Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](=O)[CH:5]=[CH2:6].O.[NH2:11][NH2:12].[Cl-].[Na+]>O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4]1[CH:5]=[CH:6][NH:12][N:11]=1
Reactant: NN
Reactant: C=CC(=O)C(OC)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(OC)c1cc[nH]n1
Reaction time: 8 h

Procedure:
A stirred solution of 1,1-dimethoxy-but-3-en-2-one in water (300 μL) was treated dropwise with hydrazine hydrate (21 mL). After standing at room temperature overnight the reaction mixture was treated with sodium chloride (108 g) and the mixture was then extracted with methyl-t-butylether (200 mL then 100 mL). The combined extracts were dried with magnesium sulfate and then evaporated to give 1H-pyrazol-3-carbaldehyde dimethyl acetal as a light brown oil (18.47 g).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[C:19](Br)=[CH:18][N:17]=2)=[O:15])([CH3:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OC(=O)C)C>[CH:1]1([CH2:4][C:5]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[C:19]([CH:30]3[CH2:32][CH2:31]3)=[CH:18][N:17]=2)=[O:15])([CH3:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(Br)cn2)no1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)no1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-Bromo-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 100c, 160 mg, 0.335 mmol) in toluene (4.8 mL) were added cyclopropylboronic acid (43.2 mg, 0.503 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12.3 mg, 17 μmol) and 2M aqueous solution sodium carbonate (335 μL, 0.670 mmol). Reaction was stirred at 80° C. for 18 hours. The reaction mixture was diluted with ethylacetate and extracted with water. The organic layer was dried on sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the mixture of epimers (151 mg, 100%). The mixture of epimers was separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first epimer collected and isolated as colorless oil; MS (ESI, m/z): 439.7 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([NH:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=2[Cl:21])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH3:26][N:27]([CH3:35])[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([NH:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=2[Cl:21])=[CH:7][C:3]=1[C:4]([C:29](=[CH:28][N:27]([CH3:35])[CH3:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:6]
Reactant: O=C(O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)C=CN(C)C
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Temperature: 90 °C
Yield: 23.3 %

Procedure:
95 mg (0.27 mmol) of 2,4-dichloro-5-(2-chloro-4,6-difluorophenylamino)benzoic acid were boiled with 0.98 ml of thionyl chloride under reflux for 3 hours. The thionyl chloride was distilled off, and the residue was mixed with 3 ml of toluene and concentrated in vacuo. The residue was taken up in 2 ml of toluene and added to a solution of 39 mg (0.27 mmol) of ethyl 3-dimethylaminoacrylate, 6 μl of triethylamine and 1 ml of toluene. The mixture was heated at 90° C. for 3 hours. The mixture was concentrated and chromatographed on silica gel (heptane:ethyl acetate=75:25 to 0:100 in 45 minutes). 30 mg (23%) of the desired product were obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][O:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[N:10][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][O:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[N:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(SCCOC(=O)c2cccc(Cl)c2)nc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(SCCOC(=O)c2cccc(Cl)c2)nc1
Reaction time: 16 h

Procedure:
A mixture of 2-[(5-nitro-2-pyridinyl)thio]ethyl 3-chlorobenzoate (5) (0.24 g, 0.71 mmol) and 10% Pd/C (0.10 g) in toluene or methanol was agitated under a hydrogen atmosphere (40 PSI) for 1 h. The reaction mixture was filtered through Celite® and concentrated to give 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51), LCMS: purity: 99%; MS (m/e): 309 (MH+), which was used without further purification. Acetyl chloride (4.6 μL, 0.064 mmol) was added to a room temperature solution of 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51) (18.9 mg, 0.061 mmol) and triethylamine (18 μL, 0.13 mmol) in anhydrous dichloromethane (1.0 mL), After 16 h, the reaction mixture was diluted with dichloromethane and washed with 1N HCl and brine and then dried over anhydrous MgSO4. Purification by silica gel chromatography provided 2-[(5-acetylamino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (52), LCMS: purity: 99%; MS (m/e): 351 (MH+).
Reaction SMILES: [C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([O:40]CC)=[O:39])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH:23]=[C:24]([CH3:25])[CH3:26])[CH2:13][CH:12]([NH:28][C:29](=[O:30])[NH:31][C:32]3[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:38]([OH:40])=[O:39])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C=C(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CC(=O)N1CC(NC(=O)Nc2cccc(C(=O)O)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 68.8 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (340 mg) was dissolved in methanol (16 ml), aqueous lithium hydroxide monohydrate (120 mg) solution (8 ml) and tetrahydrofuran (8 ml) were added, and the mixture was refluxed for 50 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (150 ml), the solution was washed with diethyl ether, acidified with 1N hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 223 mg of the titled compound (Yield: 68.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cc(N2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
1,3,5-Trifluoro-2-nitro-benzene (5.30 g, 0.0299 mol) and Potassium carbonate (4.96 g, 0.0359 mol) were mixed in Dimethyl sulfoxide (40.0 mL) and Morpholine (2.74 mL, 0.0314 mol) was added. The reaction was stirred at room temperature for 48 hours and then diluted with EtOAc and washed twice with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-40% EtOAc/hex as the eluting solvent gave 4-(3,5-Difluoro-4-nitro-phenyl)-morpholine (2.85 g, 39%) as a yellow solid. MP=112-114° C.; LCMS=245 (M+H); HNMR (CDCl3, 400 MHz) δ 6.45-6.37 (m, 2H), 3.86 (t, 4H, J=4.5 Hz), 3.33 (t, 4H, J=4.5 Hz); F19 NMR (CDCl3, 400 MHz) δ −115.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3].[CH3:21][CH:22]([N:24]([CH:37]([CH3:39])[CH3:38])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[CH3:23]>C(OCC)(=O)C>[CH3:39][CH:37]([N:24]([CH:22]([CH3:23])[CH3:21])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][NH:36][C:2]([N:4]2[C:10]3[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=3[C:8](=[O:16])[NH:7][C:6]3[CH:17]=[CH:18][CH:19]=[N:20][C:5]2=3)=[O:3])[CH2:32][CH2:33]1)[CH3:38]
Reactant: CC(C)N(CCCC1CCN(CCN)CC1)C(C)C
Reactant: Cc1ccc2c(c1)N(C(=O)Cl)c1ncccc1NC2=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)N(C(=O)NCCN1CCC(CCCN(C(C)C)C(C)C)CC1)c1ncccc1NC2=O
Yield: 46 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-[bis(methylethyl)amino]propyl]-piperidin-1-yl]ethanamine in a yield of 46% of theory. Colourless crystals, m.p. 160°-162° C. (ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:9]2[C:8]3[C:17]4=[C:16]5[C:5](=[CH:6][CH:7]=3)[CH:4]=[CH:3][C:2]([Br:1])=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:20]=1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc2ccc3c(-c4cccc(-c5ccccc5)c4)ccc4ccc1c2c43
Yield: 69.2 %

Procedure:
To a solution of 1,6-dibromopyrene (5.4 g, 15.0 mmol), [1,1′-biphenyl]-3-ylboronic acid (3.3 g, 16.5 mmol), and K2CO3 (10.4 g, 75.0 mmol) in 1,4-dioxane (320 mL) and water (50 mL) was bubbled with nitrogen for 15 min. Pd(PPh3)4 (0.87 g, 0.75 mmol) was then added to the mixture. The mixture was bubbled with nitrogen for 15 min. The resultant mixture was refluxed for 19 h. The reaction mixture was then extracted by DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography using 15% DCM/hexane (containing 0.25% triethylamine) to yield 1-([1,1′-biphenyl]-3-yl)-6-bromopyrene (4.5 g, 70% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])(=[O:5])[CH3:4].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[Cl-].[NH4+]>O1CCCC1>[C:9]([C:8]1[CH:7]=[C:6]([C:3](=[O:5])[CH2:4][C:14]([O:15][CH2:16][CH3:17])=[O:18])[CH:13]=[CH:12][CH:11]=1)#[N:10]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc(C#N)c1
Temperature: 60 °C
Yield: 100.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 8.27 g, 207 mmol, 3.00 equiv) was added to a solution of 3-acetylbenzonitrile (10.0 g, 68.9 mmol, 1 equiv) in tetrahydrofuran (300 mL). The reaction mixture was stirred at 60° C., and a solution of diethyl carbonate (12.5 mL, 103 mmol, 1.50 equiv) in tetrahydrofuran (60 mL) was added over 45 minutes. The light orange reaction mixture was stirred at 60° C. for an additional 2 h, then was cooled to 22° C. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated to ˜½ volume by rotary evaporation. The resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford ethyl 3-(3-cyanophenyl)-3-oxopropanoate (15 g, 100%) as a white solid. The crude reaction product was taken into the next step without further purification. Calcd (M+1)+: 218.1. Found: 218.0.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([OH:40])=[O:39])([C:34]([OH:36])=[O:35])[OH:33]>C(O)C>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([O-:40])=[O:39])([C:34]([O-:36])=[O:35])[OH:33]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 22.5 °C

Procedure:
In yet another example sunitinib base is dissolved in boiling ethanol, subsequently citric acid is added to the solution, which is then left to cool to about room temperature such as about 20 to 25° C. to give sunitinib citrate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH:16]([CH2:18][CH3:19])[CH3:17])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[SH:8].[N:20]([O-])=O.[Na+]>C(O)(=O)C>[CH:16]([NH:15][C:3]1[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:9])[N:6]=[C:7]2[S:8][N:20]=[N:1][C:2]=12)([CH2:18][CH3:19])[CH3:17]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1c(C)nc(S)c(N)c1NC(C)CC
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2snnc2c1NC(C)CC
Yield: 72 %

Procedure:
By treating 5-amino-4-sec.butylamino-6-mercapto-2-methylpyridine-3-carboxylic acid, ethyl ester with sodium nitrite in acetic acid as described in Example 1 e, 7-(sec.-butylamino)-5-methyl[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxylic acid, ethyl ester is obtained, yield 72% m.p. 48°-50° (ether).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[CH:20](OCC)[CH:21]([CH3:29])[CH:22](OCC)OCC)C>CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[CH:22]=[C:21]([CH3:29])[CH:20]=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)C(C)C(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cnc2c3c(nn2c1)CN(C(=O)OC(C)(C)C)C3
Temperature: 50 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (5 g; 22.3 mmol; 1 eq.) and 1,1,3,3-tetraethoxy-2-methylpropane (4.32 mL; 22.3 mmol; 1 eq.) in AcOH (50 mL) was stirred at 50° C. for 20 hours then diluted with water (250 mL). The precipitate was filtered off and dried to afford the title compound (3.5 g, 57%) as a pale beige solid. 1H NMR (DMSO-d6) δ 8.98-8.95 (m, 1H), 8.43 (d, J=2.1 Hz, 1H), 4.61-4.54 (m, 4H), 2.31 (s, 3H), 1.47 (s, 9H). HPLC (max plot) 99.7%; Rt 3.27 min. UPLC/MS: (MS+) 275.0 ([M+H]+).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH:11]=[CH2:12])[OH:10])([CH3:3])=[CH2:2].C(OCC)C>O1CCCC1>[CH3:3][C:1]1[CH2:2][CH2:12][CH2:11][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]=1
Reactant: C=CC1(O)CCCCC1C(=C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=CCCCCC(=O)CCC1

Procedure:
A mixture of 2-isopropenyl-1-vinylcyclohexan-1-ol (0.166 g; 10-3 mol) and dichloro-bis-(benzonitrile)-palladium(II) (0.038 g; 10-4 mol) in tetrahydrofuran (5 cc) is kept at a temperature of the order of 20° C. under an inert atmosphere. After a reaction time of 24 hours, diethyl ether (75 cc) is added and the mixture is then washed with water (5×15 cc). After drying over magnesium sulphate, filtration and evaporation of the solvent under reduced pressure (20 mm Hg; 2.7 kPa), 5-methylcyclodec-5-en-1-one (0.070 g) is obtained, which has the following characteristics:
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C@H:5]([C@@H:18]([CH3:25])[CH2:19][CH2:20][CH:21]=C(C)C)[CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>O=O.C(Cl)Cl>[CH3:25][C@H:18]([C@@H:5]([CH3:4])[CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:19][CH2:20][CH:21]=[O:1]
Reactant: O=[O+][O-]
Reactant: CC(C)=CCC[C@H](C)[C@@H](C)CNC(=O)OCc1ccccc1
Agent: O=O
Solvent: ClCCl
Product: C[C@@H](CCC=O)[C@@H](C)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stream of 4% ozone in oxygen was bubbled through a solution of 1.79 g (~6 mmol) of 2(R),3(S),7-trimethyl-1-benzyloxycarbonylamino-6-octene in 25 mL of methylene chloride at -78° C. until blue color persisted. Nitrogen gas was bubbled through the reaction mixture at the same temperature for 15 min. 3 mL of dimethyl sulfide was added and the mixture was stirred 15 mins and then warmed to 0° C. The solvents and other volatile materials were removed under house vacuum. Traces of solvent were then removed in vacuo to give 1.3 g of the desired aldehyde as a thick oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[CH:9]=2)[C:4](=[O:17])[O:3]1.CC(C)([O-])C.[K+].[F:25][C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[C:30]([F:32])[CH:31]=1>CN(C)C=O>[F:25][C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[C:30]([F:32])[C:31]=1[CH:11]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:17])[O:3][C:2]2([CH3:18])[CH3:1]
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: CC1(C)OC(=O)c2ccc(Cn3cncn3)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccc(C(c3c(F)cc([N+](=O)[O-])cc3F)n3cncn3)cc21
Reaction time: 5 h

Procedure:
To a solution of 3,3-dimethyl-5-[1,2,4-triazol-1-ylmethyl]-3H-isobenzofuran-1-one (4.47 g Intermediate 1) in N,N-dimethylformamide (250 ml) at 0° under nitrogen was added potassium tert-butoxide (4.53 g). After one hour 3,5-difluoronitrobenzene (3.22 g) was added and stirring continued for five hours. The reaction mixture was partitioned between water and ethyl acetate and the phases separated. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried and then evaporated to yield a brown oil. This was purified by column chromatography on Merck 9385 silica eluting initially with dichloromethane through to a 50:1 mixture of dichloromethane:methanol to yield a brown foam. The brown foam was further purified by gradient elution HPLC (water-acetonitrile-trifluoroacetic acid) to give 5-[(2,6-difluoro-4-nitrophenyl)-1,2,4-triazol-1-ylmethyl]-3,3-dimethyl-3H-isobenzofuran-1-one as a yellow foam.
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[NH:35][C:34](=[O:41])[CH:33]=[C:32]2O.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[NH:35][C:34](=[O:41])[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: COc1cc2[nH]c(=O)cc(O)c2cc1Br
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(=O)[nH]c3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 6.5 h
Yield: 52.8 %

Procedure:
To a solution of 1-t-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (4 g, 8.61 mmol) and the product from Step 1 (3.49 g, 12.92 mmol) in NMP (86 mL) under N2 was added Cs2CO3 (8.42 g, 25.8 mmol) and the mixture heated to 60° C. After 6.5 hours, the reaction was cooled to RT and partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and the solvent evaporated. The crude product (6.5 g) was purified on silica (gradient elution, 0-100% EtOAc/hexane and then 0-5% MeOH/DCM) to yield 2.26 g of the title compound. LRMS ESI+ ((M-Boc)+H)+ Calcd. 397.3 Found 399.3.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.C1(P(=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc(OC)ccc1F
Temperature: 70 °C
Reaction time: 15 h
Yield: 38.5 %

Procedure:
To a solution of 2-fluoro-5-methoxybenzaldehyde (1.54 g) in toluene (50 mL) was added ethyl (triphenylphosphoranylidene)acetate (3.83 g), and the mixture was stirred at 70° C. for 15 hr. The reaction mixture was concentrated, and diethyl ether was added. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (862 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1([C:15]([NH2:17])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CO[C:20](OC)(OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[O:16]=[C:15]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]2)[N:1]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17]1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1ccccc1)NC2=O
Yield: 30.8 %

Procedure:
A solution of tert-butyl 4-amino-4-(aminocarbonyl)piperidine-1-carboxylate (120 mg, 0.493 mmol) and trimethyl orthobenzoate (198 mg, 1.09 mmol) in toluene (7 mL) was heated at 110° C. for 18 h. The reaction was concentrated and the crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 5% methanol:dichloromethane to give the title compound (50 mg). MS: m/z=330.2 (M+1).