Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1)[C:14]([O:16]C)=[O:15].[OH:35][Li].O>C1COCC1.O>[C:14]([CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][Si:25]([CH:29]([CH3:30])[CH3:31])([CH:32]([CH3:33])[CH3:34])[CH:26]([CH3:27])[CH3:28])=[CH:20][CH:19]=1)[CH2:12][NH:3][C:2]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:4]([OH:35])=[O:11])=[O:1])([OH:16])=[O:15]
Reactant: [Li]O
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(C(CNC(=O)c2ccccc2C(=O)O)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 1.5 h

Procedure:
To methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(triisopropylsilyloxy)phenyl)propanoate (E3) in THF/H2O was added LiOH.H2O, and the solution was stirred for 1.5 h or until conversion to product was visible by LC-MS. The solution was then poured into EtOAc/NH4Cl(sat)/1 N HCl (3:1), and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, evaporated, and dried to give crude 2-(2-carboxy-2-(4-(triisopropylsilyloxy)phenyl)ethylcarbamoyl)benzoic acid (E4).
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[C:4]1[N:17]=[C:7]2[CH:8]([CH:12]([CH:14]3[CH2:16][CH2:15]3)[OH:13])[NH:9][CH2:10][CH2:11][N:6]2[N:5]=1.[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:29][C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:29][C:30]([N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([C:3]([F:18])([F:2])[F:19])[N:17]=[C:7]2[CH:8]1[CH:12]([CH:14]1[CH2:15][CH2:16]1)[OH:13])=[O:31])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: OC(C1CC1)C1NCCn2nc(C(F)(F)F)nc21
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2nc(C(F)(F)F)nc2C1C(O)C1CC1)Cc1cc(F)c(F)cc1F

Procedure:
A 160 mg portion of [2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazin-8-yl](cyclopropyl)methanol hydrochloride was coupled to (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid essentially following the procedure outlined in Example 2, Step D. Purification by preparative TCL (silica gel, 10% methanol/dichloromethane) gave 176 mg of the product as a mixture of diastereomers. HPLC (OD chiralcel column, 6% ethanol/hexane) separated the first and last eluting diastereomers. The middle fractions containing two diastereomers were further subjected to HPLC (OD chiralcel column, 3% ethanol/hexane) to provide the second and the third eluting diastereomers.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[Cl-].Br[CH2:26][O:27][C:28](=[O:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[C:8]2[C:12]([O:14][CH2:26][O:27][C:28](=[O:30])[CH3:29])=[O:13])[CH3:3]
Reactant: CC(=O)OCBr
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(C(=O)OCOC(C)=O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Yield: 48 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.18 g) in dry DMF (3.6 ml) was ice-cooled, and thereto was added triethylbenzylammoniun chloride (0.11 g). To the mixture was gradually dropped bromomethylacetate (0.16 ml) and the mixture was gradually allowed to room temperature and stirred. Forty minutes later, thereto was added ethyl acetate, and the mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated and the residue was purified with silica gel column chromatography (ethyl acetate only) to give (acetyloxy)methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.15 g, yield 48%).
Reaction SMILES: [OH:1][C@H:2]([CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C([CH2:18][C:19]([O-])=[O:20])=C>O1CCCC1>[C:19]([O:14][CH2:13][C@@H:12]([OH:15])[CH2:11][C@@H:2]([OH:1])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])(=[O:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CO
Reactant: C=CCC(=O)[O-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred 1 l round bottom flask 700 ml tetrahydrofuran and 70.7 g (0.32 mol) of (3R,5S) t-butyl 3,5,6-trihydroxyhexanoate, 41 ml (0.46 mol) vinylacetate and 6.3 g of the supported lipase Chirazyme L2™ were charged. After 3 hours stirring at ambient temperature the lipase was removed by screening and the volatiles removed by distillation under vacuum. The mass of crude oil was 78.7 g and the major component was determined to be (3R,5S) t-butyl 6-acetoxy-3,5-dihydroxyhexanoate. This material was used directly in the next stage.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>N1C=CC=CC=1>[CH2:24]([O:23][C:21]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)=[O:22])[CH3:25]
Reactant: CC1CC(=O)NN=C1c1ccc2c(N)ncnc2c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ncnc2cc(C3=NNC(=O)CC3C)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Compound 11 (0.20 g) obtained in Example 11 was dissolved in 5 ml of pyridine, and 0.1 ml of ethyl chloroformate was added to the solution. The resulting mixture was stirred at room temperature for 3 hours and then concentrated. Water was added to the residue, and the crystals precipitated were collected by filtration and dried to give 0.21 g (82%) of 6-(4-ethoxycarbonylamino-quinazolin-7-yl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Compound 53).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.C(O[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)(C)C>C1COCC1>[CH3:30][C:25]1([CH3:31])[C:26]([CH3:29])([CH3:28])[O:27][B:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:13][CH:12]4[CH:10]([CH2:11]4)[CH2:9]3)[CH:5]=[CH:6][CH:7]=2)[O:24]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1cccc(N2CC3CC3C2)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2cccc(N3CC4CC4C3)c2)OC1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
3-(3-Bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane (2.0 g, 8.4 mmol) was dissolved in 40 mL of THF and cooled to −78° C. in a dry ice acetone bath. tert-Butyl lithium (1.7 M solution in pentane, 14.8 mL, 25.2 mmol) was added dropwise and the reaction was stirred at −78° C. for 15 min. 2-Isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.4 mL, 16.8 mmol) was added and the reaction was stirred at −78° C. for 2 h. The reaction was quenched with saturated aqueous ammonium chloride and warmed to room temperature. Water was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried, filtered and concentrated. The crude residue was chromatographed using a gradient of 0% to 10% ethyl acetate/heptane to give 1.93 g (81%) of 3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-aza-bicyclo[3.1.0]hexane as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([F:17])[CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3].[Cl:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])C=CC=1>C(Cl)Cl>[Cl:18][CH2:19][CH2:20][CH2:21][NH:25][C:26]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[CH:7]=[CH:8][N:9]=[C:5]2[CH2:4][N:2]([CH3:1])[CH3:3])=[CH:11][C:12]=1[F:17])=[O:27]
Reactant: CN(C)Cc1nccn1-c1ccc(N)c(F)c1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)Cc1nccn1-c1ccc(NC(=O)NCCCCl)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 234.3 mg (1 mmol) of 4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenylamine in 5 mL of anhydrous CH2Cl2 and under N2 atmosphere were added 179 mg (1.5 mmol) of 3-chlorophenylisocyanate. The mixture was stirred for 3 days at room temperature. The volatiles were concentrated to yield quantitatively 1-(3-chloro-propyl)-3-[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenyl]-urea as a viscous oil. This compound can be was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.25 (t, J=8.6 Hz, 1H), 7.44 (dd, J=9.7 Hz, and J=2.1 Hz, 1H), 7.25 (m, 1H), 7.13 (m, 1H), 7.065 (d, J=6.5 Hz, 1H), 5.65 (t, 1H), 3.65 (t, J=6.5 Hz, 2H), 3.47 (m, 2H), 3.38 (s, 2H), 2.24 (s, 6H), 2.05 (m, 2H), ppm. LC-MS (ESI) 354.0 [M+H]+, tR=2.51 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C16H22ClFN5O[M+H]+ 354.1497. found 354.1491.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][CH2:22][C:23]([NH2:25])=[O:24].Cl.C(N(CC)CC)C>C(O)C>[CH:15]1([O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][C:4](=[O:20])[CH:3]=[C:2]3[NH:21][CH2:22][C:23]([NH2:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2c(NCC(N)=O)cc(=O)oc2c1OC1CCCC1
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (170 mg, 0.58 mmol, Example 7, Step 1), glycinamide•HCl (77 mg, 0.70 mmol), triethylamine (0.2 mL, 1.4 mmol), and ethanol (2 mL) was heated at 75° C. in a sealed vial for 30 h. The reaction was allowed to cool to rt, concentrated, diluted with dichloromethane (10 mL), and let stand. After 10 min, the free-flowing solid was filtered and dried to give 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)acetamide: 1H NMR (400 MHz, DMSO-d6): δ 7.89 (t, 1H), 7.70 (d, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 7.07 (d, 1H), 4.83 (s, 1H), 4.81 (m, 1H), 3.86 (s, 3H), 3.80 (d, 2H), 1.90-1.48 (m, 8H); MS (ESI): 333.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C@H:6]1[C@H:14]([CH3:15])[O:13][C:12](=[O:16])[C@@H:11]([NH:17][C:18](=[O:28])[C:19]2[C:24]([OH:25])=[C:23]([O:26][CH3:27])[CH:22]=[CH:21][N:20]=2)[CH2:10][O:9][CH2:8][C@@H:7]1[O:29][CH2:30][CH:31]([CH3:33])[CH3:32].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].[CH2:45]([O:47][CH2:48][C:49]([O:51][CH2:52]Cl)=[O:50])[CH3:46]>CC(C)=O>[CH2:45]([O:47][CH2:48][C:49]([O:51][CH2:52][O:25][C:24]1[C:19]([C:18](=[O:28])[NH:17][C@H:11]2[CH2:10][O:9][CH2:8][C@H:7]([O:29][CH2:30][CH:31]([CH3:32])[CH3:33])[C@@H:6]([O:5][C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([Cl:1])[CH:3]=3)[C@H:14]([CH3:15])[O:13][C:12]2=[O:16])=[N:20][CH:21]=[CH:22][C:23]=1[O:26][CH3:27])=[O:50])[CH3:46]
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCC(C)C)[C@@H](Oc3cccc(Cl)c3)[C@H](C)OC2=O)c1O
Reactant: CCOCC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOCC(=O)OCOc1c(OC)ccnc1C(=O)N[C@H]1COC[C@H](OCC(C)C)[C@@H](Oc2cccc(Cl)c2)[C@H](C)OC1=O
Temperature: 45 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
To a solution of N-((3S,7S,8S,9S)-8-(3-chlorophenoxy)-7-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (85 mg, 0.163 mmol) in acetone (2.0 mL) was added Na2CO3 (34.5 mg, 0.325 mmol), NaI (4.87 mg, 0.033 mmol), and chloromethyl 2-ethoxyacetate (37.2 mg, 0.244 mmol). The reaction was warmed to 45° C. and stirred for 16 h. The reaction was then concentrated and the residue purified by flash chromatography (SiO2; EtOAc/Hexanes) to give the title compound as a white foam (72.2 mg, 69.5%): 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=8.0 Hz, 1H), 8.29 (d, J=5.4 Hz, 1H), 7.17 (t, J=8.2 Hz, 1H), 7.04 (t, J=2.2 Hz, 1H), 6.96 (d, J=5.4 Hz, 1H), 6.95-6.87 (m, 2H), 5.82 (s, 2H), 5.23-5.06 (m, 2H), 4.25 (t, J=9.1 Hz, 1H), 4.10 (s, 2H), 3.91 (s, 4H), 3.82 (dd, J=11.8, 5.3 Hz, 1H), 3.71 (dd, J=11.1, 7.4 Hz, 1H), 3.59 (q, J=7.0 Hz, 2H), 3.37 (ddd, J=8.9, 7.4, 1.6 Hz, 1H), 3.29 (dd, J=8.8, 6.3 Hz, 1H), 3.15 (dd, J=8.8, 6.4 Hz, 1H), 1.67-1.51 (m, 2H), 1.39 (d, J=6.3 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H), 0.68 (dd, J=18.4, 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 170.88, 170.06, 163.23, 160.17, 145.87, 143.98, 141.92, 134.59, 129.98, 121.38, 116.68, 114.41, 109.87, 89.44, 83.42, 82.64, 78.00, 74.36, 74.08, 72.30, 67.80, 67.20, 56.25, 52.32, 28.62, 19.16, 19.06, 18.72, 15.01; HRMS-FAB (m/z) [M+H]+ calcd for C30H39ClN2O11, 639.2315; found, 639.2320.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:29]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:28][CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Product: Fc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, white solid (27 mg, 20%), MS (ISP) m/z=389.4 [(M+H)+], mp 147° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate E) (0.1 mg, 0.34 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.13 g, 0.41 mmol).
Reaction SMILES: C([O:9][C@H:10]([C@@H:13]1[CH2:17][C@@H:16]([CH3:18])[C@H:15]([N:19]2[C:23]3[N:24]=[C:25]([NH2:29])[NH:26][C:27](=[O:28])[C:22]=3[S:21][C:20]2=[O:30])[O:14]1)[CH2:11][CH3:12])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:29][C:25]1[NH:26][C:27](=[O:28])[C:22]2[S:21][C:20](=[O:30])[N:19]([C@H:15]3[C@H:16]([CH3:18])[CH2:17][C@@H:13]([C@@H:10]([OH:9])[CH2:11][CH3:12])[O:14]3)[C:23]=2[N:24]=1
Reactant: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC[C@H](O)[C@@H]1C[C@@H](C)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.2 %

Procedure:
To a solution of compound [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-methyl-tetrahydrofuran-2-yl]propyl] benzoate (compound 28k-A, 120 mg, 0.27 mmol) in MeOH (2 mL) was added K2CO3 (58 mg, 0.42 mmol). After being stirred at room temperature for 5 hours, the reaction mixture was adjusted to pH 7 by bubbling CO2 and then concentrated in vacuo. The residue was purified by preparative HPLC to afford 24 mg of 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hydroxypropyl]-3-methyl-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (Example 28) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+]>N1C=CC=CC=1>[Cl:21][C:16]1[CH:15]=[C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:24](=[O:26])(=[O:25])[N:23]2[CH3:22])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(F)c(Cl)c2)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)c(Cl)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 34.3 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(3-chloro-4-fluoro-phenyl)-methanone (Intermediate 376) (80 mg, 0.27 mmol), N-methylsulfamoyl chloride (Intermediate 213) (103 mg, 0.8 mmol) and NaBH4 (10 mg, 0.27 mmol) in pyridine (3 ml) gave the title compound (35 mg, 35%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[N:13]1([CH2:18][CH2:19][C:20]#[N:21])[CH:17]=[CH:16][CH:15]=[CH:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[O:12]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[C:2]1[C:14]1[N:13]([CH2:18][CH2:19][C:20]#[N:21])[CH:17]=[CH:16][CH:15]=1
Reactant: N#CCCn1cccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: N#CCCn1cccc1C1=CC(=O)c2ccccc2C1=O
Yield: 42 %

Procedure:
6.32 millimol of 1,4-naphthoquinone and 3.16 millimol of 3-(1-pyrrolyl) propionitrile were stirred in 50 ml of chloroform in a round-bottomed flask for 5 hours at room temperature, the reaction being catalysed by addition of a few milligrams of para-toluenesulphonic acid. The reaction medium was diluted with 50 ml of chloroform and then washed four times with 50 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 3-[2-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)pyrrol-1-yl]propionitrile was thus isolated in a yield of 42% after purification by chromatography on a column of silica.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:34]#[N:35])[C:16]([C:19]2[CH:24]=[C:23](B3OCC(C)(C)CO3)[CH:22]=[CH:21][C:20]=2[F:33])=[CH:17][CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([C:34]#[N:35])[C:16]([C:19]2[CH:24]=[C:23]([C:2]3[N:6]4[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]4=[N:4][CH:3]=3)[CH:22]=[CH:21][C:20]=2[F:33])=[CH:17][CH:18]=1
Reactant: Fc1cccn2c(Br)cnc12
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3c(F)cccn23)ccc1F
Yield: 54.8 %

Procedure:
3-Bromo-8-fluoroimidazo[1,2-α]pyridine (0.10 g, 0.47 mmol) and 4,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile (0.28 g, 0.83 mmol) were coupled following the procedure in Example 1 to afford 4,2′-difluoro-5′-(8-fluoroimidazo[1,2-α]pyridin-3-yl)biphenyl-2-carbonitrile as a white amorphous solid (90 mg, 55%): δH (360 MHz, CDCl3) 6.79-6.83 (1H, m), 6.94 (1H, dd, J 8 and 8), 7.73-7.46 (2H, m), 7.53-7.65 (4H, m), 7.73 (1H, s), 8.25 (1H, d, J 7); m/z (ES+) 350 (M++H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.Cl[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21]>COCCOC>[CH:20]([O:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:22])[CH3:21]
Reactant: CC(C)OCCC=CCCl
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(=O)c1ccc(OCC=CCCOC(C)C)cc1
Reaction time: 24 h

Procedure:
3.4 g (0.06 mol) of pulverised potassium hydroxide are added to a solution of 8.2 g (0.06 mol) of p-hydroxy-acetophenone and 14.6 g (0.09 mol) of 1-chloro-5-isopropoxy-2-pentene in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 60° during the course of 24 hours and is subsequently filterd. The filtrate is evaporated at reduced pressure, the residue is taken up in ether, and the ether solution is washed with saturated salt solution. The organic phase is dried with sodium sulphate and evaporated. The residue is chromatographed with hexane/ethyl acetate 4 : 1 on silica gel and then the 4'-(5-isopropoxy-2pentenyloxy)-acetophenone is obtained as colourless oil. nD20 = 1.5240.
Reaction SMILES: Cl[C:2]1C(Cl)=C(O)C(C#N)=C(C#N)[C:3]=1O.[F:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][CH2:19][NH:20]2>C1C=CC=CC=1>[CH2:2]([N:20]1[C:21]2[C:17](=[C:16]([F:15])[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1)[CH3:3]
Reactant: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N
Reactant: O=[N+]([O-])c1ccc2c(c1F)CCN2
Solvent: c1ccccc1
Product: CCn1ccc2c(F)c([N+](=O)[O-])ccc21
Yield: 70.4 %

Procedure:
2,3-Dichloro-5,6-dicyanohydroquinone (1.02 g, 4.50 mmol) was added to the solution of 4-fluoro-5-nitro-2,3-dihydro-indole (0.47 g, 2.25 mmol) in benzene (30 mL) and the mixture was refluxed for 7 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with water (3×10 mL), brine (3×10 mL), dried over anhydrous sodium sulphate and concentration in vacuo afforded the crude product. Purification by column chromatography over neutral alumina using 5% ethyl acetate in hexane as eluent afforded 1-ethyl-4-fluoro-5-nitro-indole (0.33 g, 72%) as yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C)C=O>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc2ccc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-hydroxy-1H-indole-2-carboxylic acid (2.66 g) in N,N-dimethylformamide (25.0 mL) was added lithium carbonate (1.22 g), followed by stirring at room temperature for 10 minutes. Benzyl bromide (2.14 mL) was added thereto, followed by stirring at 100° C. for 2 hours. The reaction mixture was lowered to 60° C., and 1 M hydrochloric acid (40.0 mL) was added thereto, followed by leaving to be cooled and extracting with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the crude purified product was washed with cold ethanol (5.00 mL) to obtain benzyl 6-hydroxy-1H-indole-2-carboxylate (1.95 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24]([CH:26]=O)[CH:23]=[N:22]1>>[CH3:20][N:21]1[CH:25]=[C:24]([C:26]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]4[C@@H:15]5[CH2:16][C@@H:12]([CH:13]=[CH:14]5)[C@@H:11]4[C:17]([NH2:19])=[O:18])=[C:7]3[N:8]=2)[CH:23]=[N:22]1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: Cn1cc(C=O)cn1
Product: Cn1cc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)ccnc3[nH]2)cn1
Yield: 28.2 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (23.4 mg, 0.212 mmol) were reacted to produce 19 mg (28%) of the title compound. mp: 236-238° C., 1H NMR (300 MHz, DMSO-d6): 12.76 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.64 (s, 1H), 7.10 (s, 1H), 6.63 (m, 1H), 6.38 (s, 1H), 6.32 (m, 2H), 3.92 (s, 4H), 2.86 (s, 1H), 2.73 (s, 1H), 2.22 (s, 1H), 1.41 (s, 1H), 1.09 (s, 1H). MS: 350 (M+H), HPLC: 1.60 min (G method).