lithium chloride (38 g, 0.905 mol) in acetonitrile (500 mL). The mixture was stirred at that temperature for 5 minutes, then 8-amino-5-chloro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (296d, 20 g, 0.089 mol) was added in portions. After the addition was complete, stirring was continued at 55° C. for 45 minutes. The reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (300 mL), and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with aqueous ammonium chloride (200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under vacuum to give crude 5,8-dichloro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (296e, 20 g, 90% purity, 92% yield) as a brown solid. MS: 245 [M+1].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][NH:12][C:4]=2[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: N#Cc1nc(Cl)cc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1nc(Cl)cc2c1ncn2C1CCCCO1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
6-Chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (620 mg) and p-toluenesulfonic acid monohydrate (10 mg) were suspended in ethyl acetate (10 ml) and heated to 60° C. 3,4-Dihydro-2H-pyran (0.48 ml) was added dropwise and the reaction stirred at 60° C. overnight. The reaction was quenched with 5 mL ammonium hydroxide before addition of water (100 mL) and ethyl acetate (200 mL). Organic layer was separated, dried over sodium sulphate and solvent was evaporated under reduced pressure. The crude product was dissolved in a minimum volume of EtOAc and heptane added. The resulting brown solid was collected by filtration to yield 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (630 mg). 1H NMR (DMSO) δ: 8.92 (s, 1H), 8.30 (s, 1H), 5.80 (d, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 2.19 (m, 1H), 2.11 (m, 1H), 1.62 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][N:17]=1)(=[O:14])[CH3:13].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([NH:15][C:16]1[N:17]=[CH:18][C:19](/[CH:8]=[CH:7]/[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=2)=[CH:20][CH:21]=1)(=[O:14])[CH3:13]
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(/C=C/c2cccc([N+](=O)[O-])c2)cn1
Temperature: 0 °C
Reaction time: 6 h
Yield: 90.3 %

Procedure:
A mixture of 3-nitrostyrene (7.0 g), 2-acetamido-5-bromopyridine (10.1 g), tetra-n-butylammonium chloride (13.1 g), palladium(II) acetate (0.08 g) and sodium bicarbonate (9.87 g) in N,N-dimethylformamide (70 ml) was stirred at 110pbC. for 6 hours. The reaction mixture was poured into ice-water and precipitated crystals were collected, washed with water and dried to give 3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]nitrobenzene (12.0 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4]([CH2:5][C:6](=[N:8][O:9]CC(C)(C)C)[CH3:7])[C@H:3]1[C:15]([O:17][CH:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].[CH3:35][C:36]1(C)[C@@H](CC(=NOCC(C)C)C)[C@H:37]1C(OCC1C=CC=C(OC2C=CC=CC=2)C=1)=O.CC1(C)[C@@H](CC(=NOCC2CC2)C)[C@H]1C(OC(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)=O.CC1(C)[C@@H](CC(=NOCC2CCC2)C)[C@H]1C(OC(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)=O.C(C(O)C1C=CC=C(OC2C=CC=CC=2)C=1)#C.C1(=O)N(CO)C(=O)C2CCCCC1=2.ClC1C=CC=C(Cl)C=1CO.CC1C(O)CC(=O)C=1CC=C>>[CH3:34][C:2]1([CH3:1])[C@@H:4]([CH2:5][C:6](=[N:8][O:9][CH:36]([CH3:37])[CH3:35])[CH3:7])[C@H:3]1[C:15]([O:17][CH:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: CC(C[C@H]1[C@@H](C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C)=NOCC(C)C
Reactant: CC(C[C@H]1[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C)=NOCC(C)(C)C
Agent: C#CC(O)c1cccc(Oc2ccccc2)c1
Agent: C=CCC1=C(C)C(O)CC1=O
Agent: CC(C[C@H]1[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C)=NOCC1CC1
Product: CC(C[C@H]1[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C)=NOC(C)C

Procedure:
Following procedures similar to Embodiment II above: α-cyano -3-phenoxybenzyl (1R,cis)-2,2-dimethyl-3-(2-(neopentoxyimino)propyl)cyclopropanecarboxylate, 3-phenoxybenzyl (1R,cis)-2,2-dimethyl-3-(2-(isobutoxyimino)propyl)cyclopropanecarboxylate, α-cyano-3-phenoxybenzyl (1R,cis)-2,2-dimethyl-3-(2-(cyclopropylmethoxyimino)propyl)cyclopropanecarboxylate, α-cyano-3-phenoxybenzyl (1R,cis)-2,2-dimethyl-3-(2-(cyclobutylmethoxyimino)propyl)cyclopropanecarboxylate are prepared as well as the corresponding esters in the racemic and (1R,trans) form and similar esters with other alcohols: α-ethynyl-3-phenoxybenzyl alcohol, 3,4,5,6-tetrahydrophthalimidomethyl alcohol, 2,6-dichlorobenzyl alcohol, 2-chloro-4-phenyl-2-butenl-o1 and allethrolone.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=1[N:37]=[C:38]=[O:39].Cl>C1COCC1>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([C:38]([NH:37][C:28]1[C:29]([O:35][CH3:36])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=1[O:26][CH3:25])=[O:39])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:24]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)Nc1c(OC)cc(OC)cc1OC)c1ccccc1
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
To a stirred, room temperature solution of diisopropylamine (43.4 mL, 0.310 mol) in dry THF (1.2 L) was added a 2.5M solution (124 mL, 0.31 mol) of n-butyl lithium in hexanes in one portion, and the mixture was cooled to -78° C. To the solution was added under nitrogen a solution of phenylacetic acid, ethyl ester (50.8 g, 0.309 mol) in THF (500 mL) over 15 minutes. Stirred 2 minutes. To the mixture was added a solution of 2,4,6-trimethoxyphenyl isocyanate (64.9 g, 0.310 mol) in THF (500 mL) over 10 minutes. Stirred 1.5 hours. The reaction was quenched with 1M HCl (310 mL, 0.310 mol) and allowed to warm to room temperature. The mixture was rotoevaporated to remove THF and partitioned between water and chloroform. The organic layer was washed (1M HCl; saturated NaCl), dried (Na2SO4), and rotoevaporated. The residue was chromatographed on silica gel (1.4 kg, 230-400 mesh) using petroleum ether-ethyl acetate (1:1). Fractions containing product were rotoevaporated, and the residue crystallized from ethanol-ether to give a white solid; yield 46.9 g (41%); mp 109°-111° C.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:11][CH:10]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-BOC-3-hydroxyazetidine (1.0 g, 5.77 mmol), 4-dimethylaminopyridine (7 mg, 0.058 mmol) and triethylamine (0.880 mL, 6.35 mmol) in DCM (15 mL) cooled at 0° C. was added dropwise methanesulfonyl chloride (0.45 mL, 5.77 mmol). The RM was stirred 18 h at rt, diluted with DCM, washed with a solution of saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. 3-Methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester obtained as an oil was used directly in the next step. To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g 5.57 mmol) in DMF (20 mL) stirred at 0° C. was added sodium hydride (55% in oil, 0.243 g, 5.57 mmol). After addition the mixture was stirred 1 h at rt, a solution of the above obtained 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (1.4 g, 5.57 mmol) in DMF (3 mL) was added. The RM was stirred 30 min at rt, and then 3 h at 95° C. After cooling at rt the mixture was poured in ice water and extracted with EtOAc. The combined organic phases were washed with a solution of saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (with heptane and EtOAc as eluants) to afford the title compound as an oil (tR 4.33 min (conditions 3), MH+=350.1)
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:19][CH2:18][C@@:17]34[C:20]5[C:26]6[CH2:27][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][C:11]2([C@@H:16]4[O:22][C:21]=5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=6)OCC[O:12]2)[CH2:4][CH2:3][CH2:2]1>Cl>[CH:1]1([CH2:5][N:6]2[CH2:19][CH2:18][C@@:17]34[C:20]5[C:26]6[CH2:27][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][C:11](=[O:12])[C@@H:16]4[O:22][C:21]=5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=6)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc2c3c1O[C@H]1C4(CC[C@H]5[C@@H](C2)N(CC2CCC2)CC[C@@]351)OCCO4
Agent: Cl
Product: N#Cc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(CC2CCC2)CC[C@]314
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
A suspension of (4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (31.1 g, 79.2 mmol) in 6M HCl (aq) (250 mL) was stirred at room temperature at room temperature for 24 hours. Further 6M HCl was added (25 mL) and stirred for an additional 24 hours. The reaction was poured onto ice/NH3(aq) and stirred for 30 minutes and the solid collected by suction filtration and washed with water. The solid was dissolved in dichloromethane and washed with brine, dried over MgSO4 and concentrated under reduced pressure to give (4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carbonitrile (26.1 g, 96% pure LCMS, 95% yield); [M+H]+367.2.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].C([Li])CCC.CCCCCC.P(Cl)(OCC)(OCC)=O.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][N:30]=1>O1CCCC1.O>[Br:28][C:29]1[N:30]=[CH:31][C:32](/[CH:35]=[CH:1]/[S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3])=[CH:33][CH:34]=1
Reactant: CCOS(C)(=O)=O
Reactant: O=Cc1ccc(Br)nc1
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOS(=O)(=O)/C=C/c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Ethyl methanesulfonate (1.00 mL, 9.34 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) in an oven dried round bottle under an atmosphere of argon. The solution was cooled to −78° C. and 2.5 M n-butyllithium in hexane (4.09 mL, 10.23 mmol) was added dropwise over 15 min. The mixture was stirred at −78° C. for 15 min and diethyl chlorophosphate (0.78 mL, 5.38 mmol) was added dropwise. The reaction was stirred at −78° C. for 1 h and then the temperature was allowed to reach 0° C. before recooling to −78° C. A solution of 2-bromo-5-formylpyridine (1.0 g, 5.38 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise over 15 min and the resulting mixture was stirred for 15 min and then allowed to reach ambient temperature. Water (3 mL) was added and the solvent was evaporated in vacuo. The residue was partitioned between diethyl ether and water. The aqueous phase was extracted with diethyl ether and the formed precipitate was filtered off and rinsed with diethyl ether. This was pure product which was pooled with the rest of the material after purification. The aqueous phase was extracted once more with diethyl ether and the combined organic phases were dried over magnesium sulfate and concentrated. Purification by column chromatography, using a gradient of 10-60% ethyl acetate in heptane as the eluent, gave 0.77 g pooled with the material from the extractive work up to give 1.42 g (90% yield) of the title compound.