Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([OH:12])[CH2:4][CH2:3]1.[Na].F[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[CH3:30])=[N:22][N:23]=2)[CH:20]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][N:24]1[C:21]1[N:19]2[CH:20]=[C:15]([O:12][C@@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:16]=[CH:17][C:18]2=[N:23][N:22]=1
Reactant: N[C@H]1CC[C@H](O)c2ccccc21
Reactant: C[C@H]1CCCCN1c1nnc2ccc(F)cn12
Agent: N
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.5 %

Procedure:
To a solution of Intermediate B (232 mg, 1.6 mmol) in dry DMF (10 mL) under N2 was added sodium (60% dispersion in oil, 320 mg, 8.0 mmol) and the resulting opaque brown solution was stirred at RT for 45 min (CARE: gas evolution). A solution of Intermediate 81c (342 mg, 1.46 mmol) in dry DMF (7 mL) was added and the dark brown solution stirred at 60° C. under N2 for 90 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (3 mL) and then applied to an SCX-2 cartridge (20 g), washing with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave a dark brown solid. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as a pale brown foam (262 mg, 45%). LCMS (Method 3): Rt 2.30 min, m/z 378 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:24][CH2:25][C:26]2[N:27]([CH3:31])[N:28]=[CH:29][N:30]=2)=[N:10][N:11]2[C:16]=1[CH:15]=[N:14][N:13]=[C:12]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[F:32]C1C=CC=C(F)C=1C(NN)=O>>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:32])[C:17]=1[C:12]1[N:11]2[N:10]=[C:9]([O:24][CH2:25][C:26]3[N:27]([CH3:31])[N:28]=[CH:29][N:30]=3)[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:16]2[CH:15]=[N:14][N:13]=1
Reactant: NNC(=O)c1c(F)cccc1F
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccc1F
Product: Cn1ncnc1COc1nn2c(-c3c(F)cccc3F)nncc2c1-c1ccccc1F

Procedure:
This compound was prepared using the procedure described in Example 21, steps b) to f), using 3-(2-fluorophenyl)-4-hydroxy-2-furanone (cf Example 2) instead of 3-tert-butyl-4-hydroxy-2-furanone and 2,6-difluorobenzoic hydrazide instead of 2,5-difluorobenzoic hydrazide in step e). Data for the title compound: mp=163° C.; 1H NMR (360 MHz, CDCl3) δ 3.78 (3H, s), 5.52 (2H, s), 7.16 (2H, m), 7.24-7.29 (2H, m), 7.38-7.44 (1H, m), 7.60-7.65 (2H, m), 7.85 (1H, s), 9.31 (1H, s); MS (ES+) m/e 438 [MH]+.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C[O-].[Na+].CO>CO.O>[C:1]([NH:9][CH:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:31][OH:32])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCC(NC(=O)c1ccccc1)c1ccc2ccccc2c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(CCCCC(NC(=O)c1ccccc1)c1ccc2ccccc2c1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
Ethyl 6-benzoylamino-6-(2-naphthyl)hexanoate (Reference Example 25) (0.8 g) and hydroxylamine hydrochloride (0.71 g) were suspended in methanol. To this suspension (4.2 ml) was added 4.9N sodium methoxide/methanol (4.9 ml) and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with water and the methanol was distilled off under reduced pressure. The residue was acidified with 3N HCl and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated and the crude residue was purified by silica gel column chromatography (ethyl acetate-hexane=2:1) to provide the title compound (0.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl.[C:20]([O:24][NH2:25])([CH3:23])([CH3:22])[CH3:21].N1CCCC1>C(O)CC>[C:20]([O:24]/[N:25]=[C:15](/[C:14]1[C:9]([C:7](=[O:8])[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:18])=[N:10][CH:11]=[CH:12][CH:13]=1)\[NH2:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: N#Cc1cccnc1C(=O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: C1CCNC1
Solvent: CCCO
Product: CC(C)(C)O/N=C(\N)c1cccnc1C(=O)c1cc(Cl)ccc1O
Yield: 86 %

Procedure:
A mixture of 2-(5-chloro-2-hydroxybenzoyl)-3-cyanopyridine (217 mg), O-t-butylhydroxylamine hydrochloride (158 mg), pyrrolidine (149 mg) and n-propanol (4.0 ml) was heated for 30 minutes under reflux. The reaction mixture was poured into a saturated aqueous saline solution, which was subjected to extraction with ethyl acetate. The extract solution was washed successively with an aqueous solution of potassium hydrogensulfate and a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give (Z)-2-(5-chloro-2-hydroxybenzoyl)-3-carbamoylpyridine O-t-butyloxime (251 mg) (Compound 152).
Reaction SMILES: C(OC1C=CC=CC=1)=CC.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.C1(O)C=CC=CC=1.[CH2:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1/[CH:38]=[CH:39]/[CH3:40])[CH:29]=[CH2:30]>CC(C)=O>[CH2:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=[CH:39][CH3:40])[CH:29]=[CH2:30]
Reactant: C=CCOc1ccccc1/C=C/C
Agent: CC=COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Solvent: C=CCBr
Product: C=CCOc1ccccc1C=CC

Procedure:
O-propenylphenol (67 g) was added to a stirred suspension of potassium carbonate (138 g) in dry acetone. Allyl bromide (67 g) was then added dropwise over about 20 minutes and the stirred mixture was heated under reflux for 4 hours. After this time, gas liquid chromatography indicated that the phenol had been converted to about 95% of a mixture of cis and trans 2-allyloxy-1-propenylbenzene. The mixture was filtered and the solvent removed under reduced pressure. The residue was vacuum distilled and yielded 58.9 g of almost pure 2-allyloxy-1-propenylbenzene which was identified spectroscopically. [b.p. 64-88° C. at 0.6 mbar].
Reaction SMILES: Cl[C:2]([N:4]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5]1)=[O:3].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16].O>C1C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH3:19])[C:2]([N:4]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5]1)=[O:3])[CH3:16]
Reactant: CCNCC
Reactant: CSc1cc(C(C)(C)C)nn1C(=O)Cl
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC)C(=O)n1nc(C(C)(C)C)cc1SC

Procedure:
To a stirred solution of 1-chlorocarbonyl-3-tert-butyl-5-(methylthio)pyrazole (23 g) in benzene (200 ml) at room temperature was added dropwise diethylamine (16 g, 23 ml). A white precipitate formed rapidly. The reaction mixture was refluxed (at 80°) for two hours, allowed to cool, and water (100 ml) added. The organic layer was washed once again with water, separated, dried and evaporated to give 1-(diethylcarbamoyl)-3-t-butyl-5-(methylthio)pyrazole. Recrystallisation from petrol gave the pure compound (16.5 g, 59% yield), of melting point 55°-6°.
Reaction SMILES: Cl[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:26]1([CH3:40])[CH:31]=[CH:30][C:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu].C1(C)C=CC=CC=1>[C:36]1([CH3:39])[CH:35]=[CH:34][C:33]([N:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:40])=[CH:27][CH:28]=2)[C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:38][CH:37]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: Clc1c2ccccc2c(-c2cccc3ccccc23)c2ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(N(c2ccc(C)cc2)c2c3ccccc3c(-c3cccc4ccccc34)c3ccccc23)cc1

Procedure:
In a flask were 9-α-naphthylanthracene and an equivalent amount of N-bromosuccinimide, and the reaction mixture was stirred overnight and then filtered. The filtrate was passed through a column filled with alumina. Chloroform was evaporated from the solution under a reduced pressure, and then the residue was recrystallized from petroleum ether, to give 10-chloro-9-α-naphthylanthracene. Then, in a three-necked flask were placed 10-chloro-9-α-naphthylanthracene, an equivalent amount of di-p-tolylamine, an equivalent amount of potassium carbonate, copper powder and nitrobenzene, and the mixture was stirred at 200° C. for 30 hours. After completion of the reaction, toluene was added to the mixture. The mixture was filtered to remove inorganics. Toluene and nitrobenzene were evaporated under a reduced pressure. The residue was purified by column chromatography on silica gel eluting with a 1:2 mixture of toluene and ligroin, to give 10-di-p-tolylamino-9-α-naphthylanthracene.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.ClC1C2[C:29](=[O:31])C3C(=CC=CC=3)C(=O)C=2C=CC=1>>[Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH:29]=[O:31])[C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Reactant: Clc1cccc2cc3ccccc3cc12
Product: O=Cc1c2ccccc2cc2c(Cl)cccc12

Procedure:
1-Chloroanthracene prepared from 1-chloroanthraquinone (Aldrich) by the method of H. O. House et al. (J. Org. Chem. 38. 1167 (1973)) was formylated by the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960). A mixture of a 1- and 4-chloro-9-anthracenecarbaldehydes was obtained which was partially purified by preparative HPLC using PhCH3 as the eluting solvent. The solid from the purified fraction was then recrystallized 2× from PhCH3 /CH3OH to give pure 4-chloro-9-anthracenecarbaldehyde mp 129°-131°, (C, H, Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=O)C>CO>[CH2:1]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH3:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(OCc1ccccc1)C(=O)O
Solvent: CO
Product: COC(=O)C(C)(C)OCc1ccccc1
Reaction time: 16 h

Procedure:
2-Benzyloxy-2-methylpropionic acid (4.4 g., 0.0023 mol) was dissolved in 50 ml. of methanol treated with acetyl chloride (1.61 ml., 1.78 g., 0.0023 mol), stirred for 16 hours, stripped to an oil, taken up in 75 ml. ethyl acetate, washed 1×50 ml. saturated NaHCO3 and 1×50 ml. brine, dried over MgSO4 and stripped to yield purified title product as a second oil, 4.22 g.; 1H-nmr 1.5 (s, 6H), 3.8 (s, 3H), 4.5 (s, 2H), 7.3-7.5 (m, 5H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[C:12]23[C@:28]([CH3:33])([CH2:29][CH2:30][C:31](=[O:32])[CH:11]12)[C@@H:27]1[C@H:15]([C@H:16]2[C@:24]([CH3:34])([CH2:25][CH2:26]1)[C@@H:19]([C@H:20]([CH3:23])[CH2:21][OH:22])[CH2:18][CH2:17]2)[CH2:14][CH2:13]3.[N-:35]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>CS(C)=O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C:11]1[C:31](=[O:32])[CH2:30][CH2:29][C@@:28]2([CH3:33])[C:12]=1[CH:13]=[CH:14][C@@H:15]1[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:34])[C@H:16]1[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:23])[CH2:21][OH:22]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a vigorously stirred solution of (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one benzoate (1.0 g, 2.22 mmole) in dimethyl sulfoxide (35 mL), heated to 60° C, there was added sodium azide (2.7 g) and the concentrated sulfuric acid (0.2 mL). The mixture was quickly brought to a temperature of 100° C. and held at that temperature for 1 hour. The cooled mixture was then poured onto cold water (250 mL). The resulting mixture was extracted with ether (300 mL) and the ether solution was washed with brine, dried over magnesium sulfate and filtrate and the filtrate was concentrated to give a yellow solid which was purified by chromatography to give (20S)-4-amino-21-hydroxy-20-methylpregna-4,6-dien-3-one benzoate (0.8 g, 80.1%) melting at 163°-167° C. with decomposition. IR 3470, 3366, 1718, 1682 (m), 1656, 1608 (m), 1586 (m), 1567 (m), 1274, 1268, 718 cm-1 ; MS (CI) 448 (100%, M+1), 326 (35%, M+1-PhCOOH); 1H NMR (CDCl3) δ0.82 (3H, s, C18 -Me), 1.07 (s, C19 -Me), 1.15 (d, C22 -Me), 3.71 (2H, v br, NH2), 4.07 (1H, dd, 1/2C21 -CH2), 4.35 (1H, dd, 1/2C21 -CH2), 5.98 (1H dd), 6.30 (1H dd), 7.35 (2H, t), 7.57 (1H, t), 8.04 (2H, dd).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:12]=[C:11]([C:13]([NH:15][NH2:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.[Cl:22][C:23]([Cl:27])([Cl:26])[CH:24]=O.C1C=CC=CC=1>C(OCC)(=O)C>[Cl:22][C:23]([Cl:27])([Cl:26])[CH:24]=[N:16][NH:15][C:13](=[O:14])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=2)[N:12]=1
Reactant: NNC(=O)c1cccc(Oc2cccc(C(F)(F)F)c2)n1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NN=CC(Cl)(Cl)Cl)c1cccc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.15 g, 0.000505 mol) was mixed with trichloroacetaldehyde (0.22 g, 0.000505×3.0 mol) and benzene (about 20 ml). The obtained mixture was refluxed for about 3 hours. The obtained reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[C:25]=1[CH3:35])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:33])[C:25]=1[CH3:35])(=[O:11])=[O:12]
Reactant: C1COCCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (100 mg, 0.19 mmol), DIPEA (45 mg, 1.9 eq.) and morpholine (82 mg, 5 eq.) in DMF (2 mL) was stirred at rt for 30 mins. To the mixture was added HATU (85 mg, 1.2 eq.) was added and stirring was continued for another 3 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a pale orange solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:43])[C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([CH:39]4[CH2:41][CH2:40]4)[CH2:31][CH2:30]3)=[O:28])=[CH:15][C:14]=2[Cl:42])=[N:8][C:7]=1[CH3:44])=[O:5])C.O.O.[OH-].[Li+]>O1CCOCC1>[Cl:42][C:14]1[CH:15]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[C:27]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH:39]3[CH2:40][CH2:41]3)[CH2:31][CH2:30]2)=[O:28])[C:17]([Cl:19])=[CH:18][C:13]=1[C:12]([NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:44])[N:8]=1)=[O:43]
Reactant: CCOC(=O)c1sc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)sc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a solution of 0.16 g (0.25 mmol) 2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylic acid ethyl ester (Example 45) in 2 mL dioxane were added 2 mL water and 0.013 g (0.31 mmol) lithiumhydroxide monohydrate. The resulting suspension was stirred at room temperature for 2 hours and then stirred at reflux temperature for 5.5 hours. Another 0.013 g (0.31 mmol) lithiumhydroxide monohydrate were added and heating was continued for another 8 hours. The oil bath was removed and the reaction mixture was stirred at room temperature overnight. After evaporation of the organic solvent the pH of the resulting solution was adjusted to 2 to 3 using 1M aqueous hydrochloric acid and the solution was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The product was purified by preparative HPLC (Phenomenex Gemini Column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 0.058 g (37%) of the title compound as a light brown solid. MS (ESI): m/z=624.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)=[O:3].[Cl:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[N:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([O:21][CH2:1][C:2]([C:4]2[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:18]=[N:19][CH:20]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: Oc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cncc(Cl)c1)c1cccc([N+](=O)[O-])c1
Yield: 68.3 %

Procedure:
2-Fluoro-5-nitroacetophenone (3.6 g, 20 mmol, described by Cooper, et. al. J. Med. Chem. 33:1246-1252 (1990)) and 5-chloro-3-pyridinol (3.2 g, 25 mmol) were dissolved in acetone (20 mL). After addition of solid K2CO3 (3.5 g, 26 mmol), the reaction mixture was heated to reflux for 4 hr. The reaction mixture was cooled and acetone was removed under reduced pressure. The residue was suspended in deionized water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic portions were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a brown oil which was partially purified by column chromatography (silica gel, 4:1 hexanes:ethyl acetate) to provide 4 g of 2-(5-chloro-3-pyridyloxy)-5-nitro-1-phenylethanone. This material was dissolved in ethanol (40 mL) and acetic acid (5.3 mL, 93 mmol) to which iron powder (300 mesh, 2.6 g, 46.5 mmol) was added. The reaction mixture was heated to reflux for two days. After removal of excess iron (with a magnetic stir-bar retriever), the reaction mixture was poured into 300 mL of deionized water and extracted with ethyl acetate (3×100 mL). The combined organic portions were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a brown oil which was purified by column chromatography (silica gel, 4:1 hexanes:ethyl acetate). The product 5′-amino-2′-(5-chloro-3-pyridyloxy)-1-phenylethanone was obtained as a yellow oil (1.03g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:51]1(C(OC(C)(C)C)=O)[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:51]6[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCCNCC4)c3)ccc2OC)c1
Reaction time: 3 h
Yield: 60.3 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (24 mg, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 uL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The residue was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid [36.6 mg (60%)]. LC-MS m/z 760 (M+H)+.