Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2([CH3:13])OCC[O:9]2)=[CH:5][CH:4]=1.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O.C(OCC)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]([OH:9])[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC2(C)OCCO2)cc1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CC(C)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
2-(4-Methoxybenzyl)-2-methyl-1,3-dioxolane (0.64 g, 3 mmol), sodium dodecyl sulfate (0.2 g, 0.7 mmol) and a stir bar were added to the inside of a PDMS thimble. p-Toluene sulfonic acid monohydrate (0.145 g, 0.8 mmol) dissolved in 4 mL water was added to the inside of the PDMS thimble followed by 2 mL of THF. The reaction was stirred at 25° C. for 5 hours. LiAlH4 (0.229 g, 6 mmol) and 5 mL hexanes were added to the outside of the PDMS thimble and the reaction proceeded for 24 hours. 5 mL Water was added. The PDMS thimble was swelled with 20 mL hexanes and 2×20 mL diethyl ether, the organics were combined and dried over MgSO4 and evaporated. The product was purified by flash chromatography eluting with 1:4 ethyl acetate:hexanes to yield a pale yellow oil (0.43 g, 83% yield). 1H NMR (CDCl3): δ 1.22 (d, J=5.7 Hz, 3H), 1.69 (s, 1H), 2.61 (dd, J=13.2, 7.5 Hz, 1H), 2.72 (dd, J=13.5, 4.8 Hz, 1H), 3.78 (s, 3H), 3.93-3.98 (m, 1H), 6.85 (d, J=8.4, 2H), 7.12 (d, J=8.7 Hz, 2H). 13C NMR (CDCl3): δ 22.61, 44.77, 55.18, 68.88, 113.89, 130.27, 130.43, 158.19.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(O)C>CO.ClCCl.[Cl-].[NH4+]>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH:32]=[C:6]3[S:5][C:4](=[S:7])[N:3]([CH:8]4[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]4)[C:2]3=[O:1])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(-c2ccc(C=O)o2)cc1
Reactant: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2ccc(C=C3SC(=S)N(C4CCCC(C(=O)O)C4)C3=O)o2)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 68.7 %

Procedure:
3-(4-oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (80 mg, 0.31 mmol), 5-(4-tert-butyl-phenyl)-furan-2-carbaldehyde (75 mg, 0.33 mmol), and diethylenediamine diacetate (59 mg, 0.33 mmol) were combined in a 20 mL vial with ethanol (5 mL) and stirred at room temperature for 65 h. The reaction mixture was diluted with 10% methanol in dichloromethane (200 mL) and aqueous ammonium chloride (20 mL) and stirred at room temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with 10% methanol in dichloromethane (2×100 mL). The combined organic extracts were washed with 0.6N sodium hydrogensulfite (1×20 mL) and then brine (1×20 mL), dried (sodium sulfate) and concentrated under vacuum. The residue was triturated with dichloromethane/hexanes (1:5:30 mL), filtered and dried overnight in a vacuum oven at 55° C. to afford 3-{5-[1-[5-(4-tert-butyl-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-cyclohexanecarboxylic acid (100 mg, 69%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.32 (9H, s), 1.25-1.41 (2H, m), 1.67 (1H, m), 1.87-1.92 (3H, m), 2.29-2.45 (3H, m), 4.98 (1H, m), 7.26 (1H, d, J=3.6 Hz), 7.36 (1H, d, J=3.6 Hz), 7.59-7.61 (3H, m), 7.77-7.70 (2H, m), 12.20 (1H, s); APCI-MS: 469.52; HPLC: 95%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([O:45]C)=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:63][N:64]([CH3:69])[CH2:65][CH2:66][CH2:67][NH2:68]>CN(C=O)C>[CH3:63][N:64]([CH3:69])[CH2:65][CH2:66][CH2:67][NH:68][C:43]([C:40]1[S:39][C:35]2[N:36]=[CH:37][N:38]=[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[O:47][CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[C:34]=2[C:41]=1[CH3:42])=[O:45]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 3-Dimethylamino-1-propylamine (69 μL, 0.625 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was recrystallised from DMSO to yield off-white solid (0.031 g, 51%).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:64][CH2:65][S:66][C:67]2[S:68][CH:69]=[N:70][N:71]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(O)C>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:64][CH2:65][S:66][C:67]4[S:68][CH:69]=[N:70][N:71]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCSc4nncs4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: CCO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCSc4nncs4)CS[C@H]23)cs1
Reaction time: 0.67 h
Yield: 74.1 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (535 mg: 0.51 mMol.) in a mixture of anisole (1 ml) and nitromethane (4 ml) is added a solution of aluminum chloride (0.61 g: 4.6 mMol.) in anisole (2 ml) at -30° C. and the mixture is stirred for 40 minutes. The reaction mixture is mixed with ethanol (2 ml), stirred for 5 minutes at the same temperature, diluted with 1N-hydrochloric acid (6 ml) and water (200 ml), and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove the organic solvents and passed through a styrene-divinylbenzene copolymer column. The adsorbed material is eluted with a methanol-water (4:1) mixture. The eluate is concentrated to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethylthio)-3-cephem-4-carboxylic acid as pale yellow solid (201 mg). Yield: 74%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:20][CH3:21])=[CH:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=O)[C:11]([C:16]#[N:17])=[CH:12][NH:13]3)=[CH:8][C:7]=2[CH:19]=1.P(Cl)(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:10]1[C:9]2[C:14](=[CH:15][C:6]3[CH:5]=[C:4]([O:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:19][C:7]=3[CH:8]=2)[N:13]=[CH:12][C:11]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc3[nH]cc(C#N)c(=O)c3cc2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Yield: 49.4 %

Procedure:
A mixture of 356.2 mg (1.3 mmol) of 7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in 5 mL of phosphorus oxychloride and 4 drops of DMF is heated at 100–110° C. for 4.5 hours. After cooling, the mixture is concentrated to dryness in vacuo to give a dark residue. The residue is partitioned between methylene chloride and ice-cooled saturated aqueous sodium carbonate solution. The organic layer is washed with cooled brine and dried over sodium sulfate. The organic solvent is passed through a short column of silica gel, and the column is first eluted with additional methylene chloride, then a 99:1 methylene chloride/ethyl acetate solution. Removal of the solvent yields 187.0 mg (49.4%) of the product as a bright yellow solid, mp>265° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:17]=[N:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=Nc1ccc(F)cc1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use 4-fluorophenylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (32.3% yield). 1H NMR (500 MHz, CDCl3) δ 12.0, 8.20, 7.53, 7.64, 7.59, 7.39, 7.33, 7.16, 6.91-6.98, 3.96-4.04, 3.83-3.90, 3.52-3.65, 3.37-3.45, 3.20-3.26. MS (ES+) m/z 489 (M+1).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)C.O>C1(C)C=CC=CC=1>[O:6]1[C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=2[CH:4]=[CH:5]1
Reactant: CCOC(COc1ccc(C(C)=O)cc1)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1ccc2occc2c1
Yield: 3.7 %

Procedure:
To a solution of 1-(4-(2,2-diethoxyethoxy)phenyl)ethanone (2.46 g, 7.34 mmol) in toluene (25 mL), was added PPA (2.50 g) and refluxed for 1 hour. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (44 mg (yield 3.7%)) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][CH3:16].C([BH3-])#N.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][NH:12]2)=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc2cc[nH]c2cc1OCCN(C)C
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1OCCN(C)C)NCC2
Yield: 74.6 %

Procedure:
A stirred solution of 6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (D16, 0.50 g, 2.1 mmole) in glacial acetic acid (10 ml) at room temperature was treated portionwise over 15 minutes with sodium cyanoborohydride (0.25 g, 4 mmole). After 2 hours the solution was diluted with water (50 ml), basified by addition of Na2CO3 and then extracted with ethyl acetate (2×50 ml). The combined extract was dried (Na2SO4), and concentrated in vacuo to leave the title compound as a brown oil (0.37 g, 73%).
Reaction SMILES: [C:1]([N:20]1[C:24]([C:25](OC)=[O:26])=[C:23]([C:29](OC)=[O:30])[C:22]([C:33](OC)=[O:34])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[C:1]([N:20]1[C:24]([CH2:25][OH:26])=[C:23]([CH2:29][OH:30])[C:22]([CH2:33][OH:34])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(=O)OC)c1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CO)c1CO
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of trimethyl 1-trityl-3,4,5-pyrazoletricarboxylate (3.034 g, 6.26 mmol) in dry THF (60 mL) were added 50 mL of 1.0 M LiAlH4 in Et2O. The resulting solution was stirred for about 16 h at room temperature (20-25° C.). After this time, the reaction was quenched by the slow addition of 1.5 mL of distilled water, followed by addition of 1.5 mL of 10% NaOH and 3.5 mL of water. The solids formed were removed by filtration, and 80 mL of dichloromethane was added to the filtrate. The organic phase was separated, washed with distilled water (70 mL) and, after separation from the aqueous phase, was dried over MgSO4. After separation of the organic phase, the solvent was evaporated under vacuum yielding a yellowish solid. Yield: 73% (1.823 g, 4.54 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>O1CCOCC1>[C:21]([NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[OH:14])(=[O:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(O)c(CN)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)NCc1cc(C(C)(C)C)ccc1O
Temperature: 0 °C

Procedure:
43 g (0.2 mole) of 2-aminomethyl-4-(1,1-dimethylethyl)-phenol hydrochloride are suspended in 400 ml of 1,4-dioxane, and 40 ml of pyridine are added. 40 ml (0.55 mole) of acetyl chloride are added dropwise while stirring and cooling with ice. The mixture is then stirred for 2.5 hours at 90° and poured into ice water, and the precipitate which has crystallized out is filtered off with suction.
Reaction SMILES: Cl.C([Cl:5])(=O)C.C([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25])(=O)C1C=CC=CC=1>CO>[ClH:5].[NH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cc1ccccc1CONC(=O)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccccc1CON
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of HCl in methanol (prepared by adding 20 mL of acetyl chloride slowly to 200 mL of methanol) was added the title compound of Step B (31.5 g). The mixture was heated to 60° C. for 1.5 h. The solvent was removed in vacuo. The residue was taken up in 100 mL of diethyl ether and stirred at room temperature for 30 minutes. The ether was decanted off and the solid was taken up in 100 mL of tetrahydrofuran and heated to about 50° C. The mixture was then cooled in an ice water bath and the solid was collected by filtration to provide 11.5 g (47% yield) of the title compound of Step C as a white solid melting at 169-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][CH2:11][C:12](=O)[CH3:13].C(N(CC)CC)C.Cl.[CH3:23][O:24][NH2:25]>CO.O>[CH3:23][O:24][N:25]=[C:12]([CH2:11][CH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])[CH3:13]
Reactant: CON
Reactant: CC(=O)CCc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CON=C(C)CCc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Yield: 97.8 %

Procedure:
To a stirred solution of 4-(2,4,6-trichloro-phenyl)-butan-2-one (0.9 g, 3.57 mmol) in methanol (5 ml), was added triethylamine (0.73 ml, 5.3 mmol) and O-methyl-hydroxylamine hydrochloride (0.447 g, 5.3 mmol). The reaction mixture was heated at a temperature of 60° C. for 3 hours. When the TLC confirmed the completion of the reaction, the reaction mass was allowed to attain ambient temperature. After the reaction mixture was diluted with water and methanol was evaporated off, the aqueous layer was extracted with ethyl acetate (3×30 ml). The combined ethyl acetate layers were washed with water followed by brine solution and dried over sodium sulfate before complete evaporation of the solvents to give 4-(2,4,6-trichloro-phenyl)-butan-2-one O-methyl-oxime (0.980 g) crude, which was taken up for reduction without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH:16]([C:18]([O:20]C)=[O:19])[CH2:15][CH2:14][N:13]2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH3:25][O:24][C:22]([N:13]1[CH2:14][CH2:15][CH:16]([C:18]([OH:20])=[O:19])[CH2:17][CH:12]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=1)=[O:23]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)c(C)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(F)(F)F)c(C)c1
Yield: 89.2 %

Procedure:
Dimethyl 2-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (3.09 g, 8.60 mmol) was dissolved in acetonitrile (30 mL) and water (0.6 mL), lithium bromide (5.97 g, 68.79 mmol) was added. Triethylamine (3.48 g, 34.40 mmol) was added and the resulting suspension was heated under reflux for 1 h. Water (60 mL) and MTBE were added. The organic phase was extracted with water (×2). To the pooled aqueous layer was added MTBE and the solution was acidified to pH 1 with HCl and then extracted with MTBE (×2). The organic layer was dried over Na2SO4, filtered through celite and the solvent evaporated to yield 1-(methoxycarbonyl)-2-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (2.65 g, 7.67 mmol).
Reaction SMILES: [C:1]([C:3]1([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[CH3:20])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[CH3:20])[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]1
Reactant: CN1CCCCC1C1(C#N)CN(C(=O)OC(C)(C)C)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1CCCCC1C1(CN)CN(C(=O)OC(C)(C)C)C1
Reaction time: 24 h

Procedure:
tert-Butyl 3-cyano-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate (8.1 g, 29 mmol) was dissolved in 2M ammonia in methanol (100 ml) and Raney nickel (50% slurry in water, 5.0 g (2.5 g Raney nickel)) was added and the mixture hydrogenated on a parr at 45 psi for 1 day until tlc showed completion. The reaction was filtered under nitrogen and the filtrate was evaporated to dryness to give tert-Butyl 3-(aminomethyl)-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate as an oil. m/z (M++H) 284.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:14]1[CH:15]=[CH:16][CH:17]=[C:13]1/[CH:12]=[C:4]1\[C:5](=[O:11])[N:6](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[C:3]\1=[CH:2][CH:10]=[CH:9][CH:8]=2
Reactant: C=Cc1ccccc1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: O=C1/C(=C\c2ccc[nH]2)c2ccccc2N1/C=C/c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (from Example 71 above) (500 mg, 1.49 mmol) in DMF (8 mL) and TEA (3 mL) was added styrene (0.34 mL, 2.98 mmol) (Aldrich), tri-o-tolylphosphine (361 mg, 1.19 mmol) (Aldrich) and Pd(OAc)2 (67 mg, 0.30 mmol) (Aldrich). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc 5:1) to 1,3-dihydro-(Z)-3-[(1H-pyrrol-2yl)methylene]-[(E)-2-phenylethenyl]-2H-indol-2-one. (Yield 371 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>C1COCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([N:22]([CH3:31])[C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: COc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nn(-c2cccc(N(C)C(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
According to Scheme 9 Step 1: To a solution of N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (70 mg, 0.17 mmol) in THF (3 mL) was added portionwise at 0° C. sodium hydride (55%) 11 mg, 0.26 mmol). The suspension was stirred 10 minutes at room temperature. Then, methyl iodide (87 μl, 1.40 mmol) was added dropwise and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was diluted with 100 mL of a saturated solution of ammonium chloride and the aqueous layer was extracted twice with 100 mL of DCM. The organic layers were combined to be successively dried over MgSO2, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 10 g SiO2) using CH2Cl2/MeOH 99/1 as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-N-methylacetamide (54 mg, 75%) as a white solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](N(CC)CC)C>CO.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:26][CH3:34])[N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C(O)CCC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC1CCC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 841.4 %

Procedure:
To an ice cold solution of (2S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-6-hydroxypiperidine-1-carboxylate (2 g, 4.3 mmol) in methanol (20 mL) was added pyridinium p-toluenesulfonate (108 mg, 0.43 mmol). The reaction mixture was warmed to RT and stirred overnight. Triethylamine (87 mg, 0.86 mmol) was added, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluting with 0-15% EtOAc in petroleum ether), and combined with the product of three similar runs to provide the title intermediate (3.5 g).