Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([CH3:16])([CH3:15])[CH:3]([N:13]=[O:14])[CH2:4][C:5]1[N:6]=[C:7]([N+:10]([O-:12])=[O:11])[NH:8][CH:9]=1.[NH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][NH2:21]>C(#N)C>[NH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][NH:21][C:2]([CH3:16])([CH3:15])[C:3](=[N:13][OH:14])[CH2:4][C:5]1[N:6]=[C:7]([N+:10]([O-:12])=[O:11])[NH:8][CH:9]=1
Reactant: CC(C)(Cl)C(Cc1c[nH]c([N+](=O)[O-])n1)N=O
Reactant: CC(CN)CN
Solvent: CC#N
Product: CC(CN)CNC(C)(C)C(Cc1c[nH]c([N+](=O)[O-])n1)=NO
Reaction time: 0.5 h

Procedure:
3-Chloro-3-methyl-1-(2-nitroimidazolyl)-2-nitrosobutane (1.5 g, 6.09 mmol, Example 1) was added portionwise over a period of 30 minutes to a stirred solution of 1,3-diamino-2-methylpropane (3.0 g, 34.10 mmol) in dry acetonitrile (30 mL) at 50° C. After the addition the reaction mixture was allowed to remain at 50° C. for an additional 30 minutes. The reaction mixture was then cooled and solvent was removed on a rotary evaporator to a give a paste. This was crystallized from dichloromethane-ether to afford the title product as a light yellow solid; yield: 1.36 g (75%); mp. 102-104° C. (decomp); 1H NMR (CDCl3) δ 0.89 (d, 3H, CH3), 1.22 [s, 6H, C(CH3)2], 1.51 (m, 1H, CH3CH), 2.25 (d, 2H, CH2NH2), 2.65 (m, 2H, NHCH2), 5.31 (s, 2H, imi-CH2), 7.03 & 7.21 (2s, 2H, imi-H). MS m/e 299 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 56 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using N-methylbenzylamine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 56%).
Reaction SMILES: ClC[CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([O-:7])=[O:6].[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:25]([NH:27][CH3:28])=[O:26])[C:17]([I:24])=[C:18]([C:21]([O-:23])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11].[K+].[I-].[Na+].[CH3:33]N(C=O)C>>[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:25]([NH:27][CH3:28])=[O:26])[C:17]([I:24])=[C:18]([C:21]([O:23][CH2:33][O:7][C:5](=[O:6])[C:4]([CH3:9])([CH3:8])[CH3:3])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: CNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: CNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)OCOC(=O)C(C)(C)C)c1I
Reaction time: 4 h

Procedure:
Chloromethylpivalate (7.62 g, 50.6 mmol) in dry DMF (84 ml) is added dropwise at 50° C. to a solution of potassium 5-(N-acetylamino)-3-(methylaminocarbonyl)-2,4,6-triiodobenzenecarboxylate (30.00 g, 46.0 mmol) and sodium iodide (0.37 g, 2.5 mmol) in dry DMF (450 ml). The precipitate is removed by filtration after stirring for 4 hours and the solvent is removed at reduced pressure. The residue is triturated and washed repeatedly in water and finally recrystallised from isopropanol.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[C:8]([CH3:14])=[N:9][N:10]([CH3:13])[C:11]=1[CH3:12])C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:13][N:10]1[C:11]([CH3:12])=[C:7]([CH2:6][CH2:5][CH:4]=[O:3])[C:8]([CH3:14])=[N:9]1
Reactant: CCOC(=O)CCc1c(C)nn(C)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c(C)c1CCC=O
Temperature: -78 °C

Procedure:
Dissolve 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-propionic acid ethyl ester (1.94 g, 9.23 mmol) in tetrahydrofuran (78 mL). Cool to −78° C. in a dry ice/acetone bath and treat dropwise with 1 M diisobutylaluminum hydride in toluene (10.15 mL). Stir reaction mixture at −78° C. for one hr. and add 1 M diisobutylaluminum hydride in toluene (10.15 mL). Stir reaction mixture at −78° C. for one hr. and add 1 M diisobutylaluminum hydride in toluene (10.15 mL). Stir reaction mixture at −78° C. for 1 hr. and add 1 M diisobutylaluminum hydride in toluene (10.15 mL). Stir reaction mixture at −78° C. for 1 hr. and quench with aqueous saturated potassium sodium tartrate tetrahydrate solution. Add ethyl acetate (150 mL), and stir for 3 hr. at room temperature. Separate organic layer, extract aqueous layer 3 times with ethyl acetate, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 1:1 to 100% ethyl acetate:hexanes), to give the title preparation (760 mg, 51%). GC-MS m/z=166 [M+].
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].Cl.[N:9]#[C:10][NH2:11]>>[OH2:5].[O:5]=[C:4]([CH2:3][N:1]([C:10](=[NH:9])[NH2:11])[CH3:2])[OH:6]
Reactant: N#CN
Reactant: CNCC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CN(CC(=O)O)C(=N)N
Product: O
Temperature: 95 °C
Reaction time: 1 h

Procedure:
277.7 g (1 mole) of a technical 40% by weight aqueous sodium sarcosinate solution were used. A pH value of 9.6 (at 20° C.) was adjusted with concentrated hydrochloric acid and heated to 95° C. Subsequently, 105.1 g (1.25 mole) of a technical 50% by weight aqueous cyanamide solution were added thereto with intensive stirring in such a manner that the internal temperature did not exceed 95° C. After ending of the cyanamide addition, further heating was carried out for 1 hour at 95° C. The reaction mixture was then cooled to 15° C. the crystalline precipitate was filtered off with suction and washed chloride-free by washing twice with, in each case, 120 ml of water. The residue was recrystallized from water and dried at 80° C. and 20 mbar. The yield of creatine was 73.4 g (56% of theory). The content determination by means of HPLC gave a content of 100% (creatine monohydrate obtainable pure in chemical commerce was used as standard).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:7])=[CH:5][N:6]=1.[H-].[Na+].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH2:16][CH2:15]1)=[O:13]>CS(C)=O>[CH3:1][C:2]1[N:6]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=3[C:22]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[CH2:18][CH2:19]2)=[O:13])[CH:5]=[C:4]([CH3:7])[N:3]=1
Reactant: O=C(Nc1ccccc1)c1ccccc1N1CCN(C(=O)CCl)CC1
Reactant: Cc1cnc(C)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cn(CC(=O)N2CCN(c3ccccc3C(=O)Nc3ccccc3)CC2)c(C)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To 2,5-dimethyl imidazole (0.060 g, 0.630 mmol) in 1 mL of DMSO in a reaction tube is added 60% NaH (0.030 g, 0.730 mmol). The mixture bubbles as deprotonation occurs. The mixture is stirred for 0.5 h and then 0.5 mL of a DMSO solution containing 2-[4-(2-chloro-acetyl)-piperazin-1-yl]-N-phenyl-benzamide (0.075 g, 0.210 mmol) is added. The flask is sealed and heated at 80° C. for 60 h. The product is purified via Prep HPLC (20-100% CH3CN/H2O) to give 74.7 mg of 2-{4-[2-(2,4-dimethyl-imidazol-1-yl)-acetyl]-piperazin-1-yl}-N-phenyl-benzamide in 85% yield. MS: MH+=418.9
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([CH:11]1[CH2:15][CH2:14][O:13][C:12]1=O)(=O)[CH3:9].P(Cl)(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][CH2:14][CH2:15][C:11]1[C:12](=[O:13])[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:8]=1[CH3:9]
Reactant: CC(=O)C1CCOC1=O
Reactant: Nc1ccccn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc2ccccn2c(=O)c1CCCl
Reaction time: 1 h
Yield: 52 %

Procedure:
40 g of 2-aminopyridine and 75 ml of 3-acetyl-4,5-dihydro-2(3H)-furanone were added to 1.0 L of toluene, and then 200 ml of phosphorus oxychloride was added thereto dropwise over 1 hour. The resulting mixture was slowly heated and refluxed for 5 hours. The reaction mixture was concentrated under a reduced pressure and the residue was poured to a mixture of ice and ammonia water. The resulting solid was extracted with 1.0L of dichloromethane, dried and filtered. The filtrate was concentrated under a reduced pressure to remove dichloromethane and 500 ml of isopropanol was added to the residue. The resulting crystal was filtered, washed and dried to obtain 48.1 g of the title compound as a off-white crystal (yield: 52%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:2]=1.[CH:31](=O)[CH3:32]>>[CH2:31]([N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:32]
Reactant: CC=O
Reactant: Oc1ccc(CCNc2nccc(-c3cccc(NCc4cccnc4)c3)n2)cc1
Product: CCN(Cc1cccnc1)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 25 was coupled with acetaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 426. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (s, 1H) 8.39 (d, 1H) 8.2 (d, 1H) 7.6 (d, 1H) 7.5 (s, 1H), 7.3 (m, 3H), 7.0 (d, 1H), 6.9 (d 1H), 6.8 (d, 2H), 6.5 (d, 2H), 4.6 (s, 2H), 3.6 (m, 4H), 2.8 (t, 2H), 1.2 (d, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]=[C:16]3[NH:20][N:21]=[CH:22][C:15]=23)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(OCC)C>[NH:20]1[C:16]2=[N:17][CH:18]=[N:19][C:14]([N:11]3[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]3)=[C:15]2[CH:22]=[N:21]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ncc23)CC1
Agent: Cl
Solvent: CCOCC
Product: NC1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 177 %

Procedure:
To [1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (28 mg, 0.088 mmol) was added HCl (1 ml, 4M solution in dioxane, 4 mmol). The suspension was stirred at room temperature for 1 hour, and then diluted with diethyl ether (4 ml). The ethereal layer was discarded and the solid washed with a further portion of diethyl ether (2 ml). The ethereal layer was again discarded, and the resultant solid dried under high vacuum to yield the desired product (34 mg). The free base was liberated by dissolution of this material in methanol, loading onto an acidic resin SCX-2 cartridge, and elution from the cartridge with ammonia in methanol. LC/MS Rt 0.86 [M+H]+219
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]=[C:36](C(Cl)(Cl)Cl)[O:35][N:34]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-:43].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][C:36](=[O:43])[O:35][N:34]=3)=[CH:23][CH:22]=2)[C:4](=[O:11])[C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCCc1nc(C)c(CC2CCCCO2)c(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(CC2CCCCO2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 12 h
Yield: 16.3 %

Procedure:
To a solution of 6-methyl-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one (0.46 g) and 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.95 g) in acetonitrile (20 mL) was added potassium carbonate (0.51 g), and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran-ethanol (1:1, 4 mL), 1 M sodium hydroxide (2 mL) was added and the mixture was stirred for 30 min. The reaction mixture was weakly acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.15 g, 17%) as a colorless solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]=[C:4](C)[CH:3]=1.[ClH:17]>CO>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[Cl:17]
Reactant: Cl
Reactant: CC(=O)Nc1ccc2nc(C)cc(O)c2c1
Solvent: CO
Product: Nc1ccc2nccc(Cl)c2c1

Procedure:
N-(4-Hydroxy-2-methylquinolin-6-yl)acetamide (0.05 g; see step (i) above), methanol (2 mL) and 5 N hydrochloric acid (6 mL) was refluxed for 90 minutes. The reaction mixture was evaporated and the residue dissolved in ethyl acetate and sodium carbonate solution. The organic phase was washed with water, dried (Na2SO4), filtered and concentrated to give the sub-title compound as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:7][O:8][Si:9]([CH2:14][CH2:15][CH2:16][Cl:17])([O:12][CH3:13])[O:10][CH3:11]>C(OCC)(=O)C>[Cl-:17].[CH3:7][O:8][Si:9]([CH2:14][CH2:15][CH2:16][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:12][CH3:13])[O:10][CH3:11]
Reactant: c1ccncc1
Reactant: CO[Si](CCCCl)(OC)OC
Solvent: CCOC(C)=O
Product: CO[Si](CCC[n+]1ccccc1)(OC)OC
Product: [Cl-]

Procedure:
3.0 g of pyridine and 18 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 11.3 g of trimethoxysilylpropyl chloride was dissolved in 24 g of ethyl acetate was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was refluxed over 3 days and therefrom, ethyl acetate was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, pyridine and trimethoxysilylpropyl chloride as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylpropylpyridinium chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[C:19]([I:26])=[N:20][N:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=2)(C(O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:29]([CH2:32]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:41])C=CC=CC=1>C1(C)C=CC=CC=1>[I:26][C:19]1[C:18]([CH2:17][C:11]2([N:29]=[C:32]=[O:41])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:22][N:21]([CH:23]([CH3:24])[CH3:25])[N:20]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC(C)n1cc(CC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)c(I)n1
Solvent: Cc1ccccc1
Product: CC(C)n1cc(CC2(N=C=O)CCN(C(=O)OC(C)(C)C)CC2)c(I)n1
Temperature: 120 °C
Yield: 65.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-((3-iodo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-4-carboxylic acid (430 mg, 0.90 mmol) in toluene (10 mL) was added triethylamine (0.15 mL, 1.08 mmol) and diphenylphosphoryl azide (0.24 mL, 1.08 mmol). The mixture was heated at 120° C. for 3 hours, the volatiles were removed under reduced pressure and the resultant oil was purified by flash chromatography (7-60% ethyl acetate/heptanes, 25 g silica gel) to yield tert-butyl 4-((3-iodo-1-isopropyl-1H-pyrazol-4-yl)methyl)-4-isocyanatopiperidine-1-carboxylate (280 mg) as a clear oil. FT-IR (cm−1): 2253; 1H NMR (400 MHz, CDCl3, δ): 7.27 (s, 1H), 4.50 (m, 1H), 4.03 (br. s., 2H), 2.97 (br. s., 2H), 2.65 (s, 2H), 1.65 (m, 4H), 1.50 (s, 6H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C([O-])=O.[K+]>CC#N.[Ir].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:14]([OH:19])[C:15]([F:17])([F:18])[F:16])=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: O=C(c1ccc(Br)cc1-c1ccccc1)C(F)(F)F
Agent: [Ir]
Agent: O=C[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O[C@H](c1ccc(Br)cc1-c1ccccc1)C(F)(F)F
Temperature: 40 °C
Reaction time: 12 h

Procedure:
1-(5-Bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone (1.3 g, 3.9 mmol) in CH3CN (10 mL) was reduced to the chiral alcohol using the chiral iridium catalyst (METHOD A) at RT. The reaction mixture was then charged with potassium formate (725 mg, 8.6 mmol) and the mixture was stirred at 40° C. for 12 h. Then the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by normal phase silica gel column (EtOAc:PE=1:10) to afford the title compound as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([N:14]1[C:18](=[O:19])[C:17](=[C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:22]=3[S:21]2)[S:16][C:15]1=[N:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[NH:40][CH2:41][CH3:42])[C:35]#[N:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:44][C:45]([O:47][CH3:48])=[O:46]>CC(=O)CC>[CH3:48][O:47][C:45](=[O:46])[CH2:44][O:30][C:27]1[CH:28]=[CH:29][C:22]2[S:21][C:20](=[C:17]3[S:16][C:15](=[N:31][C:32]4[CH:33]=[C:34]([C:35]#[N:36])[CH:37]=[CH:38][C:39]=4[NH:40][CH2:41][CH3:42])[N:14]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:18]3=[O:19])[N:24]([CH3:25])[C:23]=2[CH:26]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OCC(=O)OC)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 75 °C

Procedure:
To a suspension of K2CO3 (41 mg, 5 equiv) in 2-butanone (2 mL) were added the product of Example 57 (31 mg, 0.06 mmol) and methyl 2-bromoacetate (7 μL, 1.2 equiv). The resulting suspension was heated at 75° C. overnight. After cooling, the reaction mixture was filtered, and the filtrate was evaporated to give a crude material, which was purified by chromatography on silica gel, eluting with MeOH-DCM (0:100 to 3:97) to give the title compound (5 mg). 1H-NMR (CDCl3): δ 7.63 (1H, d), 7.28–7.39 (6H, m), 7.13 (1H, d), 7.08 (1H, d), 6.84 (1H, dd), 6.62 (1H, d), 5.13 (2H, s), 4.98 (1H, t), 4.88 (2H, s), 3.79 (3H, s), 3.68 (3H, s), 3.05 (2H, m), 0.99 (3H, t); MS(ESI): 586 (MH+).
Reaction SMILES: O[CH2:2][O:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.B(F)(F)F.[CH3:16][CH2:17][O:18][CH2:19]C.C(OCC)(=[O:23])C>ClCCl>[CH3:2][O:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][C:8]([CH2:19][O:18][CH2:17][CH2:16][OH:23])=[CH:7][CH:6]=1
Reactant: CCOCC
Reactant: O=C(OCO)c1ccccc1
Reactant: CCOC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(COCCO)cc1
Temperature: -5 °C
Reaction time: 0.58 h
Yield: 16 %

Procedure:
To a flame-dried 2-neck flask was added a solution of methyl-4-(hydroxymethylbenzoate (2.5 g, 15 mmol) in dichloromethane (30 mL). The reaction was purged with nitrogen and brought to −5° C. A dewar condenser (also flame-dried) containing a dry ice/acetone bath (−78° C.) was affixed to the flask and ethylene oxide-tetradeuterate was added (˜55 drops). Then BF3.Et2O (510 μL, 0.0041 mmol) was added dropwise and the reaction stirred at −5° C. for 35 minutes under nitrogen atmosphere. Monitoring by TLC (100% ethyl acetate) showed complete consumption of the starting material. The reaction was warmed to room temperature and vented to remove any excess ethylene oxide gas. The reaction was then diluted with brine and extracted with dichloromethane (2 times). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude oil. Purification by flash column chromatography (4:1 pentane:ethyl acetate) provided the product as a clear oil (520 mg, 16% yield). 1H NMR (600 MHz, CDCl3) δ 8.02 (d, 2H, J=8.2 Hz), 7.41 (d, 2H, J=8.1 Hz), 4.62 (s, 2H), 3.92 (s, 3H); 13C NMR (150 MHz, CDCl3167.1, 143.5, 130.8) δ 129.9, 127.5, 72.8, 52.4.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)=[O:17])([CH3:4])[CH3:3].[Cl:27]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH3:4][C:2]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([Cl:27])=[CH:21][NH:22]2)=[O:17])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NCCCOc1ccccc1C(=O)c1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)NCCCOc1ccccc1C(=O)c1cccc2[nH]cc(Cl)c12
Yield: 79.8 %

Procedure:
6.3 g of [2-[3-[(1,1-dimethylethyl)-amino]-propoxy]-phenyl]-(1H-indol-4-yl) methanone of Step F of Example 3 in 50 ml of acetic acid in the presence of 2.64 g of N-chloro succinimide was stirred for 2 hours at ambient temperature and was then poured into 300 ml of saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic phase was washed with salt water, dried and concentrated to dryness. After chromatography of the residue on silica (eluant:ethyl acetate triethylamine 95-5), 5.52 g of the expected product were obtained and was used as is for the following step.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]2[CH2:27][C:28]3([CH2:38][C:23]=2[CH:22]=1)[C:36]1[C:31](=[N:32][CH:33]=[CH:34][CH:35]=1)[NH:30][C:29]3=[O:37].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([NH:20][C:21]2[N:26]=[CH:25][C:24]3[CH2:27][C:28]4([CH2:38][C:23]=3[CH:22]=2)[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[NH:30][C:29]4=[O:37])=[O:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)Cn1c(=O)n(C2CCOC2)c2ccccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cn1c(=O)n(C2CCOC2)c2ccccc21)Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (±)-(2-oxo-3-tetrahydrofuran-3-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (60 mg, 0.23 mmol, described in Intermediate 16), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.