Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:36])[C:32]([O:34][CH3:35])=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:36])[C:32]([O:34][CH3:35])=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37]
Reactant: COC(=O)C(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 17 (0.070 g, 0.130 mmol) was treated with trifluoroacetic acid (0.5 mL) in chloroform (5 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 8.7:1.3, to yield the product 22 (0.035 g, 65%) as a brown solid: mp 185-186° C. IR (KBr) 3014, 1692, 1581, 1570, 1533, 1307, 1198, 722, 455 cm−1; 1H NMR (CD3OD, 300 MHz) δ 8.55 (s, 1H), 8.23 (d, J=3.2 Hz, 1H), 7.71 (d, J=3.5 Hz, 1H), 7.54 (m, 1H), 7.36 (m, 3H), 4.52 (m, 2H), 3.91 (s, 3H), 3.05 (m, 2H), 2.28 (m, 2H); 13C NMR (CD3OD, 125 MHz) δ 191.6, 169.9, 166.8, 164.9, 155.4, 138.8, 137.9, 135.7, 134.9, 132.2, 129.6, 127.2, 125.0, 124.8, 124.1, 123.9, 118.6, 109.6, 52.9, 42.5, 38.2, 28.6; ESIMS m/z (relative intensity) 420 (MH+, 100); HRESIMS calcd for C23H21N3O5 420.1559 (MH+). found 420.1554 (MH+); HPLC purity: 98.2% (1% TFA in MeOH).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:32][CH2:31]1)[CH3:17]>>[N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([N:41]2[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:33]3[CH2:34][CH2:35][CH2:36][N:30]([C:22]4[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=4)[CH2:31][CH2:32]3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:40]2)=[O:11])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: O=C(O)c1cccc(-n2cnnn2)c1
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cccc(-n5cnnn5)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 3-(1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][OH:22]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:18][C:19]([CH3:24])([CH2:20][CH2:21][OH:22])[CH3:23])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)CCO
Product: CC(C)(CCO)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 3-amino-3-methyl-butan-1-ol (CAN 42514-50-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 319.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]2[NH:19][CH:20]=[C:21]([NH2:22])[C:10]=12.[CH3:23][O:24][C@H:25]([CH3:29])[C:26](O)=[O:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[Cl:8][C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=[C:11]2[NH:19][CH:20]=[C:21]([NH:22][C:26](=[O:27])[C@H:25]([O:24][CH3:23])[CH3:29])[C:10]=12
Reactant: CO[C@H](C)C(=O)O
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
Triethylamine (430 mg, 0.592 mL, 4.25 mmol) was slowly added to a mixture of 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.849 mmol; Example 12, Step G), (R)-2-methoxypropanoic acid (106 mg, 1.02 mmol) and bis(2-oxooxazolidin-3-yl)phosphinic chloride (238 mg, 0.934 mmol) in anhydrous dichloromethane (10 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue stirred in THF (5 mL) and treated with water (20 mL). The solid, which separated, was collected by filtration and washed with water then dried under vacuum to yield (R)—N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (263 mg, 96% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.49 (br s, 1H), 9.48 (s, 1H), 8.59 (s, 1H), 7.89 (d, 1H), 3.93 (q, 1H), 3.41 (s, 3H), 1.36 (d, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:15][S:16]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)(=[O:18])=[O:17])[CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])C.[Li+].[BH4-].O.CCOC(C)=O>C1COCC1>[F:25][C:23]1[CH:24]=[C:19]([S:16]([NH:15][CH:5]([CH2:4][OH:3])[CH:6]([C:7]([F:10])([F:8])[F:9])[C:11]([F:13])([F:12])[F:14])(=[O:17])=[O:18])[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: CCOC(=O)C(NS(=O)(=O)c1cc(F)cc(F)c1)C(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(3,5-difluoro-benzenesulfonylamino)-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester in anhydrous THF (5 mL) at 0° C. was added 2M LiBH4 solution in THF (0.5 mL). The solution was allowed to warm to 25° C. and stir for 18 h. LC-MS of a reaction aliquot revealed unreacted starting material present. The reaction solution was immersed in an ice bath and 2M lithium borohydride (0.5 mL) was added and the solution allowed to warm to 25° C. and was stirred for 18 h. This procedure was repeated once more and, after 72 h, water was added to quench the reaction. The solvent was removed to give a tan solid which was transferred to a separatory funnel with EtOAc (100 mL) and washed with 1M citric acid solution (100 mL×2). The aqueous washings were combined and extracted with EtOAc (100 mL). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4), filtered and evaporated to give a peach colored solid (300 mg). This residue was adsorbed onto silica gel and purified by column chromatography, eluting with a solution of 50% EtOAc in hexanes to afford the alcohol (119 mg, 51%) as a white solid. Mass Spectrum (−ESI): 358.8 [M−H]−
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29].[O-2].[Mg+2]>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:17][S:18]([C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[N:40][S:37]([C:34]1[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=1)(=[O:39])=[O:38]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CSc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 74 %

Procedure:
879 mg (2.73 mmol) of iodosobenzene diacetate are added to a suspension of 300 mg (1.77 mmol) of 1-methylsulphanyl-4-nitrobenzene, 716 mg (3.55 mmol) of 4-nitrobenzenesulphonamide, 285 mg (7.10 mmol) of magnesium oxide and 78 mg (0.18 mmol) of rhodium(II) acetate dimer in 12 ml of dichloromethane at room temperature. The mixture is stirred for 24 h and then concentrated. The resulting residue is purified by chromatography (dichloromethane/ethanol 95:5). 484 mg (1.31 mmol; yield: 74%) of the product are obtained.
Reaction SMILES: [CH3:1][Se:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].C(N=[C:18]=[O:19])CCC.C(Cl)(Cl)=O>>[CH3:1][Se:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]=[C:18]=[O:19])(=[O:11])=[O:10]
Reactant: CCCCN=C=O
Reactant: C[Se]c1ccccc1S(N)(=O)=O
Agent: O=C(Cl)Cl
Product: C[Se]c1ccccc1S(=O)(=O)N=C=O
Temperature: 25 °C
Yield: 127.5 %

Procedure:
A solution of 2-(methylselenyl)benzenesulfonamide (6.25 g, 25.0 mmol), n-butyl isocyanate (2.81 mL, 25.0 mmol), and 1,4-diaza[2.2.2]bicyclooctane (0.1 g, 1 mmol) in mixed xylenes was heated at reflux for 0.5 hours. Phosgene was then added at such a rate that the internal temperature stayed at 133° C. or above. When consumption of phosgene ceased, the solution was cooled to room temperature and then filtered under nitrogen. Rotary evaporation gave 2-(methylselenyl)benzenesulfonyl isocyanate as a brown oil (8.8 g). This was used immediately without further purification or characterization.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:19](=[O:21])[CH3:20])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(Sc2ccccc2N)c([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1Sc1ccc(C)cc1[N+](=O)[O-]

Procedure:
The material from Example 185a (0.990 3.80 mmol) was dissolved in CH2Cl2 to which acetyl chloride (0.328 g, 4.183 mmol) was added. Reaction mixture stirred at room temperature for 1 hr at which time the title compound was collected by filtration (910 mg, 79%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]=[CH:14][C:13]=1[NH2:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:30]([O:32][CH2:33][C:34](Cl)=O)[CH3:31]>C(Cl)Cl.C(O)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:31]1[CH2:30][O:32][CH2:33][CH3:34])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCNc1c(N)cnc2cccnc12
Reactant: CCOCC(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cccnc3c2n1CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 89.2 %

Procedure:
N4-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)[1,5]naphthyridine-3,4-diamine (2.12 g, 6.67 mmol) was dissolved in 35 mL of anhydrous CH2Cl2 and the solution cooled to 0° C. and stirred under N2. Triethylamine (974 μL, 7.00 mmol) and ethoxyacetyl chloride (768 μL g, 7.00 mmol) were then added and the reaction mixture was stirred for 1 hour. The reaction mixture was then concentrated under reduced pressure to give a brown syrup. The brown syrup was dissolved in 50 mL of ethanol and treated with 4 mL of triethylamine. The mixture was heated to reflux for 3 days and then concentrated under reduced pressure. The resulting material was dissolved in 50 mL of CH2Cl2 and washed successively with H2O (2×50 mL) and brine (50 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10-20% CMA/CHCl3), gave 2.30 g of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridine as a purple solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.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>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:32]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:33])=[CH:37][CH:38]=1
Reactant: O=C(NCc1ccc(B(O)O)cc1)C1CCCC1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(-c2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CCCC1
Temperature: 80 °C

Procedure:
Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.1 equiv.), 4-[(cyclopentanecarbonyl-amino)-methyl]-phenyl-boronic acid (490 mg, 2.0 mmol) and sodium carbonate (2 equiv.) in THF/water (2:1, 15 mL) and heat the mixture at 80° C. for 6 h. Cool the reaction mixture to ambient temperature, dilute with EtOAc and wash with water. Dry the organic fraction over MgSO4, filter and concentrate in vacuo to obtain 7-chloro-6-{4-[(cyclopentanecarbonyl-amino)-methyl]-phenyl}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine, suitable for use without further purification.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH:14]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[OH:15])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][CH2:12][CH2:13][CH:14]([P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])[OH:15]
Reactant: CCOP(=O)(OCC)C(O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(OCC)C(O)CCN
Reaction time: 2 h

Procedure:
(R/S)-Diethyl 3-benzyloxycarbonylamino-1-hydroxypropylphosphonate (0.36 g, 1.04 mmol, from Step A) and palladium on carbon (10%, 0.10 g) were stirred together in methanol (5 mL) under an atmosphere of hydrogen. After 2 h, the reaction was filtered and concentrated in vacuo to give a colorless oil: 1H NMR (500 MHz, CD3OD) δ 4.10-4.22 (m, 4H), 4.00-4.05 (m, 1H), 2.85-3.00 (m, 2H), 1.85-2.00 (m, 2H), 1.34 (t, J=7.0 Hz, 6H); ESI-MS 211.8 (M+H)
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:14]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OC1CCCC1
Agent: [Rh]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of cyclopentanol (0.91 mL, 9.5 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt overnight. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue vacuum distilled at 150° C. to give 1.04 g of the product 444. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.04 (s, 2H), 1.85-1.45 (m, 8H), 1.29 (t, 3H)
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([Cl:23])[N:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:9]2=[N:8][C:7]=1[C:24]([F:27])([F:26])[F:25])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].CC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[Cl:23][C:12]1[N:13]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:9]2[N:10]([CH:11]=1)[C:6]([CH2:4][OH:3])=[C:7]([C:24]([F:25])([F:26])[F:27])[N:8]=2
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)c(-n2c(Cl)cn3c(CO)c(C(F)(F)F)nc23)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
To a solution of 6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid ethyl ester (978.3 mg, 1.904 mmol) in tetrahydrofuran (100 mL) at 0° C. was added a 1.0M solution of lithium aluminum hydride in tetrahydrofuran (5.71 mL, 5.71 mmol). The resulting solution was stirred at 0° C. for 10 min. Acetone (5 mL) was added and the solution was aded via cannula to a vigorously stirred ice-cold solution of Rochelle's salt (100 mL). The product was extracted with ethyl acetate (5×50 mL) and the combined organic extracts were dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude mixture was chromatographed on short silica gel column (hexanes-ethyl acetate 4:1) to give the desired product (614.8 mg, 90%) which was pure by LC-MS. LC/MS: tR=1.25 min., MS: [M+H]=358.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(O)C=CC=CC=1.C(O)CCC/C=C/CCCC.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]/[CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCC/C=C/CCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: CCCC/C=C/CCCCOc1ccc(C(=O)OC)cc1
Yield: 72 %

Procedure:
DEAD (256 mg, 1.47 mmol), phenol 34 (194 mg, 1.28 mmol), alcohol 26j (200 mg, 1.28 mmol), and TPP (386 mg, 1.47 mmol) in 13 ml anhydrous ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5 to 90/10 (v/v, Hex/EtOAc). Evaporation of the solvent yielded 266 mg (72%) of colorless liquid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][NH:13][C@@H:14]([CH2:22][CH2:23][CH3:24])[CH2:15][N:16]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17]1>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:13]([C@@H:14]([CH2:22][CH2:23][CH3:24])[CH2:15][N:16]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17]2)[CH3:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCC[C@@H](CN1CC[C@H](O)C1)NC
Solvent: ClCCl
Product: CCC[C@@H](CN1CC[C@H](O)C1)N(C)C(=O)c1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 2 %

Procedure:
4-Cyanobenzoyl chloride (0.800 g, 4.83 mmol) was added to a solution of (S)-1-((S)-2-(methylamino)pentyl)pyrrolidin-3-ol (Compound J7) (1 g, 5.37 mmol) and TEA (1.496 mL, 10.74 mmol) in DCM (25 mL) at 0° C. The reaction was stirred for 30 min and was then allowed to attain rt. After 1.5 h the reaction was quenched with K2CO3 (1 M aq., 25 mL) and the aqueous phase was extracted with DCM. The organic phases were pooled, dried (MgSO4), filtered and evaporated. The residue was dissolved in EtOAc and poured on an SCX-2 column (10 g). The column was washed with EtOAc and MeOH, The product was eluted with NH3 saturated MeOH. The crude product (1.200 g, 70.9%) was obtained as a yellow oil. A fraction of the crude material was purified by preparative HPLC to yield 31 mg of the title product with a purity of 99.5%. 1H NMR (400 MHz, CD3OD) δ 0.85-1.09, 1.14-1.75, 2.03-2.23, 2.29-2.61, 2.66-2.76, 2.82-3.00, 4.24-4.39, 5.49, 7.57-7.65, 7.80-7.85. HRMS (M+H)+: calculated 316.2025. found 316.2038.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH3:11][Al](C)C.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1(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)C=CC=CC=1>[CH3:11][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[Al](C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ncnc2nc[nH]c12
Temperature: 25 °C

Procedure:
A suspension of 6-chloropurine (0.2 mmol) and tetrakis(triphenylphosphino)-palladium (0.02 mmol) in dry THF (3 mL) was treated with trimethylaluminum (2M in toluene, 0.45 mmol) under nitrogen. The resulting solution was heated to reflux for 3 h, cooled to r.t., diluted with toluene (5 mL), and quenched with methanol (0.5 mL) followed by ammonium chloride (1 mmol). The mixture was heated to reflux for 2 h and filtered while hot through a Celite plug. Evaporation and purification by prep TLC afforded the 6-methylpurine. See J. Med. Chem. 1999, 42, 2064–2086.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:9])=[O:8].Cl.[CH3:42][NH:43][CH3:44].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:43]([CH3:44])[CH3:42])=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:9])=[O:8]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cc3cc(CN(C)C)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Yield: 40.1 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.455 g, 0.807 mmol) was dissolved in acetonitrile (16.0 mL), and the solution was treated with dimethylamine hydrochloride (1.31 g, 16.1 mmol), triethylamine (2.20 mL, 16.1 mmol), acetic acid (0.924 mL, 16.1 mmol) and sodium triacetoxyborohydride (0.513 g, 2.42 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=80/20) to obtain 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(dimethylaminomethyl)indol-2-yl]isoindolinone (0.192 g, 40%).
Reaction SMILES: FF.[N+:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[C-:4].[H-].[Na+].[F:13][C:14]([F:25])([F:24])/[C:15](/Cl)=[N:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[C:15]([C:14]([F:13])([F:24])[F:25])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:4]1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: FC(F)(F)/C(Cl)=N/c1ccccn1
Agent: FF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
The synthetic intermediate imine (Z)-2,2,2-trifluoro-N-(pyridin-2-yl)acetimidoyl chloride was prepared as described in Huang et al., J. Fluorine Chem., 74:279-282 (1995) and used without distillation. To ethyl isocyanoacetate (0.543 g, 4.8 mmol) in dry THF (50 mL) was added NaH (192 mg, 4 8 mmol, 60% dispersed in oil) at 0° C. and after 5 minutes, (Z)-2,2,2-trifluoro-N-(pyridin-2-yl)acetimidoyl chloride (1.0 g, 4.8 mmol) in 50 mL THF. The reaction mixture was allowed to warm to room temperature and then purified using an 80 g SiO2 column and a 50-100% EtOAc/hexanes gradient. The product eluted to yield 1.23 g (90% yield) of ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylate as a yellow oil. MS (M+1)=286.1; HPLC RT=1.08 minutes.