Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[C:23]12([CH2:33][NH2:34])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2>ClCCl.C(OCC)(=O)C.Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([NH:34][CH2:33][C:23]12[CH2:32][CH:27]3[CH2:26][CH:25]([CH2:31][CH:29]([CH2:28]3)[CH2:30]1)[CH2:24]2)=[O:6]
Reactant: O=C(O)c1cc(I)ccc1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ccc1Cl
Reaction time: 1 h

Procedure:
2-Chloro-5-iodobenzoic acid (10.0 g) was suspended in dichloromethane (160 ml) then oxalyl chloride (4.0 ml) was added followed by N,N-dimethylformamide (40 μl). After 24 h the solvent was evaporated to afford a white solid, which was then redissolved in dichloromethane (160 ml). Triethylamine (14.8 ml) was added, followed by adamantane methylamine (6.9 ml) with cooling to keep the temperature below 30° C. The resulting slightly cloudy mixture was stirred for 1 h, then solvent was evaporated to give a pale yellow solid. The solid was stirred in a mixture of ethyl acetate (400 ml) and 2 M hydrochloric acid (300 ml) until the solid dissolved to afford two clear phases. The (upper) organic phase was separated off and washed with 2 M sodium hyroxide solution (300 ml), then dried (Na2SO4) and evaporated to a yellow solid. The solid was suspended in iso-hexane (100 ml), then filtered and washed with more iso-hexane (40 ml), and the resulting off-white solid dried in vacuo at 40° C. to afford the subtitled compound (14.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH2:14][C:13](=[CH2:15])[C@@H:12]1[CH2:11][N:10]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[OH-:35].[Na+].OO>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH2:14][C@H:13]([CH2:15][OH:35])[C@@H:12]1[CH2:11][N:10]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:9]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: C=C1C[C@@]2(C(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@]12C[C@H](CO)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Reaction time: 2 h

Procedure:
(1S,5S)-3-Benzyloxycarbonyl-6-methylene-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert-butyl ester (2.00 g, 5.82 mmol) was dissolved in tetrahydrofuran (40 mL). A 9-borabicyclo[3.3.1]nonane dimmer (0.5 M solution in tetrahydrofuran) (17.5 mL, 8.73 mmol) was added dropwise, and then the mixture was stirred for two hours. A 3 M sodium hydroxide solution (3.49 mL, 10.5 mmol) and 30% aqueous hydrogen peroxide (2.47 mL) were added dropwise to the reaction solution at 0° C., and then the mixture was stirred at room temperature for 16 hours. The reaction solution was extracted with water and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=100:1→1:2) to give 1.58 g of an isomer A (less polar isomer) of the title compound and 50.0 mg of an isomer B (more polar isomer) of the title compound as colorless syrups.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH:44]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:17])[CH2:13][C:14]([NH:55][C:52]2[CH:51]=[CH:50][C:49]([C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)=[CH:54][CH:53]=2)=[O:16])[CH2:10][CH2:11]1)=[O:5]
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 60.2 %

Procedure:
DMAP (68 mg, 0.56 mmol) was added to 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (100 mg, 0.28 mmol) in DMF (2 mL) followed by EDCI (64 mg, 0.33 mmol) and HOBT (45 mg, 0.33 mmol). After 2 minutes, 4-pyridin-3-yl-phenylamine (55 mg, 0.18 mmol) was added and it was stirred at room temperature overnight. Cold water was then added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 55 mg (38.73% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(4-pyridin-3-yl-phenyl)-propionamide. LC/MS [M+H]+: 507.1, 90.55%. 1H NMR (300 MHz, DMSO-d6): δ 10.25 (d, 1H), 8.9 (bt, 1H), 8.5 (d, 1H), 8.1-8.0 (m, 1H), 7.7 (d, 5H), 7.52-7.3 (m, 4H), 3.8-3.46 (m, 8H), 3.2 (bt, 1H), 3.1 (bt, 1H).
Reaction SMILES: NN1CCCC1.Cl[C:8]1[N:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl.[NH2:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH2:23]1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C1COCC1>[CH3:19][O:18][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([NH:21][C@H:22]2[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=3)[CH2:23]2)[N:17]=1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: COc1nc(Cl)nc2ccccc12
Agent: Cl
Agent: NN1CCCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1nc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccccc12
Temperature: 100 °C
Yield: 6.5 %

Procedure:
Metal sodium (35 mg) was added to methanol (1.5 mL) to prepare a solution, and the solution was concentrated under reduced pressure, followed by addition of THF (1.5 mL). This suspension was added to a solution of 2,4-dichloroquinazoline (0.30 g) in THF (1.5 mL), and the mixture was stirred at room temperature for 2 h. To the reaction mixture was added saturated brine, the mixture was extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to obtain 2-chloro-4-methoxyquinazoline (0.27 g). (2) A mixture of 2-chloro-4-methoxyquinazoline (0.25 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.42 g), triethylamine (0.33 g), and THF (3.2 mL) was heated at 100° C. in a microwave reaction apparatus for 3 h. The reaction mixture was diluted with chloroform, washed with 1 M aqueous sodium hydroxide, and then dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-chloroform/methanol=95:5, and silica gel, hexane/ethyl acetate=1:2−ethyl acetate) to obtain the title compound (37 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].C1(C(C2C=CC=CC=2)=[NH:74])C=CC=CC=1>O1CCCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:17]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([NH2:74])=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)[CH3:18]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: CCc1nn(-c2ccccc2)c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-bromo-3-ethyl-1-phenyl-1H-indazole (300 mg, 1.00 mmol, 1.00 equiv) in tetrahydrofuran (30 mL), Xantphos (64 mg, 0.11 mmol, 0.11 equiv), Pd(OAc)2 (33 mg, 0.15 mmol, 0.15 equiv), Cs2CO3 (214 mg, 1.11 mmol, 1.11 equiv), diphenylmethanimine (200 mg, 1.10 mmol, 1.10 equiv). The resulting solution was heated to reflux for 16 h in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in tetrahydrofuran/3N hydrogen chloride (15 mL/5 mL). The resulting solution was stirred for an additional 2 h at room temperature, then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:MeOH:NH4OH (30:1:0.3) to yield 3-ethyl-1-phenyl-1H-indazol-6-amine as yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:6]1[CH3:31].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]([CH3:31])=[C:7]2[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: COC(=O)Cn1c(C)c(Cc2cnccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cnccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A mixture of [5-fluoro-3-(4-phenylsulfonylpyridin-3-ylmethyl)-2-methylindol-1-yl]acetic acid methyl ester (0.19 g) and tetrahydrofuran (1.0 mL) was treated with 2.0 M aqueous sodium hydroxide solution (3.0 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid solution, and the resulting precipitate was collected by filtration to afford the title compound as a pale yellow powder (0.15 g).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CC(C)(O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11.2 mg, 38.3%), MS (ISP) m/z=418.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-hydroxy-2-methylpropanoic acid.
Reaction SMILES: [H-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]([C:29]#[C:30][C:31]([CH3:41])([CH3:40])[CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:10][C:11]=1[N:12]([CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]1)=[O:14])=[O:6].F[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.O>CN(C=O)C>[CH3:41][C:31]([CH3:40])([CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[C:30]#[C:29][C:9]1[S:8][C:7]([C:5]([OH:4])=[O:6])=[C:11]([N:12]([C:13]([CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:22]2[CH2:23][CH2:24][CH:25]([O:28][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH2:26][CH2:27]2)[CH:10]=1
Reactant: Fc1ccccn1
Reactant: COC(=O)c1sc(C#CC(C)(C)COC2CCCCO2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)COC3CCCCO3)sc2C(=O)O)C2CCC(Oc3ccccn3)CC2)CC1
Yield: 43.6 %

Procedure:
NaH (45 mg of a 60% oil dispersion, 1.12 mmol) was added in one portion to a solution of 5-[3,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (124 mg, 0.221 mmol) and 2-fluoropyridine (0.095 mL, 1.1 mmol) in dry DMF (2.0 mL). After several minutes, the reaction was placed in a 85° C. oil bath and heated for 4 h. The reaction was cooled, water (0.50 mL) was added and the reaction mixture evaporated to dryness to provide a solid residue. The solid was washed with ethyl ether/hexanes then water, collected by centrifugation and washed with ethyl ether followed by water. The solid was collected and dried under vacuum to provide 5-[3,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid (Compound 311) (60 mg, 42%) as an off-white solid. MS (m/z): 528.3 [M+H-(2-hydroxypyridine)]+; HPLC retention time: 4.61 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(OCC)(=O)C>C1COCC1.[Zn].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].O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)[CH3:12]
Reactant: Brc1ccc2ccccc2n1
Reactant: CCOC(=O)CBr
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2ccccc2n1
Temperature: 45 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a suspension of vacuum dried Zn dust (6.0 g, 93.8 mmol) in dry THF (100 ml) was added TMSCl (0.5 ml) dropwise over 5 min under N2 atmosphere and under stirring. The mixture was stirred for 30 min and warmed to 45° C. Ethyl bromoacetate (5.2 ml, 46.9 mmol) was added dropwise via a syringe. After addition, the mixture was stirred at the same temperature for 1 h. After sedation at r. t. for 2 h, a clear orange solution was formed. The orange solution (50 ml) was carefully sucked into a syringe through a long needle and added to a mixture of 2-bromoquinoline (2.0 g, 9.6 mmol) and PdCl2(dppf) (200 mg, 0.27 mmol) in a three-neck flask. The mixture was refluxed under N2 for 3 h. The reaction was monitored with LC-MS. Ethyl acetate (200 ml) was added to dilute the mixture and water (50 ml) was added to quench the reaction. The mixture was filtered through a celite pad. The filtration was partitioned between brine and ethyl acetate. The organic layer was separated, washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified with silica column (PE/EA=3: 1) to give the title compound as orange oil (1.0 g, 48%). LC-MS (ESI+): m/e 216 (M+H)+, Rt: 0.62 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([F:12])([F:11])[F:10].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C([O:28][CH2:29][CH3:30])C.[F-].[K+]>C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)C=C)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCCCC>[F:10][C:9]([F:12])([F:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:30]1[CH2:29][O:28]1
Reactant: CCOCC
Reactant: FC(F)(F)Cc1ccccc1Br
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: FC(F)(F)Cc1ccccc1C1CO1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Bromo-2-(2,2,2-trifluoroethyl)benzene (0.5 g) was dissolved in degassed toluene and tributyl(vinyl)tin (0.67 mL), Pd2(dba)3 (0.096 g) and tri-tert-butylphosphine (0.25 mL, 1M solution) were added. Reaction mixture was heated to 40° C. After 4 hours heating was stopped and 1:1 solution of diethyl ether and pentane (10 ml) was added, followed by potassium fluoride (1.0 g). Mixture was stirred for 30 minutes after which it was filtered through a pad of silicagel and the filtrate was concentrated gently at 500 mbar vacuum. The evaporation residue was purified by column chromatography (diethyl ether-pentane) and fractions containing the product were concentrated by house vacuum distillation. The evaporation residue (0.389 g) containing toluene and the desired styrene product was dissolved in dichloromethane (12 mL) and 3-chloroperoxybenzoic acid (0.70 g) was added.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:24]1([CH2:30][CH2:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:24]1([CH2:30][CH2:31][NH:32][C:9](=[O:11])[CH2:8][CH2:7][CH:5]2[CH2:4][CH2:3][C:2](=[O:1])[O:6]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)CCC1CCC(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(CCC1CCC(=O)O1)NCCc1ccccc1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A solution of 2,3,4,5-tetrahydro-5-oxo-2-furanpropanoic acid (7.9 g) and N,N-carbonyldiimidazole (8.1 g) in dry dichloromethane (100 ml) was stirred under nitrogen at 20° for 30 minutes and a solution of 2-phenylethylamine (6.05 g) in dry dichloromethane (20 ml) was then added. The mixture was stirred at 20° for 2 hours. The solution was washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, water, dried (MgSO4), filtered and evaporated to give an oil which solidified on standing. Crystallisation from toluene gave the amide as fluffy crystals (10.4 g), mp 86°-87°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:27](I)=[C:11]2[N:12]=[C:13]([CH3:26])[N:14]=[C:15]([N:16]3[CH2:19][C:18]([NH:23][CH2:24][CH3:25])([C:20]([NH2:22])=[O:21])[CH2:17]3)[N:10]2[N:9]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:27]([C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)=[C:11]2[N:12]=[C:13]([CH3:26])[N:14]=[C:15]([N:16]3[CH2:19][C:18]([NH:23][CH2:24][CH3:25])([C:20]([NH2:22])=[O:21])[CH2:17]3)[N:10]2[N:9]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCNC1(C(N)=O)CN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)C1
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: C1COCCO1
Product: CCNC1(C(N)=O)CN(c2nc(C)nc3c(-c4ccc(C#N)cc4)c(-c4ccccc4Cl)nn23)C1
Temperature: 68 °C

Procedure:
A mixture of 1-[7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide (I-6A-1a; 50 mg, 0.098 mmol) and 4-cyanophenylboronic acid (22 mg, 0.15 mmol) in dioxane (0.8 ml) and 2M aqueous Na2CO3 (0.2 ml) was purged with nitrogen gas. Tetrakis(triphenylphosphine)palladium (12.5 mg, 0.01 mmol) was added and the mixture was heated at 68° C. for 4 days. After cooling to room temperature, the mixture was extracted from water with chloroform, the combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product. Purification on a Combiflash® using 0.4% methanol/1% aqueous ammonium hydroxide in chloroform as eluant afforded 6A-1 (23 mg, 48%) as a solid: +ESI MS (M+1) 487.1; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.47-7.34 (m, 4H), 7.01 (d, J=4.6 Hz, 1H), 5.39 (d, J=4.6 Hz, 1H), 5.30 (br d, J=9.5 Hz, 1H), 4.80 (br d, J=8.7 Hz, 1H), 4.73 (br d, J=9.5 Hz, 1H), 4.18 (br d, J=8.7 Hz, 1H), 2.64 (t, J=7.0 Hz, 2H), 2.53 (s, 3H), 1.17 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O.CN(C)C=O>ClCCCl>[Cl:19][C:10]([CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:11]
Reactant: COC(=O)C(Cc1cccc(Cl)c1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cccc(Cl)c1)C(=O)Cl
Temperature: 40 °C
Reaction time: 7 h

Procedure:
A total of 8.0 g of the residue containing 3-(3-chlorophenyl)-2-methoxycarbonylpropionic acid prepared in Step B of Example 1 was dissolved in 32.8 g of 1,2-dichloroethane under nitrogen atmosphere, and 11.8 g of thionyl chloride and 0.05 g of dimethylformamide were added thereto, followed by stirring at 40° C. for 7 hours. The resulting mixture was concentrated under reduced pressure to remove 1,2-dichloroethane and unreacted thionyl chloride to thereby yield 7.98 g of methyl 2-chloroformyl-3-(3-chlorophenyl)-propionate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)C)=[C:11]([F:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C([O-])([O-])=O.[K+].[K+].OS([O-])(=O)=O.[K+]>C(O)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OC(C)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
A solution of 3.10 g (10.9 mmol) of 2-(4-acetoxy-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester in 30 ml ethanol was treated at 0° C. with 2.26 g (16.4 mmol) of K2CO3. The mixture was stirred for 1 day at RT, the neutralized with aqueous 10% KHSO4 and extracted with ether (3×). The organic phases were washed with aqueous 10% KHSO4, aqueous 10% NaCl and dried over sodium sulfate. The crude product was purified by flash chromatography over silica gel with heptane/AcOEt 97.5:2.5 to 4:1, to give 2.48 g of the title compound as colorless crystalls.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13]Br)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].O.Cl>O1CCCC1>[CH:10]1[C:5]2[O:4][N:3]=[C:2]3[N:1]=[CH:13][CH2:12][O:11][C:7]([C:6]=23)=[CH:8][CH:9]=1
Reactant: Nc1noc2cccc(OCCBr)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C1=Nc2noc3cccc(c23)OC1
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
3-Amino-4-[(2-bromoethyl)oxy]-1,2-benzisoxazole of Example 7(a) (10.86 g, 0.0428 mole) was dissolved in 200 ml of tetrahydrofuran (THF) and 5.0 g of NaH (50% oil dispersion, 0.10 mole) was added. The reaction mixture was brought to reflux. After 30 minutes the reaction mixture was allowed to cool, an additional 1.0 g of NaH dispersion was added, and reflux was continued for 30 minutes. At the end of this time the reaction mixture was poured into H2O, acidified with concentrated hydrochloric acid, and the product extracted into ether. The organic phase was separated, dried, and concentrated, after which the residue was purified by flash chromatography (10% ethyl acetate --CH2Cl2). The material obtained in this manner retained a little yellow color, which was removed by dissolving the compound in CH2Cl2 and passing the solution over a short column of alumina. The product obtained in this manner after concentration of the solvent was recrystallized from CH2Cl2 -pentane to give 2.20 g (29%) of 4,5-dihydroisoxazolo[3,4,5-ef][1,4]benzoxazepine, mp 165°-166° C.