Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]([C@:4]1([CH3:30])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3].[OH:31][Li].O>CO>[CH3:27][C:26]([O:25][C:23]([N:5]1[C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8][C@@:4]1([CH3:30])[C:2]([OH:31])=[O:3])=[O:24])([CH3:29])[CH3:28]
Reactant: [Li]O
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(N)=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(=O)O
Yield: 93.4 %

Procedure:
A solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-2-methyl-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D7, 0.977 g, 2.29 mmol) and LiOH.H2O (192 mg, 4.59 mmol, dissolved in 7 ml H2O) in methanol (7 ml) was heated in a microwave synthesizer for 1 hour at 100° C. After evaporation of methanol, the aqueous phase was acidified to pH 3 with 1M HCl and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (white solid, 880 mg, 93%); Rf (cyclohexane:ethyl acetate=6:4): 0.24; Rt (HPLC): 6.07 min. MS: (ES/−) m/z: 410 [M−H]; C24H29NO5 requires 411; 1H NMR (500 MHz, DMSO-d6) δ(ppm): 12.92-12.23 (br. s, 1H); 7.48-7.40 (m, 4H); 7.40-7.33 (m, 2H); 7.31 (t, 1H); 6.92 (t, 2H); 5.08 and 5.06 (s, s, 2H); 4.85 and 4.76 (d, d, 1H); 2.48-2.34 (m, 1H); 2.19-2.05 (m, 1H); 1.81-1.72 (m, 1H); 1.64-1.57 (m, 1H); 1.46 and 1.43 (s, s, 3H); 1.32 and 1.03 (s, s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-:13])[C:5]2[CH:6]=[CH:7][C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22]>CN(C=O)C>[F:1][C:2]1[CH:3]=[N+:4]([O-:13])[C:5]2[CH:6]=[CH:7][C:8](=[O:12])[N:9]([CH2:22][CH:21]=[CH2:20])[C:10]=2[CH:11]=1
Reactant: O=c1ccc2c(cc(F)c[n+]2[O-])[nH]1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 7-fluoro-1,5-naphthyridin-2(1H)-one 5-oxide (0.995 g, 5.524 mmol) and potassium carbonate were stirred in anhydrous DMF (20 mL) under argon, and allyl iodide (1.5 mL, ca. 3 eq.) was added. The mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was partitioned between DCM (100 mL) and water (50 mL). The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give the crude product as a brown gum. This was purified by column chromatography on silica gel eluted with 0-10% methanol in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give 7-fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one 5-oxide (0.341 g) as a tan amorphous solid.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CO>[CH3:11][O:10][C:8](=[O:9])[C@@H:2]([NH:1][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCO)NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 105 %

Procedure:
To a cold (−15° C.) solution of Z-Glu-OMe (1.5 g) in THF (70 mL) was added N-methylmorpholine (0.616 mL) followed by isobutyl chloroformate (0.731 mL) dropwise. After 30 min stirring at −15° C., NaBH4 (576 mg) was added, followed MeOH dropwise. The reaction mixture was stirred at −10° C. for 15 min and quenched by the addition of 1M KHSO4 solution. The mixture was extracted with EA. The org. phase was washed with water, dried (Na2SO4) and evaporated off to give 1.5 g of the crude product as colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:35])[C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)[CH2:16][CH:15]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N[CH2:43][CH2:44][OH:45]>C(Cl)(Cl)Cl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:26]=[C:21]([C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[CH2:12][CH2:13][N:8]([CH2:43][CH2:44][OH:45])[CH2:9][CH2:10]3)[CH:15]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:16]2)=[O:35])[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2c2ccccc2)CC1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(CCO)CC2)C(c2ccccc2)C1

Procedure:
The title compound, MS: m/e=530.3 (M+H+), [α]58920=−8.02, [α]54620=−5.61, [α]43620=−20.05, [α]36520=−59.35 (c 0.1247, chloroform), was prepared in accordance with the general method of example 114 from (−)-4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester and 2-amino ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[CH:37]=[C:36]([CH2:38][CH3:39])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[C@@H:27]([F:40])[C@@H:26]1[OH:41]>C1(C)C=CC=CC=1.CN(C)C=O.[OH-].[Na+]>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([NH:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[CH:37]=[C:36]([CH2:38][CH3:39])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[C@@H:27]([F:40])[C@@H:26]1[OH:41])=[O:8]
Reactant: COc1cc(O[C@@H](C)C(=O)O)c(Cl)cc1Cl
Reactant: CCc1cn([C@@H]2O[C@H](CN)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Yield: 70.7 %

Procedure:
24.2 g (0.091 mol) of (S)-2-(2,4-dichloro-5-methoxy-phenoxy)-propionic acid were suspended in a mixture of 150 ml of toluene and 0.5 ml of dimethylformamide and the suspension was stirred under nitrogen. 15.0 ml (0.17 mol) of oxalyl chloride were added, with vigorous evolution of gas occurring. The mixture was stirred for 1 hour to give a homogeneous solution. The solvents were removed by evaporation, the residue was taken up in 100 ml of diethyl ether and the solution was added to a solution of 24.6 g (0.090 mol) of 1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil in 290 ml of 0.31M sodium hydroxide solution. The heterogeneous mixture was shaken vigorously for 10 minutes to give a white precipitate which was filtered off and washed firstly with water and then with diethyl ether. The crude product was recrystallized from hot methanol to give 33.1 g (69.7%) of 1-[5-[2(S)-(2,4-dichloro-5-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a white crystalline solid, m.p. 195°-196° C.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:15][S:14][N:13]=1)[CH3:4]>>[I-:2].[CH2:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]2[CH:18]=[N+:19]([CH3:1])[CH:20]=[CH:21][CH:22]=2)=[N:15][S:14][N:13]=1)[CH3:4]
Reactant: CCOCCOCCOc1nsnc1-c1cccnc1
Reactant: CI
Product: CCOCCOCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 9 mmol) and 3-(3-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([O:15][C:16](=[O:23])[CH2:17][C:18]([CH2:20][O:21][CH3:22])=O)[CH3:14].[NH3:24]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:23])=[C:18]([CH2:20][O:21][CH3:22])[NH:24][C:18]=1[CH2:20][O:21][CH3:22])=[O:23])[CH3:14]
Reactant: N
Reactant: CCOC(=O)CC(=O)COC
Reactant: O=Cc1ccccc1C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C1=C(COC)NC(COC)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Yield: 60 %

Procedure:
8.7 g of 2-trifluoromethylbenzaldehyde, 16 g of γ-methoxyacetoacetic acid ethyl ester and 5 ml of aqueous concentrated ammonia in 30 ml of ethanol are heated to the boil overnight, the mixture is cooled and 2,6-dimethoxymethyl-4-(2'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained in the form of light brown crystals of melting point 133°-134°C, in a yield of 60% of theory.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.Cl.[NH2:17][OH:18].O>C(O)C>[OH:18][N:17]=[CH:1][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)c1cc(C=O)cc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(C=NO)cc([N+](=O)[O-])c1
Yield: 49.1 %

Procedure:
A mixture of methyl 3-formyl-5-nitrobenzoate (0.418 g, 2.0 mmol), hydroxylamine hydrochloride (0.209 g, 3.0 mmol) in ethanol (5.0 mL) was heated at reflux for 2 h. On cooling, the mixture was poured into water and the precipitate collected by filtration. The cake was recrystallized from ethyl acetate-hexane and dried to give 0.22 g (49%) of methyl 3-[(N-hydroxylimino)methyl]-5-nitrobenzoate as an off-white solid, mp 144°-145° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:15]=[C:14]([C:25]([OH:27])=O)[C:13]=2[CH3:28])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:15]=[C:14]([C:25]([Cl:3])=[O:27])[C:13]=2[CH3:28])=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Thionyl chloride (1.3 ml, 22.0 mmol) was added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2.09 g, 5.5 mmol) in toluene (50 ml) maintained at room temperature. The mixture was refluxed at 110° C. for 2 hours and then cooled to room temperature. The resulting solution was evaporated and dried under a vacuum to produce crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride, which are not further purified. 27% aqueous ammonia (2 ml) was added to the solution of crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride in methylene chloride (10 ml) at 0° C. After stirring 3 hours at room temperature, the resulting solution was quenched with saturated ammonium chloride which was extracted twice with 50 ml portions of ethyl acetate. After concentrating the extract by evaporation, the crude residue was purified using a silica gel column (hexane/ethyl acetate=1/1), to obtain the title compound (2.07 g, 99%) as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[C:5]([CH2:13]C#N)=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:7]=1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.[CH3:26][N:27](C)C=O>O>[C:26]([C:2]1[CH:3]=[C:4]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[C:5]([CH2:13][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[C:6]([C:8]([CH3:11])([CH3:12])[C:9]#[N:10])[CH:7]=1)#[N:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C#N)c1cc(Br)cc(C(C)(C)C#N)c1CC#N
Reactant: c1nc[nH]n1
Solvent: O
Product: CC(C)(C#N)c1cc(C#N)cc(C(C)(C)C#N)c1Cn1cncn1
Reaction time: 24 h

Procedure:
A mixture of 2,2'-[5-bromocyanomethyl-1,3-phenylene]di(2-methylpropiononitrile) (0.33 g), 1,2,4-triazole (0.34 g) and dimethylformamide (2 ml) was stirred at 50° for 24 h. The mixture was treated with water (20 ml), and extracted with ethyl acetate, and the extract was dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography, using methanol (3% by volume) in dichloromethane as eluant, to give 2,2'-[5-cyano(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-methylpropiono-nitrile), characterised as the hydrochloride salt, mp 148°-151°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O.CCOCC>[CH2:1]([N:8]([C:9]1([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(C2(NCc3ccccc3)CC2)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CI
Product: CN(Cc1ccccc1)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.2 %

Procedure:
To a solution of benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 124, 100.0 mg, 0.33 mmol) in 5 mL of acetone was added K2CO3 (91 mg, 0.66 mmol) and iodomethane (2.28 g, 16.1 mmols). The resulting mixture was stirred at 25° C. for 20 hours, diluted with Et2O, and washed with H2O and saturated aqueous NaCl. The solution was dried (MgSO4) and concentrated under reduced pressure to give 90 mg (86%) of the title compound.
Reaction SMILES: N1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=N1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[CH3:14][C:13]1[O:15][C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc(-c2nnn[nH]2)nc1
Product: Cc1nnc(-c2ccc(Br)cn2)o1

Procedure:
In 10 ml of acetic anhydride was dissolved 1 g of 2-(5-tetrazolyl)-5-bromopyridine, followed by refluxing for 2 hours. After completion of the reaction, the same post-treatment as in Preparation Example 13 was conducted to give the title compound. 0.6 g.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[O:12][C:9]([CH2:10]O)=[CH:8][CH:7]=1)[CH3:4].S(Cl)([Cl:15])=O.CS(O)(=O)=O>C(#N)C>[ClH:15].[CH3:2][N:3]([CH2:5][C:6]1[O:12][C:9]([CH2:10][Cl:1])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: O=S(Cl)Cl
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: CN(C)Cc1ccc(CCl)o1
Temperature: 10 °C

Procedure:
Combine 5-[(dimethylamino)methyl]-furfuryl alcohol hydrochloride (1.72 kg, 8.97 mol) and acetonitrile (4.3 L). Cool to about 10° C. Add thionyl chloride (1.02 kg, 8.54 mol) dropwise, while maintaining the temperature of the reaction at below about 40° C. After the addition of thionyl chloride is complete, add methanesulfonic acid (1.3 kg, 13.5 mol). Distill to remove about 1.8 L of distillate to give the title compound as a solution.
Reaction SMILES: C([O:6][CH2:7][CH3:8])(=O)C(C)O.[CH:9]([OH:12])(C)[CH3:10].F[P-](F)(F)(F)(F)F.[N:20]1([O:29][P+:30](N2CCCC2)(N2CCCC2)N2CCCC2)[C:24]2C=[CH:26][CH:27]=[CH:28][C:23]=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.CCOC(C)=O>[NH:20]1[CH:26]=[CH:27][CH2:28][CH2:23][CH2:24]1.[PH:30](=[O:29])([O:6][CH2:7][CH3:8])[O:12][CH2:9][CH3:10]
Reactant: CCOC(=O)C(C)O
Reactant: CC(C)O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C1=CNCCC1
Product: CCO[PH](=O)OCC
Reaction time: 14 h
Yield: 46 %

Procedure:
To a solution of compound 3 (100 mg, 0.120 mmol) in dry dimethylformamide (1 mL) was added Isopropanol (20.0 μL, 0.240 mmol), Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (135 mg, 0.240 mmol), followed by addition of Diisopropylethylamine (83.0 μL, 0.480 mmol). The mixture was stirred for 14 hours, the resulting residue was diluted in EtOAc, washed with brine (3×) and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2/Isopropanol=100/4) to provide 12.2 mg of compound 11: 1H NMR (CDCl3) δ 7.71 (2H, d, J=8.9 Hz), 7.15 (2H, m), 7.0 (2H, m), 6.89 (2H, m), 5.65 (1H, m), 5.03-4.86 (4H, m), 4.34-4.19 (3H, m), 3.89 (3H, s), 3.88 (1H, m), 3.82 (2H, m), 3.65 (4H, m), 3.2-2.9 (11H, m), 2.80 (3H, m) 1.65 (2H, m), 1.86 (1H, m), 1.6 (3H, m), 1.30 (3H, m), 0.92 (6H, m).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9](I)[CH:8]=[N:7]1)[CH3:2].C([Mg]Cl)(C)C.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)[CH:8]=[N:7]1)[CH3:2]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCOCCn1cc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 85.1 %

Procedure:
A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, and N2 inlet was charged with 1-(ethoxyethyl)-4-iodo-1H-pyrazole (20, 700.0 g, 2.63 mol) and THF (5.5 L). The resulting solution was cooled to between −12° C.-−15° C. A solution of 2 M i-PrMgCl in THF (1513 mL, 3.03 mol, 1.15 equiv) was added via an addition funnel over 30 min while maintaining the reaction temperature at <−5° C. and the tan suspension was stirred at <−5° C. for 0.75 hr. The resulting reaction mixture was further cooled to −15° C. and 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (16, 734 g, 805 mL, 3.95 mol, 1.5 equiv) was added rapidly via an addition funnel with the reaction temperature increasing to ˜−5°. [Note: previous work with the analogous TMS-protected pyrazole has shown that slow addition of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane results in a lower yield.] A nearly clear light brown solution was developed followed by reformation of grayish light suspension. The cooling bath was then removed and the reaction mixture was allowed to warm to 16° C. over 0.75 hr. The mixture was poured into 50 L reparatory funnel containing a stirred saturated aqueous NH4Cl solution (4 L). The mixture was diluted with toluene (8 L), heptane (8 L) and H2O (2 L). The aqueous phase was removed and the organic phase was washed with warm (30° C.) H2O (4×3 L) and saturated brine (2×3 L). The organic phase was dried over Na2SO4, and the solvents were removed under reduced pressure. The residual toluene was further removed by co-evaporation with heptane (2 L). The residual oil was transferred to a 4 L beaker using a minimum amount of heptane (100 mL) and scratched to induce crystallization. The solid was filtered, washed with heptane (200 mL) and dried overnight in a vacuum oven at 30-40° C. The filtrate was concentrated under reduced pressure and the residue was allowed to stand overnight. The resulting solid was filtered, washed with heptane (100 mL) and dried overnight in a vacuum oven at 30-40° C. The two crops were combined to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 596 g, 700 g theoretical, 85.1%) as a white to off-white solid. For 19: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.09 (s, 1H), 8.58 (s, 1H), 7.62 (s, 1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz); C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](Cl)=[O:6].[NH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:25])=[N:21][CH:22]=2)[CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[CH3:2][N:3]([CH3:8])[CH2:4][C:5]([NH:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])=[O:25])=[N:21][CH:22]=2)[CH:13]=[CH:12][N:11]=1)=[O:6]
Reactant: CN(C)CC(=O)Cl
Reactant: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(N)c2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A suspension of 2-(dimethylamino)acetyl chloride hydrochloride (0.101 g, 0.638 mmol) in THF (5 mL) was added to a 0° C. solution of Example C1 (0.15 g, 0.455 mmol) and DIEA (0.239 mL, 1.366 mmol) in THF (5 mL), allowed to warm to RT and stirred overnight. Additional 2-(dimethylamino)acetyl chloride hydrochloride (0.200 g), DIEA (0.239 mL, 1.366 mmol) and DCM (5 mL) were added and the mixture stirred at RT overnight. The mixture was treated with 10% K2CO3, extracted with DCM (4×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via preparative TLC (MeOH/DCM/TEA) to afford N-((5-((2-(2-(dimethylamino)acetamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (86 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.44 (s, 1H), 9.95 (s, 1H), 8.26 (d, J=2.9 Hz, 1H), 8.20 (d, J=5.8 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 6.73 (dd, J=5.8, 2.4 Hz, 1H), 3.07 (s, 2H), 2.25 (s, 6H), 1.21 (s, 9H); MS (ESI) m/z: 415.2 (M+H+).
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]1([N:11]([CH3:25])[S:12]([CH2:15][C:16]2(C(O)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])[CH2:10][CH2:9]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:33])=CC=1.CC[N:45]([CH2:48]C)CC>C(Cl)Cl>[CH:8]1([N:11]([CH3:25])[S:12]([CH2:15][C:16]2([N:45]=[C:48]=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)(=[O:13])=[O:14])[CH2:9][CH2:10]1
Reactant: CCN(CC)CC
Reactant: CN(C1CC1)S(=O)(=O)CC1(C(=O)O)CCCCC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C1CC1)S(=O)(=O)CC1(N=C=O)CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a RT solution of toluene (15 mL) containing acid 1261-F (3.96 mmol, 1.0 g) was added DPPA (0.85 mL, 3.96 mmol) followed by Et3N (0.56 mL, 3.96 mmol). The reaction was stirred at RT for 10 min then refluxed for 2 hours. Reaction was cooled down to RT and diluted with DCM (50 mL). Washed with NaHCO3, brine and organic layer was dried over MgSO4. The volatile were removed and the residue was diluted with DCM (15 mL) to give 1261-G as a 0.26M solution.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:31]=[CH:30][C:11]2[C:12]([OH:29])=[CH:13][C:14]3[CH2:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=[CH:20][C:21]=4[C:22]=3[C:10]=2[CH:9]=1.[C:32](=[O:34])=[O:33].Cl>CCCCCC.C(OCC)C.C(OCC)(=O)C>[OH:29][C:12]1[C:11]2[CH:30]=[CH:31][C:8]([O:7][CH3:6])=[CH:9][C:10]=2[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:17][C:16]=3[CH:15]([C:32]([OH:34])=[O:33])[C:14]=2[CH:13]=1
Reactant: COc1ccc2c(O)cc3c(c2c1)-c1ccc(-c2ccccc2)cc1C3
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc2c(O)cc3c(c2c1)-c1ccc(-c2ccccc2)cc1C3C(=O)O
Temperature: 25 °C

Procedure:
A solution of n-butyl lithium (n-BuLi) (2.5M, 47.2 mL) in hexane was added into 500 mL two neck flask which contained 10.0 g of the product of Step 4 in diethyl ether (200 mL). The mixture was refluxed for five hours, cooled to room temperature, and poured rapidly onto crushed dry-ice. When the temperature of reaction mixture reached room temperature, ethyl acetate (150 mL) was added and the resulting mixture was acidified by concentrated hydrochloric acid. The organic layer was recovered and dried over sodium sulfate. After removing the solvent, 9.4 g of 5-hydroxy-2-methoxy-9-phenyl-7H-benzo[c]fluorene-7-carboxylic acid was obtained as a white solid. This step was repeated to produce additional product for the next step.