Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]([C:28](F)(F)F)=O.[CH2:32]([O:39][N:40]1[C:46](=[O:47])[N:45]2[CH2:48][C@H:41]1[CH2:42][CH2:43][C@H:44]2[C:49]([NH:51][NH2:52])=[O:50])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([N:51]([C:49]([C@@H:44]1[CH2:43][CH2:42][C@@H:41]2[CH2:48][N:45]1[C:46](=[O:47])[N:40]2[O:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:50])[NH2:52])(=[O:25])[CH3:28]
Reactant: O=C(O)C(F)(F)F
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(N)C(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
HATU (0.90 g, 2.48 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide TFA salt (1.0 g, 2.48 mmol), acetic acid (0.12 g, 2.07 mmol) and DIPEA (1.1 μg, 8.3 mmol) in dry DMF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The mixture was then quenched with saturated sodium chloride (50 mL) and exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 1:10 petroleum ether/EtOAc) to afford (2S,5R)—N-acetyl-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.6 g, 73%). ESI-MS (EI+, m/z): 333 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]\[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[O:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][C:22]1[C:30]2[NH:29][C:28]([CH2:31][CH2:32][CH3:33])=[N:27][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[CH3:21][C:22]1[C:30]2[N:29]=[C:28]([CH2:31][CH2:32][CH3:33])[N:27]([CH2:2][C:3]3[CH:20]=[CH:19][C:6]4/[C:7](=[CH:16]\[C:17]#[N:18])/[C:8]5[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=5[O:10][CH2:11][C:5]=4[CH:4]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCCc1nc2cccc(C)c2[nH]1
Reactant: N#C/C=C1\c2ccc(CBr)cc2COc2ccccc21
Product: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C/C#N
Yield: 76.2 %

Procedure:
[step 1] Using (E)-2-(8-bromomethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)acetonitrile (1.5 g, 4.6 mmol) obtained in Reference Example B13 and 4-methyl-2-propylbenzimidazole (EP400835; 842 mg, 4.83 mmol) and in the same manner as in Example 92, step 1, (E)-2-{8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}acetonitrile (1.47 g, 76%) was obtained. [step 2] (E)-2-{8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}acetonitrile (150 mg, 0.34 mmol) obtained in step 1 was dissolved in ethanol (1.8 mL), hydroxylamine (50% aqueous solution, 1.1 mL, 17.9 mmol) was added, and the mixture was stirred under reflux for 18 hr. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (1.8 mL), triethylamine (75 μL, 0.54 mmol) and ethyl chlorocarbonate (51 μL, 0.54 mmol) were added at 0° C., and the mixture was stirred at room temperature for 30 min. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in toluene (0.9 mL) and THF (0.9 mL), potassium tert-butoxide (80 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 20 min. 5% Aqueous citric acid solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 10/90) to give the title compound (compound 104) (119 mg, 70%).
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.[NH4+].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH2:31][CH3:32])[CH2:28][NH:29][CH3:30])[C:17](=[O:33])[C@:16]([CH2:35][C:36]([O-:38])=[O:37])([CH3:34])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O.CO>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH2:31][CH3:32])[CH2:28][N:29]([CH3:30])[CH:3]3[CH2:2][O:1][CH2:4]3)[C:17](=[O:33])[C@:16]([CH2:35][C:36]([OH:38])=[O:37])([CH3:34])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC[C@@H](CNC)N1C(=O)[C@@](C)(CC(=O)[O-])C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@@H](CN(C)C1COC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
To a solution of oxetan-3-one (17.78 mg, 0.247 mmol) in DCE (3 mL) was added 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid ammonium salt (61 mg, 0.123 mmol) obtained in Step A followed by sodium triacetoxyborohydride (78 mg, 0.370 mmol) and 3 drops AcOH. After 45 minutes, 3 ml MeOH and oxetan-3-one (12 mg, 0.17 mmol) were added. After stirring overnight, oxetan-3-one (12 mg, 0.17 mol) and sodium triacetoxyborohydride (60 mg, 0.32 mmol) were added. After 24 hours, the mixture was diluted with methanol and evaporated onto silica gel. The solid was purified by flash chromatography on silica gel (eluent: 0 to 100% [6:1:0.1 DCM/MeOH/NH4OH] in DCM). The product containing fractions were pooled, concentrated and repurified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH/DCM) to afford the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:10].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[I:32]>O1CCCC1>[C:19]([O:18][C:16]([CH2:15][NH:14][CH:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[I:32])[C:12]([O:11][CH2:9][CH3:10])=[O:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: BrCc1ccccc1I
Reactant: CCOC(=O)CNCC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1I)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At −78° C., lithium diisopropylamide solution (2 M in THF/n-heptane, 17 ml, 34 mmol) was slowly added dropwise to ethyl(tert-butoxycarbonylmethylamino)acetate (7.4 g, 34 mmol) in tetrahydrofuran (abs., 50 ml). The mixture was stirred at this temperature for 2 h. 1-Bromomethyl-2-iodobenzene (10.0 g, 46 mmol) was then slowly added dropwise, and the mixture was stirred at −78° C. for 1 h. The reaction solution was slowly (12 h) warmed to room temperature and then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate, washed, dried and concentrated. The residue obtained in this manner was then purified by column chromatography (SiO2, hexane/ethyl acetate). This gave 6.4 g (43%) of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18](Br)[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[Cu][C:22]#[N:23].[CH3:24][N:25]1CCCC1=O.O>C(OCC)(=O)C>[O:16]=[C:7]1[C:6]([O:5][C:4]2[CH:3]=[C:2]([C:22]#[N:23])[CH:19]=[C:18]([CH:17]=2)[C:24]#[N:25])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][NH:8]1
Reactant: N#C[Cu]
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Br)cc(Br)c1
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(C#N)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Temperature: 175 °C
Reaction time: 1.5 h

Procedure:
To a high pressure vessel charged with 3-(3,5-dibromophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (0.200 g, 0.484 mmol) and copper(I) cyanide (0.434 g, 4.84 mmol) was added N-methylpyrrolidinone (2 mL). The vessel was sealed and placed in an oil bath heated to 175° C. After 90 minutes, the reaction mixture was allowed to cool to room temperature. Water (25 mL) and ethyl acetate (50 mL) were added to the reaction mixture. This mixture was filtered through diatomaceous earth and the filtrate layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with brine (2×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-5% methanol in CH2Cl2 to afford the title compound. 1H NMR (DMSO-d6) δ 12.72 (s, 1H), 8.16-8.14 (m, 1H), 8.02-7.98 (m, 2H), 7.61 (d, J=7.0 Hz, 1H), 6.50 (d, J=6.9 Hz, 1H). LRMS (M+1)=305.9.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([Br:22])=[CH:17][N:16]=2)=[CH:11][CH2:10]1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Br:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([C:12]2[CH2:13][CH2:14][CH:9]([NH:7][CH3:6])[CH2:10][CH:11]=2)=[N:16][CH:17]=1
Reactant: Cc1cc(Br)cnc1C1=CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CC=C(c2ncc(Br)cc2C)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]-N-methylcarbamic acid tert-butyl ester (11.6 g) described in Reference Example 143 (5) in dichloromethane (30 ml) was added trifluoroacetic acid (10 ml) at room temperature, and stirred at 50° C. for 4 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added thereto under ice-cooling, and extracted with 10% methanol/chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with basic silica gel column chromatography (chloroform) to give N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]-N-methylamine (8.13 g) as a brown oil.
Reaction SMILES: [OH-:1].[K+].O[NH2:4].Cl.CO[C:8](=[O:40])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[CH:13][CH:12]=1.ON.C(=O)=O>CO.O>[OH:1][NH:4][C:8](=[O:40])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34])[CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[CH:13][CH:12]=1
Reactant: NO
Reactant: [OH-]
Reactant: COC(=O)/C=C/c1ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc2c[nH]c3ccccc23)cc1
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(/C=C/C(=O)NO)cc1
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A solution of 3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (12.6 g, 37.7 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (12.8 g, 53.6 mmol), (i-Pr)2NEt, (7.42 g, 57.4 mmol) in DMSO (100 mL) is heated to 50° C. After 8 hours the mixture is partitioned with CH2Cl2/H2O. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel to produce 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (13.1 g). A solution of KOH (12.9 g (87% pure), 0.2 mol) in MeOH (100 mL) is added to a solution of HONH2.HCl (13.9 g, 0.2 mol) in MeOH (200 mL) and a precipitate results. After 15 minutes the mixture is filtered, the filter cake washed with MeOH and the filtrate evaporated under vacuum to approximately 75 mL. The mixture is filtered and the volume adjusted to 100 mL with MeOH. The resulting solution 2M HONH2 is stored under N2 at −20° C. for up to 2 weeks. Then 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (5.4 g, 11 mmol) is added to 2 M HONH2 in MeOH (90 mL, 180 mmol) followed by a solution of KOH (720 mg (87% pure), 11.2 mmol) in MeOH (5 mL) and the mixture stirred overnight. Dry ice is added to the reaction and the mixture diluted with H2O resulting in the formation of a precipitate. The liquid was decanted and the solid was dissolved in MeOH and filtered. The filtrate is evaporated to afford N-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}methyl)-phenyl]-(2E)-2-propenamide (5.1 g,) which is used without further purification. The hydroxamic acid (5.0 g, 13.3 mmol) is then dissolved in 95% TFA/H2O (59 mL) and heated to 40-50° C. for 4 hours. The mixture is evaporated and the residue purified by reverse phase HPLC to produce N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide as the trifluoroacetate salt (m/z 380 [MH+]).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C=O)cc1OC

Procedure:
A flask containing vanillin (20 g, 0.13 mol), ethyl bromoacetate (28.4 g, 0.17 mol) and potassium carbonate (32.7 g, 0.24 mol) and acetone 200 mL were heated to reflux for 3 hours. The reaction was allowed to come to rt The acetone was stripped off and the residue partitioned between water and ethyl acetate. The ethyl acetate was washed with brine and dried over magnesium sulfate. The organic layer was concentrated and the solid triturated with hexanes to yield 28.4 grams of example No. 169.
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)[N:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[Cl:18])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ccccc1Cl
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2Cl)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-chlorobenzylamine in DME. ES-MS m/e (%): 328 (M{37Cl}+H+, 30), 326 (M{35Cl}+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2N=[C:10]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][CH:3]=1.Cl[C:24]1C2C=CNC=2N=C(C2C=CC=CN=2)N=1.ClC1C=C(C2C=CC=C(C)N=2)N=C2NC=CC=12>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[C:12]3[NH:14][CH:15]=[CH:16][C:11]3=[C:10]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:24]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(-c2ccccn2)nc2[nH]ccc12
Reactant: Cc1cccc(-c2nc(-c3cccnc3)c3cc[nH]c3n2)n1
Agent: Cc1cccc(-c2cc(Cl)c3cc[nH]c3n2)n1
Product: Cc1cccc(-c2cc(-c3cccnc3)c3cc[nH]c3n2)n1

Procedure:
6-(6-Methyl-pyridin-2-yl)-4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine is prepared by an analogous method to that for 2-(6-methyl-pyridin-2-yl)-4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine (Example 2) by replacing 4-chloro-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 1) with 4-chloro-6-(6-methyl-pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (Intermediate 6).
Reaction SMILES: [OH:1]S(O)(=O)=O.[OH-].[Na+:7].C(N[CH:12]([C:17]([OH:19])=[O:18])CCSC)(=O)C.[CH3:20][O:21][C:22](=[O:32])[CH:23](CCSC)NC(=O)C>C(O)(=O)C.CO>[C:22]([O:21][CH3:20])(=[O:32])[CH3:23].[C:22]([O:19][C:17](=[O:18])[CH3:12])(=[O:21])[CH3:23].[OH-:1].[Na+:7]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)C(CCSC)NC(C)=O
Reactant: CSCCC(NC(C)=O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OC(C)=O
Product: COC(C)=O

Procedure:
To this solution was added with stirring sufficient anhydrous H2SO4 to neutralize the NaOH and render the solution slightly acidic. Under these conditions the N-acetyl-D,L-methionine was converted to N-acetyl-D,L-methionine methyl ester. The remaining methanol and methyl acetate (formed from the reaction of residual acetic acid and acetic anhydride with NaOH) was removed by warming the mixture under vacuum. The remaining mixture was slurried with chloroform and filtered to removed sodium sulfate salts. The ester-chloroform solution was then water washed to remove any remaining salts. The resulting ester-chloroform solution was then warmed under vacuum to remove the chloroform. The resulting material was N-acetyl-D,L-methionine methyl ester.
Reaction SMILES: [CH2:1]1[CH2:4][CH:3]([CH2:5][N:6]2[C@@H:16]3[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]5[O:25][C@H:10]6[C:11]([CH2:13][CH2:14][C@:15]3([OH:26])[C@:9]6([C:19]=45)[CH2:8][CH2:7]2)=[O:12])[CH2:2]1.P(=O)(O)(O)O.[H][H]>CC(O)C.O.[Pt]>[CH:23]1[C:18]2[CH2:17][C@H:16]3[N:6]([CH2:5][CH:3]4[CH2:4][CH2:1][CH2:2]4)[CH2:7][CH2:8][C@:9]45[C@H:10]([C@@H:11]([OH:12])[CH2:13][CH2:14][C@@:15]34[OH:26])[O:25][C:20]([C:19]=25)=[C:21]([OH:24])[CH:22]=1
Reactant: [H][H]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)[C@H]1O5
Agent: [Pt]
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(C)O
Product: Oc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@@]4(O)[C@@H](C2)N(CC2CCC2)CC[C@]314
Reaction time: 7 h
Yield: 97.5 %

Procedure:
6-ketonalbuphine (40 g, 112.8 mmoles) was dissolved in a mixture of IPA (200 mls) and water (200 mls) containing orthophosphoric acid (1.56 mls). The pH of the reaction mixture was 6.49. The reaction mixture was hydrogenated at 40 psi hydrogen gas and 50° C. in the presence of 10% Platinum on carbon catalyst (2.4 g, 0.56 mmoles Pt). After 7 hours, the pH of the reaction mixture is adjusted with orthophosphoric acid (6.25 mls) and filtered. Ammonia solution (25 mls) was added to bring the pH to 8.5-9.0 and the precipitate filtered, washed with 50% aqueous IPA (60 mls), and dried to provide 39.33 g (97% theory) of Nalbuphine alkaloid of purity 95.6% by HPLC.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+].O1CCCC1>C1(C)C=CC=C(C)C=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[NH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:7]=1
Reactant: C1CNCCN1
Reactant: Nc1cccc(Cl)n1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)c1
Product: Nc1cccc(N2CCNCC2)n1
Yield: 5.3 %

Procedure:
To a solution of 6-chloro-2-pyridinylamine (406 mg, 3.16 mmol) and piperazine (381 mg, 4.42 mmol) in m-xylene (10 ml), were added sodium tert-butoxide (425 mg, 4.42 mmol) and bis-(tri-o-tolylphosphine)palladium(II) dichloride (124 mg, 0.158 mmol). The mixture was heated at reflux under N2 for 24 h. The reaction was cooled down and tetrahydrofuran (THF, 10 ml) added, and the mixture was filtered on a celite pad. The filtrate was evaporated and purified via flash chromatography (CH2Cl2/MeOH/NH4OH) affording 30 mg of 2-amino-6-(piperazin-1-yl)pyridine (intermediate “Ia”) as a tan solid (5% yield). H-NMR (CD3OD): 2.95 (m, 4H), 3.47 (m, 4H), 5.93 (m, 1H), 6.01 (m, 1H), 7.24 (m, 1H). M+=179.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C(N(CC)C(C)C)(C)C.[CH2:32]([O:34][C:35](=[O:41])[CH2:36][CH2:37][N:38]=[C:39]=[O:40])[CH3:33]>C(Cl)Cl>[CH3:20]/[C:10](/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])=[CH:11]\[CH2:12][S:13][CH2:14][C@@H:15]([C:16]([OH:18])=[O:17])[NH:19][C:39](=[O:40])[NH:38][CH2:37][CH2:36][C:35](=[O:41])[O:34][CH2:32][CH3:33]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: CCOC(=O)CCN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). Ethyl-3-isocyanato-propionate (143, 1 mmol) was added to the reaction mixture. The reaction solution was stirred at room temperature overnight and the solvent was removed by rotary evaporation. The remaining residue was dissolved in ethyl acetate (100 mL) and washed with 1 N HCl solution (50 mL×2). The ethyl acetate solution was dried over Na2SO4 and concentrated to a crude reaction mixture. The resulting mixture was purified by HPLC (200 mg, 43%) to yield Compound D. 1H-NMR (500 MHz, MeOH-d4): δ 1.28 (t, J=7.5 Hz, 3H), 1.62 (s, 3H), 1.63 (s, 3H), 1.69 (s, 3H), 1.70 (s, 3H), 1.98 (m, 2H), 2.06 (m, 6H), 2.52 (t, J=6.5, 2H), 2.79 (dd, J=7.0, 14.0 Hz, 1H), 2.93 (dd, J=4.5, 13.5 Hz, 1H), 3.17 (dd, J=7.5, 13.5 Hz, 1H), 3.28 (dd, J=8.5, 13.5 Hz, 1H), 3.41 (t, J=6.5 Hz, 3H), 4.16 (q, J=7.5 Hz, 2H), 4.50 (dd, J=4.5, 6.5 Hz, 1H), 5.11 (m, 2H), 5.23 (t, J=7.5, 1H). 13C-NMR (125 MHz, MeOH-d4): δ 14.6, 16.1, 16.2, 17.8, 26.0, 27.4, 27.8, 30.5, 34.4, 35.9, 36.7, 40.8, 40.9, 54.0, 61.7, 121.7, 125.1, 125.5, 132.1, 136.3, 140.5, 160.2, 173.8, 175.0; ES-MS: mass calcd for Chemical Formula: C24H40N2O5S 468.7. Found (M+Na) m/z 491.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].ClS([N:15]=[C:16]=[O:17])(=O)=O.Cl.O>C1(C)C=CC=CC=1>[N:1]1([C:16]([NH2:15])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A mixture of 2-oxindole (5.86 g, 44.0 mmoles) in toluene (160 ml) was azeotroped for one hour to dry the toluene. Then, chlorosulfonyl isocyanate (7.47 g, 52.8 mmole) was added. Hydrogen chloride was immediately evolved. The mixture was stirred and refluxed for 15 minutes and then cooled to room temperature. Water (50 ml) was added to the cooled mixture (some HCl was initially evolved) and the mixture stirred for 1.5 hours. The solid which formed was collected by filtration and dried (4.10 g). The filtrate was extracted with ethyl acetate (100 ml), the resulting extract washed with brine (2×100 ml) and dried (MgSO4). Evaporation of the extract under reduced pressure gave 4.16 g of solid. The combined solids were recrystallized by dissolution in acetonitrile (200 ml) followed by concentration of the solution under reduced pressure to about 75 ml. The small amount of amorphous material which separated was filtered off, the filtrate decolorized and concentrated under reduced pressure to about 50 ml volume, then seeded. The dark red crystals which separated were filtered and dried (3.0 g; 38%). It was identical to the product of Example 1.