Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C1C[O:28]CC1>>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][C:21]([OH:28])([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: c1cscn1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of thiazole (470 mg) in dry THF (10 mL) at −78° C. was added nBuLi (2.5 m in hexanes, 2.21 mL). After 30 minutes BOC-piperidone (1 g) was added and the reaction mixture was gradually warmed to room temperature. After stirring overnight, the reaction mixture was quenched with water, extracted with ethyl acetate, dried (MgSO4) and the solvent removed in vacuo to yield an oil which was purified using flash chromatography to yield 4-hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester. Cleavage of the BOC group with HCl yielded 4-thiazol-2-yl-piperidin-4-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[N:17]=[C:16](S(C)(=O)=O)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:34]([OH:37])([CH3:36])[CH3:35].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[N:17]=[C:16]([O:37][CH:34]([CH3:36])[CH3:35])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)O
Reactant: COc1ccc(CCNc2cc(-c3ccc(OC)c(OC)c3)nc(S(C)(=O)=O)n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCNc2cc(-c3ccc(OC)c(OC)c3)nc(OC(C)C)n2)cc1OC
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of [2-(3,4-dimethoxy-phenyl)-ethyl]-[6-(3,4-dimethoxy-phenyl)-2-methanesulfonyl-pyrimidin-4-yl]-anine [200 mg, 0.42 mmol, Intermediate (33)], and isopropyl alcohol (1 mL) in N,N′-dimethylformamide (2 mL) at 0° C. is treated with sodium hydride (60%, 102 mg, 12.7 mmol). After 1 hour at 20° C., the mixture is concentrated, and extracted twice with EtOAc (50 mL). The combined extracts are washed twice with water, dried over magnesium sulfate, filtered, and concentrated. The residue is subjected to chromatography on silica gel eluting with 60% EtOAc in heptane to afford [2-(3,4-dimethoxy-phenyl)-ethyl]-[6-(3,4-dimethoxy-phenyl)-2-isopropoxy-pyrimidin-4-yl]-amine [0.15 g, 79%, Example 17(a)] LCMS: RT=2.57 minutes, MS: 454 (M+H). 1H NMR (300 MHz, CDCl3) □7.64 (1H, d, J=2.1 Hz), 7.55 (1H, dd, J=8.4, 2.4 Hz), 6.91 (1H, d, J=8.4 Hz), 6.86-6.76 (3H, m), 6.3 (1H, s), 5.43-5.34 (1H, m), 4.83 (1H, brs), 3.99 (3H, s), 3.95 (3H, s), 3.89 (3H, s), 3.75-3.65 (2H, m), 2.91 (2H, t, J=6.9 Hz) 1.45 (6H, d, J=6 Hz). IC50=6728 nM
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:23]=[CH:22][C:21](B4OC(C)(C)C(C)(C)O4)=[CH:20][CH:19]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1.Cl[C:40]1[N:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:19]=[CH:20][C:21]([C:40]4[N:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=4)=[CH:22][CH:23]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)C(=O)O2)o1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CCc4nnc(C)o4)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine were reacted following a procedure analogous to that described in Example 1 Step 2 to afford (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 2 tR=0.984 min, m/z=499.1; 1H NMR (CD3OD) 1.50 (m, 3H), 2.25 (m, 2H), 2.42 (m, 1H), 2.35 (s, 3H), 2.38 (m, 1H), 2.42 (m, 1H), 2.49-2.55 (m, 1H), 2.65 (s, 3H), 2.90 (m, 1H), 3.05 (m, 1H), 5.52 (m, 1H), 7.07 (m, 2H), 7.25 (m, 3H), 7.32 (m, 2H), 7.69-7.76 (m, 3H), 8.06 (m, 1H)
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH2:16][NH2:17])[CH:13]=[CH:14][CH:15]=2)=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.C([O-])([O-])=O.[K+].[K+].C1N=CN([C:29]([N:31]2[CH:35]=[N:34][CH:33]=[CH:32]2)=[O:30])C=1.[O:36]1[CH2:41]CN(CCN)[CH2:38][CH2:37]1>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][NH:17][C:29]([NH:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:41][O:36][CH2:37][CH2:38]2)=[O:30])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCN1CCOCC1
Reactant: NCc1cccc(-c2cn3ncccc3n2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(NCCN1CCOCC1)NCc1cccc(-c2cn3ncccc3n2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
0.2 mmol (3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanamine and 1 mmol K2CO3 in dry Toluene were stirred for 30 min at 30° C., added with CDI (0.2 mmol), and kept to stir for 2 h. Then 0.2 mmol 2-morpholinoethanamine and DMAP (cat.) were added and the solution was heated to 60° C. for 2 h. The reaction was concentrated in vacuo and the residue was purified by column chromatography on silica gel to give the 1-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-3-(2-morpholinoethyl)urea.
Reaction SMILES: [CH:1]1([C:4]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N+:31]([O-])=O)=[CH:21][CH:20]=3)=[C:7]3[N:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.[H][H]>[Ni].CO.C1COCC1>[CH:1]1([C:4]2[C:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH2:31])=[CH:23][CH:24]=3)=[C:7]3[N:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(C)n2nc(C3CC3)c(Cc3ccc(-c4ccccc4[N+](=O)[O-])cc3)c2n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)n2nc(C3CC3)c(Cc3ccc(-c4ccccc4N)cc3)c2n1
Yield: 168.7 %

Procedure:
A solution/suspension of 1.59 g methyl 2-cyclopropyl-7-methyl-3-[(2'-nitrobiphen-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxylate and /0.5 g Raney Nickel in 30 mL methanol and 150 mL THF was stirred under 1 atm hydrogen for 2.5 hours. The mixture was filtered through Celite, stripped of solvent in vacuo, then was chromatographed on silica gel under medium pressure using 10% ethyl acetate in hexanes to give 2.50 g (17% yield) of the title compound as a light yellow crystalline solid. Rf 0.24 in 20% EtOAc/hexanes, visualized by UV, iodine, and ammonium molybdate/ceric sulfate stain.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:10]([OH:40])[CH2:11][NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=O)(C)(C)C.[Cl:45]CCl.[ClH:48].O>C(OCC)(=O)C>[ClH:45].[ClH:48].[NH2:8][C@@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:10]([OH:40])[CH2:11][NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)C
Reactant: ClCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@@H](N)CC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 250 mg of N-[N-[N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-L-leucyl]-L-valyl]-L-phenylalanine, methyl ester (slower isomer) (see example 6C) in 3 ml of ethyl acetate and 1.5 ml of dichloromethane was cooled in an ice bath under nitrogen, and then treated with anhydrous hydrogen chloride gas to saturation. Once the reaction was saturated, the ice bath was removed, the reaction was stoppered, and stirred at ambient temperature. After one hour, the reaction was concentrated to dryness in vacuo, resuspended in 5 ml of ethyl acetate, cooled in an ice bath under nitrogen, resaturated with anhydrous hydrogen chloride and stoppered. After 30 minutes, the reaction was concentrated to dryness in vacuo, then recrystallized from methanol/ether at room temperature, and refrigerated overnight to afford 200 mg of the title compound as a hydrate with 0.4 mole of water, melting point 242°-252° C., dec.
Reaction SMILES: Cl.F[C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F.C1(S([Cl:41])(=O)=O)C=CC=CC=1>>[ClH:41].[CH2:28]([N:27]1[CH2:31][CH2:30][N:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([NH:13][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=3)(=[O:12])=[O:11])=[CH:15][CH:16]=2)[CH2:25][CH2:26]1)[CH3:29]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCCN(c2ccc(NS(=O)(=O)c3ccc(F)c(F)c3)c3ccccc23)CC1
Agent: Cl
Product: CCN1CCN(c2ccc(NS(=O)(=O)c3ccccc3)c3ccccc23)CC1

Procedure:
The title compound was prepared from (intermediate 3 after reduction according to Method A) 4-(4-ethyl-1-piperazinyl)-1-naphthylamine (0.241 g, 0.945 mmol) and benzenesulfonyl chloride (0.121 mL, 0.945 mmol) by the method described above to yield HCl-salt 0.210 g (51%); 1H NMR (CD3OD) δ 8.19-8.15 (m, 1H), 7.94-7.90 (m, 1H), 7.70-7.66 (m, 2H), 7.56-7.46 (m, 2H), 7.44-7.36 (m, 3H), 7.19 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 3.75-3.40 (m, 6H), 3.34 (q, J=7.6 Hz, 2H), 3.25-3.10 (m, 2H), 1.43 (tr, J=7.6 Hz, 3H); MS (posEI) m/z 387 (M+).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:12][C:11]3[CH:10]=[N:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:15][CH:14]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccccc4)nc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 6-phenoxynicotinaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 430.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N+:9]([O-])([O-])=O.[Na+].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[N:9][C:15]1[NH:14][CH:18]=[CH:17][N:16]=1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ccccc1N=Nc1ncc[nH]1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ice water (750 cc) and concentrated hydrochloric acid (250 cc) were stirred and cooled in an ice bath. Upon the addition of 2-chloroaniline (128.0 grams, 1.0 mole) to the cooled reaction mass, a white solid precipitated out. The resulting mixture was stirred at about 0°C as sodium nitrate (69.0 grams, 1.0 mole) was added in portions over a period of about 15 minutes. After the addition was complete the reaction mass was stirred for an additional 15 minutes after which 68.0 grams (1.0 mole) of imidazole were added. The reaction mass was stirred vigorously as anhydrous sodium carbonate (160.0 grams) was added. The mixture was stirred for 3 hours after which the orange crystals were filtered and washed with water. The damp crystals were mixed with dilute hydrochloric acid and stirred at room temperature for about one hour. The mixture was filtered and the insoluble material discarded. The filtrate was made basic with sodium carbonate. The yellow crystals of 2-((2-chlorophenyl)azo)-1H-imidazole was filtered off and washed with water. The product was recrystallized from ethanol. The proposed structure was confirmed by IR and NMR spectra. The melting point was 195°-196° C.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1[C:28]2[C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.[F:30][C:31]([F:44])([F:43])[S:32]([O:35]S(C(F)(F)F)(=O)=O)(=[O:34])=[O:33]>ClCCl>[F:30][C:31]([F:44])([F:43])[S:32]([O-:35])(=[O:34])=[O:33].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][C:19]3[S:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27](=[O:29])[C:28]=3[CH:15]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1c2ccccc2sc2ccccc12
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: O=c1c2ccccc2sc2ccc([S+](c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To 320 ml of dichloromethane were suspended 20.2 g (0.1 mol) of diphenylsulfoxide and 21.2 g (0.1 mol) of thioxanthene-9-one, and 28.2 g (0.1 mol) of trifluoromethanesulfonic anhydride was added dropwise thereto at −70 to −60° C., followed by gradually warming to room temperature and reacting with stirring for 3 hours. After completion of the reaction, the obtained reaction solution was washed with water (320 ml×5 times) and the obtained dichloromethane layer was concentrated to dryness under reduced pressure. The obtained crude product was purified by column chromatography to obtain 18.6 g of objective substance as yellow glassy substance (yield: 34%).
Reaction SMILES: [NH2:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1>C(#N)C>[N+:12]([C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O-:2])([O-:14])=[O:13].[NH2:1][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1
Reactant: OCc1cccnc1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CC#N
Product: N[n+]1cccc(CO)c1
Product: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Reaction time: 24 h
Yield: 82.5 %

Procedure:
To a solution of 1-(aminooxy)-2,4-dinitrobenzene (117 g, 0.590 mol) in acetonitrile (1.18 L) was added 3-pyridinemethanol (64.1 g, 0.590 mol) at 40° C., and the mixture was stirred for 24 hr. The solvent was evaporated under reduced pressure, and the residue was washed with dichloromethane (1 L×2) to give the title compound (150 g, yield 83%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:22]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:31])[C:8]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C(c1ncccc1C)CC(C)(C)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(c1c(C)ccc[n+]1[O-])CC(C)(C)O2
Yield: 26.3 %

Procedure:
101 mg of 6-acetyl-3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran were dissolved in 5 ml of dichloromethane at room temperature and 91 mg of m-chloroperbenzoic acid were added. After 1 hour the mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water. The organic extract was dried over sodium sulphate and evaporated to give an oil. This oil was triturated with t-butyl methyl ether to give a solid which, after recrystallization from ethyl acetate/t-butyl methyl ether, gave 28 mg of 2-(6-acetyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-methylpyridine N-oxide of melting point 154-156° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[NH:27]1[CH:31]=[N:30][N:29]=[N:28]1>>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:28]2[N:29]=[N:30][CH:31]=[N:27]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1nnn[nH]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4ncnn4)=C(C=O)C[C@@H]32)C1
Yield: 16.9 %

Procedure:
The method followed that described for Synthesis Example 7, but using 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (Compound 3) (0.5 g, 1.329 mmol), 1H-tetrazole (187 mg, 1.59 mmol) and Li2CO3 (287 mg, 3.94 mmol) gave a crude product (520 mg). Flash column chromatography on elution with pet. ether/EtOAc, (5:1), gave firstly 3β-acetoxy-17-(2H-tetrazol-2-yl)-16-formylandrosta-5,16-diene (Compound 22) (92 mg, 28.2%), mp 170-172° C. (decomp.). 1H NMR (300 MHz, CDCl3): δ 1.1 (3H, s, 18-Me), 1.29 (3H, s, 19-Me), 2.04 (3H, s, 3β-OAc), 4.62 (1H, m, 3α-H), 5.42 (1H, d, J=4.2 Hz, 6-H), 8.68 (1H, s, 5'-H) and 10.46 (1H, s, 16-CHO). Analysis calculated for C23H30O3N4 : C, 67.28; H, 7.37; N, 13.65. Found: C, 67.15; H, 7.61; N, 13.45. Further elution with p. ether/EtOAc/Et3N (7:3:0.3) gave 3β-acetoxy-17-(1H-tetrazol-1-yl)-16-formylandrosta-5,16-diene (Compound 23) (146 mg, 44.6%), mp 196-198° C. (decomp.). 1H NMR (300 MHz, CDCl3): δ 1.09 (3H, s, 18-Me), 1.20 (3H, s, 19-Me), 2.04 (3H, s, 3β-OAc), 4.62 (1H, m, 3α-H), 5.43 (1H, d, J=4.8 Hz, 6-H), 8.93 (1H, s, 5'-H) and 9.92 (1H, s, 16-CHO). Analysis calculated for C23H30O3N4: C, 67.28; H, 7.37; N, 13.65. Found: C, 67.05; H, 7.65; N, 13.45.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([F:12])[CH2:11][O:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]([F:21])([F:20])[C@@H:17]([OH:19])[CH3:18]>>[F:12][C:8]1([C:7]2[C:2]([O:19][C@@H:17]([CH3:18])[C:16]([F:21])([F:20])[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5][CH:6]=2)[CH2:11][O:10][CH2:9]1
Reactant: C[C@H](O)C(F)(F)F
Reactant: N#Cc1cc(Cl)c(C2(F)COC2)cn1
Product: C[C@H](Oc1cc(C#N)ncc1C1(F)COC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carbonitrile (Example 131a) and (S)-1,1,1-Trifluoro-propan-2-ol (CAN 3539-97-7) as starting materials and isolated (1.66 g, 61%); MS (ESI, m/z): 291.4 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13]C=[CH:11][CH:10]=1.[C:18](=O)([O-])[O-].[K+].[K+]>[Pd].C1(C)C(C)=CC=CC=1>[CH3:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of the palladium catalyst formed in Example 24 (50 mg), 4-bromotoluene (1.6 mmol), phenyl boronic acid (1.6 mmol) and potassium carbonate (2.4 mmol) in xylene (10 ml) was warmed at 110° C. with stirring for 1 hour. The mixture was filtered and the solid washed with ether. The combined organic extracts were washed with water, dried and then concentrated to give 4-methyl biphenyl in 99% yield. The filtered solid was returned to the reaction flask and further 4-bromotoluene (1.6 mmol), phenyl boronic acid (1.6 mmol) and potassium carbonate (2.4 mmol) in xylene (10 ml) was added and the process repeated to give 4-methyl biphenyl in 99% yield.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([O:19][CH:20]=[CH2:21])[C@H:16]([O:22][CH2:23][O:24][CH3:25])[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:27]I.C([Zn]CC)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([O:19][CH:20]3[CH2:27][CH2:21]3)[C@H:16]([O:22][CH2:23][O:24][CH3:25])[CH2:15]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ICI
Reactant: C=CO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OCOC
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COCO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OC1CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 229 mg of 2-benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-vinyloxypyrrolidine-1-yl]pyridine, 217 μl of diiodomethane, 1.35 ml of hexane solution containing 1.0 mol of diethylzinc and 3 ml of toluene was stirred at 80° C. for 3 hours. Ammonium chloride was added to the reaction solution, and the mixture was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 15% ethyl acetate/hexane, to give 47.8 mg of the target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][CH:10]=[N:9][N:8]=2)=[CH:3][CH:2]=1.[Li]CCCC.[N:17]#N.CCOCC.[C:24]([C:31](N)([CH2:34][CH3:35])[CH:32]=[O:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:24]([CH:31]([CH2:34][CH3:35])[C@@:32]([NH2:17])([C:10]1[O:11][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[N:8][N:9]=1)[OH:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: N#N
Reactant: CCC(N)(C=O)C(=O)OC(C)(C)C
Reactant: c1cc(-c2nnco2)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCC(C(=O)OC(C)(C)C)[C@](N)(O)c1nnc(-c2ccncc2)o1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 5-pyridin-4-yl-[1,3,4]oxadiazole (11.5 g, 78.2 mmol) in THF (300 mL) was added HMPA (5 ML) and n-BuLi (1.6 M solution in 48.9 mL of hexane) dropwise under N2 at −78° C. After 1 h, MgBr.Et2O (20.2 g, 78.2 mmol) was added and the reaction mixture was allowed to warm to −45° C. for 1 h before being treated with 2-Boc-amino-butyraldehyde (9.7 g, 50.8 mmol) in THF (50 mL). The reaction mixture was stirred for 1 h, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield (S)-2-Boc-amino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol (3.5 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:4]([S:13]([CH3:12])(=[O:15])=[O:14])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1c(CCl)nc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a solution of 2-(chloromethyl)benzimidazole (80 g, 0.48 mol) and methanesulfonyl chloride (58.3 mL, 0.75 mol) in 0.5 L of methylene chloride, triethylamine (136 mL, 0.97 mol) was added dropwise under nitrogen. The resulting mixture was stirred at room temperature for 6 hours. The mixture was filtered and the filtrate was evaporated. The residue was triturated in methanol and filtered to afford 74.9 g of the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH3:7][N:8]=[C:9]=[O:10].O>CN(C=O)C>[CH3:7][NH:8][C:9](=[O:10])[NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1
Reactant: Nc1nnn[nH]1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1nnn[nH]1
Temperature: 100 °C
Yield: 89.8 %

Procedure:
5-Aminotetrazole (5.5 g, 0.065 mole) was dissolved in 75 ml of DMF. On the addition of methylisocyanate (5 g) the temperature began to slowly rise to 40° C. with the formation of a white solid. The solution was heated for 90 minutes at 100° C. and on cooling, poured into cold water. The resulting white solid was filtered, water washed and dried to give 8.3 g of product which softened at 264°-267° C. but was not melted completely at 305° C.