Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([CH2:11][C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[CH:6]=[N:7]2)=[N:3][CH:2]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:21]([NH:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[CH2:11][C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c1ncn2C[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ncnc2c1ncn2C[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
2,5-Anhydro-1-deoxy-1- (adenin-9-yl) -D-allitol (916 mg) was subjected to azeotropic dehydration with anhydrous pyridine and then suspended in 15 ml of anhydrous pyridine. To the suspension was added 2.75 g of benzoyl chloride dropwise under ice-cooling. After the mixture was reacted at room temperature for 2 hours, it was poured into a mixture of 114 g of ice, 9 g of sodium hydrogen carbonate and 100 ml of chloroform and extracted with chloroform. The chloroform layer was concentrated and ethanol/pyridine was added to the residue. Then, 13 ml of 2N-sodium hydroxide solution and 13 ml of ethanol were added under water-cooling and the reaction was carried out at room temperature for 30 minutes. This reaction mixture was neutralized by adding about 13 ml of 2N-hydrochloric acid under cooling and concentrated under reduced pressure. The residue was washed with ether and the aqueous layer was concentrated under reduced pressure. The residue was purified by reversed phase column chromatography (methanol/water) to provide 1.28 g of the desirable compound. m.p. 85°-90° C.
Reaction SMILES: ClCCl.Cl.[NH2:5][CH2:6][CH:7]([OH:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Br:24][CH2:25][C:26](Br)=[O:27]>O>[Br:24][CH2:25][C:26]([NH:5][CH2:6][CH:7]([OH:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:27]
Reactant: NCC(O)Cc1ccc(F)cc1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CBr)NCC(O)Cc1ccc(F)cc1
Yield: 97.5 %

Procedure:
To a dichloromethane suspension (16 mL) of 1-amino-3-(4-fluorophenyl)propan-2-ol hydrochloride (0.75 g, 3.64 mmol) synthesized in Reference Synthesis Example 41, triethylamine (0.92 g, 9.10 mmol) and bromoacetyl bromide (0.88 g, 4.37 mmol) were added at 0° C. and the resultant solution was stirred for 0.5 hours. After completion of the reaction, water was added thereto and extraction with chloroform from the resultant mixture was performed. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (1.03 g, yield 97%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:17]([CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])[CH2:11]2
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Reactant: CN(C)CCN
Product: CN(C)CCN1Cc2cc(Br)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate and N,N-dimethylethylenediamine (Aldrich Cat No. D158003). LCMS (M+H)+=283.1.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][NH:6][C:7]1[N:8]([CH2:33][CH2:34][CH3:35])[C:9](=[O:32])[C:10]2[NH:11][C:12]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)=[N:13][C:14]=2[N:15]=1)C.[OH-].[Li+]>C1COCC1.CO.O>[O:32]=[C:9]1[N:8]([CH2:33][CH2:34][CH3:35])[C:7]([NH:6][CH2:5][C:4]([OH:36])=[O:3])=[N:15][C:14]2[N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:11][C:10]1=2
Reactant: CCCn1c(NCC(=O)OCC)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCn1c(NCC(=O)O)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-acetic acid ethyl ester in THF (2 ml), MeOH (1 ml) and Water (1 ml) was added lithium hydroxide (0.02 g, 0.476 mmol) at 0° C. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was concentrated and water was added. It was extracted with ethyl acetate. Ethyl acetate layer was washed with water and brine. Ethyl acetate layer was dried over sodium sulphate, filtered and concentrated under reduced pressure and the residue obtained was purified by column chromatography to obtain {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-acetic acid (0.035 g, 46%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13]([C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 53.4 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (77 mg, 0.16 mmol), 3-tributylstannanyl-pyridine (0.075 mL, 0.23 mmol) and PdCl2(PPh3)2 (22 mg, 0.031 mmol) in 4 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH) to give 42 mg of the title compound as a yellow oil. MS: (+) m/z 492.56 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[CH2:16]([N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23](=[O:30])[C:22]1=[O:31])[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1.ClCCl>[OH:30][C:23]1([C:7]2[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=2)[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:22]1=[O:31]
Reactant: CCCCCN1C(=O)C(=O)c2cccnc21
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol in THF (40.0 mL) was added a solution of iso-propyl magnesium chloride (7.90 mL, 15.9 mmol, 2.0 M in THF) dropwise at 0° C. over 5 min. The reaction mixture was stirred for 30 min upon which time colorless precipitate formed. After the solvent was removed under reduced pressure, the residue was dissolved in anhydrous dichloromethane (40.0 mL) and cooled to 0° C. followed by the addition of a solution of 1-pentyl-1H-pyrrolo[2,3-b]pyridine-2,3-dione (1.84 g, 8.44 mmol) in dichloromethane (10.0 mL). The reaction mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride solution (30.0 mL). The organic layer was separated and washed with water (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ethyl acetate and ether to afford the title compound (2.20 g, 73%) as a beige solid: 1H NMR (300 MHz, CDCl3) δ 8.29 (dd, 1H), 7.74 (dd, 1H), 7.08 (dd, 1H), 6.60 (s, 1H), 6.24 (s, 1H), 5.87 (dd, 2H), 3.78 (d, 2H), 1.77-1.67 (m, 2H), 1.33-1.28 (m, 4H), 0.85 (d, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 157.7, 148.9, 147.3, 147.2, 139.7, 131.1, 127.7, 119.3, 118.3, 107.1, 101.1, 97.8, 74.6, 40.7, 29.0, 27.0, 22.3, 14.4; MS (ES+) m/z 357 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([NH:21][C:22]([C:24]2([CH3:27])[CH2:26][O:25]2)=[O:23])[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]>>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:14]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:12]([CH3:11])[CH:13]=2)=[O:23])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(N)cc1Cl
Product: Cc1cc(NC(=O)C(C)(O)CNc2ccc(C#N)c(Cl)c2)ccc1[N+](=O)[O-]

Procedure:
3-(3-Chloro-4-cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 52 starting from 4-amino-2-chlorobenzonitrile and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-3% methanol). 1H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.52 (3H, s), 3.27 (1H, dd, J=13.8 Hz, J=5.5 Hz), 3.55 (1H, dd, J=13.8 Hz, J=6.9 Hz), 6.12 (1H, s), 6.72 (1H, dd, J=8.8 Hz, J=2.2 Hz), 6.90 (1H, d, J=2.2 Hz), 6.95-6.98 (1H, m), 7.46 (1H, d, J=8.7 Hz), 7.80 (1H, dd, J=8.9 Hz, J=2.3 Hz), 7.83 (1H, d, J=2.0 Hz), 8.02 (1H, d, J=8.9 Hz), 10.05 (1H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C@H:14]1[NH:19][CH2:18][C:17]2[N:20]=[CH:21][NH:22][C:16]=2[CH2:15]1)=[O:13].[C:23](Cl)(=[O:25])[CH3:24]>CN(C)C=O>[C:23]([N:19]1[C@H:14]([C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH3:3])=[O:13])[CH2:15][C:16]2[NH:22][CH:21]=[N:20][C:17]=2[CH2:18]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1NC(=O)[C@@H]1Cc2[nH]cnc2CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)[C@@H]1Cc2[nH]cnc2CN1C(C)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
Sodium hydride (80% dispersion in mineral oil, 0.55 g, 18 mmol) was added to a solution of (S)-6-(2-methoxyphenyl)aminocarbonyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (2.00 g, 7 mmol) in anhydrous N,N-dimethylformamide (70 ml). The reaction mixture was heated to 80° C. for 30 minutes, then allowed to cool to room temperature. Acetyl chloride (1.46 g, 18 mmol) was added to the reaction mixture at 0° C. The reaction mixture was allowed to warm to room temperature, stirred overnight, and brought to pH 8. Water and N,N-dimethylformamide was distilled off under vacuum. The residue was chromatographed on silica gel with a solvent system of ammonium hydroxide/methanol/methylene chloride (1/8/92 v/v) to yield (S)-5-acetyl-6-(2-methoxyphenylaminocarbonyl)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (free base) (1.13 g, 49%). The free base was converted to the hydrochloric acid salt: m.p.: 159° C.
Reaction SMILES: C([O:9][C@H:10]1[CH2:33][C@H:32]([O:34]C(=O)NC)[C@@:31]2([CH3:39])[C:12](=[CH:13][C@@H:14]([O:41]C(OC)=O)[C@@H:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11]1)(=O)C1C=CC=CC=1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3OC(OC)=O)=C[C@H]4OC(OC)=O)CC2)C)OC1>>[CH3:25][O:24][CH:21]([O:22][CH3:23])[CH:20]([CH3:26])[C@@H:19]1[C@:27]2([CH3:40])[C@H:16]([C@H:15]3[C@H:30]([CH2:29][CH2:28]2)[C@:31]2([CH3:39])[C:12]([CH2:11][C@@H:10]([OH:9])[CH2:33][C@@H:32]2[OH:34])=[CH:13][C@H:14]3[OH:41])[CH2:17][CH2:18]1
Reactant: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: COC(=O)O[C@@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.3 %

Procedure:
The reaction and workup procedures of Example 140 were repeated except that 85 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β,7α-tris(methoxycarbonyloxy)pregn-5-ene to give 45 mg of 21,21-dimethoxy-20-methylpregn-5-ene-1α,3β,7α-triol showing the following physical properties.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1)[CH3:2].[CH3:12][C:13]1([CH3:20])[C:17]([CH3:19])([CH3:18])[O:16][BH:15][O:14]1.C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([B:15]2[O:16][C:17]([CH3:19])([CH3:18])[C:13]([CH3:20])([CH3:12])[O:14]2)=[C:6]([CH3:11])[CH:5]=1)[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: CCSc1ccc(Br)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCSc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 85 °C

Procedure:
A mixture of the product from step (i) (6.6 g), 4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (1.94 ml), triethylamine (2.4 ml), palladium acetate (0.06 g) and 2-(dicyclohexylphosphino) biphenyl (0.3 g) in dioxane (20 ml) was heated at 85° C. for 2 h. The mixture was quenched with aqueous ammonium chloride solution, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 50% isohexane/DCM. Yield 0.7 g
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([OH:9])=[O:8].[CH2:10](Br)[C:11]#[CH:12]>>[CH2:12]([C:3]1([C:7]([OH:9])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[C:11]#[CH:10]
Reactant: O=C(O)C1CCCC1=O
Reactant: C#CCBr
Product: C#CCC1(C(=O)O)CCCC1=O

Procedure:
Alternatively, a lower alkyl ester of 2-oxocyclopentanecarboxylic acid can be condensed with e.g. propargyl bromide to yield the lower alkyl ester of 1-(2-propynyl)-2-oxocyclopentanecarboxylic acid which is then reacted as described above to yield the corresponding ester of 4-(3-cyanopropyl)-6-heptynoic acid which is then reacted with 3-bromopyridine under conditions of the modified Heck reaction as described by D.E. Ames et al., Synthesis 1981, 364 to yield the ester of 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptynoic acid which is hydrogenated under conditions known in the art, e.g. in the presence of palladium on charcoal, to the lower alkyl ester of 8-amino-4-[3-(3- pyridyl)-propyl]-octanoic acid.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37]N>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:32]=1[NH:37][CH:2]=[C:6]2[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:25])[CH3:26])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1
Reactant: COc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Agent: Cl
Product: COc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c[nH]c12

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 434.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:44]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:51]=1)[CH2:45][CH2:46][CH3:47]>CN(C=O)C.O>[CH2:44]([N:48]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([CH3:57])([CH3:59])[CH3:58])=[CH:52][CH:51]=1)[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)=[O:12])[CH2:45][CH2:46][CH3:47]
Reactant: CCCCNCc1ccc(C(C)(C)C)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
To a solution of 110 mg of 1H-indole-7-carboxylic acid (0.68 mmol) and 220 mg of TBTU (0.68 mmol) in 10 ml DMF, were added 0.59 ml (3.42 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 150 mg (0.68 mmol) of butyl-(4-tert-butyl-benzyl)-amine were added. After stirring for 2 h at rt, the reaction mixture was diluted with 100 ml water and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 209 mg (82%) of a light yellow viscous oil. MS (EI) 362.2 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:32])[CH2:18][N:19]4[C:23]5=[N:24][CH:25]=[CH:26][CH:27]=[C:22]5[C:21]([C:28]([F:31])([F:30])[F:29])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1>CO.O=[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:32])[CH2:18][N:19]4[C:23]5[NH:24][CH2:25][CH2:26][CH2:27][C:22]=5[C:21]([C:28]([F:29])([F:31])[F:30])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cn1nc(C(F)(F)F)c2cccnc21)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: O=[Pt]=O
Solvent: CO
Product: O=C(Cn1nc(C(F)(F)F)c2c1NCCC2)N1CCCc2c1cnn2-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
1-[1-(4-Fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[3-(trifluoromethyl)pyrazolo[3,4-b]pyridin-1-yl]ethanone (22.2 mg, 0.05 mmol) prepared above was dissolved in 1 mL of methanol and treated with ˜20 mg of PtO2 in a septum-capped vial. The vial was purged and filled with hydrogen gas twice and then placed under a hydrogen atmosphere (balloon) and stirred overnight. The slurry was filtered and the filtrate purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide the title compound (solution was neutralized and extracted to provide the free base) as a white solid (13 mg, 60%). 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.36 (s, 0.85H), 7.71 (s, 0.15H), 7.43-7.49 (m, 2H), 7.14-7.19 (m, 2H), 5.15 (s, 0.3H), 5.00 (s, 1.7H), 4.29 (br s, 1H), 3.88-3.93 (m, 2H), 3.29 (m, 2H), 2.85 (t, J=6.3 Hz, 2H), 2.63 (t, J=6.2 Hz, 2H), 2.09 (m, 2H), 1.85 (m, 2H); MS: (ES) m/z calculated for C21H21F4N6O [M+H]+ 449.1, found 449.1.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH2:36]([Mg]Br)[CH3:37].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CCOCC>[NH2:18][CH:17]([C:16]1[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:15]=1[CH2:14][N:7]([CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1)[CH2:36][CH3:37]
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C#N)n1
Reactant: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCC(N)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 2.5 h
Yield: 87 %

Procedure:
To a solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzonitrile (Preparation 7) (300.0 mg, 0.590 mmoles) in toluene (1.2 mL) was added ethyl magnesium bromide (0.59 mL, 1.77 mmoles of a 3M solution in ether) dropwise at room temperature and the reaction mixture was stirred for 2.5 hours. The reaction was quenched by adding methanol (0.98 mL) dropwise with stirring until methanol and toluene were thoroughly mixed. To this mixture sodium borohydride (22.3 mg, 0.590 mmoles) was added in one portion and the reaction stirred for 1.5 hours. A 10% aqueous citric acid (1.5 mL) solution was added drop wise at room temperature until bubbling stopped. The reaction mixture was made basic to pH 10 with 1 N NaOH solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified using cation exchange resin (Waters Oasis MCX 6CC 500 mg LP Extraction Cartridge, Waters, Milford, Mass., USA) to yield the title compound (278.4 mg, 87% yield) as yellow gum. MS (ES+) Calc: 608.5, Found: 609.1 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>ClCCCl>[OH:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1Nc1ccccc1
Solvent: O
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)c1ccc(O)c(Nc2ccccc2)c1
Reaction time: 1.5 h
Yield: 35.2 %

Procedure:
Boron tribromide-dimethyl sulfide complex (3.1 g, 9.9 mmol) was added to a stirred suspension of 4-methoxy-3-phenylamino-N-phenyl-benzamide from Example 28 (0.9 g, 2.8 mmol) in 1,2-dichloroethane (50 mL) under an inert atmosphere, and the mixture heated to reflux. After 1.5 hours, the mixture was allowed to cool and was poured into water (125 mL) and extracted with dichloromethane (2×75 mL). The combined extracts were washed with water, then saturated brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and filtered through a short column of silica gel. The filtrate was stripped of solvent and the residue recrystallized from toluene to afford the product (0.3 g); m.p. 158-159° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[C:40]#[N:41])[O:36][CH2:35][CH2:34][C:33]2=O>C1COCC1>[F:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[C:40]#[N:41])[O:36][CH2:35][CH2:34]/[C:33]/2=[CH:2]\[O:3][CH3:4]
Reactant: N#Cc1cc2c(cc1F)C(=O)CCO2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO/C=C1\CCOc2cc(C#N)c(F)cc21
Temperature: -78 °C
Reaction time: 18 h

Procedure:
In a 250 ml, round bottom flask, (methoxymethyl) (triphenyl)phosphonium chloride (1.3 g, 3.8 mmol) was dissolved in THF (20 mL). The solution was cooled to −78° C. To above solution was added n-butyl lithium (0.49 mL, 2.50 M in Hexane, 1.05 mmol) dropwise. Reaction color changed to orange. The mixture was cooled to −78° C. and to it was added 6-Fluoro-4-oxo-3,4-dihydro-2H-chromene-7-carbonitrile (100 mg, 0.52 mmol). The reaction was let warm to RT and stirred at RT for 18 hours. The reaction was then quenched with addition of saturated ammonium chloride (5 mL) and extracted with dichloromethane. The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (hexane/EtOAc 0-50%). The desired product was obtained. LC-MS (IE, m/z): 220.3 [M+1]+.