Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[B:20]1(B2OC(C)(C)C(C)(C)O2)[O:24]C(C)(C)C(C)(C)[O:21]1.C([O-])(=O)C.[K+]>O1CCOCC1.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]>[CH:17]1([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:4]=[CH:3][C:2]([B:20]([OH:24])[OH:21])=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:19][CH2:18]1
Reactant: O=C(c1ncc(Br)cn1)N1CCN(CC2CC2)CC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: O=C(c1ncc(B(O)O)cn1)N1CCN(CC2CC2)CC1
Yield: 71.4 %

Procedure:
(5-Bromo-pyrimidin-2-yl)-(4-cyclopropylmethyl-piperazin-1-yl)-methanone (46 mg, 0.14 mmol), bis(pinacolato)diboron (43 mg, 0.17 mmol), Pd(dppf)Cl2 (12 mg, 0.014 mmol) and potassium acetate (42 mg, 0.42 mmol) in 1,4-dioxane (0.7 mL) were added to a microwave vial and the reaction mixture purged with N2 for 10 min. The reaction mixture was irradiated using a microwave reactor (300 W, 120° C., 20 min). The reaction mixture was passed through a Si-thiol cartridge (2 g) and the column washed with MeOH (4× column volumes). The solvent was removed in vacuo and purified by reverse phase preparative HPLC-MS. The sample was passed through a SCX-2 cartridge (500 mg) and the column washed with MeOH (4× column volumes). The compound was eluted from the column with 0.5M NH3/MeOH to afford 2-(4-cyclopropylmethyl-piperazine-1-carbonyl)-pyrimidine-5-boronic acid as a white solid (29 mg, 70%).
Reaction SMILES: [O-2].[Mg+2].[CH:3](O)=[O:4].C(OC(=O)C)(=O)C.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16]([OH:18])=O.C(O)(C)C>>[CH:3]([NH:13][C@@H:14]1[C:19](=[O:20])[O:21][C:16](=[O:18])[CH2:15]1)=[O:4]
Reactant: O=CO
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@H]1CC(=O)OC1=O
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
0.12 grams (0.003 mole) of magnesium oxide, a catalyst, was dissolved in 16 milliliters (ml) (0.405 mole) of 95% formic acid. 60.2 ml of acetic anhydride was then added to the aforementioned solution which was heated to 35°-40° C. for 10-15 minutes. Subsequently, 39.93 grams (0.3 mole) of L-aspartic acid was added and this mixture was stirred for 2.5 hours at 50±2° C. At this point, an additional 8.6 ml of acetic anhydride was added and the reaction continued for an additional 2.5 hours at 50±2° C. 9.2 ml (0.120 mole) of isopropyl alcohol was then added to the reaction mixture and heating was continued for an additional two hours. N-formyl aspartic anhydride was formed at this point as shown by high performance liquid chromatography (HPLC).
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:32]1[N:37]=[C:36]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2[NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:35]([Cl:50])=[CH:34][N:33]=1.C(=O)([O-])[O-]>C(O)(C)C.C(Cl)Cl>[Cl:50][C:35]1[C:36]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2[NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[N:37][C:32]([NH:29][C:27]2[C:26]([F:30])=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:33][CH:34]=1
Reactant: CCN1CCCOc2cc(N)c(F)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(F)cc21
Reaction time: 1 h

Procedure:
10-Camphorsulfonic acid (70 mg, 0.30 mmol) was added to 9-Ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (58 mg, 0.28 mmol) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (94 mg, 0.28 mmol) in Isopropyl alcohol (1 mL). The mixture was irradiated in a CEM microwave (140° C., min). MP-Carbonate (2.69 mmol/g loading; 0.22 g, 0.5793156293 mmol) and DCM (2 mL) were added and the mixture stirred for 1 h, then filtered onto a 5 g SiO2 cartridge, which was air dried. The sample was chromatographed (ISCO, 2×12 g SiO2, 0-50% EtOAc:Hex) to afford N-{(1R,2R)-2-[5-Chloro-2-(9-ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a purple film (40 mg, 30%). LCMS 513 (M+H), 1H-NMR (CDCl3): 7.92 (s, 1H), 7.76 (d, 1H, J=8.4 Hz), 6.76 (s, 1H), 6.62 (d, 1H, J=13.3 Hz), 5.39 (d, 1H, J=7.4 Hz), 5.11 (d, 1H, J=7.1 Hz), 4.09 (t, 2H, J=6.0 Hz), 3.93 (m, 1H), 3.25 (m, 5H), 2.81 (s, 3H), 2.20 (m, 2H), 2.00 (m, 2H), 1.82 (m, 2H), 1.43 (m, 4H), 1.20 (t, 3H, J=7.0 Hz). 19F-NMR: −135.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][O:12][C:8]=2[C:7]=1[CH2:19][CH2:20][CH3:21].BrC(Cl)CC.[C:27]1([CH:33]2[CH2:38][NH:37][C:36](=[O:39])[NH:35][C:34]2=[O:40])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:27]1([CH:33]2[CH2:38][NH:37][C:36](=[O:39])[N:35]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:18]=[CH:17][C:9]4[C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][O:12][C:8]=4[C:7]=3[CH2:19][CH2:20][CH3:21])[C:34]2=[O:40])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1NCC(c2ccccc2)C(=O)N1
Reactant: CCCc1c(OCCCCl)ccc2c(C(F)(F)F)noc12
Agent: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCN2C(=O)NCC(c3ccccc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
A mixture of 6-(3-chloropropoxy)-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole, prepared as for Example 7 from bromochloropropane, (36 mg, 0.12 mmol), 5-phenyldihydropyrimidine-2,4(1H,3H)-dione, from this Example step 1, (42.5 mg, 0.22 mmol), Cs2CO3 (145.7 mg, 0.45 mmol) and KI (9.3 mg, 0.056 mmol) in dry DMF was stirred at room temperature overnight. The reaction mixture was diluted with water and partitioned between ethyl acetate and water. Combined organic extracts were washed with water and brine, dried over Na2SO4 and the solvent evaporated in vacuo. The product was purified by HPLC using 30% to 70% gradient CH3CN:H2O).
Reaction SMILES: [Na].C(O[CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:25])[CH:11]2[NH:15][C:16](=[O:24])[CH2:17][C:18]2[S:19][C:20](=[O:23])[S:21][CH:22]=2)[C:8]=1[C:26]([OH:28])=[O:27])(=O)C.[S-]C#N.[K+].C(=O)(O)[O-].[Na+].[C:38]([N:42]1[C:46](=[S:47])[NH:45][N:44]=[N:43]1)([CH3:41])([CH3:40])[CH3:39].C(OC(C)C)(C)C>O.O1CCCC1>[C:26]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][S:47][C:46]1[N:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[N:43]=[N:44][N:45]=1)[CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[S:19][C:20](=[O:23])[S:21][CH:22]=1)[C:10]2=[O:25])([OH:28])=[O:27]
Reactant: CC(C)(C)n1nn[nH]c1=S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: N#C[S-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC(C)(C)n1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Temperature: 60 °C
Yield: 30.5 %

Procedure:
The sodium salt of 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (12 g.) is dissolved in water (22 cc.). Potassium thiocyanate (29 g.), sodium bicarbonate (2.45 g.) and 1-tert-butyl-5-thioxo-1,2,3,4-tetrazoline (4.6 g.) are added to this solution and the mixture is heated to 60° C. for 6 hours. After cooling, the reaction mixture is diluted with water (150 cc.) and washed with ethyl acetate (200 cc.) after having been acidified to pH 5.5 by adding 4 N hydrochloric acid. The mixture is then acidified to pH 1.5 by adding 4 N hydrochloric acid in the presence of ethyl acetate (350 cc.). After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (a total of 150 cc.). The organic extracts are combined, washed twice with water (a total of 300 cc.), dried over sodium sulphate, treated with decolourising charcoal, filtered and then concentrated to dryness under reduced pressure (20 mm Hg). The residue obtained is dissolved in tetrahydrofuran (60 cc.) and this solution is then poured into isopropyl ether (600 cc.). A product precipitates, which is isolated by filtration and dried under reduced pressure (0.1 mm Hg) to give 2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-3-[(1-tert-butyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (4.5 g.).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C@@H:11]([OH:35])[C@@H:12]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@H:13]([CH3:26])[C@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@@H:15]([CH3:17])[CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36]I.[OH-].[K+].O>CS(C)=O.C(OCC)(=O)C.CCCCCC>[C:1]1([S:7]([C:10]2[C@@H:11]([O:35][CH3:36])[C@@H:12]([O:27][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30])[C@H:13]([CH3:26])[C@H:14]([O:18][Si:19]([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:21])[CH3:20])[C@@H:15]([CH3:17])[CH:16]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@H](O)C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CO[C@@H]1C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
To a solution of compound 52 (75 mg, 0.14 mmol) and MeI (86 μL, 1.4 mmol) in DMSO (2.0 mL) was added powdered KOH (23 mg, 0.42 mmol) and the resulting mixture was stirred for 5 min (until no starting material was present by TLC, developed in 1:3 EA/hexanes) at room temperature. 5 mL of H2O was added, and extracted with diethyl ether (3×5 mL). The organic layers were combined washed with brine, dried over anhydrous Na2SO4 and concentrated. Flash chromatography (ethyl acetate/hexane, 1:10) afforded 72 mg (yield 94%) of compound 53 as a colorless oil which slowly solidified when left standing. m.p.=94.0° C.-96.0° C.; [α]20D=−39.7 (c=0.65, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.86-7.89 (m, 2H), 7.51-7.61 (m, 3H), 7.35 (d, J=7.8 Hz, 1H), 3.98 (s, 1H), 3.83 (d, J=3.9 Hz, 1H), 3.57 (d, J=9.3 Hz, 1H), 3.35 (s, 3H), 2.77 (m, 1H), 2.54 (m, 1H), 1.23 (d, J=7.2 Hz, 3H), 1.01 (d, J=7.2 Hz, 3H), 0.91 (s, 9H), 0.84 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H), −0.14 (s, 3H), −0.31 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 149.4, 140.3, 139.9, 133.4, 129.4, 128.3, 79.8, 78.7, 73.7, 59.4, 40.2, 36.6, 26.1, 28.3, 18.2, 17.7, 16.9, −4.1, −4.5, −4.6, −4.7; LRMS (CI) m/z 555 [M+H]+; HRMS (CI) calculated for C28H50O5SSi2, 555.2996; found, 555.2998.
Reaction SMILES: OC[C@]12CC[C@H]3[C@@H](CCC4[C@]3(C)CCC(=O)C=4)[C@@H]1CCC2=O.[OH:23][C@@H:24]1[C:41]2[C@:36]([CH3:43])([CH2:37][CH2:38][C:39](=[O:42])[CH:40]=2)[C@@H:35]2[C@H:26]([C@H:27]3[C@@:31]([CH2:33][CH2:34]2)([CH3:32])[C:30](=[O:44])[CH2:29][CH2:28]3)[CH2:25]1>CCCCCC.C(OCC)(=O)C>[OH:23][C@H:24]1[C:41]2[C@:36]([CH3:43])([CH2:37][CH2:38][C:39](=[O:42])[CH:40]=2)[C@@H:35]2[C@H:26]([C@H:27]3[C@@:31]([CH2:33][CH2:34]2)([CH3:32])[C:30](=[O:44])[CH2:29][CH2:28]3)[CH2:25]1
Reactant: C[C@]12CCC(=O)C=C1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(CO)CC[C@@H]12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@]12CCC(=O)C=C1[C@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Meta-chloroperbenzoic acid (11-25 g) was added to the crude 3-acetoxyandrosta-3,5-dien-17-one (i.e., from 15 g of androst-4-ene-3,17-dione) in dioxan (500 ml) and water (5 ml) and cooled to 5° C. in an ice bath. The reaction mixture was then kept at this temperature for 24 h and then diluted with water (500 ml) and extracted with ethyl acetate (3×500 ml). The organic phase was washed with sodium bisulphite (200 ml, 10%), after which a negative starch iodide test was obtained. The organic phase was then washed with a saturated solution of sodium bicarbonate (3×100 ml), a saturated solution of sodium chloride (1×100 ml) dried with sodium sulphate and evaporated to yield a solid (21.7 g). TLC (hexane-ethyl acetate, 1:3) showed no starting material and largely 6β and 6α forms of hydroxyandrost-4-ene-3,17-dione. NMR showed 6β and 6α-hydroxyandrost-4-ene-3,17-dione in a ratio of approximately 4:1. Crystallization of 16.4 g of the crude product from ethyl acetate-hexane (1:3) gave 7.75 g of 6α+6β-hydroxyandrost-4-ene-3,17-dione (with a similar 6α:6β ratio as for crude). The 6α and 6β isomers can be optionally separated if desired although both isomers alone or in admixture can be used. Recrystallization from ethyl acetate gave pure 6β-hydroxyandrost-4-ene-3,17-dione (2.4 g). And, a second crop of crystals contained the 6β and 6α isomers.
Reaction SMILES: ClC(Cl)C.CN([CH:8]=[O:9])C.P(Cl)(Cl)(Cl)=O.[CH:15]1[C:16]([C:24]([O:26][CH3:27])=[O:25])=[CH:17][N:18]2[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]2>C(#N)C>[CH:8]([C:15]1[C:16]([C:24]([O:26][CH3:27])=[O:25])=[CH:17][N:18]2[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:9]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc2n(c1)CCCC2
Solvent: CC(Cl)Cl
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cn2c(c1C=O)CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous dichloroethane (10 mL) and anhydrous DMF (0.7 mL, 9.0 mmol). The reaction mixture was cooled to 0° C. and phosphorus oxychloride (0.7 mL, 7.3 mmol) was added over a period of 2 min, while maintaining the reaction temperature between 0° C. and 10° C. The cooling bath was removed and the reaction was stirred at room temperature for 1 hour. A solution of methyl 5,6,7,8-tetrahydroindolizine-2-carboxylate 112a (1.0 g, 5.6 mmol) in acetonitrile (10 mL) was added and the mixture was stirred at room temperature for additional 3 hours. After this time, the solvent was concentrated under reduced pressure and the oily residue was taken up with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with water (20 mL), dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:1 ethyl acetate/petroleum ether to afford 192a as a white solid (406 mg, 33%). MS: (M+H)+ 208.3. 1H NMR (500 MHz, DMSO) δ 10.29 (s, 1H), 7.43 (s, 1H), 3.99 (t, J=6.0 Hz, 2H), 3.76 (s, 3H), 2.95 (t, J=6.5 Hz, 2H), 1.90-1.85 (m, 2H), 1.78-1.74 (m, 2H).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][NH:4][CH2:3]1.C=O.[C:35](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4]([CH3:35])[CH2:3]1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CCN(C)C[C@H]5F)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.9 %

Procedure:
To a solution of 8-((trans)-3-fluoropiperidin-4-yloxy)-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinoline (Example 20; 185 mg, 0.42 mmol) in CH2Cl2 (5 mL) was added formaldehyde (316 μL, 37% in water, 4.2 mmol) followed by acetic acid (30 μL, 0.51 mmol) and sodium triacetoxyborohydride (270 mg, 1.27 mmol). The mixture was stirred vigorously at ambient temperature for 48 hours, then treated with 10% aq. K2CO3 (20 mL) and stirred for 10 minutes. The mixture was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified via flash column chromatography using gradient elution (CH2Cl2 to 2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) then dissolved in CHCl3 (5 mL) and treated with 4N HCl/dioxane (2 mL). After stirring for 20 minutes at ambient temperature the mixture was concentrated. The residue was triturated with ether, filtered and dried in vacuo to provide 136 mg (61%) of desired product as the di-HCl salt as a solid. MS APCI (+) m/z 451.2 (M+1) detected.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][CH2:30][CH2:31][C:32]#[N:33]>C(OCC)(=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:33][CH2:32][CH2:31][C:30]#[N:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#CCCN
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC(=O)NCCC#N
Reaction time: 0.08 h

Procedure:
N-t-Butoxycarbonyl-β-alanine (5.8 mmol) in ethyl acetate (30 mL) and methylene chloride (7.5 mL) is cooled under nitrogen to 0° with an ice bath and treated with N-methylmorpholine (5.8 mmol). Isobutyl chloroformate (5.8 mmol) is added dropwise. After 5 minutes of stirring, 3-aminopropionitrile (6.4 mmol) in methylene chloride (5.0 mL) is added slowly. Stirring is continued for 1 hour at 0°, then for 4 hours at room temperature. Ethyl acetate (30 mL) is added and the solution is successively washed with cold water (100 ml), saturated sodium bicarbonate (10 mL) and water (10 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-(t-butoxycarbonylamino)-N-(2-cyanoethyl)propionamide.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1.CN(C)[CH:26]=[O:27].O>CCCCC.O1CCCC1>[CH:26]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(C=O)cc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
At −75° C., 13.5 ml (22.98 mmol) of a 1.7 M tert-butyllithium solution in pentane are slowly added to a solution of 6.00 g (19.16 mmol) of tert-butyl 3-(4-bromophenyl)-2,2-dimethylpropionate (Example I-2) in 80 ml of tetrahydrofuran, the temperature being kept below −60° C. The mixture is stirred for 15 min, and 1.82 g (24.90 mmol) of N,N-dimethylformamide are then added and the mixture is stirred at −75° C. for a further 4 h. The mixture is slowly warmed to −20° C. and, with vigorous stirring, admixed with 20 ml of water, and then warmed to room temperature. The aqueous phase is extracted 3× with diethyl ether and the combined organic phases are dried over sodium sulfphate/sodium carbonate and freed from the solvent under reduced pressure. Distillation of the residue under oilpump vacuum gives 2.54 g (51%) of tert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate.
Reaction SMILES: [OH-].[Na+].[CH2:3]([S:10][C:11]1[N:15]=[C:14]([SH:16])[NH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:17]I>O.ClCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:3]([S:10][C:11]1[N:15]=[C:14]([S:16][CH3:17])[NH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: Sc1nc(SCc2ccccc2)n[nH]1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSc1nc(SCc2ccccc2)n[nH]1
Reaction time: 24 h
Yield: 85.1 %

Procedure:
A solution of sodium hydroxide (16 g) in water (60 ml) was added to a suspension of 3-benzylthio-5-mercapto-1,2,4-triazole (89.2 g) in dichloromethane (400 ml) containing benzyltriethylammonium chloride (1 g) with stirring and cooling to 15°-20° C. To this mixture methyl iodide (56.8 g) was added, and stirring was continued at room temperature for 24 hours. The dichloromethane phase was separated, washed with water twice, dried over magnesium sulphate and run down to give 94 g of crude product, which was recrystallised from toluene to give 80.7 g of desired product, mp 80°-82° C.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C.C(OC(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CC1OCSC1=NO
Reactant: CN(SSc1ccc(Cl)cc1)C(=O)F
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CC1OCSC1=NOC(=O)N(C)SSc1ccc(Cl)cc1

Procedure:
4-[[O-[N-Methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl]oximino]]-5-methyl-1,3-oxathiolane was prepared according to the procedure described in Example I by reacting 4.0 g (0.03 m) of 5-methyl-4-oximino-1,3-oxathiolane, 7.55 g (0.03 m) of N-methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl fluoride and 3.07 g (0.03 m) of triethylamine in 50 ml of dioxane. Addition of isopropyl ether and ethyl acetate to the residual oil and cooling yielded 2.37 g of a white solid, m.p. 71°-73° C.
Reaction SMILES: [C:1]([Cu])#[N:2].[Na+].[I-].CN[C@@H]1CCCC[C@H]1NC.ClC1C=CC=CC=1.CCCCC[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(OCC)(=O)C>[CH3:34][C:33]1[CH:28]=[CH:29][C:30]([C:1]#[N:2])=[CH:31][CH:32]=1
Reactant: N#C[Cu]
Reactant: CCCCCCCCCCCC
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [I-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)cc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
A Schlenk tube was charged with CuCN (108 mg, 1.21 mmol), NaI (150 mg, 1.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (190 μL, 1.21 mmol) and 4-chlorobenzene (0.95 mL, 8.01 mmol) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 20 h. The resulting black suspension was allowed to reach room temperature. Ethyl acetate (3 mL) and dodecane (internal GC standard, 230 μL) were added to the reaction mixture. A 50 μL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 60% yield of 4-methylbenzonitrile.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.CS(Cl)(=O)=O.O[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=[O:24]
Reactant: COc1ccc(C=O)cc1O
Reactant: CN(C)CCO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)cc1OCCN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a solution of 2-(dimethylamino)ethanol (5.0 g, 56.0 mmol) and triethylamine (8.5 g, 84.0 mmol) in anhydrous DCM (50 mL) was added methanesulfonyl chloride (7.1 g, 62.0 mmol) at 0° C. under N2. The mixture was stirred at 0° C. for 1 hour. The solvent was removed in vacuo (6.0 g, yield 65%), and the crude was taken up in CH3CN (100 mL). 3-hydroxy-4-methoxybenzaldehyde (5.5 g, 36.0 mmol) and potassium carbonate (13.8 g, 100.0 mol) was added and reaction was refluxed under N2 overnight. An aqueous/EtOAc workup was followed, and crude was purified by silica gel column chromatography (PE:EtOAc=3:1) to give product (2.5 g, yield 31%) as yellow solid.