Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:26](=[O:37])[NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[C:12]([CH:23]([CH3:25])[CH3:24])[N:13]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:9][CH:8]=1)(=O)=O.[CH3:40][N:41]1[C:45](B(O)O)=[CH:44][CH:43]=[N:42]1.[Li+].[Cl-].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>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[F:35])[CH2:28][NH:27][C:26]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:45]3[N:41]([CH3:40])[N:42]=[CH:43][CH:44]=3)=[CH:8][CH:9]=2)[N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:12]=1[CH:23]([CH3:24])[CH3:25])=[O:37]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2n1Cc1ccccn1
Reactant: Cn1nccc1B(O)O
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: [Cl-]
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(-c3ccnn3C)cc2n1Cc1ccccn1

Procedure:
Following General Procedure BB, 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202, 39 mg, 0.07 mmol), was reacted with 1-methyl-1H-pyrazole-5-boronic acid pinocol ester (21 mg, 0.09 mmol), LiCl (9 mg, 0.18 mmol), Na2CO3 (aqueous) (2M, 0.1 ml), Pd(PPh3)4 (4 mg, 0.003 mmol) to yield the title compound as a white solid
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:8]2=[N:7][C:6]=1[CH3:17].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(#N)C>[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:3][CH2:4][C:5]4[C:10](=[O:11])[N:9]5[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:8]5=[N:7][C:6]=4[CH3:17])[CH2:31][CH2:32]3)=[N:25][O:26][C:22]=2[CH:21]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1nc2c(O)cccn2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 82.5 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride (formula-5) (11.1 grams), 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole mono hydrochloride (formula-6) (10 grams), sodium carbonate (7.5 grams), potassium iodide (0.64 grams) in acetonitrile (100 ml) was heated to 80-85° C. The reaction mixture was refluxed for 17 hrs under nitrogen. Then it was cooled to −10° C. and stirred for 30 min. The solid obtained was filtered and washed with chilled acetonitrile. The solid was taken in water and treated with sodiumhydrosulphite (hydrose) (2.0 grams). The solid was filtered and washed with water and dried at 50° C. to provide the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.[CH3:25][O:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[C:41]3[C:47]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=4[O:54][CH3:55])=[CH:46][N:45](S(C4C=CC(C)=CC=4)(=O)=O)[C:42]3=[N:43][CH:44]=2)=[CH:35][C:31]=1[C:32]([OH:34])=O)=[O:28].N1CCCC1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C)C=O.C(O)(=O)C.CO>[CH3:25][O:26][C:27](=[O:28])[NH:29][C:30]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[C:41]3[C:47]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=4[O:54][CH3:55])=[CH:46][NH:45][C:42]3=[N:43][CH:44]=2)=[CH:35][C:31]=1[C:32]([N:13]1[CH2:14][CH2:15][CH2:16][CH2:11]1)=[O:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)Nc1ccc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)cc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)Nc1ccc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)cc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (49.9 mg, 0.13 mmol) was added to a solution of 2-methoxycarbonylamino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (75 mg, 0.13 mmol), pyrrolidine (9.33, 0.13 mmol) and di-iso-propyl ethyl amine (51 mg, 0.39 mmol) in N,N-Dimethylformamide (1 ml). The reaction was stirred at room temperature for 1 hour, then methanol (2 ml) was added followed by aqueous sodium hydroxide (0.2 ml) and the reaction was stirred at room temperature for 16 hours. This solution was then neutralized with acetic acid and the compound was purified by preparative mass-triggered reverse-phase HPLC chromatography to give [4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(pyrrolidine-1-carbonyl)-phenyl]-carbamic acid methyl ester as a white solid.). 1H NMR (500 MHz, DMSO-d6) δ 1.81 (p, J=6 Hz 1H); 1.87 (p, J=6 Hz 1H); 3.41 (t, J=6 Hz 1H); 3.48 (t, J=6 Hz 1H); 3.65 (s, 3H); 3.81 (s, 3H); 7.04 (t, J=8 Hz 1H) 7.13 (d, J=8 Hz 1H); 7.29 (t, J=8 Hz, 1H); 7.60 (d, J=8 Hz 1H); 7.75 (m, 4H); 8.17 (s, 1H); 8.55 (s, 1H); 9.23 (s, br, 1H); 11.95 (s, br, 1H) (21.8 mg, 36% yield MS: m/z 471.5 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1I)[CH:7]=[O:8])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1[C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOc1cc(C=O)cc(OCC)c1I
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Yield: 82.5 %

Procedure:
3,5-Diethoxy-4-iodo-benzaldehyde (14.05 g, 43.89 mmol, 1.0 equiv; intermediate D31) was dissolved under Ar in toluene (180 mL) and water (20 mL) and treated successively with 4-fluorophenyl boronic acid (12.28 g, 87.78 mmol, 2.0 equiv), K3PO4 (50.12 g, 236.12 mmol, 5.38 equiv), tricyclohexylphosphine (2.80 g, 9.66 mmol, 0.22 equiv), and palladium(II) acetate (1.08 g, 4.83 mmol, 0.11 equiv). The reaction mixture was heated to 100° C. for 18 h under scrupulous exclusion of oxygen, when GC indicated the absence of starting iodo-compound. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of hexane/ethyl acetate (9:1). Recrystallization from hexane/ethyl acetate provided 10.44 g (83%) of the title compound as white crystals. MS (EI): 288.2 [M]+.
Reaction SMILES: [Li+].CCC[CH2-].C(NC(C)C)(C)C.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].I[CH2:21][CH2:22][CH2:23][C:24]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:28]CCO1.Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[CH3:15][C:14]([CH3:16])([CH2:21][CH2:22][CH2:23][C:24](=[O:28])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:13]([O:18][CH3:19])=[O:17]
Reactant: ICCCC1(c2ccccc2)OCCO1
Reactant: COC(=O)C(C)C
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)CCCC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
N-butyllithium (1.6N hexane solution, 2.16 ml) was added dropwise to a olution of diisopropylamine (0.529 ml) in tetrahydrofuran (5 ml) at −20° C. under nitrogen atmosphere. After stirring for 20 minutes, the mixture was cooled to −78° C., and methyl isobutyrate (0.397 ml) in tetrahydrofuran (5 ml) was added dropwise over 30 minutes. The reaction mixture was further stirred for 20 minutes, 2-(3-iodopropyl)-2-phenyl-1,3-dioxolane (1.00 g) and hexamethylphosphoramide (0.602 ml) were added. After stirring at −40° C. for 3 hours, dilute hydrochloric acid was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in acetone (30 ml), 1N sulfuric acid (10 ml) was added and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl 2,2-dimethyl-6-oxo-6-phenylhexanoate (350 mg, yield 45%) as a colorless oil from an ethyl acetate-hexane (1:7, v/v)-eluted fraction.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl>[CH3:16][S:17]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl piperidin-3-ylmethylcarbamate (500 mg) was dissolved in anhydrous dichloromethane (10 mL), and methanesulfonyl chloride (0.181 mL) was added followed by the addition of triethylamine (1.3 mL). The reaction mixture was stirred at room temperature overnight. The organic solvent was removed under vacuum. The residue was purified with flash column chromatography on silica gel eluting with 0-70% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH:10][C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: Cc1cccc(C)c1N
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCC(=O)Nc1c(C)cccc1C
Yield: 56.9 %

Procedure:
55 g (0.5 mol) of methoxyacetyl chloride were added dropwise to a solution of 61 g (0.5 mol) of 2,6-dimethylaniline and 50.5 g (0.5 mol) of triethylamine in 250 ml of toluene at 5° to 15° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours, filtered and concentrated and the residue was taken up in water. The aqueous mixture was extracted with methylene chloride and the extract was dried over sodium sulphate and concentrated by distilling off the solvent. The residue was distilled under a high vacuum. 55 g (57% of theory) of 2,6-dimethyl-N-methoxyacetyl-aniline of boiling point 122°-132° C./0.1 mm Hg and of melting point 61°-63° C. were obtained. ##STR177##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[CH:15]=CN[N:12]=1.[CH3:17][C:18]1[NH:19]C=CN=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[N:12]=[C:18]([CH3:17])[NH:19][CH:15]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(Cc1cc[nH]n1)c1ccc(Cl)cc1Cl
Product: Cc1nc(CC(=O)c2ccc(Cl)cc2Cl)c[nH]1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-2-pyrazolylethan-1-one except that 2-methylimidazole (3.7 g, 44.8 mmol) was used in place of pyrazole. The crude residue was purified on silica gel (5% MeOH/CH2Cl2) to yield a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)[O:16]1.C([O-])(=O)C.[K+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.O>[N:8]1([C:5]2[N:4]=[CH:3][C:2]([OH:16])=[CH:7][N:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Brc1cnc(N2CCOCC2)nc1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Oc1cnc(N2CCOCC2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 4-(5-bromopyrimidin-2-yl)morpholine (2 g), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.5 g), bis(triphenylphosphine)palladium chloride (180 mg), potassium acetate (2.5 g), and dioxane (20 ml) was stirred at 80° C. overnight under argon atmosphere. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (10 ml) and water (10 ml), and sodium perborate.tetrahydrate (3.5 g) was added thereto, followed by stirring at room temperature overnight. Then, a saturated aqueous ammonium chloride solution was added thereto. The aqueous layer was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 2-(morpholin-4-yl)pyrimidin-5-ol (610 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.[C:18]1([CH:28]=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[OH-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH:28]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[OH:29])[CH:3]=1
Reactant: CC(C)(C)CNc1ccc(Cl)cc1
Reactant: O=Cc1cccc2ccccc12
Agent: Cl
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1cccc2ccccc12
Reaction time: 1 h
Yield: 67.5 %

Procedure:
A solution of (4-chloro-phenyl)-(neopentyl)-amine (6.58 g, 33.3 mmol) in benzene (15 mL) was added to a solution of boron trichloride (1.0 M in xylenes; 36.6 mL, 36.6 mmol) in benzene (40 mL) at 0° C. under a nitrogen atmosphere. Once the addition was complete, the resulting mixture was heated at reflux for 2 hours and then recooled to 0° C. A solution of 1-naphthaldehyde (5.72 g, 36.6 mmol, 5.0 mL), triethylamine (6.74 g, 66.6 mmol, 9.3 mL) and benzene (15 mL) was then added and the resulting mixture stirred 1 hour before diluting with ethyl acetate and aqueous 2N hydrochloric acid. The resulting mixture was shaken vigorously, the aqueous layer alkalized with aqueous 5N sodium hydroxide, and the layers separated. The aqueous layer was extracted with ethyl acetate (2×). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (5:1 hexanes/ethyl acetate) to produce 7.95 g (67%) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[C:30]=[O:31].[NH4+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:30](=[O:31])[NH:29][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=3)[CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4[nH]ccc4c3)c2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2C1
Reaction time: 0.17 h

Procedure:
To a solution of 4-(1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (3.59 g, 10.2 mmol) in THF (100 mL) at 0° C., NaH (0.611 g, 15.3 mmol) is added. After 10 min, 1-isocyanato-3-trifluoromethyl-benzene (2.93 mL, 20.4 mmol) is added and the reaction is allowed to reach room temperature. After 2.5 h, a saturated solution of NH4Cl in water (50 mL) is added. The mixture is extracted with EtOAc (×3), and the combined organic extracts are dried and evaporated to give the crude 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester. MS (ESI) m/z 540.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]([NH2:13])=[S:12])([CH3:4])([CH3:3])[CH3:2].Br[CH:16]([CH3:20])[C:17](=O)[CH3:18].CCN(C(C)C)C(C)C>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:16]([CH3:20])=[C:17]([CH3:18])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(C)Br
Reactant: CC(C)(C)OC(=O)NCCNC(N)=S
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NCCNC(=O)OC(C)(C)C)sc1C

Procedure:
A solution of (2-thioureido-ethyl)-carbamic acid tert-butyl ester [CAS 331779-96-5] (3.6 g), 3-bromo-2-butanone (2.45 g), and DIPEA (5.5 ml) in ethanol (100 ml) was stirred overnight at RT and refluxed 1 hour. The mixture was concentrated. Ethyl acetate was added. Insoluble parts were filtered off and the remaining solution was extracted with brine. The organic layer was dried, evaporated and purified by flash chromatography yielding after crystallization 0.86 g of white crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:58][CH3:59])[C@H:42]([NH:46][C:47]([N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1)=[O:48])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:25])([CH3:26])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[C@@H:4]([OH:32])[CH2:3][C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:43](=[O:44])[C@H:42]([CH:41]([CH2:58][CH3:59])[CH3:40])[NH:46][C:47](=[O:48])[N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A solution containing the product from Example 23S (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 109E (0.018 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate. The product was then purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.011 g, 29% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.64 (d, J=6.62 Hz, 3 H), 0.72 (t, J=7.35 Hz, 3 H), 0.83 (s, 9 H), 0.93 (m, 1 H), 1.28 (m, 2 H), 1.49 (m, 2 H), 1.60 (m, 1 H), 2.61 (s, 3 H), 2.73 (m, 3 H), 2.84 (s, 3 H), 3.50 (s, 3 H), 3.62 (m, 1 H), 3.91 (m, 2 H), 4.10 (m, 2 H), 4.41 (m, 2 H), 4.80 (d, J=5.52 Hz, 1 H), 6.01 (d, J=8.46 Hz, 1 H), 6.76 (d, J=9.93 Hz, 1 H), 7.12 (m, 6 H), 7.31 (m, 3 H), 7.60 (m, 2 H), 7.86 (m, 4 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=3)[C:19]3[C:18](C4C=CC=CC=4)=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[B:44](OC)([O:47]C)[O:45]C.Cl>O1CCCC1>[C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][C:29]([B:44]([OH:47])[OH:45])=[CH:28][CH:27]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(C2(c3ccccc3)c3ccccc3-c3cccc(-c4ccccc4)c32)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)cc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
First, 4.0 g (10 mmol) of 9-phenyl-9-(4-bromophenyl)-phenyl-9H-fluorene was put in a 500 mL three-neck flask, the atmosphere in the flask was replaced with nitrogen, 100 mL of dehydrated tetrahydrofuran (abbreviation: THF) was then added to the flask, and the temperature was lowered to −78° C. Into this mixture solution, 7.6 mL (12 mmol) of a 1.59 mol/L n-butyllithium hexane solution was dropped, and the mixture was stirred for 2 hours. To this mixture, 1.4 mL (15 mmol) of trimethyl borate was added, and the mixture was stirred at −78° C. for 2 hours and at room temperature for 18 hours. After the reaction, this reaction solution was stirred while 1M diluted hydrochloric acid was added thereto until the solution became acid. This solution was subjected to ethyl acetate extraction, and an organic layer obtained was washed with a saturated saline. After the washing, magnesium sulfate was added to the organic layer to adsorb moisture. This suspension was filtered, the obtained filtrate was concentrated, and hexane was added thereto. The mixture was irradiated with ultrasonic waves and then recrystallized to obtain 3.5 g of the objective white powder in 97% yield. The reaction scheme of the synthesis method is shown in the following (A-1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[C:4]([F:14])[CH:3]=1.[OH-].[Na+].O.[BrH:18]>C(O)(=O)C>[Br:18][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:14])[N:12]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc(Br)ccc1-c1csc(Br)n1
Reaction time: 8 h
Yield: 98 %

Procedure:
2-(4-Bromo-2-fluorophenyl)-2-oxoethyl thiocyanate (2.1 g, 7.6 mmol), prepared in the previous step, in 15 mL of 33% hydrogen bromide in acetic acid was stirred overnight. The reaction was neutralized with 60 mL of 2N NaOH and 60 mL of water. The resulting residue was collected by suction filtration and placed under high vacuum to give 2.6 g of a brown paste. The crude product was purified on silica gel using a stepwise gradient of 5-20% ethyl acetate:hexane to give 2-bromo-4-(4-bromo-2-fluorophenyl)-1,3-thiazole (2.5 g, 98%), MS (ES) m/z 338 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:18]([CH:20]([NH:23][OH:24])[CH2:21][CH3:22])[CH3:19]>>[OH:24][N:23]([CH:20]([CH2:21][CH3:22])[CH2:18][CH3:19])[C:14]([NH:13][C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=1)=[O:15]
Reactant: CCC(CC)NO
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCC(CC)N(O)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 8.8 %

Procedure:
Using the method of Compound 72, 3,5-bis(trifluoromethyl)phenylisocyanate (1.3 g, 5.1 mmole) was reacted with N-(1-ethylpropyl)hydroxylamine (0.58 g, 5.6 mmole) to provide 160 mg of the desired product as a white crystalline solid, m.p. 115°-116° C. Analysis: Calculated for: C14H16F6N2O2 : %C, 46.93; %H, 4.5; %N, 7.82; Found: %C, 46.8; %H, 4.37; %N, 7.89.