Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=4[F:42])[CH:32]=3)[C:27]([CH3:44])([CH3:43])[CH2:26]2)=[O:24])[CH2:10][C@H:9]1[CH3:45])=O)(C)(C)C.C(OCC)(=O)C.[ClH:52]>O1CCOCC1>[ClH:52].[ClH:52].[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[CH2:34][C:31]1[CH:32]=[C:33]2[N:25]([C:23](=[O:24])[CH2:22][N:11]3[CH2:10][C@@H:9]([CH3:45])[NH:8][CH2:13][C@@H:12]3[CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[CH3:21])[CH2:26][C:27]([CH3:44])([CH3:43])[C:28]2=[N:29][CH:30]=1
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3F)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccc(F)cc4F)cc32)[C@@H](CN2CCOC[C@H]2C)CN1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of (2R,5S)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.103 g), ethyl acetate (10 mL) and 4 M HCl in dioxan (10 mL) was stirred at 20° C. for 18 h and the resulting solid collected by filtration to give the title compound (0.075 g). 1H NMR (Me-d3-OD): 8.76 (1H, s), 8.48 (1H, s), 7.56-7.44 (1H, m), 7.11-6.98 (2H, m), 4.27 (5H, d), 4.16-3.96 (5H, m), 3.82 (3H, s), 3.66-3.41 (5H, m), 3.18 (4H, d), 1.62 (6H, s), 1.41 (6H, br m). MS: [M+H]+=528.
Reaction SMILES: O[C:2]1[C:11](C(O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[OH-].[Na+].[NH2:17][C:18]1[CH:19]=[C:20]([P:24](=[O:27])([OH:26])[OH:25])[CH:21]=[CH:22][CH:23]=1.S(=O)(O)[O-].[Na+].C(=O)=O.Cl.S(=O)=O>O>[P:24]([C:20]1[CH:19]=[C:18]([NH:17][C:11]2[CH:2]=[CH:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=2)[CH:23]=[CH:22][CH:21]=1)([OH:27])([OH:26])=[O:25]
Reactant: Nc1cccc(P(=O)(O)O)c1
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: Cl
Agent: O=C=O
Agent: O=S([O-])O
Solvent: O
Product: O=P(O)(O)c1cccc(Nc2ccc3ccccc3c2)c1
Temperature: 80 °C

Procedure:
Water (20 parts) is set stirring and 2-hydroxy-3-naphthoic acid (9.5 parts) charged. Sodium hydroxide liquor (70° Tw -- 6.8 parts) is then added until an alkaline reaction is obtained on Brilliant Yellow test paper. 3-aminophenylphosphonic acid (8.7 parts) and sodium bisulphite liquor (40% -- 100 parts) are charged and the mixture is stirred and boiled under reflux for 18 hours. Carbon dioxide is evolved during the early part of the boiling period. After cooling to 80° C the suspension is acidified with hydrochloric acid (36% -- 59 parts) until acid reaction is obtained on Congo Red paper. During acidification the temperature is raised steadily to the boiling point and the suspension is boiled under reflux for 1-2 hours until evolution of sulphur dioxide has essentially ceased. During this period samples are spotted on to Congo Red test paper to confirm a positive acid reaction. The suspension is then cooled to room temperature, filtered and the cake washed with water (10 parts). The paste (18.2 parts) is dried an air at 50° C to give 12.9 parts of 2-(3-phosphonophenylamino)-naphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([I:16])=[CH:8][C:3]=1[C:4](=[NH:7])[NH:5][OH:6].[CH2:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][CH:21]=1)[CH2:18][CH3:19].ONC(=N)C1C=CC(OC(C)C)=C(I)C=1.ClC1C=C(C=CC=1OCCC)C(O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:14])[CH3:15])[C:9]([I:16])=[CH:8][C:3]=1[C:4]1[N:7]=[C:24]([C:23]2[CH:27]=[CH:28][C:20]([CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)[O:6][N:5]=1
Reactant: CC(C)Oc1cc(Cl)c(C(=N)NO)cc1I
Reactant: CCCc1ccc(C(=O)O)cc1
Agent: CC(C)Oc1ccc(C(=N)NO)cc1I
Agent: CCCOc1ccc(C(=O)O)cc1Cl
Product: CCCc1ccc(-c2nc(-c3cc(I)c(OC(C)C)cc3Cl)no2)cc1
Yield: 20 %

Procedure:
When the product of Step A and 4-propylbenzoic acid were substituted for N-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 20% yield, as white solid. 1H NMR (CDCl3) 8.46 (s, 1H); 8.10 (d, 2H, J=8.25 Hz); 7.34 (d, 2H, J=8.28 Hz); 6.92 (s, 1H); 7.67-7.59 (m, 1H); 2.67 (t, 2H, J=7.35 Hz); 1.72-1.65 (m, 2H); 1.43 (d, 6H, J=6.06 Hz); 0.96 (t, 3H, J=7.32 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl>C(O)CCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Yield: 70 %

Procedure:
A solution of 1-chloro-4-nitrobenzene (15 g, 94.5 mmol) in 1-butanol (75 mL) was added over 20-30 minutes to a refluxing solution of anhydrous piperazine (24.4 g, 284 mmol) in 1-butanol (75 mL) and the mixture maintained at reflux overnight. The solvent was removed under reduced pressure to afford a solid, to which was added 2N hydrochloric acid (400 mL). The aqueous layer was washed twice with ethyl acetate, cooled to below 10° C. and basified with a cold solution of 40% sodium hydroxide to pH 10, keeping temperature below 20° C. The mixture was extracted with ethyl acetate (4×200 mL) then the combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure afforded 1-(4-nitro-phenyl)-piperazine (13.7 g, 70%) as a yellow solid.
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH2:7][NH2:8].C(O[C:12](=O)[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH:16]=1)C.O>C1(C)C=CC=CC=1>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH2:24][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH2:14][CH2:13][C:12]2[NH:5][CH2:6][CH2:7][N:8]=2)=[CH:16]1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Reactant: NCCN
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(Cn2cc(CCC3=NCCN3)c3ccccc32)c(Cl)c1
Temperature: 0 °C

Procedure:
A 2M solution of trimethyl aluminium in toluene (3.32 ml) was diluted with dry toluene (30 ml), cooled to 0° C. and 1,2-diaminoethane (0.43 ml) was added. The mixture was brought to ambient temperature and a solution of 2.5 g of 3-[1-(2,4-Dichlorobenzyl)-1H-indol-3-yl]-propionic acid ethyl ester in dry toluene (20 ml) was added slowly. The reaction mixture was refluxed for 15 hours, cooled and carefully hydrolysed with water (20 ml). The organic phase was separated, dried over sodium sulphate and evaporated. The crude product was purified by column chromatography using successively methylene chloride/ethanol/aqueous ammonium hydroxide 50:49:1 and 50:43:7 respectively to yield the titled product.
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:19]=[CH:18][C:17]([CH:20](Br)[CH3:21])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[N:5]1)([CH3:3])[CH3:2].[C:24]([O-:27])(=[O:26])[CH3:25].[K+]>C(O)(=O)C>[C:24]([O:27][CH:20]([C:17]1[CH:18]=[N:19][C:10]([C:6]2[NH:7][C:8](=[O:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:23])[N:5]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:21])(=[O:26])[CH3:25]
Reactant: COC(=O)c1cc(C(C)Br)cnc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(C)OC(C)=O)cnc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A mixture of 12 g of methyl 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-(1-bromoethyl)nicotinate, 3.1 g potassium acetate and 30 mL acetic acid is stirred under nitrogen and heated at reflux for 8 hours. The reaction mixture is filtered, and the filtrate is concentrated in vacuo. The residue is triturated with ether, filtered, and concentrated in vacuo to give the desired product as an amber glass.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][C:6]#[N:7].[H-].C([Al+]CC(C)C)C(C)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C@H:31](N)[CH3:32])[CH:28]=[CH:29][CH:30]=1.[BH4-].[Na+]>>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6][NH:7][C@@H:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=1)[CH3:32]
Reactant: Cc1ccc(C=CC#N)c(C)c1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Product: COc1cccc([C@@H](C)NCC=Cc2ccc(C)cc2C)c1

Procedure:
In a similar fashion, 2,4-dimethylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(2,4-dimethylphenyl)prop-2-enyl]-1-(3-methoxyphenyl)ethylamine, 12F, as a clear, colorless oil; m/z (rel. int.) 295 (M+, 8), 294 (15), 174 (29), 160 (75), 145 (100), 135 (68), 117 (21), 105 (30), 91 (26), 77 (19).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.[OH-].[Na+]>>[O:14]1[CH2:15][CH2:16][N:1]([C:2]2[CH:10]=[CH:9][C:5]3[O:6][CH:7]=[CH:8][C:4]=3[CH:3]=2)[CH2:12][CH2:13]1
Reactant: Nc1ccc2occc2c1
Reactant: ClCCOCCCl
Agent: [Na+]
Agent: [OH-]
Product: c1cc2cc(N3CCOCC3)ccc2o1

Procedure:
5-Aminobenzo[b]furan and bis-(2-chloroethyl)ether and 40% aqueous NaOH (0.073 mole) are stirred and heated to provide the title compound.
Reaction SMILES: [N:1]([C:4]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O=S(Cl)Cl>[N:1]([C:4]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=Nc1c(C(=O)Nc2ccccc2)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-Azido-3-trifluoromethyl-benzoic acid (460 mg, 2 mmol, compound IX) was dissolved in 2 ml of SOCl2 and the reaction mixture was heated at 80° C. for 1 hour. The remaining SOCl2 was evaporated in vacuo and the residue was coevaporated with dry benzene. Dry CH2Cl2 (2 ml) was added followed by a dropwise addition of 200 μl of aniline (2 mmol). The reaction mixture was stirred at room temperature for 1 hour. Saturated aq. NaHCO3 was added and the product was extracted with CH2Cl2. The resulting amide was purified by recrystallization from methanol. The yleld was 521 mg (86%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[C:15]([N+:21]([O-])=O)=[CH:14][C:13]=1[O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34].O.[NH2:36]N.C(Cl)Cl.CO>C(O)C.[Pd]>[NH2:21][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:13]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:14]=1[NH2:36]
Reactant: NN
Reactant: COCCOCCOCCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OCCOCCOCCOC
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COCCOCCOCCOc1ccc(N)c(N)c1OCCOCCOCCOC
Yield: 89 %

Procedure:
In an oven dried 500 mL round bottom flask, equipped with a Claisen adapter, pressure equalizing dropping funnel, and reflux condenser, 1,2-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4,5-dinitrobenzene (Formula E) (20 g, 0.04 mol) is dissolved in absolute ethanol (200 mL). To this clear solution, 10% palladium on carbon (4 g) is added and the dark black suspension is heated to reflux under an argon atmosphere. Hydrazine hydrate (20 mL) in EtOH (20 mL) is added dropwise over 10 min to avoid bumping. The resulting brown suspension is heated at reflux for 1.5 h at which time the reaction mixture is colorless and TLC analysis (95/5; CH2Cl2/MeOH) displays a low R∫UV active spot corresponding to the diamine. Therefore, the mixture is hot filtered through Celite and the pad rinsed with absolute ethanol (50 mL). The solvent is removed under reduced pressure and the resulting light brown oil is dried in vacuo (in the dark) for 24 h to yield 15.55 g (89%) of 1,2-diamino-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzene (Formula F). For Formula F: FAB MS,M+: m/e 432; HRMS, M+: 432.2471 (calcd. for C20H36N2O8, 432.2482). This material is taken to the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:19]=[CH:18][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.Br[C:21]1([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23][C:22]1=[O:29].CCCCC=CCCCC.C1(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F>C(O)(=O)C.CO.C(#N)C>[CH2:33]([O:32][CH2:31][CH2:30][C:21]1([O:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:9]3[CH:18]=[CH:19][C:6]([C:2]4[O:1][CH:5]=[N:4][N:3]=4)=[CH:7][CH:8]=3)=[CH:12][CH:13]=2)[C:22](=[O:29])[NH:23][C:24](=[O:28])[NH:25][C:26]1=[O:27])[CH3:34]
Reactant: Oc1ccc(Oc2ccc(-c3nnco3)cc2)cc1
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Agent: CCCCC=CCCCC
Agent: FC(F)(F)C1(C(F)(F)F)OC(F)(F)C(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)O1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CO
Product: CCOCCC1(Oc2ccc(Oc3ccc(-c4nnco4)cc3)cc2)C(=O)NC(=O)NC1=O
Temperature: 23 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
A mixture of 4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenol (0.90 g, 2.5 mmol), 5-Bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (1.0 g, 3.6 mmol), 1,5,7-trazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 2.4 g, 6.1 mmol) and 11.7 mL of acetonitrile was shaken at 23° C. for 24 hours. The mixture was diluted with 30 mL of 25% acetic acid in methanol, filtered, and the solids were washed twice with methanol-acetic acid. The filtrate was concentrated in vacuo and purified by radial chromatography (2:1 to 1:1 hexane-ethyl acetate), affording 600 mg of 5-(2-Ethoxy-ethyl)-5-[4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-trione as a colorless solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][N:7]1C(OC(C)(C)C)=O)=[O:5].[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH2:2]([O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][NH:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)[C@H]1C=CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1C=CCN1
Reaction time: 3 h

Procedure:
(1:1) 1.5 g (0.006 mol) (R)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester were dissolved at 5° C. in 10 ml trifluoroacetic acid and stirring was continued at room temperature for 3 hours. Evaporation of the solvent in vacuo gave 2.05 g (quant.) of (R)-2,5-dihydro-1H-pyrrole-2-carboxylic acid ethyl ester trifluoroacetate (1:1) as a yellow oil. MS m/e (%): 142 (1), 68 (100), 45 (10), 41 (15). [α]D=+95.4° (c=1% in methanol).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Oc1cc(Cl)cnc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1cc(Cl)cnc1Br
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Into a solution of 2-bromo-5-chloropyridin-3-ol (2.6 g) in DMF (50 mL) was added a 1 M solution of NaHMDS in THF (15 mL), after 30 min., (2-(chloromethoxy)ethyl)trimethylsilane (2.496 g) was added. After stifling for 2 hours at rt., The reaction mixture was extracted with ethyl acetate and washed with brine. After drying and removing the solvent, the residue was purified by silica gel chromatography to provide 3.9 g of 2-bromo-5-chloro-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine. LCMS [M+H]+: 339.8. 1HNMR (400 MHz, CDCl3) ppm: δ 8.01 (d, J=2.2 Hz, 1H), 7.45 (d, J=2.2 Hz, 1H), 5.31 (s, 2H), 3.79 (t, J=8.4 Hz, 2H), 0.92 (t, J=8.4 Hz, 2H), 0.08 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH:28]=[O:29])=[C:23](B(O)O)[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:28]=[O:29])=[C:21]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=2)[CH:20]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(Br)cn1
Reactant: O=Cc1ccc(Cl)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Temperature: 90 °C

Procedure:
Ethyl 3-(5-bromopicolinamido)propanoate (2.2 g, 7.3 mmol), (5-chloro-2-formylphenyl)boronic acid (1.4 g, 7.7 mmol), Pd(dppf)Cl2 (810 mg, 1.1 mmol), and K2CO3 (2.3 g, 16.9 mmol) and PdCl2(dppf) were dissolved in wet DMF (10 mL) and the resulting mixture was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature, filtered through CELITE and the filtrate was diluted with EtOAc, washed with water and sat. aqueous NaHCO3. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([F:17])[C:7]=1[C:8]([NH2:10])=O>CN(C=O)C>[F:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([F:17])[C:7]=1[C:8]#[N:10]
Reactant: COc1cc(F)c(C(N)=O)c(F)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc(F)c(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of thionyl chloride (139.0 g, 1.17 mol) in dry DMF (150 ml) was added to a stirred solution of compound 26 (20.0 g, 0.11 mol) in dry DMF (250 ml) at room temperature. The mixture was stirred at room temperature overnight and then poured onto ice-water. The product was extracted into ether (twice), and the combined ethereal extracts were washed with water, saturated sodium hydrogen carbonate, water and dried (MgSO4). The solvent was removed in vacuo to give off-white crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:16][CH:17]=[CH:18][N:19]=2)=[CH:10][CH:9]=1.C(O[C:29]([C:31]1[CH:32]=[N:33][N:34]([CH3:37])[C:35]=1[Cl:36])=O)C.Cl>O1CCCC1.C(#N)C>[ClH:36].[Cl:36][C:35]1[N:34]([CH3:37])[N:33]=[CH:32][C:31]=1[CH2:29][N:23]1[CH2:22][CH2:21][N:20]([C:15]2[C:14]([C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:25][CH2:24]1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: CCOC(=O)c1cnn(C)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cn1ncc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a solution of 1M lithium aluminum hydride in tetrahydrofuran (1.97 mL, 1.97 mmol) under nitrogen add dropwise a solution of 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.255 g, 0.99 mmoles) in tetrahydrofuran (5 mL). After stirring for 30 min heat the solution to reflux, then add dropwise a solution of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (223 mg, 1.18 mmol) in tetrahydrofuran (2 mL) over 45 min. After 30 min cool the reaction to room temperature and then cool to 0° C. Cautiously quench with water (10 mL), add DCM (10 mL) and then pass through a phase separator. Wash the aqueous layer twice with DCM (10 mL) and pass through the separator. Combine the organic extracts and concentrate then purify by flash chromatography (silica gel column, eluting with 0-15% methanol in methylene chloride). Further purify by reverse phase HPLC to obtain the free base. Dissolve the free base (59 mg, 0.16 mmol) in the minimum quantity of 50% aqueous acetonitrile. Add 2M aqueous HCl (80 μL, 0.16 mmol) and lyophilize to give the title compound (52 mg, 12%). MS (ES): m/z=387.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]([NH2:19])=[S:18])[CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:23][C:24](=O)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[S:18][CH:23]=[C:24]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:19]=3)[CH:10]=2)=[CH:20][CH:21]=1
Reactant: O=C(CBr)CCc1ccccc1
Reactant: COc1ccc(CSc2cc(NC(N)=S)ncc2Br)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)cc1
Temperature: 75 °C
Yield: 61 %

Procedure:
1-(4-(4-methoxybenzylthio)-5-bromopyridin-2-yl)thiourea (3.0 g, 7.8 mmol) and 1-bromo-4-phenylbutan-2-one (1.77 g, 7.8 mmol) were diluted in EtOH (120 mL). Triethylamine (2.2 ml, 15.6 mmol) was added, and the solution was heated at 75° C. for 3 hours. The solution was cooled and concentrated to half the amount of solvent. The solid was filtered and rinsed with cold EtOH to provide the desired product (2.44 g, 61% yield) as a tan solid.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[O:17][CH3:18])[C:5]=1[CH3:19])(=[O:3])[CH3:2].Br[CH2:21][CH3:22]>>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:21][CH3:22])=[CH:12][C:11]=2[O:17][CH3:18])[C:5]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CCBr
Reactant: COc1cc(O)ccc1-n1c(C)cc(C(C)=O)c1C
Product: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)c(OC)c1

Procedure:
Using the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-hydroxy-2-methoxyphenyl)pyrrole (1.37 g, 5.3 mmol) and an excess of bromoethane (2.0 mL) reacted to give 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methoxyphenyl)pyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 6.99 (d, 1H), 6.59 (d, 1H), 6.53 (dd, 1H), 6.31 (s, 1H), 4.08 (q, 2H), 3.74 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 1.93 (s, 3H), 1.46 (t, 3H); MS (ESI) 288 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C@H:8]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:10](=[O:23])[C@H:9]1[N:24]1C(=O)C2=CC=CC=C2C1=O)=[O:7])[CH2:2][CH2:3][CH3:4].CNN>C(Cl)Cl>[CH2:1]([O:5][C:6]([C@H:8]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:10](=[O:23])[C@H:9]1[NH2:24])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)[C@@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1Cc1ccc(OC)cc1OC
Agent: CNN
Solvent: ClCCl
Product: CCCCOC(=O)[C@@H]1[C@H](N)C(=O)N1Cc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of 19 g of cis-1-(2,4-dimethoxybenzyl)-3-phthalimido-2-oxoazetidine-4-carboxylic acid n-butyl ester in 190 ml of methylene chloride is added 3.7 g of methyl hydrazine. The mixture is stirred overnight at room temperature. The reaction mixture is subjected to filtration, and the filtrate is concentrated under reduced pressure. To the residue is added ethyl acetate, and the insolubles are removed by filtration. The filtrate is subjected to extraction twice, with 100 ml each of 1N-HCl. The extracts are neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure to yield 12 g (87.5%) of cis-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid n-butyl ester as oily product.