Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@@H:4]([NH2:8])[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O1CCCC1>[C:16]1([CH2:15][O:14][C:12]([NH:8][C@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CC[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 411.3 %

Procedure:
A mixture of D-allylglycine (2.8 g, 24.3 mmol), 1 M aqueous sodium hydroxide solution (25 ml), and tetrahydrofuran (10 ml, distilled from ketyl) was stirred at room temperature until homogeneous then cooled in an ice-bath. To the resulting rapidly stirred solution was added about 5 mL of 1.0M aqueous sodium hydroxide solution then dropwise about 1 g of benzyl chloroformate. This was repeated 4 additional times until a total of 28 mL of 1.0M aqueous sodium hydroxide solution and 4.80 g (95%, 27 mmol) of benzyl chloroformate were added. The reaction mixture was stirred for 15 minutes at 0° C. then 30 minutes at room temperature and then extracted with 50 mL of ether. The aqueous layer was acidified (pH=1.5) the by addition of 6N hydrochloric acid solution (about 10 mL) then extracted with three-50 mL portions of ether. The three ether extracts were combined, dried (magnesium sulfate) and concentrated in vacuo to afford 6.01 g of title product as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH:17]=O.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=CCCC(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
0.097 ml of 4-tert-butylbenzylamine (0.55 mmol) and 110 mg 4,4,4-trifluoro-butyraldehyde (0.83 mmol) were dissolved in 2 ml methanol and stirred 30 min at rt and then refluxed for 2.5 h. After cooling down to rt, 25 mg (0.66 mmol) of sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was refluxed for 2¾ h. After cooling down to rt, the reaction mixture was treated with 1 drop 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:2) to give 110 mg colorless viscous oil (73%). MS (ISP) 274.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Clc1nccc(NC2CCCC2)n1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(COc2ccc(-c3nccc(NC4CCCC4)n3)cc2)cc1
Yield: 93.1 %

Procedure:
(2-chloro-pyrimidin-4-yl)-cyclopentylamine (100 mg, 0.51 mmol) was reacted with (4-benzyloxyphenyl)boronic acid (173 mg, 0.76 mmol), tetrakis(triphenylphosphino)palladium (44 mg, 0.04 mmol), and aq. 2 N sodium carbonate (1.01 mmol, 0.51 mL) as described in general procedure Q, method Q2, to give 164 mg of [2-(4-benzyloxy-phenyl)-pyrimidin-4-yl]-cyclopentyl-amine. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 4:1 then 1:1. LCMS m/z: 346 (M+1)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:16])[NH:14][NH2:15])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([NH:14][N:15]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:16])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NN=C1CCOCC1

Procedure:
B-22a was prepared analogously to B-19a starting from tetrahydro-4H-pyran-4-one (923 μL, 9.99 mmol) and tert-butylcarbazate (1.32 g, 9.99 mmol). Yield: 2.15 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12](OC)OC)[C:5]([NH2:7])=[O:6].[C:17]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([O:39][CH3:40])=[C:27]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]3)[CH:28]=2)[CH2:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O>[C:17]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([O:39][CH3:40])=[C:27]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([N:1]4[C:2]5[C:10](=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=5)[CH:11]=[CH:12]4)[CH2:34][CH2:33]3)[CH:28]=2)[CH2:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18]
Reactant: COc1cc2c(cc1CCN1CCC(=O)CC1)N(C(C)=O)CCC2
Reactant: COC(Cc1ccc(C(N)=O)cc1N)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C(C)=O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
172 mg of 3-amino-4-(2,2-dimethoxyethyl)benzamide and 127 mg of 1-(2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-one were dissolved in 5 ml of acetic acid. Thereafter, 0.65 g of sodium sulfate was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 0.16 g of sodium triacetoxyborohydride was added to the reaction solution, and the obtained mixture was then stirred for 1 hour. Thereafter, 5 ml of water was added thereto, and the obtained mixture was then stirred at 100° C. for 2 hours. The reaction solution was cooled to a room temperature, and it was then concentrated under a reduced pressure. A saturated sodium bicarbonate aqueous solution was added to the residue, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) and NH silica gel column chromatography (ethyl acetate-methanol), so as to obtain 146 mg of the subject compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1(=[O:17])[NH:15][C:14](=[O:16])[CH:13]=[CH:12]1>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:13]1[CH2:12][C:11](=[O:17])[NH:15][C:14]1=[O:16]
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: O=C1C=CC(=O)N1
Solvent: CC(=O)O
Product: Cc1ccc2[nH]cc(C3CC(=O)NC3=O)c2c1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
5-Methyl indole (10 g, 76 mmol) and maleimide (7.4 g, 76 mmol) in 77 mL of glacial acetic acid was heated at 90° C. for 24 h. The reaction mixture was cooled to RT, and the acetic acid was evaporated under reduced pressure. The residue was suspended in diethyl ether and filtered to obtain solid product (7 g).
Reaction SMILES: [O:1]([C:8]1[C:13]2[C:14]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[O:1]([C:8]1[C:13]2[C:14]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2n[nH]c3ccnc(Oc4ccccc4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(Oc2nccc3[nH]nc(NCC4CCNCC4)c23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the compound prepared in Example 435 (0.262 g) in dichloromethane (3 mL) was treated with trifluoroacetic acid (0.6 mL) at room temperature. After stirring at room temperature for 4 hours, the mixture was shaken in dichloromethane and washed with aqueous saturated sodium bicarbonate, dried, and evaporated in vacuo to provide the title compound (0.065 g) with the following physical data.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][C:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)([OH:17])[CH2:13][CH2:12]1)(OCC1C=CC=CC=1)=O.C1CCCCC=1>C(O)C.[Pd]>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:14]2([OH:17])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[CH:19]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: OC1(c2cccnc2)CCNCC1
Yield: 93.5 %

Procedure:
To a solution of 1-carbobenzyloxy-4-(3-pyridyl)piperidin-4-ol (described in example 87d) (3.17 g, 10.2 mmol) in ethanol (100 mL) was added 10% palladium on carbon (2.0 g). This was followed by cyclohexene (50 mL) in large excess. The reaction was heated to reflux under nitrogen for 2 h. The suspension was cooled, filtered and the catalyst rinsed with fresh ethanol. The filtrate was reduced in vacuo to yield 1.70 g (94%) of an off-white solid which did not require any additional purification. 1H NMR (D6 -DMSO, 300 MHz) 8.68 (d, J=2.0 Hz, 1H), 8.42 (dd, J=1.5, 4.6 Hz, 1H), 7.83 (ddd, J=1.9, 2.1, 4.0 Hz, 1H), 7.35 (dd, J=4.8, 8.0 Hz, 1H), 2.97 (ddd, J=2.3, 12.2 Hz, 2H), 2.78 (m, 2H), 1.86 (ddd, J=4.5, 12.9 Hz, 2H), 1.56 (m, 2H), 2.50 (m, 1H) MS (CI, CH4) m/z 179 (M+1,100), 207 (M+29,16), 161 (39)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[C:20]([O:19][C:17]([NH:16][CH:9]1[C:8]2[C:13](=[C:14]([CH3:15])[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc2c(c1C)SCCC2NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(C(=O)O)ccc2c1SCCC2NC(=O)OC(C)(C)C
Yield: 69.6 %

Procedure:
By a similar re action operation as in Starting Material Synthetic Example 6 using 4-(tert-butoxycarbonylamino)-8-methylthiochromane-7-carboxylic acid methyl ester (2.70 g) and potassium carbonate (4.42 g), the objective 4-(tert-butoxycarbonylamino)-8-methylthiochromane-7-carboxylic acid (1.80 g) was obtained as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]#[N:16])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O.O>[NH:17]1[C:15]([C:13]2[CH:14]=[C:10]3[N:11]([C:2](=[O:1])[NH:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=43)[N:12]=2)=[N:16][N:19]=[N:18]1
Reactant: N#Cc1cc2c3ccccc3[nH]c(=O)n2n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2c2cc(-c3nnn[nH]3)nn12

Procedure:
1.6 g (0.0076 mole) of 5,6-dihydro-5-oxopyrazolo[1,5-c]-quinazoline-2-carbonitrile (prepared as described in Example 2), 546 mg of sodium azide (0.0084 mole or 1.1 equivalent) and 449 mg (1.1 equivalent) of ammonium chloride are suspended in dimethylformamide (30 ml) and the mixture is heated at 100° under N2 for 29 hours with stirring. The reaction mixture is cooled and stripped to dryness. The crude product is suspended in water (75 ml) and treated with concentrated HCl (1.5 ml) to pH 2. The mixture is stirred for ~15 minutes and filtered; the precipitates obtained are washed well with water and air-dried to yield: 2.17 g, quantitative crude yield, m.p. 287°-289°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]2([CH3:20])[NH:16][C:15](=O)[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10](=[O:19])(=[O:18])[CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]2([CH3:20])[NH:16][C:15](=[S:31])[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10](=[O:19])(=[O:18])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CCC2)C(=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CCC2)C(=S)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of (R)-7-(5-bromo-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]nonan-9-one (1.1 g, 2.92 mmol, Eq: 1.00) in dioxane (50 ml) was added Lawesson's reagent (1.18 g, 2.92 mmol, Eq: 1.00). The reaction mixture was stirred at 80° C. for 2 hours. More Lawesson's reagent (1.55 g, 3.84 mmol, Eq: 1.00) was added and stirring continued at 80° C. for 8 hours. The reaction mixture was poured into sat. NaHCO3 solution and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give light yellow oil. The residue was chromatographed on 20 g silica gel with 0-50% ethyl acetate in heptane to give (R)-7-(5-bromo-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]nonan-9-thione (1.05 g, 2.68 mmol, 91.5% yield) as a light yellow foam. MS (ISP): m/z=392.0 [M+H]+ and 394.3 [M+2+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)CCCCC1.CC(C)([O-])C.[Na+].[OH:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[N:24][C:23]=1Cl.Cl>C1(C)C=CC=CC=1.O>[Cl:28][C:26]1[N:25]=[N:24][C:23]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:22]([OH:21])[CH:27]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: OC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1cc(Cl)nnc1Oc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
A mixture of 25.0 g (266 mmol) of phenol and 30.0 g of cyclohexanol was charged, and 25.5 g (266 mmol) of sodium t-butoxide was added to the mixture over one hour, and then stirred at 70° C. for 30 minutes. The resultant solution was cooled to 40° C., and then 8.94 g (purity: 98%; 153.1 mmol) of 4-hydroxy-3,6-dichloropyridazine was added to the cooled solution. Then, the resultant mixture was heated from 40° C. to 140° C. to effect a reaction for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of pure water and 100 g of toluene were added to the cooled mixture, and stirred for 30 minutes. Then, 41.7 g (400 mmol) of a 35% aqueous hydrochloric acid solution was added dropwise to the resultant mixture, and an organic phase containing phenol added in an excess amount was separated. 287 g of toluene was added to the resultant aqueous phase, and stirred at room temperature for 30 minutes, and then an organic phase was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-phenoxy-4-pyridazinol was added dropwise to a 35% aqueous hydrochloric acid solution at 0° C. to deposit solids, followed by filtration. The resultant solids were washed with pure water and dried under a reduced pressure, and dissolved in an organic solvent and quantitatively determined by an HPLC area percentage method, which showed that 9.94 g of 6-chloro-3-phenoxy-4-pyridazinol (yield: 84.0%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N+:21]([O-:27])[CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16].[H-].[Na+].[Cl-].[Cl-].[Ca+2]>CC(N(C)C)=O>[CH2:15]([N:17]1[C:25]2[C:20](=[N+:21]([O-:27])[CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:32][CH:33]=2)[C:18]1=[O:35])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2c1c(C)cc[n+]2[O-]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2c1c(C)cc[n+]2[O-]

Procedure:
Tetrabutylammonium fluoride (0.566 mL) was added to a solution of 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (250 mg) in THF (5 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (170 mg) as a colorless solid. 3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (126 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (170 mg) and NaH (23.83 mg) in DMA (1 mL) at room temperature. The mixture was stirred at 150° C. under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50%-100% EtOAc in hexane) to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide as colorless crystals.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.2 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (0.24 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) yielded the title compound as an off-white solid (0.1 g, 20%). MS (ISP) 513.3 [(M+H)+]; mp 242° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:22]2[CH2:24][CH2:23]2)=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].Cl.[OH-].[K+]>C(Cl)Cl.CCO.O>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:6]([C:18]([NH:20][CH3:21])=[O:19])=[C:5]3[C:9]([CH:10]=[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[C:3]([CH:22]4[CH2:24][CH2:23]4)=[CH:4]3)=[N:8]2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (viii) (3.0 g, 8.8 mmol) in DCM (90 ml) was added DIPEA (5.4 mL, 30.8 mmol.) and the reaction mixture cooled to 0° C. Methanesulfonyl chloride (1.70 mL, 22.0 mmol) was added dropwise and the reaction stirred for 2 h. Water (100 mL) was then added to the reaction and pH of the aqueous layer adjusted to pH˜5 using aq. 2N HCl. The organics were separated and the aqueous layer was extracted into EtOAc (2×100 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. A portion of the solid obtained (2.6 g) was dissolved in EtOH (166 mL), solid potassium hydroxide (2.82 g, 50.3 mmol) was added and the reaction heated at 50° C. After 2 h, the reaction mixture was cooled to RT, diluted with water (100 mL) and the pH adjusted to 5 using aq. 2N HCl. The organics were extracted into EtOAc (3×100 mL), dried (Na2SO4) and concentrated in vacuo to give 4 g crude of the desired product. A portion of the crude material (1 g) was purified by column chromatography on silica gel eluting with EtOAc:n-hexane (gradient elution from 10% to 40% v/v) to give Compound (1) (330 mg). ESI-MS m/z calculated for [M+H]+: 419.1. found: 419.1. 1H NMR (400 MHz, d6-Acetone) δ 7.79 (brs, 1H), 7.66 (s, 1H), 7.61 (brs, 1H), 7.56-7.51 (m, 2H), 7.49 (s, 1H), 7.46-7.41 (m, 2H), 3.02 (s, 3H), 2.81 (d, J=4.7 Hz, 3H), 2.11-2.01 (m, 1H), 0.96-0.90 (m, 2H), 0.66-0.59 (m, 2H).
Reaction SMILES: [C:1]([C:3]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[S:16][C:15]([N+:17]([O-])=O)=[C:14]([C:20]([NH2:22])=[O:21])[CH:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].O.NN>[Fe](Cl)(Cl)Cl>[NH2:17][C:15]1[S:16][C:12]([C:9]2[CH:10]=[N:11][C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])=[CH:7][CH:8]=2)=[CH:13][C:14]=1[C:20]([NH2:22])=[O:21]
Reactant: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Product: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c(N)s2)cn1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
Nitro reduction, Method B: 5-[6-(1-Cyano-1-methylethyl)pyridin-3-yl]-2-nitrothiophene-3-carboxamide (95 mg, 0.29 mmol) and iron (III) chloride (2.33 mg, 0.014 mmol) were put in a vial. The vial was evacuated and backfilled with argon three times. Degassed methanol (4.1 mL) was added and the solution was heated to 65° C. for 10 minutes. Hydrazine hydrate (0.04 mL, 0.86 mmol) was then added and the reaction was stirred at 65° C. for 4 hours. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo. The residue was taken up in water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:12]2[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(-c2ccc(C(=O)O)o2)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(N)cccc1-c1ccc(C(=O)O)o1
Yield: 74.4 %

Procedure:
5-(2-methoxy-3-nitro-phenyl)furan-2-carboxylic acid 4e (4.23 g, 16.09 mmol) was dissolved in 125 mL of ethyl acetate followed by addition of 423 mg of palladium on carbon (10%) and ammonium formate (4.054 g, 64.35 mmol). The reaction mixture was heated to reflux for 3.5 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid 4f (2.79 g, yield 74.4%) as a light green solid.