Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24]O)([CH3:23])(C)C>[Mo](=O)(=O)=O.CCCCCCCC>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:24][CH2:20][CH2:23][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Solvent: CCCCCCCC
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Temperature: 120 °C

Procedure:
A mixture of 55.3 grams (0.2 mol) of 4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 2.8 grams of molybdenum trioxide and 250 ml of n-octane is heated to 120° C. A solution of 90.2 grams (0.7 mol) of 70% aqueous tert-butyl hydroperoxide is added dropwise to the hot reaction mixture. Water is removed by azeotropic distillation and collected in a Dean-Stark trap. The reaction mixture is heated at reflux till the red color of the intermediate N-oxyl compound disappears. Solids are removed by filtration, and the filtrate is concentrated under vacuum to give an oil. Purification of the oil by flash chromatography on silica gel (100:3 heptane: ethyl acetate) affords 4-benzoyloxy-1-octyloxy-2,2,6,6-tetramethylpiperidine as a mixture of octyloxy isomers. Further elution of the chromatographic column with 50:3 heptane:ethyl acetate affords the title compound as a mixture of octanediyl isomers.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.[C:14]([O-])(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].S([O-])(OC(C)(C)S(OC1C=CC(O)=CC=1)(=O)=O)(=O)=O.Cl>O>[C:14]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCC(=O)[O-]
Reactant: C[C@@H](N)C(=O)O
Agent: CC(C)(OS(=O)(=O)[O-])S(=O)(=O)Oc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)N[C@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
D-alanine 1.78 g (0.02 mol) and triethylamine 2.8 ml (0.02 mol) were dissolved in 60 ml of water. Myristate of 4-hydroxyphenyldimethylsulfomethyl sulfate 9.52 g (0.02 mol) was added to the solution, and the mixture was stirred for 12 hours at room temperature. The solution reacted was adjusted to pH 2 or 3 with 1N-HCl and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-myristoyl-D-alanine 3.6 g was obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19][C:20](Cl)=O.B.C1(N(CCCBr)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]1([N:7]([CH2:20][CH2:19][CH2:18][Br:17])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCBr
Reactant: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Agent: B
Agent: BrCCCN(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N(CCCBr)c2ccccc2)cc1

Procedure:
3-[N-phenyl-N-(4-nitrophenyl)amino]-1-bromopropane is prepared from N-phenyl-N-(4-nitrophenyl)amine with 3-bromopropionyl chloride, followed by reduction with borane in tetrahydrofuran, by a procedure analogous to the preparation of 3-[N,N-diphenylamino]-1-bromopropane in Example 2.
Reaction SMILES: CN(C)[CH:3]=[O:4].Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:8]=1.C([O-])=O.[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:19][C:18]1[O:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[N:15][C:14]=1[CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2nc(Cc3cccc(Br)c3)c(C)o2)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2nc(Cc3cccc(C=O)c3)c(C)o2)cc1
Temperature: 110 °C
Reaction time: 9 h

Procedure:
N,N-Dimethylformamide (30 ml) was added to 9.48 g of 1-bromo-3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzene, 2.83 g of sodium formate and 0.97 g of bis(triphenylphosphine)palladium (II) dichloride, and the mixture was stirred for 9 hours at 110° C. under bubbling carbon monoxide. To the reaction solution was added water, and extracted with ethyl acetate, filtered to remove insolubles, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 3.58 g of the objective compound as colorless crystals. M.p. 98–99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[S:17][CH:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH2:18].O1CCN(CCNC(C2SC3C(OC4C=CC(N[C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)=[S:48])=CC=4F)=NC=NC=3C=2)=O)CC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[S:17][CH:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:18][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[S:48]
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3cc(C(=O)NCCN4CCOCC4)sc23)c(F)c1
Reactant: Nc1ccc(Oc2ncnc3ccsc23)cc1Cl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3ccsc23)cc1Cl
Yield: 9 %

Procedure:
Starting from the amine 172 and following the procedure described above for the synthesis of compound 26a (scheme 4, example 22), title compound 173 was obtained in 9% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.35 (s, 1H), 11.89 (s, 1H), 8.72 (s, 1H), 8.48(d, J=5.6 Hz, 1H), 8.04(d, J=8.8 Hz, 1H), 7.69(d, J=2.8 Hz, 1H), 7.68(d, J=5.6 Hz, 1H), 7.40(dd, J=2.8 and 8.8 Hz, 1H), 7.36-7.30 (m, 4H), 7.30-7.24 (m, 1H), 3.84 (s, 2H). LRMS (M+1) (100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21](OB(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:23]2[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:17]([O:16][CH3:15])=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.1 %

Procedure:
3-(tert-Butoxycarbonylamino)piperidine (200 mg, 1.00 mmol), 3-(methoxycarbonyl)phenylboric acid (360 mg, 2.00 mmol) and molecular sieves 4 Å (100 mg) were suspended in dichloromethane (10 mL). To this suspension, copper (II) acetate (182 mg, 1.00 mmol) and triethylamine (0.280 mL, 2.00 mmol) were added and the mixture was stirred at room temperature for 15 hours. Subsequently, the reaction mixture was filtered through Celite and a saturated aqueous sodium bicarbonate solution was added to the filtrate. This mixture was extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1->5:1) to give a colorless oil. This product was further purified by silica gel column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.) hexane:ethyl acetate=10:1) to give 154 mg (46%) of the desired compound as a colorless powder.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][OH:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([N:5]([CH2:16][C:17]([OH:21])=[O:18])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCO)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCN(CC(=O)O)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dissolve N-butyl-N-(2-hydroxy-ethyl)-4-methyl-benzenesulfonamide (10 mmol) in acetone (50 mL) and cool to 0° C. Add a slight excess of Jones reagent dropwise and allow the reaction to stir for 4 hours at 0° C. Add excess isopropanol and filter the reaction through a plug of diatomaceous earth. Rinse the plug with acetone (2×50 mL) and methylene chloride (3×50 mL). Combine the filtrates and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide [butyl-(toluene-4-sulfonyl)-amino]-acetic acid.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:34]([C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])#[N:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:34]([C:36]([CH3:41])([CH3:40])[C:37]([N:6]1[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH2:5]1)=[O:38])#[N:35]
Reactant: CC(C)(C#N)C(=O)O
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(C(=O)C(C)(C)C#N)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide (30 mg, 0.042 mmol), 2-cyano-2-methylpropanoic acid (14.39 mg, 0.127 mmol), BOP (56.3 mg, 0.127 mmol) and Hunig's Base (0.052 mL, 0.297 mmol) in DMF (0.25 mL) was stirred at rt for 2 hr. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (6 mg, 0.011 mmol, 26% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.79 (dd, J=9.4, 2.0 Hz, 1H), 8.14 (d, J=5.0 Hz, 1H), 8.06-7.93 (m, 2H), 7.38 (dd, J=8.2, 3.2 Hz, 1H), 7.20-7.10 (m, 1H), 5.07-4.87 (m, 1H), 4.57 (s, 2H), 4.36-4.14 (m, 2H), 3.97 (s, 2H), 3.95-3.68 (m, 2H), 3.46 (s, 3H), 2.68-2.44 (m, 1H), 1.83-1.39 (m, 8H), 1.07-0.95 (m, 3H). MS (ES+) m/z: 547.1 (M+H); LC retention time: 1.19 min (analytical LCMS Method H).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Mg].O1C2C=CC=CC=2C=C1[Mg]Br.CN(OC)[C:25]([C:27]1([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:28]1)=[O:26]>>[C:34]([O:33][C:31]([NH:30][C:27]1([C:25]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[CH:6]=2)=[O:26])[CH2:29][CH2:28]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: Brc1cc2ccccc2o1
Agent: Br[Mg]c1cc2ccccc2o1
Agent: [Mg]
Product: CC(C)(C)OC(=O)NC1(C(=O)c2cc3ccccc3o2)CC1

Procedure:
Alternatively, the starting bromobenzofuran may be reacted with magnesium metal under standard conditions to prepare the corresponding Grignard reagent, benzofurylmagnesium bromide. This Grignard reagent is then reacted with the Weinreb amide, N-methyl N-methoxy 1-(tert-butoxycarbonylamino)cyclopropane-1-carboxamide, to provide 1-(tert-butoxycarbonylamino)-1-(benzofurylcarbonyl)cyclopropane. This ketone is then reduced under standard conditions, typically with sodium borohydride in methanol or ethanol, to provide 1-(tert-butoxycarbonylamino)-1-(benzofuryl(hydroxymethyl))cyclopropane. This alcohol is then converted to the corresponding acetate and reduced to the corresponding methylene by treatment with samarium iodide as previously described. The resulting 1-(tert-butoxycarbon-yl)-1-(benzofurylmethyl)cyclopropane is treated with acid under standard conditions to provide the compounds of the present invention. If necessary or desired, the Weinreb amide may be reduced by reaction with lithium aluminum hydride to provide the corresponding aldehyde essentially as described by Fehrentz and Castro (Synthesis, 676 (1983)). This aldehyde is then reacted with the Grignard reagent previously described to prepare 1-(tert-butoxycarbonylamino)-1-(benzofuryl(hydroxymethyl))cyclopropane, which is then subjected to the reaction conditions previously described to prepare the compounds of the present invention. The requisite Weinreb amide, N-methyl N-methoxy 1-(tert-butoxycarbonylamino)cyclopropane-1-carboxamide, may be prepared from the commercially available 1-amino-1-carboxycyclopropane by standard methods well known in the art.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.O>C(O)(=O)C>[N:4]1([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]#[N:9])[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1ccccc1N
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccccc1-n1cccc1

Procedure:
Anthranilonitrile (10.0 grams, 85.0 mmol) was dissolved in 350 mL of acetic acid. To this was added 2,5-dimethoxytetrahydrofuran (11.0 mL, 85.0 mmol). This was stirred at reflux for 2 hours after which time the reaction mixture was pored into water and the product extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and chromatographed on a silica gel column using a mobile phase of 1:1 dichloromethane-hexane to afford the title compound as a white solid. NMR confirms structure.
Reaction SMILES: C([Mg]Br)C.[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)#[CH:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:21]=1[CH:33]=[O:34]>C(OCC)C.C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:21]=1[CH:33]([OH:34])[C:6]#[C:5][C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: O=Cc1c(COC2CCCCO2)noc1-c1ccccc1Cl
Reactant: C#Cc1cncnc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(C#Cc1cncnc1)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Yield: 40.1 %

Procedure:
Add 3M ethylmagnesium bromide (36 mL, 109 mmol) in diethyl ether to a 0° C. solution of 5-ethynyl-pyrimidine (8.1 g, 77 mmol) in THF (75 mL). Add 5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carbaldehyde (10 g, 31 mmol) in THF (75 mL) and stir 15 h at RT. Quench the reaction with 1N HCl and extract with diethyl ether (2×150 mL). Wash the organic phase with brine (150 mL), dry over sodium sulfate, filter and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 1:1 to 3:7 hexanes/EtOAc) gives the title compound (5.3 g, 40%): 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.35 (s, 2H), 7.44–7.62 (m, 4H), 5.65 (t, J=14 Hz, 1H), 5.08–5.28 (m, 1H), 4.80–4.95 (m, 2H), 4.42–4.60 (m, 1H), 3.80–4.01 (m, 1H), 3.51–3.68 (m, 1H), 1.54–1.90 (m, 6H); TLC Rf=0.20 (3:7 Hexanes:EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C)C=O.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc2ncc(Br)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (3.0 g, 14.1 mmol) in a mixture of N,N-dimethylformamide and tetrahydrofuran (30 mL, 2:1) at 0° C. was added 60% sodium hydride in mineral oil (0.68 g, 17.0 mmol) and the reaction mixture was stirred for 30 minutes, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.7 mL, 14.9 mmol). The reaction mixture was stirred for 16 hours at room temperature then it was quenched by the careful addition of water and diluted with ethyl acetate (250 mL), washed with brine (3×150 mL), dried over sodium sulfate, filtered and concentrated. Gradient column chromatography (10% to 30% ethyl acetate in hexane) provided 6-bromo-2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridine (4.4 g, 92%). 1H NMR (400 MHz, CDCl3): 8.41 (s, 1H), 8.12 (s, 1H), 5.67 (s, 2H), 3.62 (m, 2H), 2.76 (s, 3H), 0.96 (m, 2H), 0.00 (s, 9H). MS (EI) for C13H20BrN3OSi: 342, 344 (MH+, Br iotope pattern).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CCS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CCS(=O)(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (54 mg, 51%), MS (ISP) m/z=419.3 [(M+H)+], mp 153° C., was prepared in accordance with the general method of example 36 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and ethanesulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)([CH3:33])[CH3:31]
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87.0 mg, 0.213 mmol) and propan-2-amine (18.89 mg, 0.319 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-isopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (62.1 mg, 0.138 mmol, 64.9% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.13 (d, J=6.57 Hz, 6 H) 1.84-2.01 (m, 3 H) 2.12-2.22 (m, 1 H) 2.41 (d, J=4.29 Hz, 4H) 3.36-3.47 (m, 1H) 3.49-3.64 (m, 5 H) 3.95-4.10 (m, 2 H) 6.81 (d, J=8.84 Hz, 1 H) 6.99 (d, J=2.02 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.94 (dd, J=9.09, 2.53 Hz, 1H) 7.97 (d, J=7.83 Hz, 1 H) 8.57 (d, J=2.53 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C24H31N7O2, 450; found, 450.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([OH:14])[CH3:13])=[CH:8][CH:7]=1.CS[CH:17](SC)[CH2:18][N+:19]([O-:21])=[O:20]>>[OH:14][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]2[O:10][C:9]([CH2:11][N:12]([OH:14])[CH3:13])=[CH:8][CH:7]=2)=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:8]=1)[CH3:13]
Reactant: CN(O)Cc1ccc(CSCCN)o1
Reactant: CSC(C[N+](=O)[O-])SC
Product: CN(O)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCSCc2ccc(CN(C)O)o2)o1
Yield: 45.6 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N-hydroxy-N-methyl-2-furanmethanamine base (1.48 g) and 1,1-bis-(methylthio)-2-nitroethane (0.57 g) was heated at 98°-100° for 3 hr. The oily residue was chromatographed (silica/acetone) and the appropriate eluate evaporated to give the title compound (0.78 g) as an amber oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(#N)C.CC1(C)[O:29][C@@H:28]([CH2:30][O:31][NH2:32])[CH2:27][O:26]1.Cl>C1(C)C=CC=CC=1>[OH:29][C@H:28]([CH2:27][OH:26])[CH2:30][O:31][NH:32][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Agent: Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(NOC[C@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 1.5 h

Procedure:
To a flask containing 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (2.6 kg, 6.6 mol) and N,N′-carbonyldiimidazole (1.1 kg, 6.8 mol) under nitrogen atmosphere, was added 12 L of dry acetonitrile. After stirring at 22°±5° C. for about 90 minutes, a solution of (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in toluene was added (8.5 L total volume, about 8 moles of amine). The solution was stirred for at least 6 hours at 22°±5 C. Aqueous hydrochloric acid (9 L, 1.5 molar) was added, and after stirring for about 5 minutes, the layers were separated. Aqueous hydrochloric acid (9 L, 1.5 molar) was added to the remaining top layer, and after stirring for about 20 hours, the layers were separated. The remaining top layer was concentrated by vacuum distillation, and then diluted with 15 L toluene and 2 L ethanol. The mixture was warmed to 35–45° C. and diluted with 20 L warm water, then cooled to 0–5° C. The product was collected by filtration and washed with 2 L toluene. The product was recrystallized by dissolving in 12 L toluene and 2 L ethanol (50°±5 C), adding 10 L water and cooling to 0–5° C. After collecting the product by filtration and washing with toluene, the product was dried in a vacuum oven resulting in 2.6 kg of N-[(R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.