Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=1)[O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].[H-].[Na+]>CN(C=O)C>[CH3:28][O:27][C:25](=[O:26])[C@@H:24]([O:23][C:22]1[CH:21]=[C:20]([CH:32]=[CH:31][CH:30]=1)[CH2:19][N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2)[C:10]([CH3:11])=[C:2]1[CH3:1])[CH3:29]
Reactant: COC(=O)[C@H](C)Oc1cccc(CBr)c1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(O[C@@H](C)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of allyl 2,3-dimethyl-1H-indole-5-carboxylate (1.0 g, 4.4 mmol, 1 equiv) and (S)-methyl 2-(3-(bromomethyl)phenoxy)propanoate (1.30 g, 4.84 mmol, 1.1 equiv) in anhydrous DMF (30 mL) under argon atmosphere was added sodium hydride (211 mg, 8.8 mmol, 2 equiv) in small portions. The mixture was stirred 2 h at room temperature. The reaction mixture was then quenched slowly with a solution of HCl 0.5 N. The residue was dissolved in AcOEt, washed with a saturated NaHCO3 solution and brine, dried over MgSO4. The crude was purified by flash chromatography (AcOEt/Hexane 0->60%) to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:26][C:27]1[CH:28]=[C:29]([CH:33]([CH3:38])[CH2:34][C:35](Cl)=[O:36])[CH:30]=[CH:31][CH:32]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:35](=[O:36])[CH2:34][CH:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([Br:26])[CH:28]=3)[CH3:38])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(CC(=O)Cl)c1cccc(Br)c1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1)c1cccc(Br)c1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. γ-(3-Bromophenyl)butanoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl- 1,3,4-thiadiazol-2-yl)-3-methyl-6-[γ-(3-bromophenyl)-butanoyloxy] -2(1H)-pyrimidinone as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[O-:23][C:24]#[N:25].[Na+]>C1C=CC=CC=1>[C:24]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:23])[NH2:25]
Reactant: COC(=O)c1ccc(OCCCNc2ccc(Cl)cc2)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OCCCN(C(N)=O)c2ccc(Cl)cc2)cc1
Temperature: 40 °C
Yield: 99.4 %

Procedure:
Methyl 4-[3-[N-(4-chlorophenyl)amino]propoxy]benzoate (2.5 g) and sodium cyanate (1.02 g) were dissolved and suspended in benzene (7.5 g), and to the mixture was added dropwise trifuluoroacetic acid (1.19 g) under heating with stirring at 40° C. Three hours later, the reaction solution was concentrated under reduced pressure, and water was added to the residue. The resulting precipitate was crushed, and collected by filtration to give the desired product (2.82 g). mp. 141°-142° C.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[CH:11][C:12]3[C:13]([CH:19]([CH3:21])[CH3:20])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[C:22]1([C:32](Cl)=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[F:18][C:15]1[CH:14]=[C:13]([CH:19]([CH3:21])[CH3:20])[C:12]2[C:11]([C:32]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[O:33])=[C:10]3[CH:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][CH2:8][N:9]3[C:17]=2[CH:16]=1
Reactant: CC(C)c1cc(F)cc2c1cc1n2CCC1C(C)C(=O)[O-]
Reactant: O=C(Cl)c1cccc2ccccc12
Product: CC(C)c1cc(F)cc2c1c(C(=O)c1cccc3ccccc13)c1n2CCC1CC(=O)O

Procedure:
Starting from methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 44, Step 2) and 1-naphthoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:16]>>[CH2:1]([O:8][CH:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:16]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=c1ccocc1OCc1ccccc1
Product: O=C1C=CN=CC1OCc1ccccc1
Reaction time: 72 h

Procedure:
This method is adapted from that of Bartulin et al., J. Heterocyclic Chem. 29:1017-1019 (1992), which is hereby incorporated by reference. A 3-benzyloxy4-pyrone, prepared as in Method B, is added to an ethanolic solution of aqueous ammonia. The reaction mixture is stirred for approximately 3 days, concentrated under reduced pressure, triturated with acetone, and the solid recrystallized from ethanol to yield the corresponding 3-benzyloxypyrid-4-one. To a solution of this pyrid-4-one in aqueous ethanol containing one equivalent of sodium hydroxide was added an equivalent of n-alkyl bromide. The reaction mixture was heated under reflux for 24 hours after which it was cooled, concentrated under reduced pressure, and extracted with an appropriate solvent. After washing, the organic phase with water, it is dried over magnesium sulfate. The product is obtained upon concentration of the solution under reduced pressure. Crude 1-alkyl-3-benzyloxypyrid-4-one in acetic acid containing 40% hydrobromic acid is then heated on a steam bath for 30 minutes. The 1-alkyl-3-hydroxypyrid-4-one precipitates and is subsequently recrystallized from benzene in good yield with a narrow melting point and appropriate NMR spectrum. ##STR6##
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][O:24][C:25](=[O:42])[CH:26](OS(C(F)(F)F)(=O)=O)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:28]1([CH2:27][CH:26]([O:22][C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([C:10]4[NH:11][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[CH:13]=3)[CH:18]=2)[C:25]([O:24][CH3:23])=[O:42])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A mixture of 6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.300 g, 1.05 mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.492 g, 1.58 mmol) and cesium carbonate (0.685 g, 2.10 mmol) in acetone (50 mL) was stirred under nitrogen at ambient temperature overnight. The acetone was removed under reduced pressure and the residue partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted two times with EtOAc. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40L column (120 g Silica Gel, 60 Å) using 25% to 60% methylene chloride in hexane as the eluent gave methyl 3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoate as a grayish solid (0.447 g, 95%), mp 140–141° C. Elemental Analysis for C30H25NO3 Calc'd: C, 80.51; H, 5.63; N, 3.13. Found: C, 80.26; H, 5.70; N, 2.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=S)[NH:11][NH2:12].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: COc1ccccc1NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccccc2OC)n[nH]c1C
Temperature: 25 °C

Procedure:
A suspension of 10.0 g (0.0507 mole) of 4-(2-methoxyphenyl)-3-thiosemicarbazide and 8.35 g (0.0507 mole) of ethyl 2-chloroacetoacetate in 150 mL of absolute ethanol was stirred for ~16 hr at room temperature. Alcoholic hydrogen chloride (2N, 50 mL) was added, the mixture heated at reflux for 1.0 hr, and the solution filtered while hot to remove the precipitated sulfur. The filtrate was evaporated under reduced pressure, and the residue dissolved in hot ethanol, treated with charcoal and filtered through Celite®. The solution deposited 10.0 g of product, mp 162°-172° C. A similar recrystallization from absolute ethanol left 8.1 g, mp 155°-175° C. This product was dissolved in absolute ethanol, treated with charcoal, and filtered through Celite® 3 times. The filtrate deposited 4.3 g of product while standing for ~16 hr, mp 155.5°-159° C. which was a mixture of free base and hydrochloride salt. This last filtrate was left open to the atmosphere, and after approximately 50% of the solvent had evaporated, a solid precipitated and was collected by filtration: 1.4 g, mp 184°-191° C.
Reaction SMILES: [CH2:1]1[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCCCCCCN
Reactant: CCCCC1CO1
Product: CCCCC(O)CNCCCCCCNCC(O)CCCC

Procedure:
Condensation of 1-hexene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxyhexylamine] (I: R = CH3 (CH2)3, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].Cl.[CH2:6]([C:13]1([OH:42])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[CH2:22][NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[ClH:4].[CH2:6]([C:13]1([O:42][C:1](=[O:3])[CH3:2])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[CH2:22][NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)Cl
Reactant: O=C(NCC(CCN1CCC(O)(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1(Cc2ccccc2)CCN(CCC(CNC(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
0.12 g of acetyl chloride is added to 0.4 g of N-[4-(4-benzyl-4-hydroxypiperidyl) -2-(3,4-dichlorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride (Compound 7), obtained according to Example 1, dissolved in 10 ml of dichloromethane in the presence of two equivalents of triethylamine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([OH:16])[C@H:12]([NH2:15])[CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:17][CH:18]([Cl:23])[C:19](OC)=[O:20]>CO>[Cl:17][CH:18]([Cl:23])[C:19]([NH:15][C@H:12]([CH2:13][F:14])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[OH:16])=[O:20]
Reactant: COC(=O)C(Cl)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Yield: 69.8 %

Procedure:
To a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (5 g, 0.02 moles) in methanol (50 ml) was added methyl dichloroacetate (14.5 g; 0.10 g) and heated to reflux at 60° C. to 65° C. for 18 hours. After completion of reaction, methanol was distilled off from reaction mass, toluene (25 ml) and water (5 ml) were added. The product thus precipitated was filtered, washed with methylene chloride (20 ml) and crystallized from 2-propanol/water (5:1) to give 5 g of Florfenicol with 99% HPLC purity.
Reaction SMILES: [CH3:1]O.S(=O)(=O)(O)O.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10].O>C1(C)C=CC=CC=1>[CH3:1][O:24][C:23]([C@H:20]1[CH2:21][CH2:22][C@H:17]([C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13]2)[CH2:18][CH2:19]1)=[O:25]
Reactant: CO
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)OC)CC2)CC1

Procedure:
Methyl alcohol (200 ml) and conc. sulfuric acid (15 ml) were added to trans-4-(trans-4'-propylcyclohexyl)cyclohexanecarboxylic acid (68.2 g, 0.27 mol) and the mixture was heated under reflux for 4 hours, followed by cooling, adding water (200 ml) and toluene (100 ml), transferring the resulting mixture to a separating funnel, three times washing the toluene layer with water (each time 100 ml), distilling off toluene, adding ethyl alcohol (40 ml) to the residue, recrystallizing, filtering off and drying to obtain the objective trans-4-(trans-4'-propylcyclohexyl)cyclohexanecarboxylic acid methyl ester (65 g) (yield: 90.2%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1>C(O)(=O)C>[Cl:4][CH2:21][C:20](=[O:22])[C:14](=[N:13][O:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:24][CH:23]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C(=O)CCl
Reaction time: 8 h

Procedure:
Sulfuryl chloride (39.26 g.) was added to a solution of ethyl 2-(4-chlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 75.03 g.), in acetic acid (75 ml.), and then stirred at 37° to 40° C. for 8 hours. After air was bubbled into the reaction mixture, the mixture was added to ice water. The mixture was extracted with methylene chloride, and the extract was washed with sodium bicarbonate saturated aqueous solution and sodium chloride saturated aqueous solution in turn. The solution was dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-chloro-2-(4-chlorobenzyloxyimino)-3-oxobutyrate (syn isomer), 77.23 g.).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:23][C:24]([CH3:32])([C:28]([F:31])([F:30])[F:29])[C:25](O)=[O:26].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][C:35]=1[NH:42][C:43]1[N:47]([CH3:48])[C:46]2[CH:49]=[C:50]([N:54]3[CH2:59][CH2:58][CH2:57][CH:56]([C:60]([F:63])([F:62])[F:61])[CH2:55]3)[C:51]([Cl:53])=[CH:52][C:45]=2[N:44]=1>CN(C=O)C>[NH2:23][C:24]([CH3:32])([C:28]([F:31])([F:30])[F:29])[C:25]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([Cl:33])=[C:35]([NH:42][C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[C:50]([N:54]4[CH2:59][CH2:58][CH2:57][CH:56]([C:60]([F:63])([F:62])[F:61])[CH2:55]4)[C:51]([Cl:53])=[CH:52][C:45]=3[N:44]=2)[CH:36]=1)=[O:26]
Reactant: CC(N)(C(=O)O)C(F)(F)F
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C(C)(N)C(F)(F)F)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TBTU (106 mg, 0.3 mmol) followed by TEA (126 μL, 0.9 mmol) were added to 2-amino-3,3,3-trifluoro-2-methylpropanoic acid (57 mg, 0.4 mmol) in DMF (2 mL). After 5 min at rt a mixture of 4-chloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzylamine (142 mg, 0.3 mmol) and DMF (2 mL) was added to the reaction mixture and stirred at rt overnight. The reaction mixture was purified by chromatography to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1C[C@@H]1[C@H](C)CCCN1C(OCC1C=CC=CC=1)=O.[F:30][C:31]1([F:47])[CH2:36][CH2:35][N:34]([C@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH:33]([CH2:45]O)[CH2:32]1>>[F:30][C:31]1([F:47])[CH2:36][CH2:35][N:34]([C@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH:33]([CH2:45][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:32]1
Reactant: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: C[C@@H](c1ccccc1)N1CCC(F)(F)CC1CO
Product: C[C@@H](c1ccccc1)N1CCC(F)(F)CC1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared following the same general protocol as described for (2S,3R)-benzyl 2-((1,3-dioxoisoindolin-2-yl)methyl)-3-methylpiperidine-1-carboxylate in Example A1 using (4,4-difluoro-1-((S)-1-phenylethyl)piperidin-2-yl)methanol (1.1 g, 97%). MS (ESI) 285 (M+H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:20][CH:19]([NH2:21])[CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH:19]([NH:21][C:5](=[O:7])[CH3:6])[CH2:20]2)=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: NC1CN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC1CN(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
Acetic anhydride (0.6 ml) was added to a solution of 1-(4-nitrophenyl)-azetidin-3-ylamine (0.5 g ) in pyridine (1.2 ml). After one hour, volatile fractions were removed. This resulted in the product with the molecular weight of 235.24 (C11H13N3O3); MS (ESI): 236 (M+H+).
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)(=O)C.C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]([C:6]2[N:7]3[C:12]([CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:5]=2)=[O:22])=[CH:19][CH:18]=1)#[N:21]
Reactant: CC(=O)c1cc(C(=O)c2ccc(C#N)cc2)n2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: c1ccccc1
Product: N#Cc1ccc(C(=O)c2ccc3ccccn23)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A solution of 1-acetyl-3-(4-cyanobenzoyl)indolizine (12) (1.56 grams, 5.69 mmol), ethylene glycol (1 mL), and p-toluenesulfonic acid (2.16 grams, 11.38 mmol) in benzene (150 mL) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). The combined layers were concentrated in vacuo. Purification by flash column chromatography (Rf 0.3, ethyl acetate in hexane) afforded 3-(4-cyanobenzoyl)indolizine (13) as a light yellow solid (1.12 grams, 80%). 1H NMR (CDCl3) δ 6.56 (d, J=4.8, 1H), 7.04 (t, J=6.9, 1H), 7.28 (m, 2H), 7.61 (d, J=9.0, 1H), 7.78 (m, 2H), 7.89 (m, 2H), 9.98 (d, J=7.2, 1H). ESMS calcd (C16H10N2O2): 246.1. found: 247.1 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)[NH2:3].C([O-])(=O)C.[Na+].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>O.C(O)C>[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[N:3][NH:2][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)NCc1ccc(NN)cc1
Reactant: C1=COCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)NCc1ccc(NN=CCCCCO)cc1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a solution of 23.9 g of crude N-[(4-hydrazinylphenyl)methyl]methanesulfonamide hydrochloride in 175 mL of water and 300 mL of ethanol was added sufficient sodium acetate to bring the pH to 4. To the resulting suspension was added 10.4 mL (114 mmol, 1.3 equiv.) of 3,4- dihydro-2H-pyran. The mixture was then stirred for twenty hours at room temperature. The ethanol was removed in vacuo. The pH was raised to 10 by adding solid potassium carbonate and the mixture was extracted three times with 50 mL portions of methylene chloride. The combined organic layers were washed with 25 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and filtered to give an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide to yield 11.1 g (39%, two steps) of pure N-[[4-[2-(5-hydroxypentylidene)hydrazinyl]phenyl]methyl]methanesulfonamide.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:10][CH3:11]>C1(C)C=CC=CC=1>[CH3:11][CH:10]1[C:3]2[CH:2]=[C:1]([OH:8])[CH:6]=[CH:5][C:4]=2[O:7][CH:9]1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: CC=CN1CCOCC1
Solvent: Cc1ccccc1
Product: CC1c2cc(O)ccc2OC1N1CCOCC1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Benzoquinone (300 g, 2.8 mol) was added in toluene (1.5 L) and cooled with a dry ice/isopropyl alcohol (IPA) bath. 4-Propenyl-morpholine (prepared as above in EXAMPLE I) (380 g, 3 mol) was added dropwise with stirring. The reaction mixture was aged for overnight, filtered and subsequently air dried to provide 3-methyl-2-morpholin-4-yl-2,3-dihydro-benzofuran-5-ol (628 g, 2.7 mol).
Reaction SMILES: [Li].[C:2]1(OCC=C)[CH:7]=CC=C[CH:3]=1.C(O[C:15]([CH:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:25])=[C:18]1[CH2:26][CH3:27])=[O:16])C>O1CCCC1.CCOCC>[CH2:26]([C:18]1[CH:17]([C:15](=[O:16])[CH2:7][CH:2]=[CH2:3])[C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][C:19]=1[CH3:25])[CH3:27]
Reactant: CCOC(=O)C1C(CC)=C(C)CCC1(C)C
Reactant: C=CCOc1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(=O)C1C(CC)=C(C)CCC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A few crystals of diphenyl are added to a suspension, cooled to 5°-10° C and held under a nitrogen atmosphere, of 2.4 g (0.35 g-atoms) of finely cut lithium wire in 40 ml of absolute tetrahydrofuran. 2 ml of a solution of 9.4 g (70 mmol) of allyl phenyl ether in 10 ml of absolute ether are then added. After a greenish coloration sets in, the rest of the solution is added dropwise at -15° C. After completion of the addition, the mixture is stirred for 30 minutes at 0° C. The resulting allyl lithium solution is decanted off from excess lithium and transferred to a dropping funnel. This solution is added dropwise to a solution, cooled to -60° C and maintained under nitrogen, of 4.48 g (20 mmol) of 2-ethyl-3,6,6-trimethyl-2-cyclohexene-1-carboxylic acid ethyl ester in 40 ml of absolute ether. After completion of the addition, the mixture is left to warm to room temperature, poured on to ice-water and extracted with three portions of hexane. The combined hexane extracts are washed neutral with three portions of water, dried over sodium sulphate and evaporated. By fractional distillation of the residue there are obtained 3.75 g (85%) of 2-ethyl-3,6,6-trimethyl-1-[but-3-enoyl]-2-cyclohexene; boiling point 57°-58° C/0.04 mm Hg; nD20 = 1.4865.