Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:35]=4[NH:34][CH:33]=[CH:32]5)=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:35]=4[NH:34][CH:33]=[CH:32]5)=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc3[nH]cc(-c4cccc5cc[nH]c45)c3c2)cc1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cnc3[nH]cc(-c4cccc5cc[nH]c45)c3c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-5-[3-(1H-indol-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (308 mg, 0.66 mmol) in dichloromethane (9 mL) was added trifluoroacetic acid. The resulting solution was stirred for 2 hours at room temperature. The solution was concentrated to give the crude 2-amino-5-[3-(1H-indol-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid which was used in next step without further purification. MS: m/z 369 (M+H+).
Reaction SMILES: B(F)(F)F.[C:5]([O:10][C:11](=[O:15])[CH2:12]CC)(=[O:9])[CH2:6][CH2:7][CH3:8].[CH:16](=[O:18])[CH3:17].[C:19]([O-])(=O)[CH3:20].[Na+]>>[C:16]([O:15][CH:11]([O:10][C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH3:12])(=[O:18])[CH2:17][CH2:19][CH3:20]
Reactant: CC(=O)[O-]
Reactant: CC=O
Reactant: CCCC(=O)OC(=O)CCC
Agent: FB(F)F
Agent: [Na+]
Product: CCCC(=O)OC(C)OC(=O)CCC
Reaction time: 2 h

Procedure:
To ice-cooled BF3 -etherate (8.66 g.. 61 mmol.) is added dropwise via a syringe, over one hour, a mixture of butyric anhydride (6.58 g., 41.6 mmol.) and acetaldehyde (1.22 g., 27.7 mmol.). The reaction mixture is stirred for an additional 2 hours, 10% aq. sodium acetate solution (28 ml.) is added, and the mixture again stirred for 45 minutes. The oily layer is extracted into ether (2×25 ml.), and the combined ethereal extracts are washed with saturated aqueous sodium bicarbonate solution until no further evolution of CO2 is observed. The organic phase is then washed with water, dried over magnesium sulfate, filtered, concentrated and the residue is fractionally distilled at 8-12 mm. Hg, the fraction distilling at up to 62° C. being collected. Yield 2.18 g. (39%). 1H H-NMR ppm (CDCl3): 6.88 (q. J=5.6 Hz, 1H), 2.30 (dt, J=0.75, 7.5 Hz. 4H), 1.65 (sextet. J=7.5 Hz. 4H). 1.47 (d. J=5.5 Hz, 3H). 0.95 (t, J=7.5 Hz, 6H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH2:14])[CH2:12][CH3:13].[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>>[Cl:15][CH2:16][CH2:17][NH:18][C:19]([N:14]([CH2:11][CH2:12][CH3:13])[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:20]
Reactant: CCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C=NCCCl
Product: CCCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 69.1 %

Procedure:
3.0 g of L-arabinose, 1.5 g of n-propylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 4.1 g of 1-(2-chloroethyl)-3-n-propyl-3-L-arabinopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC.Cl.[CH3:31][NH:32][O:33][CH3:34]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([N:32]([O:33][CH3:34])[CH3:31])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: CNOC
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a stirred solution of 6-chloropyridazine-3-carboxylic acid (12.5 g, 0.078 mol) in CH2Cl2 (80 mL) at 0° C. were added triphosgene (11.6 g, 0.039 mol), Et3N (55 mL, 0.4 mol), and N,O-dimethylhydroxylamine hydrochloride (7.6 g, 0.078 mol). The reaction mixture was stirred at room temperature for 2 h. The salt was filtered, after removal of the solvent in vacuo, the residue was purified by column chromatography to afford 6-chloro-N-methoxy-N-methylpyridazine-3-carboxamide (13.5 g, 86%). 1H NMR (DMSO-d6, 400 MHz): δ 8.08 (d, J=9.2 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 3.33 (s, 3H), 8.06 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH2:9][N:10]([CH:18]([CH3:27])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)CC2C=CC=CC=2)=[CH:4][C:3]=1[S:29]([NH2:32])(=[O:31])=[O:30].[H][H]>[Pd]=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH2:9][NH:10][CH:18]([CH3:27])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][C:3]=1[S:29]([NH2:32])(=[O:31])=[O:30]
Reactant: [H][H]
Reactant: CC(CCc1ccccc1)N(Cc1ccccc1)CC(O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: O=[Pd]
Product: CC(CCc1ccccc1)NCC(O)c1ccc(Cl)c(S(N)(=O)=O)c1
Product: Cl

Procedure:
A solution of 2-chloro-5-[1-hydroxy-2-[N-(1-methyl-3-phenylpropyl)-N-(phenylmethyl)amino]ethyl]-benzenesulphonamide (0.5 g) was hydrogenated over palladium oxide (0.05 g) for 18 hours (64 ml of hydrogen taken up; theory 48 ml). The catalyst was filtered off, washed with ethanol, and the resulting solution evaporated to dryness under reduced pressure to give the product as a white foam, 0.3 g, m.p. 88-94°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])[CH:14]=2)[C:9](=[O:23])[N:8]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=1[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[CH:14]=2)[C:9](=[O:23])[N:8]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=1[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)OCC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of ethyl (E)-3-[4-butoxy-3[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.67 g, 1.3 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) as added 1N sodium hydroxide (3 mL). The obtained mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl-acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.53 g, 84.1%) as crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[C:7]([Cl:10])(Cl)=[O:8].C(Cl)(=O)N>ClC(Cl)C>[CH3:1][NH:2][C:3]([N:5]([CH3:6])[C:7]([Cl:10])=[O:8])=[O:4]
Reactant: O=C(Cl)Cl
Reactant: CNC(=O)NC
Agent: NC(=O)Cl
Solvent: CC(Cl)Cl
Product: CNC(=O)N(C)C(=O)Cl
Temperature: 80 °C

Procedure:
To a cold suspension of 22 g. (0.25 m.) of sym-dimethylurea in dichloroethane was added dropwise with stirring a cold solution of 30 g. (0.3 m.) of phosgene in 90 ml. of dichloroethane. After the addition of the phosgene solution was complete, the reaction mixture was allowed to stir at room temperature for one hour and was then heated to 80° C. and purged with nitrogen for one hour. The reaction mixture was evaporated under reduced pressure and the residual gum was extracted twice with 350 ml. portions of either. The extracts were combined and evaporated to provide 25 g. of the carbamoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O-:9])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](I)[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:26][CH3:27])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CCI
Reactant: Cc1c(NC2CCCCCC2)cc(Cl)cc1C(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCCCCC1
Temperature: 80 °C
Yield: 25.2 %

Procedure:
To a stirred solution of 5-chloro-3-(cycloheptylamino)-2-methylbenzoate (0.8 g, 2.70 mmol) in dry DMF (10 mL), cesium carbonate (1.76 g, 5.4 mmol) and ethyl iodide (2.11 g, 13.5 mmol) were added and the resulting reaction mixture heated at 80° C. for 18 h. On completion, the mixture was cooled to room temperature and filtered, the residue washed with ethyl acetate and the filtrate concentrated before purification by column chromatography to afford the desired methyl 5-chloro-3-(cycloheptyl(ethyl)amino)-2-methylbenzoate (0.220 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:3]=1[O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1
Reactant: Cn1ccc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CS(=O)(=O)Nc1cccc(Cl)c1F
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(Cl)cccc4NS(C)(=O)=O)cc23)n1

Procedure:
The compound of Example 98 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using N-(3-chloro-2-fluorophenyl)methanesulfonamide, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [F:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C([O:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][N:27]=1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([CH2:28][C:23]2[C:22](=[O:21])[NH:27][CH:26]=[CH:25][N:24]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)Oc1nccnc1C=O
Reactant: Fc1ccccc1C(F)CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]ccnc1CN1CCC(CC(F)c2ccccc2F)CC1
Reaction time: 8 h
Yield: 5.3 %

Procedure:
After dissolving 64 mg of 4-[2-fluoro-2-(2-fluorophenyl)ethyl]piperidine in 3 ml of tetrahydrofuran, 61 mg of 3-tert-butoxy-2-pyrazinecarboxaldehyde and 90 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate). Two milliliters of a 4N hydrogen chloride/ethyl acetate solution was added to the obtained product while stirring, and the stirring was continued for 2.5 hours at room temperature. A 1N sodium hydroxide solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether/n-hexane was added to the residue and the insoluble portion was filtered out to obtain the title compound (5 mg, 5% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2].[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([C:37](O)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:37]([C:32]3[C:31]([C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:40])[F:41])=[CH:26][CH:27]=4)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:38])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CN2CCN(c3ccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a stirred solution of 4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (0.29 g), 4′-trifluoromethyl-biphenyl-2-carboxylic acid (0.26 g), HOBt (0.16 g), and Et3N (0.12 g) in CH2Cl2 (15 mL) was added at room temperature EDCl (0.23 g) and the mixture was stirred at room temperature for 4 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2/AcOEt (90/10) and the solid obtained was recrystallized from EtOH to give the title compound (0.48 g) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.O.[Li+].[OH-].[CH2:35]1COCC1>CO.C(Cl)Cl>[OH:17][C:14]1[CH:15]=[CH:16][C:10]2[C:9]([O:19][C:20]3[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH3:35])=[CH:3][CH:4]=3)[S:12][C:11]=2[CH:13]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(OC)ccc23)cc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a 30 mL vial containing a mixture of of (E)-methyl 3-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate and (E)-methyl 3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acylate (32 mg, 0.07 mmol) in THF (3 mL), MeOH (1 mL), and H2O (2 mL) was added LiOH (9.14 mg, 0.38 mmol). The reaction mixture was stirred for 60 min at room temperature and then concentrated in vacuo, diluted with water, and acidified to pH 2 with 6 M HCl causing a precipitate to form. The mixture was diluted with 20 mL DCM and 2 mL MeOH. The organic layer was collected (phase separator) and concentrated in vacuo to afford the crude product. The sample was purified by supercritical fluid chromatography (CHIRALCEL® OJ-H column, 45% MeOH in CO2) to afford (E)-3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (17 mg, 0.04 mmol, 53% yield) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ ppm=7.64 (d, J=8.59 Hz, 2 H), 7.55-7.62 (m, 2 H), 7.51 (d, J=16.17 Hz, 1 H), 7.30 (d, J=2.02 Hz, 1 H), 7.13 (d, J=8.59 Hz, 1 H), 6.90-7.04 (m, 4 H), 6.83 (dd, J=2.02, 8.59 Hz, 1 H), 6.38 (d, J=16.17 Hz, 1 H), 3.75 (s, 3 H), LC/MS (m/z, M−H): 417.5.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:13].CCCC.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:29][C:28]([C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])=[N:27]1.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.O.C(O)C>[F:13][C:3]1[CH:4]=[C:5]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH:30]2[N:26]([C:20]3[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=3[F:18])[N:27]=[C:28]([C:46]([F:52])([F:51])[C:47]([F:48])([F:50])[F:49])[CH2:29]2)[CH:32]=1
Reactant: CS(=O)(=O)c1cc(F)c(Br)cc1F
Reactant: CC1(C)OB(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)OC1(C)C
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: O
Solvent: CCCC
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)c(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)cc1F
Temperature: 88 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
To 1-bromo-2,5-difluoro-4-(methylsulfonyl)benzene (19.0 mg, 0.07 mmol), were added 1,2-dimethylethane (1.5 mL) and Pd(PPh3)4 (8.1 mg, cat.). To the reaction mixture, were added 1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5-dihydro-1H-pyrazole (35 mg, 0.07 mmol) prepared in Step 1, ethanol (350.0 uL), and a 2N sodium carbonate solution (350.0 uL). The reaction mixture was stirred at 88° C. for 2 hours. Distilled water was added to the reaction mixture, which was then extracted with diethyl ether two times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 10.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:22]>ClCCCl>[Cl:22][C:4]1[C:5]2[CH2:9][CH2:8][CH2:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2c1CCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a solution of 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.87 g, 72.5 mmol) in DCE (200 ml) was added DIEA (15 mL, 86.1 mmol). The mixture was stirred at room temperature for 30 minutes and then added POCl3 (15 mL, 163.9 mmol) was added slowly. The mixture was stirred at room temperature for 1 hour and then refluxed for 12 hour. After cooling, the solvent was removed and the residue was dissolved in CHCl3 (200 ml). The mixture was basified by adding ice-cooled concentrated aqueous ammonia (15 mL). The organic phase was separated. The aqueous phase was washed with CHCl3 (3×100 mL). The organic phase was combined, dried and concentrated. The residue was subject to chromatography on silica gel, eluted by Hexanes/ethyl acetate (4:1) to afford 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.7 g, 51%). 1H NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 3.12-3.01 (m, 4H), 2.23-2.14 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH:18]([CH3:20])[CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH:18]([CH3:20])[CH3:19])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:21]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CC(C)C1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CC(C)C1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5-isopropyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.02 (s, 1H), 7.83 (dd, J=7.1, 2.2 Hz, 1H), 7.67 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (m, 2H), 7.53 (m, 1H), 7.52 (m, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.05 (dd, J=3.6, 1.3 Hz, 1H), 7.02 (dd, J=5.0, 3.7 Hz, 1H), 4.21 (d, J=14.4 Hz, 1H), 3.90 (d, J=14.4 Hz, 1H), 2.81 (m, 1H), 0.91 (m, 6H); Anal. Calc. for C22H10ClFNO2S: C, 63.53; H, 4.60; N, 3.37. Found: C, 63.34; H, 4.92; N, 2.97.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([N+:16]#[C-:17])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Br:18][C:19]1[S:23][C:22]([CH:24]=O)=[CH:21][CH:20]=1.Cl(O)(=O)(=O)=O>C(Cl)(Cl)Cl>[Br:18][C:19]1[S:23][C:22]([C:24]2[N:1]=[C:2]3[CH:7]=[N:6][CH:5]=[CH:4][N:3]3[C:17]=2[NH:16][C:9]([CH3:15])([CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: Nc1cnccn1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2cnccn12
Temperature: 50 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
4.76 g (50.0 mmol) of 2-aminopyrazine were dissolved together with 8.76 ml (50.0 mmol) of 1,1,3,3-tetramethyl-butylisonitrile and 5.42 ml (50.0 mmol) of 5-bromothiophene-2-carbaldehyde in chloroform (40 ml) After addition of perchloric acid (5 ml), the mixture was stirred at 50° C. for 16 h. After cooling to RT, washing was performed 2× with a sat. aq. sodium carbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated under a vacuum. After carrying out column chromatography (EA/DCM 1:3) with the group, 11.39 g (28.0 mmol, 56% of theoretical) of [2-(5-bromothiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine were obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O.[Br:18][C:19]1[CH:20]=[N:21][C:22](Cl)=[N:23][CH:24]=1>O>[Br:18][C:19]1[CH:20]=[N:21][C:22]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:23][CH:24]=1
Reactant: Clc1ncc(Br)cn1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Brc1cnc(-n2cccn2)nc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 126.1 %

Procedure:
Pyrazole (130 mg) and cesium carbonate (610 mg) were added to a DMAc (10 ml) solution containing 5-bromo-2-chloropyrimidine (300 mg), followed by stirring at 120° C. for 0.5 hours. The reaction mixture was adjusted to room temperature and water was added to the mixture. Next, the organic layers were collected, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and a yellow solid of 5-bromo-2-(pyrazol-1-yl)pyrimidine (440 mg) was thus obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1OC)[CH:9]=2)=O.Cl.[NH2:28][CH2:29][C@@:30]([OH:35])([CH3:34])[C:31]([OH:33])=[O:32].[CH3:36][O-].[Na+]>CO>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:28][CH2:29][C@@:30]([OH:35])([CH3:34])[C:31]([O:33][CH3:36])=[O:32])=[O:2])[N:6]=1)#[N:26]
Reactant: C[C@](O)(CN)C(=O)O
Reactant: C[O-]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@](C)(O)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 140 °C

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (20 mg, 0.06 mmol), (S)-3-amino-2-hydroxy-2-methylpropanoic acid hydrochloride (20 mg, 0.13 mmol) and NaOMe (14 mg, 0.25 mmol) in MeOH (2 mL) was heated at 140° C. in a microwave for 2 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 9 mg. 1H NMR (CDCl3, 200 MHz): δ=13.78 (s, 1H), 8.39 (d, 1H, J=9.8 Hz), 8.20 (t, 1H, J=5.9 Hz), 7.60-7.42 (m, 4H), 7.32-7.24 (m, 1H), 7.18-7.12 (m, 2H), 4.11-3.93 (m, 1H), 3.82 (s, 3H), 3.61-3.51 (m, 2H), 1.50 (s, 3H).