Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH3:2][C:3]([O:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C@H:14]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:15](OC1C=CC([N+]([O-])=O)=CC=1)=[O:16])=[O:8])([CH3:5])[CH3:4]>C1COCC1>[CH2:31]([O:30][C:28]([NH:27][C@H:14]([C:15]([NH2:1])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7]([O:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[O:8])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(N)=O

Procedure:
A stream of NH3 was passed over a solution of Z-Lys(Boc)ONp (10.2 g, 2.0 mmole, Bachem) in THF (200 ml) for about 3 hr. A precipitate formed. The solvent was removed and the residue triturated and thoroughly washed with ether. The dried protected amide weighed 5.8 g (75%), m.p. 140°-142°, [α]D24 +1.9° (c 1.3. DMF): RfB, 0.54; RfG, 0.54.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[C:5]([CH3:11])[N+:6]([O-:10])=[C:7]([CH3:9])[CH:8]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C(Cl)(Cl)Cl>[N:12]1([C:3]2[CH:4]=[C:5]([CH3:11])[N+:6]([O-:10])=[C:7]([CH3:9])[CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: Cc1cc(Cl)cc(C)[n+]1[O-]
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(N2CCCCC2)cc(C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A quantity (1.94 g., 0.01 mole) of 4-chloro-2,6-lutidine-1-oxide hydrochloride with 6 ml. piperidine, and 10 ml. water were sealed in a reinforced bottle and heated, with stirring, in an oil bath at the temperature 155° to 160° C. for 41/2 hrs. After cooling the reaction mixture to 25° C. and diluting it with 25 ml. water, several portions of chloroform were used to extract the objective product. The chloroform extracts were combined, dried over anhydrous sodium sulfate, treated with charcoal, and filtered. The filtrate was pale yellow. The chloroform was removed by evaporation under reduced pressure. The solid residue thus obtained was triturated with technical hexane (Skellysolve B, a mixture of isomeric hexanes having a boiling range between 142° and 156° F.) and then crystallized from about 10 ml. ethyl acetate. There was thus obtained 1.06 g. (50% yield) of 4-piperidino-2,6-lutidine-1-oxide as buff-colored crystals having a melting point at 87° to 90° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[C:5]2[CH2:9][CH2:10][N:11]=[C:12]3[C:13]([Cl:18])=[C:14](N)[C:15](=[O:16])[C:3]1=[C:4]23.N([O-])=[O:20].[Na+].Cl>CC(O)=O.O1CCOCC1.O>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[C:5]2[CH2:9][CH2:10][NH:11][C:12]3=[C:13]([Cl:18])[C:14]([C:15](=[O:16])[C:3]1=[C:4]23)=[O:20]
Reactant: CSc1c2c3c(n1C)C(=O)C(N)=C(Cl)C3=NCC2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CSc1c2c3c(n1C)C(=O)C(=O)C(Cl)=C3NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A solution of 20 mg of isobatzelline A in 2 ml of HOAc and 1 ml of dioxane is allowed to react with 20 mg of NaNO2 in 5 ml of H2O at 0° C. for 2 hours. After addition of 3 ml of 1N HCl, the solution was stirred at room temperature overnight, and extracted with 10 ml CHCl3 /MeOH (1:1) twice. The concentrated extract was further fractionated on a Superco LC-NH2 column (50 ml×3 ml) with 1% MeOH/CHCl3, and subsequently purified on a HPLC LiChrosorb-NH2 column (3% MeOH/CHCl3) to give 4 mg of batzelline A.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1([C:22]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=[CH:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:3]([C:2]=2[C:18]2[CH:17]=[C:16]([C:22]4[N:23]=[C:24]([C:2]5[CH:3]=[CH:8][CH:9]=[CH:10][CH:15]=5)[N:25]=[C:26]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:27]=4)[CH:21]=[C:20]([C:2]4[C:15]5[C:10]([CH:9]=[C:8]6[C:3]=4[CH:4]=[CH:5][CH:6]=[CH:7]6)=[CH:11][CH:12]=[CH:13][CH:14]=5)[CH:19]=2)=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: c1ccc(-c2ncnc(-c3ccccc3)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4c5ccccc5cc5ccccc45)cc(-c4c5ccccc5cc5ccccc45)c3)n2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
In a stream of argon, 0.62 g (2.13 mmol) of 9-bromoanthracene, 0.50 g (0.89 mmol) of 2-(3,5-bis(4,4,5,5-tetramethyl)-1,3,2-dioxabororan-2-yl)phenyl]-4,6-diphenyl-1,3,5-triazine and 18.7 mg (0.027 mmol) of dichlorobis-(triphenylphosphine)palladium were suspended in 40 mL of tetrahydrofuran, and the temperature of the obtained suspension was elevated to 70° C. 1.34 mL (5.34 mmol) of an aqueous 4N NaOH solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 3 hours. The resultant reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was purified by silica gel column chromatography using a hexane/chloroform (5:1-2:1) mixed solvent as an eluent to give 0.32 g of the target 2-[3,5-di(9-anthryl)phenyl]-4,6-diphenyl-1,3,5-triazine as white solid (yield: 54%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[C:5]([F:18])=[CH:4][CH:3]=1.[NH3:19]>CO.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH:15]([F:17])[F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:19])=[N:13]2)[C:5]([F:18])=[CH:4][CH:3]=1
Reactant: N
Reactant: Fc1ccc(Br)nc1[C@]1(C(F)F)COCC(=S)N1
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1=N[C@@](c2nc(Br)ccc2F)(C(F)F)COC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 31 %

Procedure:
To a solution of (R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-morpholin-3-thione (611 mg, 1.79 mmol) in methanol (15 ml) was added ammonia (5.12 ml, 35.8 mmol, 7M in methanol), the vial was sealed and the reaction mixture was stirred at rt for 20 h. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with aq. sodium thiosulfate solution (10%), water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (640 mg) was chromatographed over silica gel (14 g, dichloromethane/methanol 95/5+0.5% NH3) to give the title compound. 180 mg (31% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=2[CH:15]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[CH2:33][O:34][CH3:35])=[O:27])[S:25][C:18]=12>>[CH3:35][O:34][CH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26]([C:24]1[S:25][C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:17]=2[O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=3[CH:15]=2)[CH:23]=1)=[O:27]
Reactant: COC(=O)c1c(C)sc2cc(O)ccc12
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)OC)c(C)sc4c3)c2s1
Yield: 40 %

Procedure:
This material was prepared from the reaction of methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (85.8 mg, 0.386 mmole) with 7-chloro-2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 2a (100 mg, 0.322 mmole) and CS2CO3 (524 mg, 1.61 mmole) in a manner similar to that previously described for example 1 to give a brown solid (64 mg,40%). 1H NMR (DMSO-d6, 300 MHz) δ8.70 (1H, d, J=4.90 Hz), 8.51 (1H, d, J=9.04 Hz), 8.15 (1H, s), 8.14 (1H, s), 7.54 (1H, dd, J=2.17, 8.95 Hz), 6.91 (1H, d, J=5.46 Hz), 4.47-4.38 (1H, m), 4.07-3.90 (2H, m), 4.03 (3H, s), 3.72-3.50 (2H, m), 3.42, 3.39 (3H, s), 2.94 (3H, s), 2.21-1.93 (4H, m).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:25][CH:26]1[C:44](=[O:45])[N:28]2[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH2:31][S:32][C@H:27]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])[C:15]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]4[N:39]([CH3:40])[N:38]=[N:37][N:36]=4)[CH2:31][S:32][C@H:27]23)=[O:17])[N:13]=1)=[O:7]
Reactant: [N-]=[N+]=NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(NC=O)n3)[C@H]2SC1
Yield: 58.8 %

Procedure:
N,N-Dimethylformamide (0.207 g.), phosphoryl chloride (0.436 g.), 2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetic acid (syn isomer, 0.65 g.), 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.85 g.), trimethylsilylacetamide (2.71 g.) and ethyl acetate (20 ml.) were treated in a similar manner to that of Example 5-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.80 g.).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:23][CH:22]3[C:24]([OH:26])=O)[CH:19]=2)[NH:14][CH:13]=1)=[O:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C@@H:21]3[CH2:23][C@H:22]3[C:24]([N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)=[O:26])[CH:19]=2)[NH:14][CH:13]=1)=[O:11]
Reactant: CN1CCNCC1
Reactant: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncc(C3CC3C(=O)O)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[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: CN1CCN(C(=O)[C@@H]2C[C@H]2c2cnc3[nH]cc(C(=O)Cc4cccc(F)c4F)c3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-{3-[(2,3-Difluoro-phenyl)-acetyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-cyclopropanecarboxylic acid, (93 mg, 0.26 mmol), was combined with DIEA, (67 mg, 0.52 mmol), and HBTU, (113 mg, 0.3 mmol) in 1 mL DMF and stirred at rt for ˜15 min. Then N-methyl piperazine, (26 mg, 0.26 mmol), was added and the reaction stirred at rt for 4 hours. The DMF was evaporated under vacuum, water added and the suspension extracted with dichloromethane. The solvent was evaporated under vacuum and the residue purified by silica chromatography, (eluent: 5% methanol/DCM), affording trans-2-(2,3-Difluoro-phenyl)-1-{5-[2-(4-methyl-piperaz ine-1-carbonyl)-cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-ethanone, (35 mg, Rf 0.5) and the cis isomer (16 mg, Rf 0.3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.C(O)C.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1
Reactant: COC(=O)CC1CCCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)CC1CCCC(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
(3-Oxo-cyclohexyl)-acetic acid methyl ester (240 mg, 1.39 mmol) was dissolved in 5 ml THF and 5 ml ethanol and cooled to 0-5° C. Sodium borohydride (79 mg, 2.09 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NaHCO3-solution and extracted three times with ethyl acetate. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (240 mg, 100%) was obtained as a light yellow oil and used without any further purification for the next step.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[C:18]([CH2:19][CH3:20])=[C:17]([CH2:21][N:22]3[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)[C:16]([CH2:36][CH3:37])=[N:15]2)=[C:9]([CH3:38])[CH:8]=1.[CH3:39][C:40]([CH3:42])=[O:41]>O1CCCC1>[CH2:34]([O:33][CH2:32][C@H:31]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][N:22]1[CH2:21][C:17]1[C:16]([CH2:36][CH3:37])=[N:15][N:14]([C:10]2[C:11]([CH3:13])=[CH:12][C:7]([C:40]([OH:41])([CH3:42])[CH3:39])=[CH:8][C:9]=2[CH3:38])[C:18]=1[CH2:19][CH3:20])[CH3:35]
Reactant: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(C(C)(C)O)cc2C)c1CC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of n-butyl lithium (2.5 M hexane solution; 0.16 ml, 0.39 mmol) chilled to -78° C., a solution of (R)-2-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-3-ethoxymethyl-1,2,3,4-tetrahydro-isoquinoline (180 mg, 0.35 mmol) in anhydrous tetrahydrofuran (1.0 ml) was added dropwise. After stirring at -78° C. for 10 minutes, anhydrous acetone (0.078 ml, 1.1 mmol) was added. The resulting mixture was warmed to ambient temperature, and stirred at that temperature for 1 hour. The reaction was quenched by addition of aqueous ammonium chloride (2 ml) and then extracted with ethyl acetate/water (5 ml of each). The separated organic extract was then extracted with an equal volume solution of aqueous ammonium chloride. The combined aqueous extracts were then extracted with a fresh equal-volume portion of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow oil. Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:2 in volume) afforded the title compound (120 mg) as a faint yellow oil.
Reaction SMILES: C(O[C:5]([CH2:10][C:11](=[O:19])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:6][C:7]([OH:9])=[O:8])(=O)C.S(=O)(=O)(O)O>O>[O:19]=[C:11]1[CH:10]=[C:5]([CH2:6][C:7]([OH:9])=[O:8])[C:14]2[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:12]1
Reactant: CC(=O)OC(=CC(=O)O)CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cc(=O)[nH]c2ccccc12
Temperature: 100 °C
Yield: 52.2 %

Procedure:
150 g (0.57 mol) of 3-acetyloxy-5-oxo-5-phenylamino-2-pentenoic acid are poured in small portions while stirring into 500 ml of 95-97% sulphuric acid, and the reaction medium is then heated to 100° C. for 2 h. After being cooled, this solution is poured into a mixture of 1 kg of ice and 500 ml of water while stirring. The solid thereby obtained is drained. It is washed with 3 times 100 ml of water and dried for 8 h at 60° C. 60.5 g (52%) of 2-oxo-1,2-dihydro-4-quinolineacetic acid, melting point 213°-215° C., are obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:12][CH:13]=2)=[CH:5][CH:4]=1>Br>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]2[NH:12][CH:13]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[N:10]=2)[CH:15]=1
Reactant: COc1ccc(-c2c[nH]c(-c3cccnc3)n2)cc1
Agent: Br
Product: Oc1ccc(-c2c[nH]c(-c3cccnc3)n2)cc1

Procedure:
A mixture of 4-(p-methoxyphenyl)-2-(3-pyridyl)imidazole (2.0 g.) and 48% HBr (100 ml.) is heated to reflux for 20 hrs. After cooling, the precipitate is filtered off and crystallized from isopropanol-methanol to give 2.05 g. of 2-(3-pyridyl)-4-(4-hydroxyphenyl)imidazle of m.p. 315°-318° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([O:19]C)=[O:18])[CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([OH:19])=[O:18])[CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2ccn(-c3cccc(Cl)c3)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc2ccn(-c3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.2 %

Procedure:
A mixture of the product of Step 1 (0.1 g) and LiOH (3 mL, 1N) in 15 mL of 1:1:1 THF/MeOH/H2O was stirred for two days at room temperature and heated at 55° C. for 20 h. The mixture was cooled and treated with 5 mL of 1N HCl, followed by extraction with 30 mL of EtOAc. The EtOAc extract was dried over Na2SO4, filtered and concentrated to give the crude product (0.1 g) which was used for next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:22](=[O:23])[CH2:21][CH2:20][C@@:19]2([CH3:24])[C@H:3]1[CH2:4][C@H:5]([CH3:26])[C@@H:6]1[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:25])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:11]([CH3:14])([OH:13])[CH3:12].[CH3:27]I.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[CH3:27][O:13][C:11]([CH3:14])([C@@H:10]1[C@:15]2([CH3:25])[C@H:7]([C@H:6]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:24])[C@H:3]([N:2]([CH3:1])[C:22](=[O:23])[CH2:21][CH2:20]2)[CH2:4][C@@H:5]3[CH3:26])[CH2:8][CH2:9]1)[CH3:12]
Reactant: C[C@H]1C[C@H]2N(C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)(C)O)CC[C@H]3[C@H]12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
To a solution of 20 mg (0.06 mmol) 20-hydroxy-4,7β,20-trimethyl-5α-4-azapregnan-3-one (from Example 2) in 4 ml dry dimethylformamide at 0° C. was added methyl iodide (10 eq, 0.6 mmol) and sodium hydride (5 eq, 0.3 mmol) were added and the reaction was stirred at RT for 48 hours. Aqueous ammonium chloride was added and the reaction mixture was poured onto 100 ml water and extracted with three 25 ml portions of ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, and evaporated. The product was purified via HPLC on a 19×300 mm 8 micron silica column using 5% isopropanol/hexane eluent at 20 ml/min to yield 15 mg (0.04 mmol, 67% yield) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>C(#N)C.C(OCC)(=O)C>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: O=C1CCc2ccccc2C12CCNCC2
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CCc2ccccc2C12CCN(CCCOc1cccc3[nH]ccc13)CC2

Procedure:
A solution of 1-chloro-3-(1H-indole-4-oxy)propane, 3,4-dihydro-2-oxospiro[naphthalene-1(2H),4'- piperidine] and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 37% overall yield. FDMS m/e=388 (M+ of free base).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1([CH:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:6]
Reactant: NCC(c1cccnc1)N1CCOCC1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC(c1cccnc1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].NCCC(O)=O.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C.O>[CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[C:4](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: NCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1
Yield: 84.7 %

Procedure:
A suspension of 100 kg of 4-methyl-3-oxo-N-phenyl-pentanamide (Example B) in 660 kg of hexanes is treated with agitation under nitrogen with 8 kg of β-alanine, 47 kg of benzaldehyde, and 13 kg of glacial acetic acid. The resulting suspension is heated to reflux with removal of water for 20 hours. An additional 396 kg of hexanes and 3 kg of glacial acetic acid is added and reflux continued with water removal for one hour. The reaction mixture is cooled to 20°-25° C. and the product is isolated by filtration. The product is purified by slurrying in hexanes at 50°-60° C., cooling, and filtration. The product is slurried twice with water at 20°-25° C., filtered, and dried in vacuo to yield 110 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, mp 143.7°-154.4° C.
Reaction SMILES: C([C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:7][CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][NH:10][CH2:9]1)=[O:6])C.[N:28]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[C:4]1([C:5]([NH:7][CH:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[CH2:11][N:10]([C:29]([NH:28][CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[O:30])[CH2:9]2)=[O:6])[CH:24]=[CH:25][CH:26]=[CH:27][CH:3]=1
Reactant: O=C=NCC1CCCO1
Reactant: CCc1ccccc1C(=O)NC1CNCC(c2ccc(C(F)(F)F)cc2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)NCC2CCCO2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80 mg (0.23 mmol) of ethyl-N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 2 ml of THF, and 29 mg (0.23 mmol) of 2-(isocyanatomethyl)tetrahydrofuran and 35 μl (0.25 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 88 mg (81% of theory)
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: COc1cccc(C(=O)O)c1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(OC)c1Br
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 2-bromo-3-methoxybenzoic acid (718 mg, 3.11 mmol) in methanol (20 mL) was added a catalytic amount of concentrated sulfuric acid and the mixture was brought to reflux for 20 h. On cooling to room temperature, the solution was concentrated and the residue was taken into ethyl acetate and washed with water, saturated aqueous sodium bicarbonate (2×) and brine then dried over sodium sulfate. The solution was then filtered and concentrated to give methyl 2-bromo-3-methoxybenzoate (610 mg, 80%). MS (EI) for C9H9BrO3: 245 (MH+).