Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=O)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[I:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[N:19][C:18]2[CH:20]=[CH:21][C:15]([I:14])=[CH:16][CH:17]=2)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc(C=Nc2ccc(I)cc2)c1O
Temperature: 25 °C
Yield: 96 %

Procedure:
An amount of 5.84 mmol of 3-tert-butyl salicylaldehyde (1) (1.04 g/1 ml) was dissolved in 150 ml of toluene. After addition of 4-iodoaniline (1.53 g/7 mmol/1.2 equivs.) and a few crystals of para-toluenesulfonic acid, the reaction mixture was stirred under reflux for three hours applying a Dean-Stark-trap. After cooling down to room temperature, sodium hydrogencarbonate solution (150 ml) was added. The organic phase was separated and filtered over sodium sulphate and silica. Removing the solvent and recrystallization from ethanol at −20° C. gave the title compound in a 96% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.O>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:17][CH2:18][C@@H:14]([OH:13])[CH2:15]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: OC1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1N1CC[C@@H](O)C1
Temperature: 110 °C
Yield: 81.2 %

Procedure:
A mixture of 2-chloro-5-nitroanisole (0.59 g, 3.1 mmol) and 3-hydroxy pyrrolidine (0.55 g, 6.2 mmol) was heated neat to 110° C. over night. Reaction mass was diluted with ethyl acetate and the organic layer was given water and brine wash, dried over Na2SO4, concentration yields dark red solid (0.6 g, 82% yield). LC-MS, [M+H]+=239.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C@H:3]([OH:17])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[O:9][CH2:8][CH2:7]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[F:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([F:26])[CH:22]=1)[CH2:18][C@H:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[C@H:3]([OH:17])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[O:9][CH2:8][CH2:7]1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@H]1CCOc2ccc(I)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@H]1CCOc2ccc(I)cc21
Temperature: 0 °C

Procedure:
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-yl]amino}butan-2-ol (1 equiv) was dissolved in DCM with TEA (2 equiv) then cooled to 0° C. and treated with MsCl (1.25 equiv)while stirring. The reaction mixture was removed from the cold bath, brought to ambient temperature, then quenched with MeOH and concentrated. The residue was dissolved in EtOAc and washed with 1M HCl (2×10 mL). The organics were dried and concentrated and chromatographed over silica gel. 1H NMR (CD3OD) δ 7.74 (d, J=2.0 Hz, 1H), 7.53 (dd, J=2.0, 8.7 Hz, 1H), 6.88 (m, 2H), 6.77 (m, 1H), 6.67 (d, J=8.7 Hz, 1H), 4.23-4.39 (m, 2H), 4.25 (br m, 1H), 4.12 (m, 1H), 3.87 (td, J=3.1, 7.8 Hz, 1H), 3.29 (dd, J=3.5, 13.9 Hz, 1H), 3.11 (s, 3H), 3.05 (dd, J=3.2, 12.7 Hz, 1H), 2.98 (dd, J=7.9, 12.6 Hz, 1H), 2.74 (dd, J=11.0, 13.9 Hz, 1H), 2.14 (br m, 2H). MS (ESI+) calcd for C20H23F2IN2O4S m/z 553.38 (M+H)+. Found 553.4.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:28]2[CH2:30][CH2:29]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:31][NH:32][C:33](=N)[CH2:34][CH2:35][CH3:36]>>[CH:28]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:31][N:32]=[C:33]([CH2:34][CH2:35][CH3:36])[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:29][CH2:30]1
Reactant: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC(N(C(=O)c3cnc(-c4ccc(S(C)(=O)=O)cc4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-butyramidine following a procedure analogous to that described in Example 6. LC (method 10): tR=1.87 min; Mass spectrum (ESI+): m/z=511 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C1(P(C2CC2)C2CC2)CC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([CH:20]3[CH2:22][CH2:21]3)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: C1CC1P(C1CC1)C1CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CCOc3nc(C4CC4)cnc3C2)cc1
Temperature: 100 °C
Yield: 15.9 %

Procedure:
A suspension of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (493 mg), cyclopropylboronic acid (280 mg), palladium acetate (20 mg), tricyclopropylphosphine (51 mg) and potassium tert-butoxide (663 mg) in toluene (8 mL) was stirred under an argon atmosphere with heating at 100° C. for 2 hr. Water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 5→25% ethyl acetate/hexane) to give the title compound (79.9 mg, 16%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][CH2:24][O:25][CH2:26][C:27]([NH2:29])=[NH:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:29][C:27](=[NH:28])[CH2:26][O:25][CH2:24][CH2:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)=[O:6]
Reactant: N=C(N)COCCc1ccc2ccccc2c1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccc2ccccc2c1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-(2-naphthalen-2-yl-ethoxy)-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-[1-imino-2-(2-naphthalen-2-yl-ethoxy)-ethyl]-nicotinamide as yellow oil. MS: m/e=402.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.[CH2:26]([O:28]CC)[CH3:27]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=1
Reactant: CCOCC
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g of (+/-)-cis-8,9-dimethoxy-6-(4-aminophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine is suspended in 10 ml of acetic anhydride and the suspension is stirred at RT for 1 h. The solution is treated with diethyl ether, and the precipitate is filtered off with suction and extracted with sodium hydrogencarbonate solution/ethyl acetate. After drying and concentration of the organic phase, the residue is recrystallized from ethyl acetate/methanol. 0.63 g (56.0% of theory) of the title compound of m.p. 218° C. is obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH2:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21].O>O1CCOCC1>[CH2:18]([NH:19][C:20](=[O:21])[O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)[CH2:17][CH2:16][CH3:15]
Reactant: CCCCN=C=O
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: C1COCCO1
Product: CCCCNC(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 92.4 %

Procedure:
1-(Phenylmethyl)piperidin-4-ol (10 g, 52.2 mmol) was stirred in dioxane (90 ml) at room temperature. N-butyl isocyanate (5.0 g, 52.2 mmol) in dioxane (10 ml) was added and the reaction mixture was heated under reflux for 24 h. Water (20 ml) was added and the reaction mixture was concentrated in vacuo to give a brown oil. The crude product was partitioned between diethyl ether and water and the organic extracts were dried (MgSO4) to give the title compound as an oil (14 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-bromo-2-trifluoromethyl-benzenesulfonyl chloride (5.00 g, 15.46 mmol) in THF (5 ml) was added to a solution of morpholine (1.62 ml, 18.55 mmol) and triethylamine (2.15 ml, 15.46 mmol) in tetrahydrofurane. The reaction mixture was stirred for 12 h at RT. Ethyl acetate (80 ml) was added, the organic phase was separated and washed with water (20 ml), hydrochloric acid (1 M, 20 ml) and brine (20 ml) and dried over sodium sulphate. After evaporation the product was obtained (5.708 g, 99%) and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](S(C4C=CC=CC=4)(=O)=O)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH:32][C@H:33]1[CH2:37][CH2:36][O:35][CH2:34]1.C1COCC1.O>C(O)(C)(C)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][C@H:33]4[CH2:37][CH2:36][O:35][CH2:34]4)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O[C@H]1CCOC1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1S(=O)(=O)c1ccccc1
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
810 g of 4-(3-chloro-4-fluoro-phenylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline and 175.5 g (S)-3-hydroxytetrahydrofuran (1.3 eq) are placed at 20° C. in 1.04 l tert-butanol and 198 ml DMF, 2556 g K-tert.-butoxide in THF (24%) (3.6 eq) are added dropwise at 20° C. and then stirred for 4 h at 25° C. After a further 2 h at 40° C. the mixture is heated to 45° C. for about 2 h. 2.8 l of water are added and then about 3 l solvent are distilled off under reduced pressure. 2.8 l water are added again and about 900 ml solvent are distilled off under reduced pressure. After the addition of 1.6 l methanol the mixture is cooled to 20° C. The suspension is suction filtered and rinsed with a mixture of 3.2 l water and 1.6 l methanol. The residue is dried overnight at 50° C. under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[N:11]([Si](C)(C)C)=[N+:12]=[N-:13].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(Cl)Cl>[N:11]([CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:10][OH:9])=[N+:12]=[N-:13]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Brc1cccc(C2CO2)c1
Agent: CC(C)[O-]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Solvent: ClCCl
Product: [N-]=[N+]=NC(CO)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.7 %

Procedure:
To a solution of 2-(3-bromo-phenyl)-oxirane (2.5 g, 12.6 mmol) in CH2Cl2 (20 mL) was added azidotrimethylsilane (2.5 mL, 18.84 mmol), followed by aluminium isopropoxide (256 mg, 1.26 mmol). The reaction mixture was stirred at room temperature for 18 h. Sodium potassium tartrate 1M (30 mL) was added, the aqueous layer was extracted with CH2Cl2, and the organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the crude compound is purified by flash chromatography (10% EtOAc/Hex) to provide 2-azido-2-(3-bromo-phenyl)-ethanol (876 mg, 29%). To a solution of 2-azido-2-(3-bromo-phenyl)-ethanol (876 mg) in THF (10 mL) was added polymer supported triphenylphosphine (3 mmol/g) (2 g, 6 mmol), and the mixture was heated to 60° C. for 30 min. The polymer was then filtered and washed with CH2Cl2. The polymer was suspended in THF (20 mL) and concentrated NH4OH (10 mL) was added, and this mixture was agitated for 24 h. The polymer was filtered and the liquid phase was evaporated in vacuo to afford the title compound (110 mg, 14%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][C:19]1[CH:20]=[C:21]([Cl:25])[CH:22]=[N:23][CH:24]=1>CO.[Ni]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][C:19]1[CH:20]=[C:21]([Cl:25])[CH:22]=[N:23][CH:24]=1
Reactant: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1Oc1cncc(Cl)c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Oc2cncc(Cl)c2)c(C(=O)NCc2ccco2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a 0.08M solution of N-(2-furanylmethyl) 5-nitro-2-(3-chloro-5-pyridyloxy)benzamide (3.7 g, 10 mmol, prepared in Example 35.2) in MeOH was added a 50% aqueous slurry of Raney nickel (˜6 mL). Hydrogen was then bubbled through the resulting solution for one minute. The resulting mixture was stirred at ambient temperature under one atmosphere of hydrogen for 16 hr. The crude reaction mixture was filtered through a pad of Celite® and the filter cake was washed 3× with MeOH. NOTE: Raney nickel is pyrophoric and should always be kept wet with solvent during the filtration. The Raney nickel can be quenched by adding 6M aqueous HCl. The filtrate was concentrated in the presence of benzene to azeotropically remove water. The residue was purified by chromatography (1-3% MeOH in CH2Cl2) to yield 2.6 g (76%) of N-(2-furanylmethyl) 5-amino-2-(3-chloro-5-pyridyloxy)benzamide as a pale brown solid.
Reaction SMILES: F[C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:11]3[CH2:15][C@H:14]([OH:16])[CH:13]=[CH:12]3)[C:6]=2[C:5]([F:17])=[CH:4][N:3]=1.[NH3:18]>>[NH2:18][C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:11]3[CH2:15][C@H:14]([OH:16])[CH:13]=[CH:12]3)[C:6]=2[C:5]([F:17])=[CH:4][N:3]=1
Reactant: N
Reactant: O[C@@H]1C=C[C@H](n2cnc3c(F)ncc(F)c32)C1
Product: Nc1ncc(F)c2c1ncn2[C@H]1C=C[C@@H](O)C1
Temperature: 100 °C

Procedure:
Liquid ammonia (100 mL) was added to (1S,4R)-4-(4,7-difluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-enol (3-2) (220 mg, 0.6 mmol, 1 equiv). The resulting solution was heated in a high pressure vessel to 100° C. for 3 days. The mixture was then concentrated and purified via reverse phase chromatography (5-95% CH3CN/water with 0.1% TFA modifier) to yield (1S,4R)-4-(4-amino-7-fluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-enol (3-3) as a white solid. LRMS m/z (M+H) 235.0 found, 235.1 required.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([CH2:12][C:13]([OH:15])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:29][N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([CH2:36][NH2:37])[CH2:31]1>CN(C)C=O>[Cl:25][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:29][N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([CH2:36][NH:37][C:13](=[O:15])[CH2:12][N:10]2[N:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11]2)[CH2:31]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cn1nnc(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cn1nnc(-c2ccccc2)n1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 22 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A solution of (5-phenyl-2H-tetraazol-2-yl)acetic acid (0.082 g) in N,N-dimethylformamide (2 ml) under nitrogen was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethylammonium hexafluorophosphate (0.152 g) and N,N-diisopropylethylamine (0.139 ml) followed by a solution of Intermediate 9 (0.110 g) in N,N-dimethylformamide (3 ml), and the mixture was stirred at 22° C. for 4 h. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (20 ml). The solution was washed with 10% aqueous citric acid (20 ml), brine (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml) and brine (20 ml), dried (MgSO4) and evaporated in vacuo. Purification by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate, followed by trituration of the resultant product with diethyl ether, gave the title compound as a white solid (0.184 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([CH2:31][CH2:32][CH2:33]Cl)(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1.C([O-])(=[O:37])C.[K+].[I-].[K+]>C(O)C>[NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([CH2:31][CH2:32][CH2:33][OH:37])(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCO)CC2)nc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The chloride (80 mg, 0.18 mmol, Example 293) was dissolved in ethanol (1 mL). To it was added potassium acetate (86.5 mg, 0.88 mmol) and potassium iodide (8 mg, 0.05 mmol). The mixture was heated in a pressure tube in a microwave for 30 minutes. The mixture was filtered and the solid was washed with ethanol (4 mL). The filtrate (about 5 mL) was treated with 5% potassium hydroxide (2 mL) and the solution was stirred at room temperature for 30 minutes. The solution was neutralized with trifluoroacetic acid and concentrated. The residue was purified by reversed phase HPLC to give a pale yellow solid. 25 mg, 28%. MS (ES) MH+=500.
Reaction SMILES: [CH:1]1([C:7](=[O:18])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:1]1([C:7](=[O:18])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH2:32][CH2:31]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCC(C(=O)C1CCCCC1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.3 %

Procedure:
To a solution of 0.84 g of Compound 5c and 1.19 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of dichloromethane, 1.48 g of sodium triacetoxyborohydride and 0.98 ml of acetic acid were added and the resulting mixture was stirred at r.t. for 5 h. After overnight resting, the organic layer was washed with excess of 1M NaOH then with water, dried (Na2SO4) and the solvent was evaporated under vacuum. The crude was purified by flash chromatography eluting with petroleum ether-EtOAc 7:3 to give 1.45 g (99%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[CH:4][C:3]=1[F:17].[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:38][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=3)[N:14]=2)=[CH:4][C:3]=1[F:17]
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1cc(/C=C/c2nc(CCl)co2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)c(F)c3)n2)cc1
Yield: 62.9 %

Procedure:
Using 2-[(E)-2-(4-chloro-3-fluorophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (291 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (300 mg) and 65% sodium hydride (39.5 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (333 mg) as colorless needle crystals.
Reaction SMILES: COC1C=CC([O:7][CH2:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:17])=[O:10])=CC=1.N1C=CC=CC=1.[N+]([O-])([O-])=O.[Ce].[NH4+]>C(#N)C.O>[OH:7][CH2:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:17])=[O:10]
Reactant: COc1ccc(OCC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
(S)-2-[[(S)-2-[(p-Methoxyphenoxy)acetyl]-1-pyrrolidinyl] -carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (500 mg) was dissolved in acetonitrile (8 ml) and water (2 ml), and thereto were added pyridine (0.22 ml) and ammonium cerium nitrate (1.47 g). The mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice water and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (203 mg) (see Table 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:6]=[C:5]([O:20][CH3:21])[C:4]=1[O:22][CH3:23]>C1COCC1.[Ni]>[CH3:21][O:20][C:5]1[CH:6]=[C:7]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:22][CH3:23]
Reactant: COc1cc(C=Cc2ccc([N+](=O)[O-])cc2)cc(OC)c1OC
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1cc(CCc2ccc(N)cc2)cc(OC)c1OC
Yield: 76.7 %

Procedure:
The title compound was prepared from 1,2,3-trimethoxy-5-[2-(4-nitrophenyl)ethenyl]benzene (9.5 g, 0.03 mol) and Ra—Ni (1.0 g) in THF (50 mL) at 21-26° C. (ΔP=9.6 psi) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure yielded a tan powder, 6.6 g (0.023 mol, 74%) of the desired product. mp 91-93° C.