Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[C:6]([Cl:19])[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([Cl:19])[CH:5]=1)[NH:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20]
Reactant: COC(=O)c1ccc(N=Cc2cccc(Br)c2)c(Cl)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)c2c(c1)C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 4-[(3-bromo-benzylidene)-amino]-3-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7](I)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nn2C1CCC1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 1-cyclobutyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (60.0 mg, 0.190 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (64.4 mg, 0.194 mmol), Na2CO3 (50.5 mg, 0.476 mmol), and Pd(PPh3)4 (13.7 mg, 0.0119 mmol) in DMF (4 mL)/water (1 mL) for 5 min, then the mixture was heated under nitrogen to 80° C. (bath temp.) for 17 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined extracts were washed with brine and dried over MgSO4. MgSO4 was filtered off, and the filtrate was concentrated and chromatographed on an SCX column (1 g/6 mL barrel). The amine-containing fraction was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-11)→1% MeOH in CH2Cl2 (12-28)→2% MeOH in CH2Cl2 (29-46)], yielding the title compound as off-white solid. 1H NMR (CDCl3, 400 MHz): δ=1.87-2.04 (m, 2H), 2.48-2.58 (mc, 2H), 2.86-2.98 (mc, 2H), 5.50 (quint, J=8.0 Hz, 1H), 5.57 (brs, 2H), 7.47-7.52 (m, 1H), 7.53-7.58 (m, 2H), 7.96 (dd, J=1.6, 8.3 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 8.19-8.23 (m, 2H), 8.31 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 8.49-8.52 (m, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=14.99 (−), 29.91 (2C, −), 50.61 (+), 98.68 (Cquart), 119.59 (+), 126.53 (+), 126.97 (Cquart), 127.56 (2C, +), 128.66 (+), 128.79 (2C, +), 129.00 (+), 129.53 (+), 134.83 (Cquart), 136.53 (+), 139.14 (Cquart), 143.40 (Cquart), 148.22 (Cquart), 154.00 (Cquart), 155.53 (+), 157.92 (Cquart), 158.18 (Cquart). MS (ES+): m/z 393.1 (53) [MH+]. HPLC: tR=3.1 min (OpenLynx, nonpolar—5 min), 3.6 min (OpenLynx, polar—5 min).
Reaction SMILES: O(Cl)[Cl:2].[C:4]([C@@:7]1([OH:32])[C@:11]([C:13](=[O:15])[CH3:14])([OH:12])[C@@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:9][C@H:8]1[N:21]1[C:31]2[N:30]=[C:28]([NH2:29])[NH:27][C:25](=O)[C:24]=2[N:23]=[CH:22]1)(=[O:6])[CH3:5]>CCN(C1C=CC=CC=1)CC>[Cl:2][C:25]1[N:27]=[C:28]([NH2:29])[N:30]=[C:31]2[C:24]=1[N:23]=[CH:22][N:21]2[C@@H:8]1[O:9][C@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C@@:11]([C:13](=[O:15])[CH3:14])([OH:12])[C@@:7]1([C:4](=[O:6])[CH3:5])[OH:32]
Reactant: ClOCl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Yield: 69 %

Procedure:
500 ml of acetic anhydride and 500 ml of pyridine were added to 45 g of guanosine, and the reaction mixture was stirred for 12 hours at room temperature. The precipitated crystalline was separated by filtration and washed with water. The filtrate was concentrated under reduced pressure, and the precipitated crystalline was obtained by filtration. The first and second crystals were put together to give 2',3',5'-O-triacetylguanosine (yield: 94.4%). (ii) 375 ml of phosphoruos oxychloride and 20 ml of diethylaniline was added to 55 g of 2',3',5'-O-triacetylguanosine, and the reaction mixture was refluxed with heating for 3 minutes. The solution was concentrated to 100 ml under reduced pressure, poured into ice-cold water and extracted with dichloromethane. The dichloromethane layer was washed to be neutralized and dried over sodium sulfate anhydrate. After purification by silica gel column chromatography, the solution was concentrated under reduced pressure to give 40 g of 6-chloro-2-amino-9-(2,3,5-O-triacetyl-β-D-ribofuranosyl)-9H-purine (yield 69%).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:15][N:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].Cl>CC(O)=O>[C:18]1([CH2:17][CH2:16][N:14]2[CH2:15][C:11]3([CH2:10][C:9](=[O:28])[C:8]4[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=4)[O:24]3)[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)C1)O2
Yield: 107.5 %

Procedure:
(±)-(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-pyrrolidine]-6-yl]-acrylic acid methyl ester (280 mg, 0.71 mmol) was hydrolyzed with HCl and AcOH following the procedure described in Example 1, Step A, giving (±)-(E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-pyrrolidine]-6-yl]-acrylic acid as a white solid (288 mg, 98%). The acid was treated with NH2OTHP according to the procedure described in Example 1, Step C, giving (E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-pyrrolidine]-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (103 mg, 0.22 mmol, 31%). Finally, removal of THP protecting group following the procedure described in Example 1, Step D gave (±)-(E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-pyrrolidine]-6-yl]-N-hydroxy-acrylamide hydrochloride (33.7 mg, 36%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([OH:14])=O)=[N:9]2)=[CH:4][N:3]=1.[CH2:15]([N:17](CC)[CH2:18]C)C.ClC(OCC)=O.CNC>CC(C)=O.C1(C)C=CC=CC=1.C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([N:17]([CH3:18])[CH3:15])=[O:14])=[N:9]2)=[CH:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc2cnc(Br)cc2n1
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CC(C)=O
Product: CN(C)C(=O)c1ccc2cnc(Br)cc2n1
Temperature: 2.5 °C
Reaction time: 0.42 h
Yield: 41.1 %

Procedure:
7-Bromo-1,6-naphthyridine-2-carboxylic acid (Preparation 64, 232 mg 0.92 mmole) was azeotroped with ethanol (10 mL) and then with toluene (2×12 mL). The residue was dissolved in acetone (3 mL) with triethylamine (260 uL, 1.85 mmole) and cooled in ice. Ethyl chloroformate (195 uL, 2.03 mmole) was added and the reaction stirred at 0-5° C. for 25 minutes. Dimethylamine (2M in THF, 2.2 mL, 4.4 mmole) was added and the reaction stirred at 0-5° C. for 10 minutes followed by room temperature for 50 minutes. The acetone was evaporated and the residue partitioned between ethyl acetate (25 mL) and water (8 mL). The organic layer was washed with water (8 mL), brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 9:1 ethyl acetate:acetone to afford the title compound (106 mg, 41%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:27][N:28]([CH:37]=[O:38])[O:29]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[C:23]([O:24][CH3:25])=[N:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[CH3:26])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:27][N:28]([CH:37]=[O:38])[OH:29])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[C:23]([O:24][CH3:25])=[N:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[CH3:26])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccnc1NC(=O)[C@@H]1CCN(C)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1nccnc1NC(=O)[C@@H]1CCN(C)N1C(=O)[C@H](CC1CCCC1)CN(O)C=O
Reaction time: 1 h
Yield: 56.8 %

Procedure:
(3S)-2-[(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-methyl-N-[3-(methyloxy)-2-pyrazinyl]-3-pyrazolidinecarboxamide (96 mg, 0.183 mmol) was dissolved in methanol (11 mL). To this mixture was added 20% palladium hydroxide on carbon (26.8 mg, 0.038 mmol). The reaction mixture was degassed and placed under 1 atm of H2. After 1 h, the reaction mixture was filtered and concentrated. The residue was purified by RP-HPLC to afford (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-1-methyl-N-[3-(methyloxy)-2-pyrazinyl]-3-pyrazolidinecarboxamide (45 mg, 0.104 mmol, 54.3% yield) as white foam solid. LC-MS (ES) m/e 435.4 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[C:25]1([CH:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:32]2[CH:33]=[CH:34][C:35](=[O:38])[NH:36][N:37]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Br[CH2:46][C:47]1[CH2:48][CH2:49][C:50]2[C:55]([CH:56]=1)=[CH:54][CH:53]=[CH:52][C:51]=2[O:57][CH3:58].Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:58][O:57][C:51]1[CH:52]=[CH:53][CH:54]=[C:55]2[C:50]=1[CH2:49][CH2:48][C:47]([CH2:46][N:36]1[C:35](=[O:38])[CH:34]=[CH:33][C:32]([CH:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[N:37]1)=[CH:56]2
Reactant: COc1cccc2c1CCC(CBr)=C2
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)=C2
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of potassium tert-butoxide (0.39 g) and 18-crown-6 (0.08 g) in dry N,N-dimethylformamide (4 ml) was added 6-diphenylmethyl-3(2H)-pyridazinone (0.83 g) at room temperature. After ten minutes, 3-bromomethyl-1,2-dihydro-8-methoxynaphthalene (0.80 g) was added to the solution and stirred at the same temperature overnight. The reaction mixture was poured into ethyl acetate and 1N hydrochloric acid and the organic layer was separated, washed with water, aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 2-[(3,4-dihydro-5-methoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.55 g).
Reaction SMILES: C([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)C.C(NCC1CCNC1)C.N12CCCN=C1CCCCC2>C(#N)C>[F:15][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([F:13])[CH:10]=1)[NH:3][CH:4]=[C:5]([C:17]([OH:19])=[O:18])[C:6]2=[O:16]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: CCNCC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1c[nH]c2c(F)cc(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 22.50 g (83.03 mmole) 1-ethyl-1,4-dihydro-4-oxo-6,7,8-trifluoro-3-quinolinecarboxylic acid, 225 ml acetonitrile, 11.25 g (87.08 mmole) N-ethyl-3-pyrrolidinemethanamine and 12.6 g (83.03 mmole) 1,8-diazabicyclo[5.4.0]undec-7-ene was refluxed 1 hour then was stirred at room temperature overnight. The solid was filtered and washed with ether to give 26.33 g of 1-ethyl-7-[3-(ethylamino)-methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 208°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:13]([CH:16]=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C

Procedure:
A mixture consisting of 3,5-dimethoxybenzaldehyde (20 g), nitromethane (20 ml), ammonium acetate (8 g) and acetic acid (80 ml) was refluxted for 11/2 hours and the reaction mixture was poured into ice water. The yellow solid which separated was filtered and dried under high vacuum to yield the title compound (22.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23]C2CCCCO2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30]C2CCCCO2)[CH2:12][C:11]1=[O:37].C(O)(=O)C>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:30])[CH2:12][C:11]1=[O:37]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CC(=O)CCCCC(=O)OC)OC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(=O)OC
Temperature: 45 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a solution of 480 mg of (13E)-(11α,15S)-6,9-dioxo-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Example 1) in 1 ml of tetrahydrofuran was added 3 ml of 65% (v/v) aqueous acetic acid and the mixture was stirred at 45° C. for 3 hours. The reaction mixture was diluted with 16 ml of water and extracted with a mixture of ethyl acetate and n-hexane (1:1). The extract was washed with water, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and n-hexane (1:1) as eluent to give 177 mg of the title compound having the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2([OH:20])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.C[O:22][C:23](=[O:46])[C@H:24]([C@@H:43]([CH3:45])O)[NH:25]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2([O:20][C@H:43]([CH3:45])[C@@H:24]([C:23]([OH:46])=[O:22])[NH2:25])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2ccc(Cl)s2)c2ccccc2-c2ccccc21
Product: C[C@@H](OC1(c2ccc(Cl)s2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(5-chlorothien-2-yl)-9H-fluoren-9-ol (Example 31) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][C:5]1[N:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[O:33]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH2:35][CH:34]1C(Cl)=O.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(O)(=O)C>[O:33]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH2:35][CH:34]1[C:3](=[O:22])[CH2:4][C:5]1[N:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1
Reactant: O=C(Cl)C1COc2ccccc2O1
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)C2COc3ccccc3O2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 2 %

Procedure:
(6-Methyl-2-p-tolyl-imidazo[1,2,a]pyridin-3-yl)-acetic acid methyl ester 35a (447 mg, 1.5 mmol) was dissolved in anhydrous THF (15 mL) and cooled to −78° C. Potassium hexamethyldisilazide (0.5M in toluene, 3.0 mL, 1.5 mmol) was added slowly and the resulting bright orange solution was stirred at −78° C. for 10 minutes. 2,3-Dihydro-benzo[1,4]dioxine-2-carbonyl chloride (150 mg, 0.76 mmol) dissolved in anhydrous THF (10 mL) was added dropwise to the enolate solution. The resulting yellow solution was stirred for 1 h at −78° C. and quenched with H2O (30 mL). After the solution warmed to room temperature, it was washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. The crude keto-ester (0.76 mmol) was dissolved in concentrated acetic acid (4.5 mL) and concentrated HCl (4.5 mL). A reflux condenser was attached and the yellow solution was heated at 120° C. for 16 h. The solution was cooled to room temperature and saturated aqueous K2CO3 was added slowly until pH=6. The suspension was poured into saturated aqueous K2CO3 and washed with EtOAc (3×50 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. Purification was affected via silica gel column chromatography with 0–5% MeOH/CH2Cl2, then semi preparative reverse phase HPLC. Conditions: 20 mL/min flow rate, gradient of 40–80% CH3CN/H2O over 20 minutes, monitoring at 254 nm. The product eluted at 14.3 minutes. Product fractions were collected and concentrated to remove CH3CN, then washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. Final purification by silica gel column chromatography with 0–5% MeOH/CH2Cl2 yielded 1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-ethanone (6.0 mg, 2%) as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.56–7.50 (m, 3H), 7.42 (s, 1H), 7.23 (d, J=8.07, 2H), 7.04 (dd, J=1.1, 9.2 Hz, 1H), 6.95–6.89 (m, 4H), 4.82–4.80 (m, 1H), 4.51–4.42 (m, 2H), 4.33–4.26 (m, 2H), 2.40 (s, 3H), 2.31 (s, 3H). Mass spectrum (m/e) 399 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17](O)=[O:18].C(N(CC)C(C)C)(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:9][C:17](=[O:18])[CH:12]3[CH2:13][O:14][CH2:15][CH2:16][N:11]3[C:6]=2[N:7]=1
Reactant: O=C(O)C1COCCN1
Reactant: Nc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2,4-Dichloropyrimidin-5-amine (25 g, 152 mmol) and morpholine-3-carboxylic acid hydrochloride (28.1 g, 168 mmol) were dissolved in DMSO (200 mL) to give a yellow suspension. To the suspension was added N,N-diisopropylethylamine (106 mL, 610 mmol) and the mixture was heated to 100° C. for 18 hours. The mixture was cooled to room temperature and poured into ice. Water was added until the total volume was 1 L. The resulting beige suspension was stirred overnight before the solid was collected on a fritted-glass funnel of medium porosity. The solid was washed with water (3×) and then dried under a stream of nitrogen overnight to afford the title compound as a light yellow solid that was used without further purification (18.6 g, 51%). ESI-MS m/z [M+H]+ calc'd for C9H9ClN4O2, 241.04; found 241.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[NH2:41][C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][N:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:41][C:42]1[N:43]=[CH:44][C:45]([C:29]2[CH:28]=[CH:27][C:26]([C:9]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:16](=[O:17])[C:15]4[N:14]=[CH:13][N:12]([C:18]5[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=5)[C:21]#[N:22])[C:11]=4[N:10]=3)=[CH:31][CH:30]=2)=[CH:46][CH:47]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(C#N)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 3-{1-(4-chloro-phenyl)-6-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-purin-9-yl}-benzonitrile (prepared as described in example 43, 0.800 g, 1.45 mmol) in N,N-dimethylformamide (30 mL) is degassed with argon for 0.5 h. Then 2-amino-5-bromopyridine (0.37 g, 2.18 mmol), cesium carbonate (0.95 g, 3.63 mmol), Pd(dppf)2Cl2 (0.1 g, 0.181 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 4 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford 3-[2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile. LC-MS calculated for C29H18ClN7O (M+H+) 516.1, found 516.0.
Reaction SMILES: FC1C=C(CCC2C=CC=CC=2)C(OC)=C2C=1NC=C2CCO.[CH2:24]([NH:31][CH2:32][CH2:33][C:34]1[C:42]2[C:37](=[CH:38][C:39]([F:51])=[CH:40][C:41]=2[O:43]CC2C=CC=CC=2)[N:36]([CH2:52][CH3:53])[CH:35]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][CH2:32][CH2:33][C:34]1[C:42]2[C:41]([OH:43])=[CH:40][C:39]([F:51])=[CH:38][C:37]=2[N:36]([CH2:52][CH3:53])[CH:35]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCn1cc(CCNCc2ccccc2)c2c(OCc3ccccc3)cc(F)cc21
Agent: COc1c(CCc2ccccc2)cc(F)c2[nH]cc(CCO)c12
Product: CCn1cc(CCNCc2ccccc2)c2c(O)cc(F)cc21
Yield: 37 %

Procedure:
Following the procedure (step 2-1, scheme 23) used to prepare compound 23-2, compound 26-7 gave compound 26-8 in 37% yield (67.5 mg) as off-white solid. 1H NMR (300 MHz, MeOD-d6) δ (ppm): 7.41 (d, J=20.1 Hz, 5H), 6.96 (s, 1H), 6.59 (dd, J=9.9, 2.1 Hz, 1H), 6.19 (dd, J=11.2, 2.0 Hz, 1H), 4.20 (s, 2H), 4.05 (q, J=7.3 Hz, 2H), 3.37 (dd, J=13.4, 6.1 Hz, 2H), 3.26-3.16 (m, 2H), 1.37 (t, J=7.2 Hz, 3H). LRMS: calc 312.16. found 313.1 [MH]+.