Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][C:23]=3[N:24]2[CH3:27])=[CH:20][CH:19]=1>>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][C:23]=5[N:24]4[CH3:27])=[CH:20][CH:19]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(n(C)c3cc(Br)ccc23)C1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Product: CN1CCc2c(n(C)c3cc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)ccc23)C1
Product: Cl
Yield: 35 %

Procedure:
4-(4-Chlorobenzyloxy)pyridin-2(1H)-one (82 mg, 0.34 mmol) and 7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (97 mg, 0.34 mmol) were reacted following the procedure for Example 30 (step g) to provide the title compound (28 mg, 17%) as a yellow solid: mp 290-296° C.; 1H NMR (500 MHz, CD3OD) δ 7.83 (d, J=7.6 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.50-7.46 (m, 3H), 7.44-7.42 (m, 2H), 7.08 (dd, J=8.3, 1.8 Hz, 1H), 6.41 (dd, J=7.6, 2.6 Hz, 1H), 6.21 (d, J=2.6 Hz, 1H), 5.21 (s, 2H), 4.86-4.84 (m, 1H), 4.49 (d, J=15.4 Hz, 1H), 3.88-3.84 (m, 1H), 3.72 (s, 3H), 3.55-3.50 (m, 1H), 3.21-3.16 (m, 5H); ESI MS m/z 434 [M+H]+; HPLC (Method B) 98.6% (AUC), tR=14.0 min.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([O:5][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:4]
Reactant: O=C(O)[C@@H](O)CC1CCC1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COC(=O)[C@@H](O)CC2CCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A mixture of 432 mg (3.0 mmol) of 2-(S)-hydroxy-3-cyclobutyl propanoic acid (from EXAMPLE 19, Step D), 0.61 mL of 4-(methoxy)benzyl chloride and 0.63 mL of TEA was stirred at rt for 20 h. The reaction mixture was partitioned between 100 mL of ether and 50 mL of H2O and the layers were separated. The organic layer was washed with 50 mL of sat'd NaHCO3, 50 mL of 2.0 N HCl, 2×50 mL of H2O and 50 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 30 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 598 mg (75%) of the title compound: 1H NMR (500 MHz) δ 1.56-1.94 (6H), 1.98-2.12 (m, 2H), 2.44-2.56 (m, 1H),2.64 (br s, 1H), 3.82 (s, 3H), 4.11-4.13 (m, 1H), 5.19 (ABq, J=25.0, 2H), 6.90 (d, J=9.0, 2H), 7.30 (d, J=9.0, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCc1ccccc1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-benzyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.3 mmol 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of benzylamine. LC/MS [7.55 min; 448 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]2[N:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:10][C:3]=12.[CH:25]([NH:28][C:29]1([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:27])[CH3:26].CCN(CC)CC>CCO>[ClH:1].[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:4]2=[CH:5][N:6]=[N:7][C:2]([N:32]3[CH2:31][CH2:30][C:29]([NH:28][CH:25]([CH3:27])[CH3:26])([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33]3)=[C:3]2[N:10]=1
Reactant: CC(C)NC1(C(N)=O)CCNCC1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)nncc32)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)NC1(C(N)=O)CCN(c2nncc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Product: Cl
Temperature: 25 °C
Yield: 44.6 %

Procedure:
A solution of 4-chloro-2-(2-chloro-phenyl)-1-(4-chloro-phenyl)-1H-imidazo[4,5-d]pyridazine (I-2h, 11 mg, 0.29 mmol), 4-isopropylamino-piperidine-4-carboxylic acid amide (6 mg, 0.032 mmol) and NEt3 (8 μl, 0.06 mmol) in EtOH (1 ml) was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethylene glycol (1.5 ml) and NEt3 (8 μl) was added. The reaction mixture was heated at 120° C. for 1.5 hours and at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and diluted with H2O. The aqueous solution was extracted with CH2Cl2 (3×) and the combined organic extracts were washed with sat'd aq NaCl, dried, and concentrated in vacuo. The residue was purified on a chromatotron plate (1 mm) using 10:1 CH2Cl2/MeOH(NH3) to give the free amine 2A-1 (8 mg) as a solid: +APCI MS (M+1) 523.9; 1H NMR (CD3OD) δ1.08 (6H, d), 1.80–1.87 (2H, m), 2.16–2.25 (2H, m), 2.95–3.08 (1H, m), 4.18–4.30 (2H, m), 4.32–4.42 (2H, m), 7.30–7.70 (8H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)C(=O)[O:10][N:9]=2)=[N:5][O:6][N:7]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C.C(Cl)Cl.CN(C1C=CN=CC=1)C.CO>[Cl:20][C:15]1[CH:14]=[C:13]([NH:12][C:8]([C:4]2[C:3]([CH2:2][NH:1][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])=[N:7][O:6][N:5]=2)=[N:9][OH:10])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 164.7 %

Procedure:
3-[4-(Aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (10 mg, 0.003 mmol) was dissolved in ACN (0.2 mL) and DCM (0.2 mL). Phenyl isocyanate (7.6 mg, 0.064 mmol) DIPEA(0.012 mg, 0.096 mmol) and DMAP (0.4 mg, 0.03 mmol) were added and stirred at rt for 6 hrs. The reaction was then diluted with MeOH and purified by preparative LCMS. The intermediate was stripped to dryness, redissolved in EtOH (1 mL) and 1 M of sodium hydroxide in water (0.06 mL) was added. The reaction was stirred at rt for 1 hour, quenched with acetic acid and diluted with MeOH. The crude was purified by preparative LCMS to afford the desired product (2.0 mg). MF=C17H14ClFN6O3; LCMS calculated for C17H15ClFN6O3(M+H)+: m/z=405.1.
Reaction SMILES: [CH:1]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][C:7](=O)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.B#B.CSC.O.[OH-].[Na+]>O1CCCC1>[CH:1]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Cc2cccn2-c2ccccc2N1
Agent: B#B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: c1ccc2c(c1)NCCc1cccn1-2
Yield: 99.9 %

Procedure:
To a solution of 0.070 g of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-6-one in 2 ml of tetrahydrofuran is added 0.45 ml of a 2.0M solution of diborane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 3 hours, poured into water and made basic with 2N NaOH. The tetrahydrofuran is removed under vacuum and the residual aqueous mixture extracted with diethyl ether. The extract is washed with brine, dried (Na2SO4) and the solvent removed to give 0.065 g of a colorless oil; one spot by thin layer chromatography (silica gel) with ethyl acetate-hexane (1:2) as solvent (Rf 0.81).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][Si:14]([CH2:17][Mg]Cl)([CH3:16])[CH3:15].CCOCC>O1CCCC1>[O:1]1[C:10]2[CH:9]=[C:8]([CH:11]([OH:12])[CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=Cc1cc2c(cn1)OCCO2
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)c1cc2c(cn1)OCCO2

Procedure:
A solution of aldehyde (c) (1.2 g) in tetrahydrofuran (20 ml) was treated at 0° C. under argon with a solution of trimethylsilylmethylmagnesium chloride in ether (1M; 8 ml, 8 mmol). After 2 hours the mixture was partitioned between ether—half saturated aqueous ammonium chloride solution. The organic extract was dried and evaporated affording an oil (1.6 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.N1C=CN=C1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.C1(C)C=CC=CC=1.O>[Si:28]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:6][CH2:7]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 12A (6.5 g, 26.5 mmol) in DMF (20 mL) was added imidazole (3.61 g, 53.0 mmol), followed by tert-butylchlorodimethylsilane in toluene (9.22 mL, 26.5 mmol) portionwise while cooling with an ice bath. Upon completion of the addition, the resulting mixture was stirred at 40° C. for 3 h. There was still some starting material left, so more 50% tert-butylchlorodimethylsilane in toluene (2.5 mL) was added, and the mixture was stirred briefly at room temperature. The mixture was diluted with water and extracted with hexane (3×). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide 12B (9.1 g, 96% yield) as a white solid. MS (ES): m/z=360.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (dd, 2H, J=5.5, 3.1 Hz); 7.62 (dd, 2H, J=5.5, 3.1 Hz); 3.96-4.15 (m, 1H); 3.56-3.72 (m, 1H); 2.17-2.29 (m, 2H); 1.85-1.92 (m, 2H); 1.61-1.69 (m, 2H); 1.31-1.43 (m, 2H); 0.82 (s, 9H); 0.00 (s, 6H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)/C=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].Cl>O.CO>[C:14]1([CH:13]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccccc1O
Reactant: O=C/C=C/c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
A solution of 5.00 g (36.7 mmol) of 2'-hydroxyacetophenone, 4.85 g (36.7 mmol) of trans-cinnamaldehyde, 11.10 g NaOH (in 20 mL of water) and 250 mL MeOH was stirred for 23 hours before the solution was poured into 1000 mL water. The resulting mixture was neutralized with dilute HCl and the yellow precipitate was collected by filtration. Recrystallization from MeOH gave a pure intermediate chalcone product. Further oxidation of the above chalcone was carried out with excess H2O2 (30%) in basic (NaOH aq.) MeOH solution for 12 hours. This solution was poured into water, and neutralized with dilute HCl. The resulting light yellow precipitate was collected by filtration and the pure desired product was obtained by recrystallization from MeOH with 7% overall yield. MP: 189°-191° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 0.04. Extinction coefficient εmax (M-1 cm-1) 26,000. λmax (abs)=374 nm and λmax (em)=600 nm.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]2[C:11]=1[CH2:12][C:13]#[N:14].[I-].C[CH:17]=[N+:18]=[CH:19]C.[CH2:21](Cl)Cl>>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([OH:10])=[C:8]([CH2:17][N:18]([CH3:19])[CH3:21])[CH:7]=[CH:6][N:5]2[C:11]=1[CH2:12][C:13]#[N:14]
Reactant: ClCCl
Reactant: CC=[N+]=CC
Reactant: Cc1nc2c(O)cccn2c1CC#N
Agent: [I-]
Product: Cc1nc2c(O)c(CN(C)C)ccn2c1CC#N

Procedure:
Stir a mixture of 24 g (0.13 mol) 2-methyl-8-hydroxyimidazo[1,2-a]pyridin-3-acetonitrile and 26 g (0.14 mol) N,N-dimethylmethyleneammonium iodide in 4L methylene chloride at ambient temperature for 4 days. Isolate the resulting solid by filtration, treat with 200 ml dilute ammonium hydroxide and extract continuously with methylene chloride for 4 hr. Remove the methylene chloride under reduced pressure and obtain 20 g 2-methyl-7-dimethylaminomethyl-8-hydroxy-imidazo[1,2-a]-pyridin-3-acetonitrile.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6](=[O:13])C(=O)[NH:8]2)=[CH:4][CH:3]=1.[OH-:14].[Na+].OO.Cl>>[NH2:8][C:9]1[C:10]([F:11])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:13])=[O:14]
Reactant: O=C1Nc2c(ccc(F)c2F)C1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Nc1c(C(=O)O)ccc(F)c1F
Temperature: 65 °C

Procedure:
6,7-Difluoroisatin (22.2 g) was added to a solution of sodium hydroxide (2N, 185 ml). Hydrogen peroxide (30%, 36 ml) was added at 40° C. or less over 20 minutes. After 1 hour the mixture was heated to 65° C. for 0.5 hours, cooled, poured onto water and acidified with concentrated hydrochloric acid. The resulting solid was filtered, washed with water and recrystallised from ethyl acetate/cyclohexane to give 2-amino-3,4-difluorobenzoic acid (11.3 g) as an orange solid, m.p. 207-208° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Li+].[OH-]>CO.O1CCCC1.O>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cnc(Oc2cccc(C(F)(F)F)c2)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Oc2cccc(C(F)(F)F)c2)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
To a solution of methyl 5-bromo-6-(3-(trifluoromethyl)phenoxy)nicotinate (610 mg, 1.62 mmol) in methanol (4.00 mL), tetrahydrofuran (THF) (4 mL) and water (2.000 mL) was added LiOH (117 mg, 4.87 mmol) at rt. The reaction mixture was stirred at rt for 3 h, quenched with HCl and concentrated. Purification via ISCO system (ethyl acetate/petroleum ether=1/10) afforded the title product (600 mg).
Reaction SMILES: CO.[CH3:3][Si](C=[N+]=[N-])(C)C.[F:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:21][CH:20]=[C:19]([OH:31])[C:18]=3[C:17]2=[O:32])=[CH:13][CH:12]=1.C(O)(=O)C>C(Cl)(Cl)Cl>[F:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:21][CH:20]=[C:19]([O:31][CH3:3])[C:18]=3[C:17]2=[O:32])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of chloroform (10 mL) and methanol (10 mL) was added trimethylsilyl diazomethane (2.0 M in hexanes, 5 mL, 0.01 mole). After stirring for 10 minutes at room temperature, ethyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (1.6 g, 3.5 mmol) in chloroform was added. After 7 hours, methanol (5 mL) and trimethylsilyl diazomethane (2.5 mL, 0.005 mole) was added to the reaction mixture. After 1 hour, glacial acetic acid (3 mL) was added with gas evolution observed. The solution was stirred for 0.5 hour. The product mixture was concentrated under vacuum. The residual material was subjected to column chromatography on silica gel eluting with 0-100% ethyl acetate in hexanes. The appropriate fractions were combined and concentrated to afford the title compound as a foam.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:26][CH2:25]1)=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:24]1([C:22]([NH:21][NH:20][C:18]([C@H:13]2[CH2:12][CH2:11][C@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])=[O:23])[CH2:26][CH2:25]1
Reactant: [H][H]
Reactant: O=C(NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1)C1CC1
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O)C1CC1
Yield: 99 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N′-(cyclopropylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 197 (0.27 g, 0.75 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g) The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)—N′-(cyclopropylcarbonyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 198 (0.20 g, 98%) as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1COCC1.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>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cccs1
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: COCCOC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cccs2)cc1
Temperature: 85 °C
Yield: 77.8 %

Procedure:
To a stirred degassed solution of 4-bromobenzaldehyde (371 mg, 2.00 mmol) and thiophene-2-boronic acid (287 mg, 2.24 mmol) in DME/THF (5 mL, 4:1) were added a 2 M Na2CO3 solution (3.0 mL) and Pd(PPh3)4 (110 mg, 0.095 mmol). The reaction mixture was flushed with argon and maintained under argon while being heated at 85° C. over 2 days. The mixture was then cooled and diluted with EtOAc (35 mL) and water (30 mL). The aqueous layer was washed with EtOAc (2×10 mL) and the combined organic extracts dried (Na2SO4), filtered and concentrated. Purification of the resultant oil by column chromatography on silica gel (Hexanes/EtOAc, 4:1) afforded the title compound (293 mg, 78%) as a yellow solid. 1H NMR (CDCl3) δ7.14 (dd, 1H, J=5.1, 3.6 Hz), 7.40 (dd, 1H, J=5.1, 0.9 Hz), 7.46 (dd, 1H, J=3.6, 0.9 Hz), 7.76 (d, 2H, J=8.4 Hz), 7.88 (d, 2H, J=8.4 Hz), 10.00 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=O)[CH3:19])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.O>O1CCCC1>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ccc2c(c1)CN(Cc1ccccc1)C2

Procedure:
2-benzyl-5-acetamidoisoindoline prepared above was dissolved in 30 ml of anhydrous tetrahydrofuran and to the solution was dropwise added 600 mg of lithium aluminum hydride dissolved in 10 ml of tetrahydrofuran over 10 minutes. After the mixture was refluxed for 2 hours, ether saturated with water was added to it. The resulting precipitatess were removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (chloroform/methanol =25/1) to obtain 2.19 g of 2-benzyl-5-ethylaminoisoindoline as a dark brown oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[In+3].[CH:5]1([Mg]Br)[CH2:7][CH2:6]1.[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[CH3:11]>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.C1COCC1>[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([CH:5]2[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH3:11]
Reactant: Br[Mg]C1CC1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [In+3]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2CC2)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Indium trichloride (2.2 g, 10 mmol) and THF (50 mL) were combined under nitrogen and cooled to −70° C. Cyclopropylmagnesium bromide solution (33 mL, 30 mmol, 0.92 M) was added dropwise while maintaining the reaction temperature ≦−60° C. After the addition was complete, the reaction was stirred 0.5 h with cooling then 0.5 h with the cooling bath removed. The resulting solution was added via cannula to a refluxing solution of ethyl-4-iodobenzoate (5.5 g, 20 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (421 mg, 0.60 mmol) and THF (100 mL) under nitrogen. After 24 h, the contents of the reaction flask were cooled and the solvent was removed in vacuo. Water (100 mL) and 5% KHSO4 were added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried with NASO4 and filtered. The filtrate was removed in vacuo and the remaining residue was purified by flash column chromatography (hexane:EtOAc 95:5) to give 4-cyclopropyl-benzoic acid ethyl ester as an orange oil.
Reaction SMILES: S(Cl)(=O)(=O)O.[CH2:6]1[S:8][CH2:7]1.[CH3:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:12].[ClH:22]>N1C=CC=CC=1.C(Cl)Cl.O>[Cl:22][CH2:7][CH2:6][S:8][N:10]([CH3:9])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:12]
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: C1CS1
Reactant: Cl
Agent: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CN(SCCCl)C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
27 g of chlorosulfuric acid were slowly added at 0° C to a mixture of 12 g of ethylene sulfide and 200 ml of methylene chloride and the mixture was stirred at 0° C for 10 minutes and was then cooled to -20° C. A mixture of 32.6 g of N-methyl-N'-(3,4-dichlorophenyl)-urea in 210 ml of pyridine was added to the reaction mixture after which the temperature returned to 0° C. The mixture was stirred at 0° C for 10 minutes and was then poured into a mixture of ice, water, hydrochloric acid and methylene chloride. The mixture was stirred for 30 minutes and the decanted organic phase was washed, dried, filtered and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel and the product was eluted witn 9-1 benzene-ethyl acetate mixture and was crystallized from isopropyl ether to obtain 10 g of N-(2-chloroethylthio)-N-methyl-N'-(3,4-dichlorophenyl)-urea melting at 62° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]1([N:47]=[C:48]=[S:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.NC(N)=S>>[C:41]1([NH:47][C:48]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[S:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: S=C=Nc1ccccc1
Agent: NC(N)=S
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=S)Nc3ccccc3)cn2)cc1
Yield: 155.2 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.0 mg, 0.148 mmol) and phenyl isothiocyanate (53.0 μl, 0.447 mmol) instead of o-tolyl isothiocyanate, thiourea was formed in the same manner as Example 1-D-210, to obtain a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid phenylamide as a brown solid (155 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-216) as a yellow powder (34.5 mg, 55%).