Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7])[CH2:5][CH2:4]1.[H-].[Na+].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>C1COCC1>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH2:2][C:3]1([C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7])[CH2:4][CH2:5]1
Reactant: CCCNC(=O)C1(CO)CC1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)C1(COc2cccc(N)c2C#N)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A solution of 1-(hydroxymethyl)-N-propylcyclopropanecarboxamide (Example 183c) (0.67 g, 4.25 mmol) in anhydrous THF (10 mL) was treated with NaH (0.17 g, 4.25 mmol, 60% suspension in mineral oil) at 0° C., under a nitrogen atmosphere. The obtained mixture was stirred at 0° C. for 10 min and at rt over 30 min. Then, a solution of 2-amino-6-fluorobenzonitrile (0.53 g, 3.86 mmol) in THF (5.0 mL) was added and the obtained mixture was heated at reflux overnight. The cold mixture was quenched with saturated aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (3×50 mL). The combined extract was washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel using gradient hexanes→hexanes/EtOAc (4:6), to give 0.75 g (71%) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.51 (t, J=6.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 6.19 (d, J=8.4 Hz, 1H), 5.97 (broad s, 2H), 4.13 (s, 2H), 3.04 (q, J=6.4 Hz, 2H), 1.43 (hex, J=6.8 Hz, 2H), 1.05-1.11 (m, 2H), 0.78-0.86 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]([F:39])([F:38])[C:31](N1C=CN=C1)=[O:32]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:18])[CH:16]([CH3:17])[C:31](=[O:32])[C:30]([F:29])([F:38])[F:39])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)C(F)(F)F
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C(=O)c1ccc(OCc2ccccc2)cc1)C(=O)C(F)(F)F
Temperature: -60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4′-benzyloxypropiophenone (6.0 g) in THF (120 ml) at −60° C. was added 38 ml of 1N lithium bis(trimethylsilyl)amide (LiHMDS), and the mixture was stirred at under −60° C. for 45 mins. 1-(Trifluoroacetyl)-imidazole (3.4 ml) was added and the mixture was stirred at −60° C. for 1 hour and at 0° C. for 30 min. The raction mixture was quenched with 0.5N HCl, the mixture was poured into EtOAc and water, and the EtOAc layer was separated, washed with brine, died over MgSO4, and concentrated to give 1-[4-(benzyloxy)phenyl]-4,4,4-trifluoro-2-methyl-1,3-butanedione.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1([C:23](=[O:36])[NH:24][C@@H:25]([C@H:30]([O:32][C:33](=[O:35])[CH3:34])[CH3:31])[C:26]([O:28][CH3:29])=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:33]([O:32][C@H:30]([CH3:31])[C@H:25]([NH:24][C:23]([C:12]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15][NH:11]1)=[O:36])[C:26]([O:28][CH3:29])=[O:27])(=[O:35])[CH3:34]
Reactant: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)OCc1ccccc1)[C@@H](C)OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1)[C@@H](C)OC(C)=O
Reaction time: 4 h
Yield: 75.3 %

Procedure:
To a stirring solution of compound 5 (4 g, 8.06 mmol) in ethanol (50 mL) was added 10% Pd/C (1.2 g) and the reaction mixture was stirred under H2 atmosphere (balloon pressure) for 4 h. It was filtered through celite pad and the filtrate was concentrated under reduced pressure to yield compound 6 (2.2 g, 75%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[I:20]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCCl.O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:10]([I:20])=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c(Br)cnc2c1ccn2COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: Cc1c(Br)cnc2c1c(I)cn2COCC[Si](C)(C)C
Yield: 39 %

Procedure:
5-Bromo-4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.439 mmol) was dissolved in anhydrous 1,2 dichloroethane (6 mL), and N-iodosuccinimide (198 mg, 0.879 mmol) was added. The solution was stirred at 23° C. for 15 hours when ethyl acetate was added. A solution of water (25 mL) and aqueous saturated sodium bicarbonate (25 mL) was added. Layers were mixed well. The organic layer was stirred over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified by flash silica gel chromatography by using a gradient of ethyl acetate in hexanes to afford 5-Bromo-3-iodo-4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.171 mmol, 39%) as a white soft solid. 8.39 (s, 1H), 7.93 (s, 1H), 5.54 (s, 2H), 3.47 (t, 2H), 2.85 (s, 3H), 0.79 (s, 2H), −0.11 (s, 8H); MS [MH+] m/z: 466.9, 468.9
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:45])([F:44])[C:31]1([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][NH:33][CH2:32]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:33]5[CH2:34][CH2:35][C:31]([C:30]([F:45])([F:44])[F:29])([NH2:36])[CH2:32]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)NC1(C(F)(F)F)CCNC1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC(N)(C(F)(F)F)C5)n4)n[nH]c3cn2)cn1
Yield: 47.3 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 3-(trifluoromethyl)pyrrolidin-3-ylcarbamate were reacted. The product was deprotected and purified to give 286 as a white solid (47.3% over two steps). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.65 (s, 1H), 8.09 (s, 1H), 7.86 (s, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.44 (d, J=7.4 Hz, 1H), 6.51 (d, J=8.3 Hz, 1H), 3.91-3.86 (m, 4H), 3.84-3.65 (m, 3H), 2.47 (s, 2H), 2.38-2.27 (m, 1H), 2.05 (dd, J=12.3, 6.1 Hz, 1H); 1 proton not seen. LC/MS: m/z 429.2 [M+1]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[C:18]=[S:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(#N)C>[C:8]([C:12]1[CH:21]=[CH:20][C:15]([CH2:16][NH:17][C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[S:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccc(CNC(=S)Nc2ccccn2)cc1
Yield: 32.9 %

Procedure:
2-aminopyridine (86 mg) was dissolved in acetonitrile (10 ml) and to the solution were added 4-t-butylbenzylisothiocyanate (190 mg) and triethylamine (140 μl), followed by refluxing for 27 hours. The resulting mixture was extracted with water and dichloromethane, dried, concentrated under reduced pressure, and then crystallized (dichloromethane/petroleum ether) to yield the compound (90 mg, 33%) as a white solid.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([C:7]1[CH:25]=[CH:24][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18](C([O-])=O)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)#[N:6].FC(F)(F)C(O)=O>O>[NH:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]#[N:6])=[CH:25][CH:24]=2)[CH2:16][CH2:17]1
Reactant: N#Cc1ccc(OCCCC2CCN(C(=O)[O-])CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(OCCCC2CCNCC2)cc1
Reaction time: 0.33 h

Procedure:
To a chloroform (100 mL) solution of 14.0 g of tert-butyl=4-[3-(4-cyanophenoxy)propyl]-1-piperidinecarboxylate was dropwise added 40 mL of trifluoroacetic acid under cooling with water over a period of 10 minutes. This mixture was stirred at the same temperature for 20 minutes, and then stirred at room temperature for 35 minutes. After distilling off the solvent under reduced pressure, chloroform and water were added. A sodium hydroxide aqueous solution was added thereto for adjustment to pH 13.0. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, which was then washed with a sodium hydroxide aqueous solution and dried with potassium carbonate, followed by distilling off the solvent under reduced pressure to provide 10.3 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile as pale yellow solid form.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:26][C:27]1[O:31][C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[N:29][C:28]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:28]4[N:29]=[C:30]([C:32]5[S:33][CH:34]=[CH:35][CH:36]=5)[O:31][C:27]=4[CH3:26])=[CH:9][CH:8]=3)[C:4]([OH:3])=[O:25])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 78. 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, 1H, J=3.90 Hz, J=1.47 Hz), 7.35 (dd, 1H, J=5.37 Hz, J=1.47 Hz), 7.13 (d, 2H, J=8.31 Hz), 7.04 (dd, 1H, J=5.37 Hz, J=3.90 Hz), 6.78 (d, 2H, J=8.79 Hz), 6.60 (d, 1H, J=8.30 Hz), 6.42 (d, 1H, J=2.44 Hz), 6.33 (dd, 1H, J=8.31 Hz, J=2.44 Hz), 5.88 (d, 2H, J=0.98 Hz), 4.15 (t, 2H, J=6.35 Hz), 3.16 (d, 1H, J=13.92 Hz), 3.04 (d, 1H, J=13.92 Hz), 2.93 (t, 2H, J=6.35 Hz), 2.31 (s, 3H), 1.30 (s, 3H); HRMS (ES+) m/z exact mass calcd for C27H26NO7S 508.1430, found 508.1425.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:15]=[CH:16][C:17]([O:25]CC2C=CC=CC=2)=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])=[N+]=[N-].C(Cl)Cl>CO.[C].[Pd]>[NH2:1][CH2:4][C@@H:5]([C:14]1[CH:15]=[CH:16][C:17]([OH:25])=[C:18]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:19]=1)[O:6][Si:7]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:12][CH3:13]
Reactant: CC[Si](CC)(CC)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC[Si](CC)(CC)O[C@@H](CN)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of N-[5-((R)-2-azido-1-triethylsilyloxyethyl)-2-benzyloxyphenyl]methanesulfonamide (1.84 g) and 10% palladium-carbon (0.18 g) in methanol (15 mL) /methylene chloride (15 mL) was stirred at room temperature for 5 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to afford N-[5-((R)-2-amino-1-triethylsilyloxyethyl)-2-hydroxyphenyl]methanesulfonamide as a crude product. The crude N-[5-((R)-2-amino-1-triethylsilyloxyethyl)-2-hydroxyphenyl]methanesulfonamide was dissolved in tetrahydrofuran (40 mL), and 2,5-dioxopyrrolidin-1-yl (4-bromophenoxy)acetate (1.39 g) was added to the solution. After being stirred at room temperature for 3 hrs, the reaction mixture was concentrated in vacuo, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to afford the title compound (1.01 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][O:4][C:5]1[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1.[CH2:25](OC1OC(C(O)=O)=CC=1)CCCCCCCCC/C=C\CC>>[CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][O:4][C:5]1[O:9][C:8]([C:10]([CH3:25])=[O:12])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCC(C)COc1ccc(C(=O)O)o1
Reactant: CC/C=C\CCCCCCCCCCOc1ccc(C(=O)O)o1
Product: CCCCCCCCCCCCC(C)COc1ccc(C(C)=O)o1

Procedure:
In the procedure of Example 4(B) 5-(2-methyltetradecyloxy)-2-furancarboxylic acid was substituted for cis-5-(11-tetradecenyloxy)-2-furancarboxylic acid to yield methyl 5-(2-methyltetradecyloxy)-2-furyl ketone, M.P. 45°-47° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([NH2:17])[CH:8]=1)([CH3:6])[CH3:5].[CH3:19][C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:21]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([NH:17][C:26]([C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[N:23][CH:24]=2)=[O:27])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1cn(NC(=O)c2cnc(-c3ccccn3)nc2C)c2ccc(F)cc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (0.85 mmol) and 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (201 mg, 0.935 mmol) in DMF (8.5 mL) is stirred at 40° C. for 0.5 h. The mixture is treated with DMTMM (246 mg, 0.89 mmol) and stirred at 60° C. for 1 h. The mixture is concentrated in vacuo, diluted with saturated aqueous Na2CO3 (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 2-{5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indol-3-yl}-2-methyl-propionic acid methyl ester, which is used in the next step without further purification.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=[O:5])#[N:2].[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>C(O)C>[C:1]([C:3](=[C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=1)[S:10][CH3:11])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: CC(C)c1ccc(N)cc1
Solvent: CCO
Product: CSC(Nc1ccc(C(C)C)cc1)=C(C#N)C(N)=O
Temperature: 75 °C
Yield: 62 %

Procedure:
To a solution of 1.50 g (2-cyano-3,3-bis(methylthio)acrylamide) in 15 mL of ethanol. was added 1.084 mL (1.0 eq.) of 4-isopropylaniline, and the reaction was stirred at 75° C. until starting amide was absent as confirmed by HPLC. Once complete (18 hrs), the reaction was brought to room temperature and filtered to obtain 2-cyano-3-((4-isopropylphenyl)amino)-3-(methylthio)acrylamide as an off white to light yellow powder as product. Product was allowed to dry under vacuum for 1 hr (1.360 g, 62% yield).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]4[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=4)=[CH:18][C:12]=3[N:11]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:18][C:12]=2[N:11]=1
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCCN3C(=O)c4ccccc4C3=O)nc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCCN)nc2c1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
##STR69## 0.54 g (1.26 mmol) of 6-[2-(4-phthalimidobutyl)-1H-benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 0.3 ml (6.3 mmol) of hydrazine hydrate are boiled in 20 ml of ethanol for 2 hours. After cooling to room temperature, the solution is filtered, the filtrate is concentrated by evaporation under vacuum and the residue is taken up with 10 ml of 2N hydrochloric acid. The resulting solution is again filtered and is then adjusted to pH 11 with 3N sodium hydroxide solution and concentrated by evaporation to half its original volume. On cooling in an ice bath, a colourless solid crystallizes, which is recrystallized from ethanol. 0.26 g (69%) of crystals are obtained which melt at 185° to 187° C. and resolidify but thereafter do not melt until heated to 280° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[C:10]([C:20]([O:22][CH3:23])=[O:21])[NH:9][C:8]1=[O:24].[CH3:25][O:26][C:27]([C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O1CCOCC1>[CH3:25][O:26][C:27]([C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)=[C:10]([C:20]([O:22][CH3:23])=[O:21])[NH:9][C:8]2=[O:24])[CH2:33][CH2:34]1)=[O:28]
Reactant: COC(=O)c1[nH]c(=O)n(CCCCCBr)c1-c1ccc(F)c(F)c1
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1[nH]c(=O)n(CCCCCN2CCC(C(=O)OC)(c3ccccc3)CC2)c1-c1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a stirred solution of 1-(5-bromopent-1-yl)-5-(3,4-difluorophenyl)-2,3-dihydro-4-methoxycarbonyl-2(1H)-imidazolone (0.357 g, 0.88 mmol) in dioxane (10 mL) was added 4-methoxycarbonyl-4-phenylpiperidine (0.388 g, 1.77 mmol), potassium carbonate (0.544 g, 2.65 mmol) and sodium iodide (0. g, 1.77 mmol), and the mixture refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (40 mL) and water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4.4:0.6) to yield 0.235 g (48%) of the required product as a colorless oil. Hydrochloride salt (recrystallized from ether) : white solid; m.p. 180-182° C. Analysis calculated for C29H34ClF2N3O5.1.7 H2O: C, 57.23; H,6.19. Found: C, 57.14; H, 6.20.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])CCC.[CH3:16][C:17]1([CH3:31])[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18]1>C1COCC1>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([C:22]2([OH:23])[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:18][C:17]2([CH3:31])[CH3:16])=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: COc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2(C)C)ccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 5-bromo-2-chloro-anisole (1.613 g, 7.3 mmol) in THF (15 mL) at −78° C. was added n-butyl lithium (4.75 mL, 7.6 mmol, 1.6 M) dropwise over 15 min and the resulting solution was allowed to stir at −78° C. for 1 h. A solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (prepared in the manner described in International Patent Application WO 04/043965, 754 mg, 3.32 mmol) in THF (5 mL) was added dropwise via canula. The reaction was stirred for 2 h at −78° C. then allowed to warm to rt slowly over 30 min at which time the mixture was heated at 50° C. for 30 min. The reaction was cooled to rt, quenched by the addition of aq NH4Cl, diluted with water and extracted into EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified via column chromatography (15% to 33% to 50% EtOAc/heptane to afford tert-butyl 4-(4-chloro-3-methoxyphenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (728 mg, 60% yield).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:29])[CH2:23][C:24]=1[CH2:25][CH:26](Cl)[Cl:27])[CH:20]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:19]2=[O:38])=[O:16])([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.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:29])[CH2:23][C:24]=1[CH:25]=[CH:26][Cl:27])[CH:20]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C:19]2=[O:38])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(Cl)Cl)CS(=O)C12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCl)CS(=O)C12
Yield: 100.2 %

Procedure:
A solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2,2-dichloroethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (product 11f) (3.3 g) and triethylamine (0.88 cc) in dry tetrahydrofuran (50 cc) is stirred at 25° C. for 16 hours and the reaction mixture is then diluted with ethyl acetate (200 cc). The organic solution is washed with distilled water (5×60 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 35° C. This yields a product (11e) (3.1 g) in the form of a hard orange foam.
Reaction SMILES: S(F)(=O)(=O)O.C(=O)=O.[CH:9]([OH:12])([CH3:11])[CH3:10].C=CC.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH2:21])=O.[OH-].[Na+]>C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](=[NH:21])[O:12][CH:9]([CH3:11])[CH3:10]
Reactant: NC(=O)c1ccccc1Cl
Reactant: CC(C)O
Agent: O=C=O
Agent: O=S(=O)(O)F
Agent: [Na+]
Solvent: ClCCl
Solvent: C=CC
Product: CC(C)OC(=N)c1ccccc1Cl

Procedure:
Ten grams (0.100 moles) of fluorosulfuric acid is placed in a flask equipped with a dry ice condenser and maintained at -78° (dry ice/isopropanol bath) under an atmosphere of dry nitrogen. To this is added about 25 ml of propylene with moderate stirring giving an orange-colored solution. The reaction mixture is stirred for 15 min. and then diluted with 100 ml of methylene chloride, precooled to -50° C. To this is added at once 15.6 g (0.100 moles) of 2-chlorobenzamide and the mixture stirred at ambient temperature for 18 hrs. giving a deep purple-red solution. The reaction mixture is then poured into 300 ml. of 1 N sodium hydroxide with rapid stirring. After standing briefly the layers are separated. Dilution with saturated sodium chloride solution and methylene chloride facilitates separation of the layers. The turbid organic phase is dried (Na2SO4), filtered through celite filter aid, and the solvent removed in vacuo. The residue is triturated with hexane (Skellysolve B®) and filtered, thereby removing any unreacted 2-chlorobenzamide. The filtrate is distilled under reduced pressure to afford 1-methylethyl 2-chlorobenzenecarboximidate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[N-:17]=[N+:18]=[N-:19].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:17]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:4]=1)[CH3:9])=[N+:18]=[N-:19]
Reactant: CC(O)c1ccc(F)c(N2CCOCC2)c1
Reactant: [N-]=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(N=[N+]=[N-])c1ccc(F)c(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluoro-3-morpholin-4-yl-phenyl)ethanol (3.7 g) and diphenylphosphory azide (6.765) in toluene (24 mL) at 0° C. was added a solution of DBU (3.74 g) in toluene (2 mL) and the resulting solution was stirred at 0° C. for 2 hours. The reaction mixture was warmed to room temperature and then stirred for 16 hours. The reaction was diluted with ethyl acetate and quenched with water. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (10% ethyl acetate in hexane) to give 3.71 g of the title compound as an oil.