Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=[N+]([O-])c1cc(N=C=S)ccc1Cl
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(Cl)c([N+](=O)[O-])c1
Yield: 70.9 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.973 g, 4.00 mmol) and 4-chloro-3-nitrophenyl isothiocyanate (0.859 g, 4.00 mmol) to afford the product (1.296 g); m.p. 174-175° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][CH:29]=O>ClCCl.CCCCCC.O>[Br:21][C:20]([Br:24])=[CH:29][CH2:28][CH2:27][C:26]([F:32])([F:31])[F:25]
Reactant: BrC(Br)(Br)Br
Reactant: O=CCCC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)CCC=C(Br)Br

Procedure:
To a −78° C. solution of oxalyl chloride (4.13 mL, 47.4 mmol) in 60 mL of dichloromethane was added dimethylsulfoxide (4.76 mL, 67.1 mmol). After 10 minutes, 4,4,4-trifluorobutanol was added dropwise (5.059 g, 39.49 mmol), followed by dropwise addition of triethylamine (11.01 mL, 78.9 mmol). The solution was alowed to warm to room temperature over 30 minutes, and was quenched by the addition of saturated NH4Cl solution. The organic layer was separated and washed with brine to provide a solution of 4,4,4-trifluoro-1-butanal. To a second solution containing triphenylphosphine (31.1 g, 118 mmol) and carbontetrabromide (19.65 g, 59.2 mmol) in 50 mL of dichloromethane a 0° C. was added dropwise the aldehyde solution described above. Five minutes after complete addition, the reaction was diluted with 250 mL of hexane and 500 mL of water. The Organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material was triturated repeatedly with diethyl ether to remove triphenylphosphine oxide, giving the titled product.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:7]1[C:12]2[N:13]([CH3:17])[C:14](=O)[NH:15][C:11]=2[CH:10]=[CH:9][N:8]=1)[CH2:4][CH2:5][CH3:6].[Cl:18]C1N(C)C2C(C(CCC)CCC)=CC=CC=2N=1>>[Cl:18][C:14]1[N:13]([CH3:17])[C:12]2[C:7]([CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][CH3:1])=[N:8][CH:9]=[CH:10][C:11]=2[N:15]=1
Reactant: CCCC(CC)c1nccc2[nH]c(=O)n(C)c12
Reactant: CCCC(CCC)c1cccc2nc(Cl)n(C)c12
Product: CCCC(CC)c1nccc2nc(Cl)n(C)c12

Procedure:
Prepared from 4-(hexan-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one according to the method described previously for 2-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazole in 68% isolated yield.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[CH2:17][CH3:18]>O>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[N:2][OH:3])[CH2:17][CH3:18]
Reactant: CCC(=O)c1ccco1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Hydroxylamine hydrochloride (3.3 g, 47.8 mmol) and sodium acetate (3.9 g, 47.8 mmol) were added to 20 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(Furan-2-yl)propan-1-one (5.4 g, 43.5 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (20 mL) was added and the product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 6.1 g of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3].[CH3:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][N:22]([S:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=4)(=[O:37])=[O:36])[CH2:21][CH2:20]3)[N:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3]
Reactant: CCOc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCC
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc1OCC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-diethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B2*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: CO.C([O:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][C:30](=[O:32])[CH3:31])[CH:14]=1)=[O:12])C1C=CC=CC=1.[H][H]>O.[C].[Pd]>[C:30]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:15]1[CH:14]=[C:13]([C:11]([OH:12])=[O:10])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)(=[O:32])[CH3:31]
Reactant: [H][H]
Reactant: CC(=O)Oc1ccccc1-c1cc(C(=O)OCc2ccccc2)c2ccccc2n1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(=O)Oc1ccccc1-c1cc(C(=O)O)c2ccccc2n1
Yield: 85 %

Procedure:
A suspension of 50% hydrated 10% palladium-carbon (180 mg) in water (1 mL) was added to a methanol (10 mL) solution of 2-(2-acetoxyphenyl)-4-quinolinecarboxylic acid benzyl ester (940 mg, 2.34 mmol) obtained above, and the mixture was stirred for 7 hours in a hydrogen atmosphere. The catalyst was filtered off through celite, and then, the solvent was distilled off to obtain the title compound (610 mg, 1.99 mmol).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:38]=[C:9]2[C:10]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[C:11]([CH3:27])[C:12]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[CH:13][N:8]2[N:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C=O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([N:15]2[C:14]([C:12]3[C:11]([CH3:27])=[C:10]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)[C:9]4[N:8]([N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)[N:38]=4)[CH:13]=3)=[CH:18][CH:17]=[N:16]2)=[CH:20][CH:21]=1)#[N:26]
Reactant: CN1CCNCC1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN3CCN(C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 76.2 %

Procedure:
2-Chloro-N-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 17, 150 mg, 0.28 mmol) was stirred in dry DMF (3 mL), then K2CO3 (83 mg, 0.60 mmol) and 1-methylpiperazine (56 mg, 0.56 mmol) were added. Stirring was continued for 2 hrs at RT then the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water followed by saturated brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography eluting with a gradient of 2-5% MeOH in DCM followed by 10% (2M NH3 in MeOH) in DCM to give the title compound as a white solid (128 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].C1COCC1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24].Cl>O>[NH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[NH:24][C:10]([NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[S:11]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NC1CCCCC1NC(=S)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
A solution of 1,3-dichloro-2-isothiocyanatobenzene (100 mg) and abs. THF (3 ml) was added dropwise slowly over a half hour to a solution of trans-1,2-diaminocyclohexane (139.9 mg) and abs. THF (3 ml). The solution was stirred at room temperature for a further 90 minutes. The reaction mixture was subsequently added to water, acidified with hydrochloric acid and extracted once with ethyl acetate. Afterwards, the mixture was basified using potassium carbonate, and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 128 mg of the desired product were obtained.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([O:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][O:15][C:11]=2[CH:10]=1)[CH2:6][CH3:7])C.[OH-].[Na+]>CO>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[CH:23]=[CH:24][C:9]([O:8][CH:5]([CH2:6][CH3:7])[C:4]([OH:25])=[O:3])=[CH:10][C:11]=3[O:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(CC)Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)O

Procedure:
A solution of 3.6 g of ethyl-2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyrate, 30 ml of 15% sodium hydroxide solution and 30 ml of methanol, is stirred under reflux for 3 hr. The methanol is evaporated and the solution is poured into dilute hydrochloric acid/ice affording a flocculant precipitate. The precipitate is collected, dried in vacuo and recrystallized from toluene to afford 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyric acid, mp 144° C.
Reaction SMILES: [C:1](/[N:3]=[C:4](\OC1C=CC=CC=1)/[N:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)#[N:2].O.[NH2:32][NH2:33].O>CO>[F:23][C:18]1[CH:17]=[C:16]([N:5]([CH2:6][CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:4]2[NH:3][C:1]([NH2:2])=[N:33][N:32]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: N#C/N=C(\Oc1ccccc1)N(CCCOC1CCCCO1)c1ccc(F)c(F)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: Nc1nnc(N(CCCOC2CCCCO2)c2ccc(F)c(F)c2)[nH]1
Temperature: 25 °C

Procedure:
To a solution of (Z)-phenyl N′-cyano-N-(3,4-difluorophenyl)-N-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)carbamimidate (73 mg, 176 μmol) in methanol (0.5 mL) was added hydrazine hydrate 25% in water (35.2 mg, 34.8 μl, 176 μmol). The reaction was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using methylene chloride/methanol 19:1 (v/v) as eluent. The title compound was obtained as a light yellow viscous oil (46 mg, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH3:28])[CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)[CH3:2].[CH3:30]I>C1COCC1>[CH2:1]([O:3][C:4](=[O:29])[C:5]([CH3:30])([CH3:28])[CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[N:8]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(C)Cc1cc(C)n(Cc2cc(Br)ccc2OCC2CCCC2)n1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1cc(C)n(Cc2cc(Br)ccc2OCC2CCCC2)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
To a solution of 3-{1-[5-bromo-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-propionic acid ethyl ester (0.14 g, 0.3 mmol) in dry THF (5 ml) under a N2 atmosphere at −78° C. was added lithium bis(trimethylsislyl)amide (1.8 ml, 1M in THF). The mixture was stirred for 1 hour before addition of a THF solution (1 ml) of MeI (0.255 g, 0.18 mmol). After stirring 3 hours more at −78° C. the mixture was left at RT for 16 hours. The reaction was quenched with sat NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (10 g SiO2 cartridge, eluent 95-90% iso-hexane-5-10% EtOAc) to yield 0.033 g of 3-{1-[5-bromo-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2,2-dimethyl-propionic acid ethyl ester which was converted to the title compound following the method in Example 1, Step 8.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11](C#CC3C=CC=CC=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.FC1C=CC=CC=1.[Br:31]C1C=CC(CCl)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:31][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: ClCc1ccc(Br)cc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Fc1ccccc1
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Yield: 86 %

Procedure:
Synthesis of 4-fluoro-4'-phenylethynylbenzophenone In a 250 mL flask equipped with a nitrogen inlet, overhead stirring assembly, and reflux condenser was placed fluorobenzene (117 g, 1.2 mol), and 4-bromobenzyl chloride (39.8 g, 0.181 mol). The mixture was cooled to 0° C. an anhydrous aluminum chloride (27 g, 0.20 mol) was added. The mixture was stirred at 23° C. for 16 hours. The resulting slurry was poured into 2 L of acidic (HCl) water. The organics were extracted with methylene chloride, and dried over magnesium sulfate. The slurry was filtered and the methylene chloride was removed under reduced pressure. Recrystallization from ethanol afforded 43.3 g (86%) of 4-bromo-4'-fluorobenzophenone as white crystals: mp 106°-107° C. (Lit 107°-108° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]3[N:19]=[C:20](S(C)(=O)=O)[N:21]=[C:17]3[N:16]=[C:15]([CH3:26])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[O-:27][CH2:28][CH3:29].[Na+]>C(O)C>[CH2:28]([O:27][C:20]1[N:21]=[C:17]2[N:16]=[C:15]([CH3:26])[CH:14]=[C:13]([NH:12][C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=3)[N:18]2[N:19]=1)[CH3:29]
Reactant: Cc1cc(Nc2ccc(C(F)(F)F)c(F)c2)n2nc(S(C)(=O)=O)nc2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2nc(C)cc(Nc3ccc(C(F)(F)F)c(F)c3)n2n1
Temperature: 120 °C

Procedure:
Intermediate 14 (0.19 g, 0.488 mmol) was added to sodium ethoxide (ALDRICH, 0.1 g, 1.464 mmol) in ethanol (4 mL). The mixture was heated under microwave irradiation at 120° C. for 30 minutes and solvent was removed under vacuum to yield a yellowish residue. The crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 90:10 to 0:100%) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[F:19][C:20]([F:28])([F:27])[C:21]([F:26])([F:25])[C:22](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][C:5]2[NH:17][C:22]([C:21]([F:26])([F:25])[C:20]([F:28])([F:27])[F:19])=[N:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)cc2Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Product: FC(F)(F)C(F)(F)c1nc2cc(Cl)c(Oc3ccc(Cl)cc3Cl)cc2[nH]1
Yield: 15 %

Procedure:
A solution of 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine (100 mg, 0.33 mmol) in pentafluoropropanoic acid (5 ml) was stirred overnight at 80° C. in an oil bath. The reaction was then quenched by the addition of water (20 ml), adjusted to pH 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-dichlorophenoxy)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (21.4 mg, 15%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[I:17]N1C(=O)CCC1=O>>[I:17][C:5]1[N:6]=[C:2]([CH3:1])[NH:3][C:4]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ncc(-c2ccc(S(C)(=O)=O)cc2)[nH]1
Product: Cc1nc(I)c(-c2ccc(S(C)(=O)=O)cc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Step 2 (750 mg, 3.2 mmol) in 10 mL of CFI3CN was added N-iodosuccinimide (710 mg, 3.2 mmol). The mixture was stirred at 25° C. for 1 h, cooled to −20° C. The precipitate was collected by filtration, washed with cold Et2O and dried to give 4-iodo-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-imidazole. LCMS: [M+1]+=362.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]6[NH:32][C:33]([NH:35]C(=O)OC)=[N:34][C:29]6=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:42]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]6[NH:32][C:33]([NH2:35])=[N:34][C:29]6=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:42])=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ncncc3Cc3ccc(F)cc3)CCO4)nc2[nH]1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc5nc(N)[nH]c5n4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 100 °C
Yield: 46 %

Procedure:
To a solution of methyl [5-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3H-imidazo[4,5-b]pyridine-2-yl]carbamate (0.70 g, 0.129 mmol) in methanol (3 mL) was added 2 M aqueous potassium hydroxide (3 mL) and the mixture was heated at 100° C. for 1 hour. After cooling to room temperature the reaction mixture was concentrated and then diluted with water (5 mL) and the pH adjusted to 9 with 1 M hydrochloric acid. The resulting precipitate was collected by filtration, dissolved in a minimum of methanol and purified by preparative reverse phase HPLC to afford 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3H-imidazo[4,5-b]pyridin-2-amine (0.0283 g, 46% yield. 1H NMR (400 MHz, methanol-d4): 8.45 (s, 1H), 7.75 (d, 1H), 7.51 (d, 1H), 7.17 (d, 1H), 7.11-7.06 (m, 3H), 7.01-6.96 (m, 3H), 4.55 (s, 2H), 4.30 (t, 2H), 4.00 (s, 2H), 3.89 (t, 2H), 2.22 (s, 3H); MS (EI) for C27H24FN7O: 482 (MH+)
Reaction SMILES: Br[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C[O-]
Reactant: COC(=O)c1nccnc1Br
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nccnc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 2 g of methyl 3-bromopyrazine-2-carboxylate (prepared as described by J. H. Jones, W. H. Holtz, E. J. C. Cragoe, J. Med. Chem., 1969, 12, 285-287) in 50 mL of methanol was added 4 mL of 30% NaOMe in methanol. After stirring 30 min the reaction was quenched with 6 mL of acetic acid and concentrated under reduced pressure. The residue was partitioned between 50 mL ethyl acetate and 50 mL saturated NaHCO3, the extract dried over MgSO4. Concentration under reduced pressure gave a white crystalline solid: MS (m+1)=169.1; 1H NMR (400 MHz, CDCl3) 8.3 (m, 2H), 4.1 (s, 3H), 4.0 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[CH3:16]C(C)([O-])C.[K+].CI>O1CCCC1>[CH3:16][O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1]
Reactant: OCCCCOCc1cc(Br)ccc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCCCCOCc1cc(Br)ccc1F
Temperature: -78 °C

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butanol (897 mg, 3.24 mmol) in tetrahydrofuran (22 ml) was cooled to −40° C. and then treated with potassium t-butoxide (3.56 ml of a 1 M solution in tetrahydrofuran, 3.56 mmol). The resulting orange solution was stirred for thirty minutes, cooled to −78° C. and treated with methyl iodide (0.40 ml, 6.48 mmol). The reaction was warmed to 0° C. and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 687 mg (73%) as a clear oil.
Reaction SMILES: CN(C)C1C=CC(C=O)=CC=1.[CH2:12]1[C@H:19]([OH:20])[C@H:18]2[N:14]([C@H:15]([CH2:23][OH:24])[C@@H:16]([OH:22])[C@@H:17]2[OH:21])[CH2:13]1>>[CH2:12]1[C@H:19]([OH:20])[C@H:18]2[N:14]([CH2:15][C@H:23]([OH:24])[C@@H:16]([OH:22])[C@@H:17]2[OH:21])[CH2:13]1
Reactant: OC[C@@H]1[C@@H](O)[C@H](O)[C@H]2[C@@H](O)CCN21
Agent: CN(C)c1ccc(C=O)cc1
Product: O[C@H]1[C@H](O)[C@@H](O)CN2CC[C@H](O)[C@H]12

Procedure:
Australine (FIG. 1) was isolated by repeated preparative centrifugal thin-layer chromatography as a colorless oil which was crystallized from acetone with some difficulty as small, dextrorotatory prisms, m.p. 148°-149°. The moleoular formula was determined by high-resolution mass spectrometry to be C8H15NO4. The alkaloid formed a tetraacetate derivative under mild acetylation conditions indicating the presence of four primary or secondary hydroxyl groups. However, on thin layer chromatography this alkaloid gave a weak blue-gray spot with acetic anhydride-Ehrlich's spray reagent rather than the intense purple spot characteristic of polyhydroxyindolizidine alkaloids. The latter color is produced by dehydration and rearrangement to give a pyrrole ring system which undergoes condensation with the 4-dimethylaminobenzaldehyde at the position alpha- to the nitrogen atom (70). The pyrrole ring generated from australine must therefore bear a substituent blocking the alpha-position. Moreover, the electron impact mass spectrometry (EIMS) showed no ion corresponding to the six-membered ring fragment, resulting from cleavage of bonds B to the nitrogen atom in the pyrrolidine ring moiety (17), typical for castanospermine and other indolizidine alkaloids. Instead, the base peak occurred at m/z 158[M-31]+, indicating loss of an exocyclic --CH2OH group. The fundamental ring system was thus shown to be of the pyrrolizidine type. Other major fragments observed in the mass spectrum were typical for this class of compound, resulting from cleavage of either of the five-membered rings at bonds B to the nitrogen atom. The masses of these ions were such that a single --OH group had to reside on one ring while the remaining two --OH groups and the --CH2OH moiety fully substituted the alternate ring. In all saturated necine bases previously isolated, such as rosmarinecine (FIG. 3) which bear the --CH2OH group at the 1-position, the major mass spectral fragments result from cleavage of the ring system. In contrast, the major fragment from australine is a consequence of the loss of --CH2OH, indicating that this substituent must be B to the nitrogen atom at the 3-position.