Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:8])[CH2:5][S:6][CH3:7].C(N(CC)CC)C.[CH2:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH2:25][CH3:26])[C:19]=1[C:27](=[O:31])[C:28](Cl)=[O:29])[CH3:17].O>C1(C)C=CC=CC=1>[CH2:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH2:25][CH3:26])[C:19]=1[C:27](=[O:31])[C:28]([N:2]([CH3:1])[N:3]=[C:4]([CH3:8])[CH2:5][S:6][CH3:7])=[O:29])[CH3:17]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Reactant: CNN=C(C)CSC
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CSC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a 200 ml volume four-necked flask, 1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine (5-0-1) (5.0 g), toluene (anhydrous) (9.6 g), and triethylamine (6.97 g) were added under a nitrogen atmosphere at room temperature. To the mixture, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a) (9.57 g) dissolved in toluene (28.8 g) was added dropwise at 0° C. over 2 hours, and stirred at room temperature for 2 hours. To the reaction mixture was added water (30 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 10.96 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(1)-39).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][CH:26]([F:28])[F:27])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:25][CH:26]([F:28])[F:27])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1coc(-c2ccnc(N(CC(F)F)C(=O)OC(C)(C)C)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CC(F)F)c1cc(-c2nc(C(=O)O)co2)ccn1
Reaction time: 0.75 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 2-(2-((tert-butoxycarbonyl)(2,2-difluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (69.4 mg) in methanol (5 mL) was added 1M aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred for 45 min. The reaction mixture was neutralized with 1M hydrochloric acid, and the methanol was evaporated under reduced pressure. The residue was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (57.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][C:57]([CH3:61])([CH3:60])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([NH:56][C:22]([C:19]1[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:17][CH:18]=1)=[O:24])([CH3:61])[CH3:60]
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (50 mg, 0.15 mmol) and TBTU (54 mg, 0.17 mmol) in DMF (2 mL) was added DIPEA (130 μL, 0.76 mmol). Then 2-amino-2-methyl-1-propanol (16 μL, 0.167 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (56 mg, 92%) as a white foam. MS: m/e=402.4 [M+H]+.
Reaction SMILES: [S:1]([C:17]1[CH:22]=[C:21]([C:23]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[OH:31])[C:2]1[CH:7]=[C:6]([C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].O.O.O.O.C([O-])(=O)C.[Co+2:46].C([O-])(=O)C>CC(O)C>[S:1]([C:17]1[CH:22]=[C:21]([C:23]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[O-:31])[C:2]1[CH:7]=[C:6]([C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[O-:16].[Co+2:46]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(Sc2cc(C(C)(C)CC(C)(C)C)ccc2O)c1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)CC(C)(C)c1ccc([O-])c(Sc2cc(C(C)(C)CC(C)(C)C)ccc2[O-])c1
Temperature: 140 °C

Procedure:
A mixture of 2,2'-thiobis(4-t-octylphenol) (44.2 g.) and anhydrous potassium carbonate (6.9 g.) was heated in refluxing 2-propanol for about 0.5 hr. and then cobalt (II) acetate tetrahydrate (12.5 g.) was added. The reaction mixture was stirred at reflux temperature for about 4 hr. during which a precipitate of pink solids was formed. The mixture was filtered and the solids were washed with water and dried. The solids were recystallized from 2-propanol and the resulting pink solid, m.p. 355°-357° C. was dealcoholated by heating at 140° C. at less than 0.1 mm of mercury to give the cobalt 2,2'-thiobis-(4-t-octylphenolate) as a brownish solid m.p. greater than 360° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[O:24]=[C:25]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:26][CH2:27][C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:28](=[O:29])[CH2:27][CH2:26][C:25](=[O:24])[N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(O)CCC(=O)N1CCCC1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCC(=O)N1CCCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-oxo-4-(pyrrolidin-1-yl)-butanoic acid to yield (3aR,4S,7aR)-4-(4-oxo-4-pyrrolidin-1-yl-butyryloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=467; RT=2.88 min; UPLC Method II
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([C:12]#[N:13])=[C:8]([C:10]#[N:11])[N:9]=1)[CH2:2][CH2:3]C.C(C1NC(C#N)=C(C#N)N=1)CC.[H-].[Na+].C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH2:1]([C:5]1[N:6]([C:14]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([C:12]#[N:13])=[C:8]([C:10]#[N:11])[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCCc1nc(C#N)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCc1nc(C#N)c(C#N)[nH]1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Product: CCCc1nc(C#N)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following a procedure similar to that described in Preparation 5(i), but using 7.8 g of 2-propylimidazole-4,5-dicarbonitrile (prepared as described in Preparation 10), 2.14 g of sodium hydride (as a 55% w/w dispersion in mineral oil) and 17.1 g of trityl chloride, 14.6 g of the title compound were obtained as crystals, melting at 107° C. (with decomposition and with a yellow coloration at 102° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.CCO.Cl>[Fe].O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([NH2:1])[N:7]=3)[CH:10]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: Cc1cc(Nc2cccc(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2cccc(NC(=O)c3ccc(N)cc3)c2)nc(N)n1
Yield: 14.2 %

Procedure:
To a refluxing suspension of amide E3 (7.89 g, 20.00 mmol) in 2:1 EtOH:H2O (500 mL) were sequentially added Fe dust (4.40 g, 79 mmol) and c.HCl (2% v/v, 10 mL), and the resulting mixture refluxed for ˜14 h. After this time, the hot reaction mixture was filtered through a pad of Celite, and the solvent was removed under reduced pressure. The residue was re-dissolved in hot H2O, and the resulting suspension filtered through a pad of Celite. Solvent was removed under reduced pressure, and the residue dried via three MeOH azeotrope cycles. The resulting residue was reprecipitated from acidified MeOH:EtOAc to give amine E4 as an amorphous tan solid (0.95 g, 12%); 1H NMR (400 MHz, DMSO): δ 12.71 (br s, 1H, pyrimidinyl-N+—H), 10.55 (br s, 1H, ArC(O)NHAr), 9.95 (s, 1H, ArNHAr), 8.10-7.40 (m, 7H, ArH & ArNH2), 7.32 (m, 1H, ArH), 6.77 (d, J=8.30 Hz, 2H, ArH), 6.18 (s, 1H, ArH), 2.28 (s, 3H, ArCH3); LCMS (APCl+): 335 (100%).
Reaction SMILES: C[NH:2][CH2:3][C:4]1[N:11]2[C:7]([S:8][CH:9]=[CH:10]2)=[CH:6][N:5]=1.C(O)=O.C(O[C:19](=[O:21])[CH3:20])(=O)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:20][C:19]([NH:2][CH2:3][C:4]1[N:11]2[C:7]([S:8][CH:9]=[CH:10]2)=[CH:6][N:5]=1)=[O:21]
Reactant: CNCc1ncc2sccn12
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: ClCCl
Product: CC(=O)NCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 100 mg (0.59 mmol) of the above-obtained 5-(N-methylamino)methylimidazo[5,1-b]thiazole in 3 ml of methylene chloride was added a mixture which had been prepared in advance by reacting 1 ml of formic acid with 0.2 ml of acetic anhydride at 50° C. for 10 minutes. The mixture was stirred at room temperature for one hour, and then refluxed for 3 hours. To this was added a mixture which had been prepared in advance by reacting 5 ml of formic acid with 2 ml of acetic anhydride at 50° C. for 10 minutes, and the mixture was refluxed for an additional 2 hours. To the reaction solution cooled to room temperature was added 3 ml of toluene, and the mixture was concentrated to dryness under reduced pressure. To the residue were added methylene chloride and a 50% aqueous solution of potassium carbonate, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried over anhydrous potassium carbonate, concentrated under reduced pressure, and purified by flash column chromatography using silica gel, eluting with a 9:1 mixture of ethyl acetate and methanol to give 89 mg (yield 77%) of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[ClH:28]>CCOC(C)=O.CCO.[Pd]>[ClH:28].[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N)c2)cc1
Yield: 95 %

Procedure:
A solution of 4,5-difluoro-2-methoxy-4′-(3-nitro-benzyloxy)-biphenyl (300 mg, 0.808 mmol) and 10% Pd/C (45 mg) in EtOAc (2 mL), EtOH (13 mL) and 6N HCl (150 uL) was hydrogenated at 50 psi for 1.5 hrs. The reaction mixture was filtered through Celite and evaporated to dryness to give 289 mg (95%) of 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamine hydrochloride. LC-MS (ES) calculated for C20H17F2NO2, 341.36; found m/z 342 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1>CN1C(=O)CCC1>[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: CC1CCCN1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Solvent: CN1CCCC1=O
Product: Cc1nc(C#Cc2ccc(N3CCCC3C)nc2)cs1
Temperature: 180 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 0.30 mL (2.5 mmol, 3 eq) 2-methylpyrrolidine and 2 mL NMP were combined. The reaction mixture was heated in the microwave at 180° C. for 30 min, quenched with pH 10 PBS; extracted with DCM. Silica gel chromatography (gradient 10% to 50% EtOAc/Hexanes) gave 2-(2-methylpyrrolidin-1-yl)-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (L-001120970). The mono HCl salt was made by dissolving the free base into diethyl ether, adding 1 eq of HCl, and isolated by filtration. LC-MS calculated for C16H17N3S 283, observed m/e 284.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>O1CCCC1>[CH3:12][C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]2[NH:1][C:32](=[O:33])[N:13]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:3]=2[CH:4]=1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-{[2-amino-5-methyl-4-(trifluoromethyl)phenyl]amino}-1-piperidine-carboxylate (D58) (2.92 mmol, 1.1 g) was dissolved in 5 ml of tetrahydrofuran and CDI (1,1′-(oxomethanediyl)bis-1H-imidazole) (1.5 eq., 4.4 mmol, 0.71 g) was added at room temperature; the mixture was stirred at 50-60° C. overnight. The mixture was cooled to room temperature and it was partitioned in ethyl acetate/H2O; the two layers were separated and the aqueous phase was extracted with ethyl acetate (2×); the organic phases were combined and washed with citric acid solution (10% aqueous), brine and they were dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (ethyl acetate-n-hexane)) to yield the title compound, 900 mg, 81%, M+−H=398.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[O:23]([CH2:30][CH2:31][CH2:32][CH2:33]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCOc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCOc2ccccc2)CC1
Yield: 50.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.50 g) as starting compound and 4-phenoxybutyl bromide (1.37 g) were reacted and treated in the same manner as in Example 168 to give 0.91 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-phenoxybutyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-:12].[CH3:13][O-:14].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[C:6]([O:14][CH3:13])[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-:12]
Reactant: C[O-]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C)[n+]([O-])c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
2-Bromo-6-methyl-4-nitro-pyridine 1-oxide (4 g, 17 mmol) was dissolved in methanol (anhydrous, 100 ml), and sodium methoxide (1.8 g, 33 mmol) was added. The mixture was stirred at room temperature for 90 minutes, diluted with water (90 ml) and concentrated under reduced pressure to half of its volume. The mixture was extracted with DCM (5×), the combined organic phases were dried (sodium sulfate) and concentrated to dryness under reduced pressure to yield 3.3 g of yellow crystals, 15 mmol, 88%) MS(APCI) m/z=217.9 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]([CH3:17])=[N:10]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][CH:28]([N:31]([C:14]([C:13]2[N:9]([CH3:8])[N:10]=[C:11]([CH3:17])[CH:12]=2)=[O:15])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N(CC(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)n(C)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
Triethylamine (1.8 ml, 12.8 mmol) and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (0.5 g, 3.2 mmol) is added to a stirred solution of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 3.2 mmol), and diethyl ether (30 ml). The reaction is stirred for 5 minutes at room temperature. The reaction is poured into 5% citric acid and extracted with ethyl acetate. The ethyl acetate is washed with sodium bicarbonate and brine and dried over sodium sulfate. The sodium sulfate is filtered off and the crude product is concentrated on a rotary evaporator to yield (1.15 g, 96% crude) of 4-{[(1,3-dimethyl-1H-pyrazol-5-yl)-carbonyl]-isobutyl-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=379 (M++1); 1H NMR (CD3OD) (broad peaks due to rotamers) δ=6.29-6.17 (1H, br m), 4.23-4.10 (2H, br m), 3.98-3.90 (1H, br m), 3.78 (3H, br s), 3.25 (2H, d), 2.89-2.57 (2H, br m), 2.25 (3H, s), 2.20-2.04 (1H, br m), 1.86-1.70 (3H, br m), 1.46 (9H, s), 1.00-0.74 (6H, br m).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([I:26])C(=O)C1>C(Cl)Cl>[OH:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]([I:26])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(Nc1cccnc1O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cc(I)cnc1O)OCc1ccccc1
Yield: 65.6 %

Procedure:
To a solution of benzyl (2-hydroxypyridin-3-yl)carbamate (16.1 g, 65.9 mmol) in DCM (500 mL) was added NIS (17.8 g, 79.1 mmol) and the mixture heated at reflux overnight. After cooling, the mixture was filtered to afford benzyl (2-hydroxy-5-iodopyridin-3-yl)carbamate (16 g, 65% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.72 (s, 1H), 7.29-7.40 (m, 5H), 5.21 (s, 2H); MS (ES) m/z 370 (M+H).
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Br:5])/[Br:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.Cl>C(O)(=O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:6](=[O:7])[C:4]([Br:5])=[C:2]([Br:3])[CH:1]=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=c1c(Br)c(Br)cnn1-c1ccc(F)cc1
Temperature: 115 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Mucobromic acid (5.0 g, 19.4 mmol) dissolved in acetic acid (110 mL) was treated with 4-fluorophenyl hydrazine.HCl, and the heterogeneous mixture brought to reflux at a bath temperature of 115° C. for 15 hours. During the course of reaction, the mixture became a homogeneous deep red solution, and upon cooling to 23° C., a crystalline precipitate formed. The solution was poured into ice water (1000 mL) and stirred for 20 minutes. The yellow/brown crystals were filtered off, washed with additional cold water, and dried in vacuo to provide 5.8 g (86%) of product. (J. Het. Chem., 1993, 30, 1501; Heterocycles 1985, 23, 2603) 1H NMR (300 MHz, DMSO-d6) δ 7.31–7.41 (m, 2H), 7.57–7.64 (m, 2H), 8.29 (s, 1H). MS (DCI+) m/z 347 (Br79Br79 M+H)+, m/z 349 (Br79Br81 M+H)+, m/z 364 (Br79Br79 M+NH4)+, and m/z 366 (Br79Br81 M+NH4)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:7]=1.[CH3:30][CH:31]1[NH:35][C:34](=[O:36])[CH2:33][CH2:32]1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:35]4[C:34](=[O:36])[CH2:33][CH2:32][CH:31]4[CH3:30])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][O:10][C:9]3=[O:13])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCOC3=O)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3N3CCOC3=O)CC2)c(C)c1
Yield: 21 %

Procedure:
Using 3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (207 mg) described in Preparation Example 168 and 5-methylpyrrolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 352, the title compound (50 mg) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:21]=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:19][C:18]=3[S:26]([NH:29]C(C)(C)C)(=[O:28])=[O:27])[CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:6][N:7]=1)[CH3:2].C1(OC)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:49]([O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:50]>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH2:52]([O:51][C:49]([NH:29][S:26]([C:18]1[S:19][C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:21][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9](=[O:10])[CH2:8][N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[CH2:1][CH3:2])[CH:12]=1)(=[O:28])=[O:27])=[O:50])[CH2:53][CH2:54][CH3:55]
Reactant: CCc1nccn1CC(=O)c1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Reactant: CCCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(C(=O)Cn2ccnc2CC)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 47 %

Procedure:
To a solution of 3-{3-[2-(2-ethylimidazol-1-yl)acetyl]phenyl}-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (74.5 mg, 0.153 mmol; see step (b)) in TFA (3 mL) was added anisole (150 μL) and the reaction mixture was stirred for 28 h at ambient temperature. The reaction mixture was concentrated in vacuo and dried in vacuo overnight. To the crude product dissolved in CH2Cl2 (7 mL) was added Na2CO3 (72.9 mg, 0.688 mmol), water (2 mL) and butyl chloroformate (33.0 μL, 0.260 mmol), and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (8:92) as eluent to give the sub-title compound in 47% yield, over two steps, (38.5 mg, 0.0724 mmol).