Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:11][CH:2]1[CH2:3][C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].[H-].[Na+]>C1(C)C=CC=CC=1>[OH:1][CH2:11]/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CC(C)COC(=O)CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)/C=C/CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To an ice cold solution of isobutyl 3,4-epoxybutanoate (300 g, 1.9 mol) in toluene (2.5 l), sodium hydride (55% suspension in oil, 3 g, 0.07 mol) was added portionwise. The solution was stirred at 0°-5° C. for 1 hour, then 55% sodium hydride (3 g, 0.07 mol) was added again. After stirring at room temperature for 1 hour the solution was washed with brine (0.4 1) containing 10% hydrochloric acid (60 ml), then twice with brine (300 ml each). The organic solution was dried over anhydrous sodium sulfate and evaporated to dryness. Distillation of the residue afforded 175 g (58.3%) of the title compound as a colourless oil, b.p. 89°-90° C. (0.5 mmHg). NMR (CDCl3): deltaH =7.05 (dt, J=15 and 4 Hz, 1H, CH=CH--CO), 6.12 (dt, J=15 and 2 Hz, 1H, CH=CH--CO), 4.40 (c.a, 2H, CH2OH). MS (E.I., 70 eV, 1.5 mA) m/z=127 (M--CH2OH)+, 85 (M--C3H5O2)+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](Cl)=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2].[F-:21].[K+]>CS(C)=O>[N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:21])=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2]
Reactant: CCOC(=O)COc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 89.9 %

Procedure:
A suspension of ethyl 2,4-dinitro-5-chlorophenoxyacetate (2.0 g) and potassium fluoride (0.57 g) in dimethylsulfoxide (10 g) was stirred at a temperature of 90° to 101° C. After cooling, the reaction mixture was diluted with ice water (200 ml) and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution in order, dried over anhydrous magnesium sulfate and concentrated to give ethyl 2,4-dinitro-5-fluorophenoxyacetate (1.7 g; yield, 89.9%). M.P., 59.0°-59.5° C. (recrystallized from methanol).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[N:23]=[CH:24][N:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([CH3:37])[CH:29]=2)[CH:26]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[N:23]=[CH:24][N:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([CH3:37])[CH:29]=2)[CH:26]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cc1cc(Cn2cnc(CC(N)C(=O)O)c2)ccc1[N+](=O)[O-]
Product: Cc1cc(Cn2cnc(CC(Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)c2)ccc1[N+](=O)[O-]

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-[1-(3-methyl-4-nitro-benzyl)-1H-imidazol-4-yl]-propionic acid to provide the title compound in good yield. LCMS m/z 510 (M+1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[CH:16].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].C(O)(=O)C>ClCCCl>[CH2:25]([N:27]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]#[CH:16])=[CH:18][CH:19]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: C#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C#Cc1ccc(CN(CC)CC)cc1
Reaction time: 18 h
Yield: 63.3 %

Procedure:
Sodium triacetoxyborohydride (1.22 g, 5.76 mmol) was added to a solution of 4-ethynylbenzaldehyde (0.50 g, 3.84 mmol) in 1,2-dichloroethane (18.75 mL) at rt. Diethylamine (0.61 mL, 5.76 mmol) and acetic acid (0.12 mL, 1.92 mmol) were then added under N2 atmosphere to the mixture at rt and the reaction was stirred for 18 h. The reaction was quenched with sat. sodium bicarbonate solution (10 mL) and the mixture was stirred for 15 min. Dichloromethane (18.75 mL) was then added and the layers were separated. The aqueous layer was extracted using dichloromethane (10 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was then removed under vacuum at 40° C./200 mbar. The resultant oily residue was purified by silica gel column chromatography using dichloromethane: methanol (100 to 90:10) gradient to give the title compound as pale yellow thick oil (0.455 g, 63.2%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.0 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 3.78 (s, 2H), 3.08 (s, 1H), 2.72-2.66 (m, 4H), 1.13 (t, J=7.2 Hz, 6H); MS ESI 187.9 [M+H]+, calcd for [C13H17N+H]+ 187.14.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(O)c2ccc3c(c2)OCCO3)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc3c(c2)OCCO3)cc1

Procedure:
To a stirred solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-methoxy-phenyl)-methanol (2.03 g crude, 7.5 mmol) in CH2Cl2 (20 mL) at room temperature was added activated MnO2 powder (3.4 g, 39 mmol) and kept adding 2˜3 equivalents of MnO2 every 3˜5 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-methoxy-phenyl)-methanone as an brown oil (2.09 g, 103% crude yield): 1H NMR (CDCl3) δ 3.88 (s, 3H, OCH3), 4.30-4.34 (m, 4H, CH2CH2), 6.91-6.97 (m, 3H, Ar), 7.26-7.36 (m, 2H, Ar), 7.78-7.81 (m, 2H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:20][CH:19]=2)[CH:8]=[CH:9][C:10]=1[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])([CH3:3])[CH3:2].C(OC(=O)C)C.[ClH:40]>C(OCC)(=O)C>[ClH:40].[ClH:40].[NH2:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[CH:19][CH:20]=1
Reactant: CC(C)Nc1cc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Nc1cc(-c2ccc(CCN)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [2-[3′-(isopropylamino)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (411 mg) in ethyl acetate (2 ml) was added hydrogen chloride ethyl acetate solution (4N, 2 ml) and stirred at room temperature overnight. The reaction mixture was evaporated and the residue was pulverized with diisopropyl ether. The resulting solid was collected by filtration and dried to give 4′-(2-aminoethyl)-3-(isopropylamino)-N-(methylsulfonyl)-4-biphenylcarboxamide dihydrochloride (281 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][S:25](=[O:32])(=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:23]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([C:18]3[CH:23]=[C:22]([O:24][S:25](=[O:31])(=[O:32])[N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[CH:21]=[N:20][CH:19]=3)[NH:8]2)=[CH:12][CH:13]=1
Reactant: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3n2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Reaction time: 1 h

Procedure:
6-Chloro-2-(5-diethylsulfamoyloxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester is redissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) is added. After 1 h, saturated aqueous sodium bicarbonate is added and following extraction with dichloromethane, the organic layer is dried over sodium sulfate and concentrated to give diethyl-sulfamic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester, which is used in the next step without further purification. MS (ESI) m/z 378.1 (M+H)+
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25](=[O:32])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[BH4-].[Na+]>CO>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([OH:32])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)CC2CCCC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)CC2CCCC2)n1
Yield: 20.3 %

Procedure:
To a solution of 1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2-H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl-2-cyclopentylethanone (123 mg, 0.207 mmol) in methanol (15 mL) was added sodium borohydride (7.8 mg, 0.207 mmol) at room temperature. After 1 hour the solvent was removed under reduced pressure, the residue dissolved in 20 mL of ethyl acetate (20 mL) and washed with water (10 mL). The combined organics were dried with anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in dichloromethane and purified by flash chromatography on a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 0-60% ethyl acetate in heptane) to yield the title compound as a clear oil (0.025 gm). 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H) 7.62 (s, 2H) 7.56(d, J=7.8 Hz, 1H) 7.34 (s, 1H) 4.96-4.92 (m, 1H) 4.85 (s, 2H) 4.81 (q, J=15.3 Hz, J=16.1 Hz, 2H) 4.2 (s, 3H) 1.9-1.4 (m, 11H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+].CO>[Fe].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cc(Br)ccc1F
Yield: 93.8 %

Procedure:
3.0 g of 5-bromo-2-fluoronitrobenzene, 3.8 g iron powder and 7.3 g ammonium chloride were heated at 80° C. for 2 hours in a solution mixture of 30 mL methanol and 30 mL water. The reaction mixture was filtered through Celite, the methanol was evaporated, and the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate and filtered through a column with a small amount of silica gel. The solvent was evaporated to give 2.43 g of the title compound (yellow oil).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[Br:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].C(N(CC)CC)C.C(O)C>C1(C)C=CC=CC=1.C(Cl)Cl.O>[Br:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:9]=1[C:10]([O:5][CH2:1][CH3:2])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
281 mg (2.21 mmol) of oxalyl chloride are added to a solution of 220 mg (1.01 mmol) of 2-bromo-4-fluorobenzoic acid in 5 ml of absolute toluene under argon, and the mixture is stirred at RT for 4 hours. The solvent is removed in vacuo, and the residue is taken up three times in DCM and the solvent is removed each time in vacuo. A yellow oil is obtained and is dissolved in a little DCM. 213 mg (2.10 mmol) of triethylamine and 2 ml of ethanol are added to the solution, and the mixture is stirred at RT for three hours. The reaction mixture is diluted with twice the volume of distilled water and extracted with DCM. The solvent of the organic phase is removed in vacuo, and the residue is chromatographed on silica gel (eluent: DCM/methanol 20:1). 100 mg (39% of theory) of the product are obtained.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:24]([O:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:14]2[O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9](=[O:46])[N:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=[O:49]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.O.ClCCl.[Hg](OC(C)=O)OC(C)=O>[CH2:1]([C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:24]([O:25][C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:14]2[O:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9](=[O:46])[N:8]=1)[C:2](=[O:49])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Reactant: CC(C)=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 14a (0.77 g, 1.2 mmol) in 50 mL acetone is treated with a 0.1 M solution of Hg(OAc)2 (15 mL) in aqueous acetic-H2O (1:1) and the mixture stirred at room temperature for 18 hr. The reaction is further diluted with dichloromethane (100 mL), washed with cold saturated NaHCO3 solution, dried over magnesium sulfate and evaporated in vacuo. The resulting residue is flash-chromatographed using chloroform/acetone 19:1 to afford a yellowish solid. This solid is triturated with cold methanol to afford 15a, 0.47 g, 59%. 1H-NMR (DMSO-d6): 12.5 (s, 1H, enol); 8.0-7.4 (m, 16H, H-6 plus aromatic 6.15 (d, 1H, H-1′, J=2 Hz); 5.90 (m, 3H, H-5,2′,3′; 5.39 (s, 1H, vinylic, Jvinyl, allyl=<1 Hz)); 2.30, 1.47, 1.24 and 0.86 (4 m, 9H, n-butyl). Anal. Calcd for C36H34N2O8: C, 67.70; H, 5.37; N, 4.39. Found: C, 67.51; H, 5.28; N, 4.28.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[N:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[N:30]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1cccc(Cl)n1
Product: C[C@@]1(c2cc(NC(=O)c3cccc(Cl)n3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R1=Me) and 6-chloro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3=[C:29]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH:30]=[CH:31][N:17]3[N:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C.Cl>O1CCOCC1>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:30]=[CH:31][N:17]3[C:18]=2[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:20][C:15]([C:13]2[CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=[N:11][CH:12]=2)=[N:16]3)=[CH:37][CH:36]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccc(F)cc4)ccn3n2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccc(F)cc4)ccn3n2)c1
Temperature: 50 °C
Yield: 71.4 %

Procedure:
To a stirred solution of N-(tert-butyl)-5-(5-(4-fluorophenyl)-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (30.0 mg, 0.0560 mmol) in dioxane (5 mL) was added 2 mL of 5 N HCl in dioxane. The contents were heated at 50° C. for 12 h. The solvents were removed under reduced pressure to give a white solid. The solid was purified by preparative HPLC (Condition B-61 as described in general methods) to give 5-(5-(4-fluorophenyl)-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (19.0 mg, 44.0%) as an off-white solid. LCMS Condition B-23: retention time 1.91 min, [M+1]=476.2. HPLC Condition B-1: retention time 8.03 min, Purity=98.30%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.93 (d, J=4.8 Hz, 2H), 6.84 (d, J=2.8 Hz, 1H), 7.25-7.52 (m, 5H), 7.52-7.62 (m, 4H) 7.79 (t, J=1.6 Hz, 1H), 7.88 (d, J=2.8 Hz, 1H), 8.35 (s, 1H), 8.92 (s, 1H), 9.05 (s, 1H), 9.65 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OB(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(COC)OC.O.C1C=CC([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)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COc1ccc(OB(O)O)cc1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2oc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1c(O)c2cc(-c3ccc(OC)cc3)ccc2oc1=O
Yield: 68.6 %

Procedure:
To a mixture of 6-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (150 mg, 0.5 mmol; example 2-b) in dimethoxyethane (DME) was added 4-methoxyphenylboroic acid (92 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) and 2N aq Na2CO3 (0.62 mL). The resulting mixture was purged with N2 for 1 min and heated to reflux for 2 h. Reaction mixture was diluted with water (50 mL) and acidified by 1 N aq HCl to pH=3-4. Precipitate was collected and dissolved in EtOAc. Insoluble was filtered off and the filtrate was dried over MgSO4, filtered, and concentrated. The crude product was triturated with MeOH (10 mL) and filtered. Resulting solid was dried in vacuo to give the title compound (112 mg). MS ESI(+) m/e: 327 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]2[NH:28][C:14]3[C:15]([O:26][CH3:27])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])=[CH:18][C:13]=3[N:12]=2)[N:7]([CH3:29])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C[O-].[K+:37]>CO>[C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]2[N-:28][C:14]3[C:15]([O:26][CH3:27])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])=[CH:18][C:13]=3[N:12]=2)[N:7]([CH3:29])[N:6]=1)([CH3:4])([CH3:2])[CH3:3].[K+:37]
Reactant: COc1nc(-c2ccccc2Cl)cc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[nH]c12
Agent: C[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(-c2ccccc2Cl)cc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[n-]c12

Procedure:
A 50 mL, single neck round bottom flask was charged with 2-(3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl)-6-(2-chlorophenyl)-4-methoxy-3H-imidazo[4,5-c]pyridine (1.99 g, 4.27 mmol, prepared as described in Example 35 above), tetrahydrofuran (4.00 mL), and methanol (4.00 mL) to yield a solution. The solution was treated with potassium methoxide (˜25% w/w in methanol, 1.20 mL, 4.28 mmol). The resulting solution was then concentrated to yield potassium 2-(3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl)-6-(2-chlorophenyl)-4-methoxyimidazo[4,5-c]pyridin-3-ide as a yellow foam. 1H NMR (DMSO-d6) δ: 7.71 (dd, J=7.6, 1.7 Hz, 1H), 7.50 (dd, J=7.9, 1.3 Hz, 1H), 7.39 (td, J=7.5, 1.2 Hz, 1H), 7.35 (s, 1H), 7.27-7.34 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 1.39 (s, 9H)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[N:3]=1.CI.[C:19](=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][CH3:19])=[O:15])=[CH:11][CH:12]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(CC(=O)O)cc2)no1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)Cc1ccc(-c2noc(C)n2)cc1

Procedure:
Reaction of equimolar amounts of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylacetic acid, methyl iodide and potassium carbonate gives methyl 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylacetate (“D”).
Reaction SMILES: [F:1][C:2]1[CH:54]=[CH:53][CH:52]=[CH:51][C:3]=1[CH2:4][C:5]1([CH2:49][OH:50])[CH2:10][CH2:9][CH2:8][N:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[F:1][C:2]1[CH:54]=[CH:53][CH:52]=[CH:51][C:3]=1[CH2:4][C:5]1([CH2:49][OH:50])[CH2:10][CH2:9][CH2:8][N:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NN4CCCC(CO)(Cc5ccccc5F)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NN4CCCC(CO)(Cc5ccccc5F)C4)cc23)ccn1
Reaction time: 0.25 h

Procedure:
In a flask, N-(3-(2-fluorobenzyl)-3-(hydroxymethyl)piperidin-1-yl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide (crude, from previous step) was reacted with trifluoroacetic acid (3 mL) for 1 hour. After reaction completion triethylsilane (0.1 mL) was added, and the reaction was stirred for an additional 15 minutes. The reaction was concentrated and rinsed with diethyl ether. The resulting remaining precipitate was dried and further purified using HPLC to give the titled compound. LC-MS: 474.22 [M+H]. LC/MS RT=2.18 min.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO.O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([OH:18])[CH2:16][CH2:17]2)=[O:11])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-(p-nitrobenzyloxycarbonyl)-4-piperidone (5.46 g) in methanol (54 ml) and tetrahydrofuran (27 ml) was added sodium borohydride (373 mg), followed by stirring at 0° C. for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 1-(p-nitrobenzyloxycarbonyl)-4-hydroxypiperidine.
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1Cc2ccc([N+](=O)[O-])cc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 80.6 %

Procedure:
To a solution of 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (2.0 g, 9.1 mmol) in 1,4-dioxane (20 mL) was added DDQ at room temperature. After refluxing for 2.5 h, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-1H-indole (1.6 g, 80%).