Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]2[CH2:15][CH2:14][N:13]([CH3:16])[C:5]2=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)CCN(C)C.[Li]CCCC.COB(OC)OC.[C:38]([O:41]O)(=[O:40])[CH3:39].C(N(CC)CC)C.C(OC(=O)C)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C.O>[C:38]([O:41][C:2]1[C:3]([CH3:17])=[C:4]2[CH2:15][CH2:14][N:13]([CH3:16])[C:5]2=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:40])[CH3:39]
Reactant: CC(=O)OO
Reactant: CCCCCc1nc2c(c(C)c1Br)CCN2C
Agent: CN(C)CCN(C)C
Agent: CN(C)c1ccncc1
Agent: COB(OC)OC
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCCCc1nc2c(c(C)c1OC(C)=O)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 33.0 mg (0.11 mmol) of 5-bromo-1,4-dimethyl-6-pentyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 1 mL of THF was added 16.5 μL (0.11 mmol) of tetramethylethylenediamine (TMEDA) at −78° C. followed by 139 μL (0.22 mmol, 1.6 M in hexanes) of n-BuLi. After 30 min, 27.2 μL (0.24 mmol) of trimethoxy boron was added and the resulting mixture was stirred for another 1 h. To the reaction mixture was added slowly 51.4 μL (0.24 mmol, 32 wt %) of peracetic acid and the solution was then warmed to 0° C. over a period of 30 min. The mixture was diluted by 5 mL of H2O and extracted with three 5-mL portions of EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and the solvent was concentrated under diminished pressure. The resulting oil was dissolved in 2 mL of CH2Cl2 at 0° C., followed by the addition of 92.8 μL (0.66 mmol) of triethylamine, 1.40 mg (0.01 mmol) of DMAP and 31.4 μL (0.33 mmol) of acetic anhydride. The reaction mixture was stirred at room temperature for 1 h and quenched by the addition of 2 mL of sat aq NH4Cl. The solution was then extracted with three 5-mL portions of EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and the solvent was concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (20 1.7 cm). Elution with 100:1 hexanes/ethyl acetate gave 2a as a yellow oil: yield 26.7 mg (88%); silica gel TLC Rf 0.1 (3:7 EtOAt/hexanes); 1H NMR (CDCl3) δ 0.90 (t, 3H, J=7.0 Hz), 1.32-1.37 (m, 4H), 1.64 (quint, 2H, J=7.5 Hz), 1.95 (s, 3H), 2.31 (s, 3H), 2.47 (t, 2H, J=8.0 Hz), 2.85 (t, 2H, J=8.0 Hz), 2.89 (s, 3H) and 3.44 (t, 2H, J=8.0 Hz); 13C NMR (CDCl3) δ 14.0, 20.6, 22.5, 24.7, 28.4, 29.6, 31.8, 32.5, 33.3, 52.4, 120.1, 134.7, 136.5, 149.7, 161.2 and 169.9; mass spectrum, m/z 276.2 (M)+ (theoretical 276.2); mass spectrum (APCI), m/z 277.1910 (M+H)+ (C16H25N2O2 requires 277.1916).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[S:20][C:15]3=[N:16][CH2:17][CH2:18][CH2:19][N:14]3[C:13]=2[O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][C:10]([C:12]2[S:20][C:15]3=[N:16][CH2:17][CH2:18][CH2:19][N:14]3[C:13]=2[O:21][CH2:22][C:23]([OH:25])=[O:24])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)COC1=C(C(=O)Nc2cc(Cl)cc(Cl)c2)SC2=NCCCN21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COC1=C(C(=O)Nc2cc(Cl)cc(Cl)c2)SC2=NCCCN21
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
In 8 ml of ethanol was suspended 650 mg of N-(3,5-dichlorophenyl)-6,7-dihydro-3-ethoxycarbonylmethoxy-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide obtained in Example 113. To the suspension was added 2 ml of 1N sodium hydroxide aqueous solution at room temperature, followed by stirring at the same temperature for 30 minutes. The mixure was made acidic with a concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and diethylether, and dried to obtain 484 mg of the titled compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:45][S:42]([C:39]1[CH:40]=[CH:41][C:36]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]4[N:32]=[CH:33][CH:34]=[CH:35][C:23]=4[N:22]3[C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)=[CH:37][CH:38]=1)(=[O:43])=[O:44]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(S(C)(=O)=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 86.2 %

Procedure:
tert-Butyl[1-(4-{2-[4-(methylsulfonyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (51 mg) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 23 hours. The mixture was concentrated, then sat.NaHCO3 aq. was added. The mixture was extracted with AcOEt+MeOH, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated to afford the desired product (37 mg, 72%, 2 steps) as a pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.60 (s, 1H), 8.09 (dd, J=4.6 Hz and 1.7 Hz, 1H), 7.98 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.37 (td, J=7.4 Hz and 1.7 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.6 Hz, 2H), 7.14 (td, J=7.4 Hz and 1.7 Hz, 2H), 6.92 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.74 (dd, J=8.0 Hz and 5.2 Hz, 1H), 3.21 (s, 3H), 2.45-2.39 (m, 2H), 2.18-2.13 (m, 2H), 2.08-2.00 (m, 1H), 1.75-1.67 (m, 1H). LCMS: 534 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[CH:13][CH:12]=1.Cl>O1CCOCC1.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:15][CH:16]=1
Reactant: COC(=O)CCc1ccccc1OCCOC1CNCCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccccc1COCCCOc1ccc(C2CCNCC2OCCOc2ccccc2CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of 0.057 g of methyl 3-{2-[2-(4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxy)ethoxy]phenyl}propionate (Example 52) in 1 ml of dioxane and 0.2 ml of 2N NaOH is stirred at 80° C. over 40 minutes. The reaction mixture is cooled to room temperature and made neutral with 0.5N HCl. The mixture is subsequently extracted with ethyl acetate (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a yellow solid from the residue. Rt=426.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[O:7]([CH2:14][CH2:15][OH:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:4]([O:16][CH2:15][CH2:14][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: OCCOc1ccccc1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OCCOc1ccccc1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
Diketene (84 g) was added dropwise with stirring to 140 g of 2-phenoxyethanol heated at 100° C. After the addition was completed, the reaction mixture was refluxed for an additional 22 hours. The reaction mixture was fractionally distilled to obtain 90.6 g of 2-phenoxyethyl acetoacetate, BP 140°-145° C./0.3 mm.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[C:19]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH3:40]>>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:33][NH:32][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:19]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:20][C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:40]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)c(OC/C=C(\C)CCC=C(C)C)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1OC/C=C(\C)CCC=C(C)C
Yield: 76 %

Procedure:
In a manner identical to Example 15, 2,4-digeranyloxybenzoic acid (2.13 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 2.03 g (76%) of the aimed compound.
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:29][S:30]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:33]1([S:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:13][CH:12]=2)[C:6]([OH:43])=[O:5])(=[O:32])=[O:31])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)cc1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
45 mg (0.074 mmol) of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield 50 mg. MS (ES+): m/e=552 (M+H+).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([C:22]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23]4)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:9]([F:31])[CH:8]=1.Cl>C1COCC1>[F:31][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22]3([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH:2]=[O:1]
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)cc2s1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)cc3s2)c(F)c1
Temperature: 70 °C

Procedure:
A mixture of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylcyclopropyl)-benzo[d]thiazole (0.061 g, 0.14 mmol) and 5N HCl (3.50 mL, 0.14 mmol) in THF (7.0 mL) was heated to 70° C. for 3 h. The reaction was cooled and concentrated in vacuo, placed in an ice bath, and basified with 5 N aq. NaOH. The solid was collected by filtration, rinsed with water and MeOH, and was dried in vacuo to afford 3-fluoro-4-(6-(1-phenylcyclopropyl)-benzo[d]thiazol-2-yl)benzaldehyde. MS (ESI) m/z: Calculated: 373.1; Observed: 374.0 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:16])[CH2:14]Br)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.[F-:36].[K+]>C(#N)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:16])[CH2:14][F:36])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O=C(CBr)C1CCN(Cc2ccccc2)C1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=C(CF)C1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a solution of 1-benzyl-3-(2-bromoacetyl)pyrrolidin-2-one (2.2 g, 7.43 mmol, Example 14) in acetonitrile (25 mL) was added 18-crown-6 (0.980 g, 3.72 mmol) and potassium fluoride (spray dried) (2.16 g, 37.2 mmol). The reaction mixture was immersed in an oil bath at 80° C. After 1 hour, the mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude residue was then purified by chromatography (99:1 dichloromethane/methanol then 98:2 dichloromethane/methanol) to afford the title compound (0.515 g): 1H NMR (CDCl3) δ 7.36-7.19 (m, 5H), 4.93 (m, 2H), 4.46 (m, 2H), 3.61 (m, 1H), 3.48 (m, 2H), 2.74 (m, 2H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CC(N(C)C)=O.[Br:19][CH2:20][CH2:21][CH2:22]Br>O>[Br:19][CH2:20][CH2:21][CH2:22][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1CCCBr
Yield: 77 %

Procedure:
90 g of potassium phthalimide was mixed with 300 ml of dimethylacetamide and stirred. 74 ml of 1,3-dibromopropane was added to the system. The system was then allowed to undergo reaction at a temperature of 120° C. over 4 hours. The reaction solution was poured into 1 l of water. The resulting crystals were filtered off with suction. The crude crystals were recrystallized from ethanol to obtain 100 g of N-(3-bromopropyl)-phthalimide (7). (Yield: 77%; m.p. 65° C.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14]O)=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][Br:37])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(CCCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of [4-(3-Hydroxy-propyl)-phenoxy]-acetic acid methyl ester (2.45 g, 10.9 mmol) in DCM (60 mL) is added polymer-supported triphenylphosphine (7.26 g, 21.8 mmol) and carbon tetrabromide (3.47 g, 11.99 mmol) and the resulting reaction mixture is stirred at RT for 15 h. The reaction mixture is filtered to remove the polymer-supported reagent, and then concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc:iso-hexane, 1:5) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 7.14 (2H, d), 6.86 (2H, d), 4.69 (2H, s), 3.83 (3H, s), 3.40 (2H, t), 2.74 (2H, t), 2.15 (2H, m).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@H:5]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:6][C:7]([O:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)=[O:8])C.[OH-].[Na+].Cl>CCO>[O:12]1[CH2:13][CH2:14][C@H:10]([O:9][C:7]([NH:6][C@H:5]([C:4]([OH:19])=[O:3])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:8])[CH2:11]1
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)O[C@H]1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)O[C@H]1CCOC1)C(=O)O
Yield: 96.4 %

Procedure:
To a solution of N-(((3S)-tetrahydrofuran-3-yloxy)carbonyl)-L-leucine ethyl ester (2.9 g, 11 mmol) in EtOH (100 mL) was added 1M NaOH (33 mL). The mixture was stirred under ice-cooling condition for 3 hours, and then adjusted to pH 3 by the addition of HCl thereto. The solution was concentrated in vacuo, and the residue was extracted with ethyl acetate (100 mL). Then, the organic layer was separated, washed with 1M HCl and saturated aqueous NaCl, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was crystallized from ethyl acetate and hexane to give N-(((3S)-tetrahydrofuran-3-yloxy)carbonyl)-L-leucine (2.6 g, 85%) as colorless crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][C:11]2[C:12]([CH3:20])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)[CH2:5]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[OH-].[Na+]>O>[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][C:11]2[C:12]([CH3:20])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)[CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCCC(Oc2ccc3[nH]ncc3c2C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCCC(Oc2ccc3[nH]ncc3c2C)C1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 26.7 %

Procedure:
A mixture of the 5-[(1-acetylpiperidin-3-yl)oxy]-4-methyl-1H-indazole (55.1 mg, 0.202 mmol) obtained in Example 455, lithium aluminum hydride (40 mg, 1.1 mmol) and tetrahydrofuran (2 ml) was stirred at 80° C. for 2.5 hours. The reaction mixture was ice-cooled, followed by adding thereto water (0.04 ml), a 2N-aqueous sodium hydroxide solution (0.08 ml) and water (0.12 ml) in that order. The precipitate was removed by filtration and the solvent was distilled off. Thereafter, the residue oil was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate/triethylamine=5/15/1) to obtain 5-[(1-ethylpiperidin-3-yl)oxy]-4-methyl-1H-indazole (14 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12](C)[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][N:23]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]2[CH3:30])=[C:9]1[C:31]([O:33][CH2:34][CH3:35])=[O:32].N1C=CC=CC=1.C1C=C[NH+]=CC=1.Br[Br-]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:10]([CH2:19][O:20][CH2:21][CH2:22][N:23]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]2[CH3:30])[NH:11][C:12]2[CH2:17][O:16][C:14](=[O:15])[C:13]1=2
Reactant: CCOC(=O)C1=C(COCCn2c(C)nc(C)c2C)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(COCCn2c(C)nc(C)c2C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-(2,4,5-trimethylimidazol-1-yl)ethoxymethyl)-1,4-dihydropyridine (3.0 g) in chloroform (50 cm3) stirred at 0° C. under N2 was treated with pyridine (790 mg) followed by pyridinium bromide perbromide (2.1 g) in portions over five minutes and the mixture stirred at 0° C. for one hour and then heated at reflux temperature for three hours. The solution was cooled, washed with 2N hydrochloric acid (2×50 cm3) and brine (50 cm3), dried over MgSO4 filtered and evaporated to dryness. The residue was purified by silica-gel column chromatography eluting with diethylamine/ethyl acetate (1:9). The appropriate fractions were evaporated to dryness and taken up in ethyl acetate (25 cm3) from which the title compound crystallised as a colourless solid (440 mg). M.p. 215°-217° C.
Reaction SMILES: I.CO[C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:18]([CH3:22])[C:19]([OH:21])=[O:20].S([O-])(O)=O.[Na+]>C(OC(=O)C)(=O)C>[CH3:22][CH:18]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[O:20][C:19]1=[O:21]
Reactant: COc1c(Oc2ccccc2Cl)cccc1C(C)C(=O)O
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1C(=O)Oc2c(Oc3ccccc3Cl)cccc21
Yield: 47.6 %

Procedure:
Hydriodic acid (55-58%, 20 ml) was added to a solution of 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]propionic acid (2.7 g) in acetic anhydride (10 ml) under ice-cooling. The mixture was refluxed under heating for 30 minutes. The reaction mixture was poured into aqueous solution of sodium hydrogen sulfite and extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite and water, dried and evaporated. To the oily residue was added acetic anhydride (10 ml), and the mixture was refluxed under heating for 30 minutes. After cooling, the mixture was evaporated, and the oily residue was dissolved in diethyl ether. The solution was washed with saturated aqueous sodium bicarbonate and water, dried and then evaporated. The residue was subjected to column chromatography on silica gel (40 g) and eluted with benzene, and the eluate was evaporated. The oily residue was crystallized with n-hexane to give 3-methyl-7-(2-chlorophenoxy)-2,3-dihydrobenzofuran-2-one (1.15 g). mp 92°-95° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>CCCCO>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (5 mL), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (153 mg, 1.00 mmol, 1.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.5 mL). The resulting solution was stirred overnight at 130° C. and concentrated under vacuum. The crude product was purified by applying onto a C18 Column (water/acetonitrile) to afford 150 mg (41%) of 148 as a white solid. LC-MS (ES, m/z): 355 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.97 (s, 1H), 7.69 (d, 1H), 7.48 (m, 5H), 7.25 (m, 2H), 7.11 (m, 2H), 6.58 (d, 1H), 5.65 (q, 1H), 1.71 (d, 3H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=1)CCC.O>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: C=Cc1cc([Sn](CCCC)(CCCC)CCCC)sn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Yield: 68.6 %

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (75 mg, 0.150 mmol), 5-(tributylstannyl)-3-vinylisothiazole (90 mg, 0.225 mmol) and tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075 mmol) in toluene (4.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid (59.2 mg, 69%). ESI-MS m/z [M+H]+ calc'd for C27H34FN5O6S, 576. found, 576.