Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A suspension of 5-fluoropicolinaldehyde (10.0 g, 79.94 mmol) in MeOH (160 mL) was treated with sodium borohydride (9.073 g, 239.8 mmol) in portions. The mixture was stirred at ambient temperature for 16 hours. The mixture was quenched with water, concentrated under reduced pressure, diluted with water and extracted with EtOAc. The combined organic extracts were dried (phase separator silicone treated filter paper), and concentrated under reduced pressure to give a clear oil, which was triturated with ether. The resulting solid was collected by filtration to afford (5-fluoropyridin-2-yl)methanol (10.15 g, 99% yield).
Reaction SMILES: O.[NH2:2]N.C[N:5](C)[CH:6]=[CH:7][C:8]([C:10]1[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=1[O:12][CH2:13][CH:14]([OH:29])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=O.Cl>C(O)C>[NH:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=2[O:12][CH2:13][CH:14]([OH:29])[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[N:2]1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccccc1OCC(O)CN1CCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: OC(COc1ccccc1-c1cc[nH]n1)CN1CCN(c2ccc(Cl)cc2)CC1
Yield: 88 %

Procedure:
15 ml of hydrazine hydrate are added to 8.0 g (0.017 mole) of 1-[2-(3-Dimethylamino-1-oxo-propenyl)-phenoxy]-3-[4-(4-chlorophenyl)-piperazin-1-yl]-propan-2-ol.HCl (Example 4b) in 100 ml of ethanol, and the mixture is refluxed for 3 days. The solvent is distilled off and the residue is recrystallized from ethanol. 6.2 g (88%) of a product of melting point 120°-121° C. are isolated.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH3:5][O:6][C:7](=[O:17])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:9]O.[Na]>O>[CH3:5][O:6][C:7](=[O:17])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:9][N:3]([CH3:4])[CH3:2]
Reactant: CNC
Reactant: COC(=O)C(=CO)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: COC(=O)C(=CN(C)C)c1ccccc1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
97 weight-parts of dimethylamine hydrochloride are dissolved in 250 weight-parts of water, and 200 weight-parts of sodium 3-hydroxy-2-phenyl acrylic acid methyl ester are added. The mixture is stirred for 2 hours, and the organic phase is separated and distilled. 148 weight-parts of 3-dimethylamino-2-phenyl acrylic acid methyl ester are obtained, corresponding to a yield of 72.2% of the theory.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[NH3:25]>CO.O>[C:20]([O:19][C:17](=[O:18])[NH:16][CH:4]([C:3](=[O:2])[NH2:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: N
Reactant: COC(=O)C(CCCc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: COc1ccc(CCCC(NC(=O)OC(C)(C)C)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-tert-butoxycarbonylamino-5-(4-methoxy-phenyl)-pentanoic acid methyl ester (5.6 g, 16.6 mmol) in MeOH (100 mL) is treated with aqueous ammonia solution (100 mL of a 28% solution in water, 28 mmol) and stirred at RT overnight. The organic solvent is removed in vacuo and the remaining aqueous portion is extracted with EtOAc (×3). The combined organic extracts are washed with brine and then dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[N:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=3)[C:9]2=[O:12])=[N:4][CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Oc1nccc2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)cnc2ccn1Cc1cccc(F)c1

Procedure:
The alkylation of 7-bromo-1-hydroxy-5-azaisoquinoline (1.00 g, 4.40 mmol) using 3-fluorobenzyl bromide (1.27 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 2-(3-Fluorobenzyl)-7-(3-phenyl-prop-1-ynyl)-2H-5-azaisoquinolin-1-one
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[CH2:15][CH2:14][O:13][C:12]21[CH2:21][C@@H:20]1[C@H:16]2[CH2:17][C@H:18]([OH:22])[CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]1[CH2:15][CH2:14][O:13][C:12]21[CH2:21][C@@H:20]1[C@H:16]2[CH2:17][C:18](=[O:22])[CH2:19]1
Reactant: O[C@@H]1C[C@@H]2CC3(OCCO3)[C@@H]2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C[C@@H]2CC3(OCCO3)[C@@H]2C1
Temperature: -78 °C

Procedure:
A tetrahydrofuran solution (120 mL) of (±)-(1′R,2′R,4′S,6′R)-spiro[1,3-dioxolan-2,7′-[3]oxatricyclo[4.2.0.02,4]octane] (J. Chem. Soc. Perkin Trans. 1, 1980, 852) (20.0 g, 119 mmol) was gradually added dropwise to a tetrahydrofuran suspension (480 mL) of lithium aluminum hydride (6.77 g, 178 mmol) with stirring at 0° C. The mixture was stirred overnight at room temperature, and tetrahydrofuran (200 mL), water (6.8 mL), a 15% aqueous sodium hydroxide solution (6.8 mL), and water (20.4 mL) were then added thereto while the reaction solution was cooled on ice. The mixture was stirred at room temperature for 3 hours. The mixture was filtered through Celite and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography (separation from positional isomers in regard to hydroxyl groups) to obtain (±)-(1R,3R,5R)-spiro[bicyclo[3.2.0]heptane-6,2′-[1,3]dioxolan]-3-ol as an oil substance (7.78 g, 38%). Dimethyl sulfoxide (9.11 mL, 128 mmol) was added to a methylene chloride solution (110 mL) of oxalyl chloride (5.50 mL, 64.2 mmol) with stirring at −78° C., and the mixture was stirred at this temperature for 5 minutes. Then, a methylene chloride solution (30 mL) of the above-obtained alcohol (7.28 g, 42.8 mmol) was added thereto. The mixture was stirred at this temperature for 15 minutes. Then, triethylamine (23.7 mL, 171 mmol) was added thereto, and the mixture was heated to room temperature and stirred. The mixture was separated into aqueous and organic layers by the addition of 0.1 M hydrochloric acid. The organic layer was washed with 0.1 M hydrochloric acid, water, and saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (6.61 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:39]=[CH:38][C:37]([O:40]CC4C=CC=CC=4)=[CH:36][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])=O.[NH4+]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:19]=3[S:20][C:21]=2[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:27]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 89.8 %

Procedure:
6-Benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-[(1-pyrrolidinyl)methyl]phenyl ketone (105 mg, 0.16 mmol) in THF (5.0 mL) was treated sequentially with a solution of ammonium formate (25% in H2O, 3 mL) and 10% palladium on carbon (50 mg) at ambient temperature. The resulting mixture was stirred at ambient temperature under argon for 9 h before filtration through diatomaceous earth followed by rinsing with dichloromethane and methanol. The filtrate was extracted with dichloromethane (30 mL×3) which extracts were washed with water (50 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:10:85) afforded the product as a yellow solid (80 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.P(Br)(Br)[Br:12].O>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Br:12]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: BrP(Br)Br
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(Br)cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 252.1 %

Procedure:
20.0 g of 5-bromo-2-chlorobenzyl alcohol was dissolved in 100 ml of ethylene glycol dimethyl ether. To this solution, 9.4 g of phosphorus tribromide was added at −20° C., followed by stirring at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with toluene, and washing with an aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 24.9 g of a crude product of 5-bromo-2-chlorobenzyl bromide as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[CH:7]([C:15]([F:18])([F:17])[F:16])[O:8]2.[Cl:22]Cl>C(O)(=O)C.[Zn]>[Cl:22][C:12]1[C:3]([O:2][CH3:1])=[C:4]2[C:9](=[CH:10][C:11]=1[O:13][CH3:14])[O:8][CH:7]([C:15]([F:16])([F:17])[F:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2
Reactant: ClCl
Reactant: COc1cc(OC)c2c(c1)OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc2c(c(OC)c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Reaction time: 2 h
Yield: 17.2 %

Procedure:
The solution of the 5,7-dimethoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid from Example 34 (WO 00/23433) (150 mg, 0.49 mmole) in acetic acid (1.0 mL) was stirred at 10° C. The pre-prepared solution of Cl2 (gas) in acetic acid (1.1 mL, 0.64 mmol) was added to above solution. The mixture was stirred for 2 hours. After Cl2 (gas) was blown away, Zn powder (5 eq) was added to the mixture and the mixture was stirred for 30 min. Zn salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by RPHPLC and eluted with 30 to 85% ACN in water with 0.05% TFA. The Ist peak fractions were combined to give the desired compound 28.6 mg (17.2%) as mono-chloro compound: LCMS m/z 339.05 (M+H) at 5.474 min. ESHRMS m/z 337.0112 (M−H, C13H9O5F3Cl, Calc'd 337.0085). 1H NMR (CDCl3/400 MHz) 7.90 (s, 1H), 6.67 (s, 1H), 5.82 (q, 1H, J=6.8 Hz), 3.97 (s, 3H), 3.94 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC(O)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC(O)CC2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-hydroxypiperidin-1-yl)benzamido)-4-phenylbenzoate (0.22 g) in methanol (2.2 mL) and ethyl acetate (1.1 mL), 10% palladium-carbon (0.11 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.18 g of tert-butyl 2-(2-hydroxy-5-(4-hydroxypiperidin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][C:28]2([C:41]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][NH:38][C:39]=4[CH:40]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1)[CH3:24].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[CH2:23]([N:25]1[CH2:30][CH2:29][C:28]2([C:41]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][N:38]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:22])[C:39]=4[CH:40]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1)[CH3:24]
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Reactant: CCN1CCC2(CC1)COc1cc3c(cc12)NCC3
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(-c4nnc(C)o4)cc2C)cc1)CC3
Temperature: 45 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A stirred suspension of 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11, 0.53 g, 1.8 mmole) in thionyl chloride (8 ml) was heated at about 45° C. for 30 minutes, then concentrated in vacuo. The yellow solid was dissolved in THF (10 ml)/dichloromethane (5 ml) and added to a stirred solution of 1'-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D109, 0.46 g, 1.8 mmole) and triethylamine (0.50 ml, 3.6 mmole) in THF (15 ml) at 5° C. under argon. The solution was stirred at room temp. for 2 h, then concentrated in vacuo. The residue was treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 3% methanol/chloroform and the yellow oil obtained passed through a short basic alumina column eluting with ethyl acetate to afford the title compound as a beige foam (0.62 g, 68%). This was converted to its hydrochloride (mp 269-273° C.) and mesylate (mp 275-279° C.) salts.
Reaction SMILES: N12CCN(CC1)CC2.Cl[C:10]1[C:11]2[S:21][CH:20]=[CH:19][C:12]=2[NH:13][C:14](=[O:18])[C:15]=1[C:16]#[N:17].[N:22]1([C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(N(C)C)=O>[O:18]=[C:14]1[NH:13][C:12]2[CH:19]=[CH:20][S:21][C:11]=2[C:10]([N:25]2[CH2:26][CH2:27][N:22]([C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[O:29])[CH2:23][CH2:24]2)=[C:15]1[C:16]#[N:17]
Reactant: N#Cc1c(Cl)c2sccc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2[nH]c1=O
Temperature: 110 °C
Yield: 89.5 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (3.19 g, 28.48 mmol) was added to a solution of 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile (26) (3.0 g, 14.24 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (3.07 g, 15.60 mmol) in dry DMA. The solution was heated at 110° C. for 1 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried to yield 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile (4.72 g, 89%) as white solids. MP 293° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.89 (m, 8H), 7.02 (d, J=5.6 Hz, 1H), 7.20 (dd, J=3.6, 5.2 Hz, 1H), 7.54 (dd, J=1.2, 3.6 Hz, 1H), 7.84 (dd, J=1.2, 5.2 Hz, 1H), 8.16 (d, J=5.2 Hz, 1H) ppm; MS m/z=371 amu (M++1).
Reaction SMILES: CS(O)(=O)=O.C([O:13][C:14]1[CH:35]=[CH:34][C:17]([C:18]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31](=[NH:33])[NH2:32])[CH:27]=3)[CH:22]=2)=[O:19])=[CH:16][CH:15]=1)C1C=CC=CC=1>[Pd].CN(C=O)C>[OH:13][C:14]1[CH:35]=[CH:34][C:17]([C:18]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31](=[NH:32])[NH2:33])[CH:27]=3)[CH:22]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(OCc4ccccc4)cc3)ccc2c1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(O)cc3)ccc2c1
Yield: 96.5 %

Procedure:
To 50 ml of anhydrous DMF, were added 4.0 g of 6-amidino-2-naphthyl 4-benzyloxybenzoate methanesulfonate and 0.4 g of 10% Pd-C. The mixture was subjected to catalytic hydrogenation. After absorption of a stoichiometric amount of hydrogen, the reaction mixture was removed of Pd-C by filtration. After adding ethyl-ether to the stirred filtrate, the precipitate was collected by filtration and recrystallized from a DMF-ethylether mixture to obtain 2.4 g of a white powder of 6-amidino-2-naphthyl 4-hydroxybenzoate methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]([NH2:33])[C@@H:25]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:33][C@@H:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:24][C@H:25]5[OH:34])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 120 °C
Yield: 21.9 %

Procedure:
A stirred mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (150 mg, 0.384 mmol) from Step 3 of Example 61, (1R,2R)-(−)-trans-1-amino-2-indanol (114 mg, 0.768 mmol), and DIEA (99 mg, 0.768 mmol) in anhydrous DMA (3 mL) in a sealed vial was heated in a Biotage microwave synthesizer at 120° C. for 30 min. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (40 mg, 22%) as a white solid. 1H NMR (499 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.36-8.44 (m, 2H), 7.45 (s, 1H), 7.12-7.24 (m, 6H), 5.51 (s, 2H), 5.47 (d, J=5.2 Hz, 1H), 5.01 (t, J=7.6 Hz, 1H), 4.34 (m, 1H), 3.15 (dd, J=7.1, 15.5 Hz, 1H), 2.73 (dd, J=7.6, 15.5 Hz, 1H). LCMS (ESI) m/z 476 and 478 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:57])[C:7]([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[S:47][CH:48]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18](=[O:43])[CH2:19][C:20]([CH2:41]Cl)=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-:58].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:57])[C:7]([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[S:47][CH:48]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18](=[O:43])[CH2:19][C:20]([CH2:41][I:58])=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS(=O)[C@H]23)cs1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)CS(=O)[C@H]23)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (2.68 g, 3.18 mmol) in acetone (40 mL) was added sodium iodide (0.715 g, 4.77 mmol). The mixture was stirred at room temperature over 3 h. LCMS indicated completion of the reaction. The solid was filtered off, the filtrate was concentrated under vacuum to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (2.97 g, 3.18 mmol, 100% yield) as a dark red solid. LCMS: (M+H)+: 934.0.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[O:9]1CCC[CH2:10]1.C=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:9][CH2:10][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1
Reactant: O=[N+]([O-])c1cc[nH]c1
Reactant: C1CCOC1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccn(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
840 mg of 3-nitro-1H-pyrole, 15 ml of tetrahydrofuran and 15 ml of formaldehyde 36% in water were mixed. 0.5 ml of tetrabutylammonium hydroxide 10% in water was added at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 1-hydroxymethyl-3-nitro-1H-pyrole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9](OOC(=O)C1C=CC=CC=1)(=[O:16])C1C=CC=CC=1.FC(F)(F)C(O)=O>CO>[Cl:8][C:5]1[N:6]=[C:7]([CH2:9][OH:16])[C:2]([F:1])=[CH:3][N:4]=1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: OCc1nc(Cl)ncc1F
Temperature: 65 °C
Yield: 24.7 %

Procedure:
To a solution of 5-fluoro-2-chloropyrimidine (500 μL, 5.24 mmol) in methanol (50 mL) is added benzoyl peroxide (1.5 g, 6.0 mmol) and trifluoroacetic acid (450 μL, 5.95 mmol). The resulting colorless clear solution is degassed by bubbling nitrogen through for 5 minutes and it is then heated at 65° C. for 18.5 hours. The solution is then cooled and concentrated. The resulting residue is diluted with chloroform (50 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and the layers are separated. The aqueous layer is re-extracted with chloroform (50 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated to dryness under reduced vacuum. The residue is purified by flash silica gel column chromatography, eluting with gradient of ethyl acetate/dichloromethane (0% to 30%) to give the title compound (210 mg, 25%). 1H-NMR (CDCl3): δ (ppm) 8.42 (s, 1H), 4.85 (s, 2H), 3.57 (br, 1H).