Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:10][Si:11]([CH3:14])([CH3:13])Cl>BrCCBr.C1COCC1>[CH3:10][Si:11]([CH3:14])([CH3:13])[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cl)c1
Reactant: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1cccc([Si](C)(C)C)c1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A solution of m-chlorotoluene (25.3 g, 0.20 mol), 1,2-dibromoethane (2.18 g, 11.6 mmol) and THF (40 cm3) was added to magnesium turnings (5.35 g, 0.22 mol). The mixture was heated under reflux in an atmosphere of argon for 4 h, after which the heating bath was removed and trimethylchlorosilane (23.9 g, 0.22 mol) was added so that gently reflux was maintained. The mixture was stirred for another 30 min and then separated between 5% NaHCO3 (100 cm3) and dichloromethane (3×100 cm3). The organic extract was washed with brine and dried (MgSO4). The solvent was removed under reduced pressure affording the title compound (29.4 g, 89%) as a pale yellow liquid, which was used without purification in the next reaction. All spectroscopic data were identical to those reported in the literature (Eisenhut et al., ibid).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[CH:9](C=C)=O.C1CC=CC=1>>[CH:5]12[CH2:9][CH:2]([CH:1]([CH:7]=[O:8])[CH2:6]1)[CH:3]=[CH:4]2
Reactant: C=CC=O
Reactant: O=CC1CC=CCC1
Agent: C1=CCC=C1
Product: O=CC1CC2C=CC1C2

Procedure:
Examples of suitable cyclic polyaldehydes are trans-1,3-cyclohexanedicarboxaldehyde; cis-1,3-cyclohexanedicarboxaldehyde; trans-1,4-cyclohexanedicarboxaldehyde; cis-1,4-cyclohexanedicarboxaldehyde; a mixture of 1,3-cyclohexanedicarboxaldehydes and 1,4-cyclohexanedicarboxaldehydes, preferably a 1-to-1 mixture thereof; exo,exo-2,5-norbornanedicarboxaldehyde; exo,exo-2,6-norbornanedicarboxaldehyde; exo,endo-2,5-norbornanedicarboxaldehyde; exo,endo-2,6-norbornanedicarboxaldehyde; endo,endo-2,5-norbornanedicarboxaldehyde; endo,endo-2,6-norbornanedicarboxaldehyde product (endo and exo mixture); 3-(3-formylcyclohexyl)propanal; 3-(4-formylcyclohexyl)propanal; 2-(3-formylcyclohexyl)propanal; 2-(4-formylcyclohexyl)propanal; and cyclododecane-1,4,8-tricarbaldehyde. The trans-1,3-cyclohexanedicarboxaldehyde; cis-1,3-cyclohexanedicarboxaldehyde; trans-1,4-cyclohexanedicarboxaldehyde; and cis-1,4-cyclohexanedicarboxaldehyde can be prepared by a process comprising hydroformylating 3-cyclohexene-1-carboxaldehyde using the hydroformylating conditions described later. The 1:1 mixture of 1,3- and 1,4-cyclohexanedicarboxaldehydes can be prepared by a process comprising reacting acrolein and 1,3-butadiene in a Diels-Alder reaction to give 3-cyclohexenecarboxaldehyde (also called 1,2,3,6-tetrahydrobenzaldehyde), and hydroformylating the 3-cyclohexenecarboxaldehyde. The exo,exo-2,5-norbornanedicarboxaldehyde; exo,exo-2,6-norbornanedicarboxaldehyde; exo,endo-2,5-norbornanedicarboxaldehyde; exo,endo-2,6-norbornanedicarboxaldehyde; endo,endo-2,5-norbornanedicarboxaldehyde; and endo,endo-2,6-norbornanedicarboxaldehyde product (endo and exo mixture) can be prepared by a process comprising reacting acrolein and cyclopentadiene in a Diels-Alder reaction to give a 2-norbornene-5-carboxaldehyde, and hydroformylating the 2-norbornene-5-carboxaldehyde. The 3-(3-formylcyclohexyl)propanal; 3-(4-formylcyclohexyl)propanal; 2-(3-formylcyclohexyl)propanal; and 2-(4-formylcyclohexyl)propanal can be prepared by a process comprising hydroformylating vinyl cyclohexene. The cyclododecane-1,4,8-tricarbaldehyde can be prepared by a process comprising trimerizing 1,3-butadiene to give 1,4,8-cyclododecatriene, and hydroformylating the 1,4,8-cyclododecatriene.
Reaction SMILES: C([O:4][C:5](=[O:29])[C@@H:6]([CH2:26][O:27][CH3:28])[CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)=[O:17])[CH2:9][O:10][CH2:11][O:12][CH2:13][CH3:14])C=C.N1CCOCC1>C1COCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([O:12][CH2:11][O:10][CH2:9][C@@H:8]([NH:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)=[O:17])[CH2:7][C@H:6]([CH2:26][O:27][CH3:28])[C:5]([OH:29])=[O:4])[CH3:14]
Reactant: C=CCOC(=O)[C@@H](COC)C[C@@H](COCOCC)NC(=O)c1ccc(C#N)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: CCOCOC[C@H](C[C@H](COC)C(=O)O)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
To the solution of the compound prepared in Example 5 (1.45 g) and morpholine (0.38 ml) in THF (3.6 ml), tetrakis(triphenylphosphine) palladium(0) (20 mg) was added, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with 1N aqueous solution of hydrochloride and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.33 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[N:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[N:15][C:14]([NH2:17])=[CH:13][N:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1cnc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1cnc(N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
A solution of 2-(5-nitro-pyrazin-2-yl)-malonic acid diethyl ester (425 mg, 1.5 mmol) in ethanol (10 mL) at 25° C. was treated with ammonium formate (510 mg, 8.1 mmol) and 10% palladium on activated carbon (51 mg). The mixture was heated to 95–100° C. for 4 h and then was stirred at 25° C. overnight. At this time, the catalyst was removed by filtration through a pad of celite (ethanol wash). The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 ethyl acetate/hexanes) afforded 2-(5-amino-pyrazin-2-yl)-malonic acid diethyl ester (131.5 mg, 37%) as a light tan solid: EI-HRMS m/e calcd for C11H15N3O4 (M+) 253.1063, found 253.1065.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:40]=[CH:41][C:42]([OH:50])=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:44]=1)[OH:38]>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][CH:31]([NH:35][CH2:36][CH:37]([C:39]5[CH:40]=[CH:41][C:42]([OH:50])=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:44]=5)[OH:38])[CH2:32][CH2:33]4)=[CH:26][CH:27]=3)[C:18](=[O:20])[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(NC5CCN(Cc6ccccc6)CC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 21) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 9) according to the procedure of Example 1 as a pale yellowish solid; mp>210° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.8 Hz, 2 H), 2.50-3.50 (m, 6 H), 2.92 (s, 3 H), 3.47 (s, 2 H), 3.70-4.00 (m, 2 H), 4.47 (dd, J=7.9, 4.3 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.95-7.05 (m, 2 H), 7.17 (d, J=1.9 Hz, 1 H), 7.20-7.55 (m, 8 H); MS (ES) m/z:353.1 ((M+2H)2+, 100%); 705.1 (MH+, 5%); HRMS Calcd. for C36H45N6O5S2 (MH+): 705.2893. Found: 705.2921.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[C:8]([C:24](=[O:26])[NH2:25])[CH:7]=[N:6][N:5]2[CH:27]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.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]>[C:24]([C:8]1[CH:7]=[N:6][N:5]2[CH:27]=[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)(=[O:26])[NH2:25]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1
Temperature: 130 °C
Yield: 85.1 %

Procedure:
A solution of (S)-tert-butyl 3-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)piperidine-1-carboxylate (75 mg, 0.17 mmol), phenylboronic acid (31.3 mg, 0.26 mmol), and PdCl2(dppf) 6.3 mg, (0.009 mmol) in DMF (1.5 mL) was added aq. K3PO4 (2M, 0.26 mL) then heated at 130° C. for 25 min. The mixture was poured into ethyl acetate (with 20% heptane) and washed with water then sat. aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (50-75% ethyl acetate in heptane) to afford the title compound (63 mg, 85% yield). LCMS 436.16 (M+H)+; HPLC (conditions L): retention time=4.02 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:5][CH:4]=1.C(O)C.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[N:22][OH:23])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2cccc(C=NO)c2)cc1
Temperature: 85 °C
Yield: 102.8 %

Procedure:
3-(4-Methoxyphenoxy)benzaldehyde (Aldrich, Cat. #195898) (0.10 g, 0.44 mmol) was dissolved in ethanol (2.1 mL, 37 mmol) and water (0.43 mL) at r.t., and the hydroxylamine hydrochloride (0.061 g, 0.88 mmol) and sodium acetate (0.072 g, 0.88 mmol) were added. The reaction was heated in a sealed tube to 85° C. for 2 h., and allowed to cool to r.t. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3-(4-methoxyphenoxy)benzaldehyde oxime (0.11 g, 100%) as an oily residue.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:18].[C:19]([Cu])#[N:20]>CN1C(=O)CCC1>[Cl:18][C:3]1[C:4]2[N:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:5]=2[CH:16]=[CH:17][C:2]=1[C:19]#[N:20]
Reactant: CCc1nc2c(Cl)c(Br)ccc2n1CC(F)(F)F
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCc1nc2c(Cl)c(C#N)ccc2n1CC(F)(F)F
Temperature: 220 °C
Yield: 49.2 %

Procedure:
5-Bromo-4-chloro-2-ethyl-1-(2,2,2-trifluoroethyl)-1H-benzimidazole (0.036 g, 0.106 mmol) and CuCN (0.020 g, 0.222 mmol) were combined in NMP (3 mL) and heated to 220° C. for 20 min in a microwave. The cooled mixture was partitioned between Et2O and water, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.015 g): 1NMR (400 MHz, CDCl3) δ7.56 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.68 (q, J=8.2 Hz, 2H), 2.96 (q, J=7.4 Hz, 2H), 1.45 (t, J=7.4 Hz, 3H); MS (ESI) m/z 288 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH:32]([NH2:35])([CH3:34])[CH3:33]>>[OH:27][C:23]1[CH:22]=[C:21]([CH:8]2[C:9]3[NH:10][C:11]4[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4)[C:17]=3[CH2:18][C:6]3([CH3:30])[C:5](=[O:31])[N:4]([CH2:3][CH2:2][NH:35][CH:32]([CH3:34])[CH3:33])[C:28](=[O:29])[N:7]23)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: CC(C)N
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNC(C)C)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and isopropyl amine as starting materials. MS: m/z (MH+)=463.2
Reaction SMILES: C([C:4]1([OH:33])[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[C:16]([O:22][CH2:23][CH3:24])[C:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:14][C:13]=1[CH2:12][CH2:11]3)C=C.C1OCCOCCOCCOCCOCCOC1.[CH3:52][CH:53](O)[CH3:54].[NH4+].[Cl-]>C1COCC1>[CH2:54]([C@@H:8]1[C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH3:6])[C:4](=[O:33])[CH2:9]1)[C:18]1[CH:17]=[C:16]([O:22][CH2:23][CH3:24])[C:15]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:14][C:13]=1[CH2:12][CH2:11]3)[CH:53]=[CH2:52]
Reactant: CC(C)O
Reactant: C=CCC1(O)CC[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)c(OCC)cc4[C@H]3CC[C@@]21C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC[C@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4cc(OCC)c(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
KH 30% in oil (89.98 mmol) was suspended in THF (50 ml), under N2 atmosphere. 17-Allyl-3-(benzyloxy)-2-ethoxy-estra-1,3,5(10)-trien-17-ol (7.7 g, 17.30 mmol) and 18-Crown-6 (88.25 mmol) were dissolved in THF (200 ml) and added dropwise in 40 min. The mixture was stirred for 3 h at RT. The mixture was carefully poured into IPA via canula. The mixture was poured into aq. sat. NH4Cl (1 l). The water layer was extracted with EtOAc (3×250 ml). The combined organic layers were washed with brine (1×500 ml), dried over Na2SO4 and concentrated in vacuo. Purification via filtration over Silica (eluens heptan to 40% DCM in heptan) provided 4.2 g (9.51 mmol, 55%) of (XXX-(C2-D)-2c).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C@H:29]([CH2:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C@H:29]([OH:28])[CH2:35][CH3:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC[C@@H](O)CC(=O)OC
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC[C@@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (58 mg, 54%), MS (ISP) m/z=431.5 [(M+H)+], mp 161° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl (R)-3-hydroxy-pentanoate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29]Br.CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29][N:9]([CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:11]
Reactant: Cc1cccnc1CNC(C)c1ccccn1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)C(C)c1ccccn1

Procedure:
Using General Procedure A, reaction of (3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amine and 2-bromomethyl-5-cyano-benzoic acid methyl ester in CH3CN with DMAP, KI, and DIPEA gave 5-cyano-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzoic acid methyl ester as an amber oil. 1H NMR (CDCl3) δ 1.26 (t, 1H, J=7.3 Hz), 1.58 (d, 3H, J=6.7 Hz), 1.73 (s, 1H), 2.04 (s, 1H), 2.09 (s, 3H), 3.73-3.94 (m, 1H), 3.87 (s, 3H), 4.08-4.19 (m, 4H), 6.92-6.98 (m, 1H), 7.14-7.20 (m, 1H), 7.23 (d, 1H, J=8.0 Hz), 7.34 (d, 1H, J=7.8 Hz), 7.48-7.53 (m, 1H), 7.64-7.69 (m, 2H), 7.92 (d, 1H, J=1.6 Hz), 8.21 (d, 1H, J=3.0 Hz), 8.57 (d, 1H, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=1)[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=2)[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH:7]=1
Reactant: Cc1cc(N)c2cnn(-c3cccc(C(=O)OCc4ccccc4)c3)c2c1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)OCc2ccccc2)c1)C(F)(F)F
Temperature: 85 °C
Reaction time: 21 h
Yield: 65.3 %

Procedure:
A mixture of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 350 mg, 1.2 mmol), phenylmethyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (Intermediate 29, 357 mg, 1.0 mmol) and ytterbium(III) triflate (124 mg, 0.2 mmol) in acetonitrile (2 mL) was heated at 85° C. for 18 hours when the temperature was raised to reflux temperature and heating continued for a further 21 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (50 mL) and aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted again with dichloromethane (50 mL) and the combined organic extracts were dried over anhydrous sodium sulphate and evaporated. The residue was purified by silica gel chromatography using the Flashmaster II (50 g cartridge) eluting with a 1:1 cyclohexane:ethyl acetate gradient over 40 minutes to give the title compound as a white solid (424 mg).
Reaction SMILES: [C:1]1([C:11]2([CH2:16]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C-:22]#[N:23].[Na+].C(OCC)(=O)C>CS(C)=O.CCCCCC>[C:1]1([C:11]2([CH2:16][C:22]#[N:23])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2cccc3ccccc23)CCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CCC1(c2cccc3ccccc23)CCCC1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
To a stirred solution of methanesulfonic acid 1-naphthalen-1-yl-cyclopentylmethyl ester (341) (2.1 g, 6.90 mmol) in dimethyl sulfoxide (10.0 mL) were added KI (115 mg, 0.69 mmol) and NaCN (507 mg, 10.35 mmol) and the reaction mixture was stirred at 140° C. for 2 h (silica TLC, 10% ethyl acetate in hexane; Rf=0.5). The reaction mass was cooled to room temperature, quenched with FeSO4 solution (15 mL) and diluted with water (100 mL). The resulting solid was separated through filtration and washed well with ethyl acetate. The biphasic layer was separated in a separating funnel. The organic part was washed with brine (2×50 mL), dried and concentrated in vacuo to get a crude mass which was purified by Combi-Flash using a mixture of ethyl acetate and hexane as gradient eluent to get pure (1-naphthalen-1-yl-cyclopentyl)-acetonitrile (342) (710 mg, 44%) as a yellow gummy liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]2[O:10][CH2:9]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N-]=[N+]=[N-].[Na+]>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C@@H:8]2[O:10][CH2:9]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C2CO2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc([C@H]2CO2)cc1
Reaction time: 0.25 h

Procedure:
To 1 ml of Tris-SO4 buffer (50 mM, pH=7.3) containing 0.25 mM of para-nitro styrene oxide and 0.5 mM of NaN3, 0.7 mg of purified enzyme, obtained according to Example 1, was added. The reaction was stopped after 15 min and the solution was extracted with diethylether. The organic phase was analysed by chiral HPLC. The remaining (S)-para-nitro styrene oxide was obtained with an e.e. >99% and the product (R)-2-azido-1-(para-nitro-phenyl)-ethanol with an e.e. of 96%. The other regio-isomer 2-azido-2-(para-nitro-phenyl)-ethanol was formed in a ratio of 1:217 compared to (R)-2-azido-1-(para-nitro-phenyl)-ethanol. From this we concluded that the enzymatic azidolysis is almost absolutely regioselective (β selectivity>99%). The observed lower regioselectivity during a kinetic resolution on a longer time scale was due to the unwanted chemical side reaction.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH:40]1([CH2:46][N:47]=[C:48]=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([CH2:46][NH:47][C:48]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C=NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)NCC3CCCCC3)CN2C1=O
Yield: 29 %

Procedure:
Prepared by way of method III using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and cyclohexylmethyl isocyanate (53 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 36 mg (29%) of 18-cyclohexylmethylaminocarbonyloxyl-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.0% pure (HPLC), MS m/z 708 (M−H)−, HRMS calcd. 708.3278 and found 708.3269, mp 142-144° C.