Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]1([CH3:18])[CH2:6][C@@H:5]([C:7]([O:9]C)=[O:8])[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:14]([O:13][C:11]([N:4]1[C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][Si:2]([CH3:18])([CH3:1])[CH2:3]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)[C@@H]1C[Si](C)(C)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[Si](C)(C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-1-tert-butyl 5-methyl 3,3-dimethyl-1,3-azasilolidine-1,5-dicarboxylate (3.1 g, 11.3 mmol, Eur. J. Org. Chem., 807-811 (2000)) in THF (10 mL) and MeOH (15 mL) was added a solution of lithium hydroxide monohydrate (2.9 g, 68 mmol) in water (15 mL). The resulting reaction mixture was stirred at rt for 4 h and the pH was adjusted to 1 using 1N HCl. The resulting aqueous layer was extracted with ethyl ether (2×). The organic solution was dried over MgSO4 and concentrated in vacuo to afford the title compound as a glassy material (2.9 g, 99%). 1H NMR (400 MHz, CDCl3) δ 4.91-4.53 (m, 1H), 3.06-2.47 (m, 2H), 1.61-1.04 (m, 11H), 0.27 (d, J=6.8 Hz, 6H); MS(ESI+) m/z 260.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH2:25][CH2:26][CH3:27])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.Br[C:31]1[N:36]=[C:35]([C:37]([O:39]C)=[O:38])[CH:34]=[CH:33][CH:32]=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>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH2:25][CH2:26][CH3:27])[C:9]([O:13][CH2:14][C:15]3[CH:16]=[C:17]([C:31]4[N:36]=[C:35]([C:37]([OH:39])=[O:38])[CH:34]=[CH:33][CH:32]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: CCCc1c(OCc2cccc([Sn](C)(C)C)c2)ccc2c1ccn2CC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCc1c(OCc2cccc(-c3cccc(C(=O)O)n3)c2)ccc2c1ccn2CC(C)(C)C
Temperature: 110 °C

Procedure:
1-(Bromomethyl)-3-iodobenzene was used to alkylate 1-(2,2-dimethyl-propyl)-4-propyl-1H-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (3.4 g, 7.3 mmol), hexamethyldistannane (5.0 g, 15 mmol), Pd(PPh3)4 (0.80 g, 0.69 mmol), and THF (40 mL) was heated at 60° C. for 18 h under N2 and then allowed to cool to rt. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography to give 1-(2,2-dimethylpropyl)-4-propyl-5-{[3-(trimethylstannyl)-benzyl]oxy}-1H-indole as a yellow oil. A mixture of the above stannane (0.35 g, 0.70 mmol), methyl 6-bromopyridine-2-carboxylate (0.22 g, 1.0 mmol), Pd(PPh3)4 (0.10 g, 87 μmol), and degassed toluene (10 mL) was heated at 110° C. for 24 h under N2 and then allowed to cool to rt. The reaction mixture was purified by silica gel chromatography (hexanes:ethyl acetate—1:0→2:1) to give a yellow oil. MS (ESI): 471.1 (M+H). A similar procedure as outlined in example 26 was followed for the saponification of the above ester. 1H NMR (DMSO, 500 MHz) 13.18 (br s, 1H), 8.31 (s, 1H), 8.19 (d, 1H), 8.12 (d, 1H), 8.09 (t, 1H), 8.01 (d, 1H), 7.61-7.53 (m, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.00 (d, 1H), 6.40 (d, 1H), 5.19 (s, 2H), 3.91 (s, 2H), 2.84 (t, 2H), 1.68-1.58 (m, 2H), 0.93 (s, 9H), 0.91 (t, 3H). MS (ESI): 457.1 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[CH3:22]/[C:23](/[CH:31]=[O:32])=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H][H]>>[CH3:22]/[C:23](/[CH2:31][OH:32])=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [H][H]
Reactant: C/C(C=O)=C/c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C/C(=C\c1ccccc1)CO
Yield: 93.7 %

Procedure:
Into a stainless steel autoclave equipped with a glass inner tube, Cu(NO3)(PPh3)2 (11.7 mg, 0.018 mmol) and triphenylphosphine (28.3 mg, 0.108 mmol) were introduced. The inside of the autoclave was then replaced with nitrogen. To the autoclave, an ethanolic solution of sodium hydroxide (0.03 M) (6.0 mL, 0.18 mmol) and α-methyl cinnamic aldehyde (1.26 mL, 9 mmol) were added, and stirring was performed at a hydrogen pressure of 5 MPa at 50° C. for 16 hours. The hydrogen was released with great care, and the conversion was analyzed by GC (>99%). The contents were concentrated, and then purified by silica gel chromatography. Thus, 1.25 g of the α-methyl cinnamic alcohol was obtained (yield: 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[O:17][C:18]([CH:24]([CH3:26])[CH3:25])=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=2)=[O:15])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6]>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[O:17][C:18]([CH:24]([CH3:26])[CH3:25])=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:20]=2)=[O:15])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)ccc1C(=O)O
Yield: 88 %

Procedure:
The aforementioned ester (65 mg, 0.181 mmol) was hydrolyzed with sodium hydroxide in a conventional manner, and extraction and recrystallization were performed to obtain the title compound (25, 55 mg, 87%) as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=O)[NH:32][CH:33]=2)=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:26][C@H:24]1[NH:25][C@@H:20]([CH3:19])[CH2:21][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:32][CH:33]=2)=[O:28])[CH2:23]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (42 mg, 36%).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[NH2:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:9])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Reactant: O=C(O)c1csc(Br)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(NC(=O)c1csc(Br)c1)c1ccccc1
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a solution of 5-bromo-3-thiophenecarboxylic acid (1 g, 4.85 mmol)[prepared according to J. Org. Chem. 1976, 41, 2350.], 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate (1.1 g, 4.85 mmol)[from Preparation 1] and diisopropylethyl amine (2.5 mL, 14.60 mmol) in DCM (50 mL) at 25° C. was added PyBrOP (2.5 g, 5.30 mmol) in one portion. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1% MeOH in DCM) affording the title compound (1.4 g, 68%) as a white solid: LC-MS (ES) m/z=426 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[N:12]([O-])=O.[Na+]>O.Cl>[F:11][C:8]([F:9])([F:10])[C:4]1[CH:3]=[C:2]([NH:1][NH2:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(C(F)(F)F)c1

Procedure:
m-Aminobenzotrifluoride (48.34 g: 0.3 mole) was cooled and treated with concentrated hydrochloric acid (137 ml) added dropwise. The paste was stirred at 0° and a solution of sodium nitrite (19.1 g) in water (137 ml) was added at 0°-5° with stirring. An almost clear solution was obtained. Then a solution of stannous chloride dihydrate (191.3 g) in concentrated hydrochloric acid (137 ml) was added dropwise with stirring at 0°-10°.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].O.[NH2:36][NH2:37].C(=O)([O-])O.[Na+]>CN(C=O)C>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:37][N:36]=1)([O-:33])=[O:32]
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-nitrophenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (619 mg, 1.3 mmol) produced in Synthesis Example 37 in DMF (6 mL) was added hydrazine monohydrate (purity of 80%, 233 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-nitrobenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (565 mg, yield 92%).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:5]1.[Cl-].[Cl-].[Ca+2].Cl>C(O)C>[OH:5][CH:6]1[CH2:7][CH:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]([CH2:4][OH:3])[CH2:10]1
Reactant: O=C(NC1CC2CC1C(=O)O2)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Product: O=C(NC1CC(O)CC1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
NaBH4 (0.580 g, 15.2 mmol) was added to a solution of benzyl 3-oxo-2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate (1.0 g, 3.8 mmol) and CaCl2 (0.85 g, 7.6 mmol) in ethanol (50 mL) at 0° C. After being stirred at room temperature for 12 hours, the reaction mixture was treated with concentrated HCl. The volatiles were removed, and the residue was extracted with CHCl3 (3×100 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was re-crystallized from petroleum ether to afford benzyl 4-hydroxy-2-(hydroxymethyl)cyclopentylcarbamate (750 mg, 75% yield) as a solid. 1H NMR (500 MHz, (CD3)2SO) δ 7.38-7.31 (m, 5H), 7.25 (d, J=13.5 Hz, 1H), 4.99 (s, 2H), 4.53 (d, J=4 Hz, 1H), 4.48 (t, J=10 Hz, 1H), 4.09 (d, J=4 Hz, 1H), 3.73 (t, J=15.5 Hz, 1H), 3.46-3.43 (m, 1H), 3.31-3.28 (m, 1H), 1.99 (d, J=7 Hz, 1H), 1.80-1.74 (m, 2H), 1.57 (t, J=12.5 Hz, 1H), 1.26 (s, 1H).
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1B(O)O.Br[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[S:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][CH3:7]
Reactant: Brc1cccs1
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)cc1-c1cccs1
Temperature: 85 °C
Yield: 243.3 %

Procedure:
To dioxane (113 ml) is added 2-methoxy-5-fluorophenylboronic acid (4.25 g, 24.9 mmol), 2-bromothiophene (3.65 g, 22.7 mmol, 0.9 eq.) and potassium carbonate (2M, 37 ml). Palladium (0) tetrakistriphenylphoshine (0.03 eq.) is then added and the resulting mixture is heated to 85° C. for 3 hours. The reaction is cooled to room temperature and poured into ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate. The organic layers are combined, and dried over sodium sulfate, concentrated to a brown oil and the resulting residue is flash chromatographed in 20% toluene/hexanes to afford 11.5 g of 2-(thien-2-yl)-4-fluoroanisole (90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][N:22]([CH3:33])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][CH2:31][NH2:32])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:32][CH2:31][CH2:30][NH:29][C:26]3[CH:27]=[CH:28][C:23]([N:22]([CH3:33])[CH3:21])=[CH:24][CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CN(C)c1ccc(NCCN)cc1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCNc1ccc(N(C)C)cc1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 2-(4-dimethylaminophenylamino)-ethylamine analogously to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=O)=[CH:4][CH:3]=1.NN.FC1C=CC(NO)=CC=1.[F:22][C:23]([N:26]=[C:27]=[O:28])([F:25])[F:24]>O1CCCC1.[Pd]>[F:22][C:23]([F:25])([F:24])[NH:26][C:27]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:10])=[O:28]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C=NC(F)(F)F
Agent: [Pd]
Agent: NN
Agent: ONc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(NC(F)(F)F)N(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
p-Fluoronitrobenzene (14.1 grams; 0.1 mol) is dissolved in tetrahydrofuran (100 ml). Ten percent palladium on charcoal catalyst (0.1 gram) is added to the solution followed by hydrazine (6.0 ml; 0.1 mol), and the resulting mixture stirred at room temperature for about 48 hours with cooling as necessary. The reaction mixture, containing N-(4-fluorophenyl)hydroxylamine, is dried over anhydrous magnesium sulfate and filtered. To this solution is added trifluoromethyl isocyanate (11.1 grams; 0.1 mol) and the solution is stirred for about 15 minutes. The reaction mixture is concentrated by evaporation of solvent and the resulting precipitate is recovered by filtration to yield 1-trifluoromethyl-3-(4'-fluorophenyl)-3-hydroxyurea.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH2:27][CH2:28]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NC3CCOCC3)cc2n1
Yield: 57 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (85 mg, 0.27 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (61 mg, 57%) which was obtained as a yellow solid. MS: m/e=403.5 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3]1.O.[OH-].[Li+:23]>O1CCOCC1.CO.O>[CH3:1][C@@H:2]1[N:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([O-:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[Li+:23]
Reactant: COC(=O)c1cccc2oc(N3CCOC[C@@H]3C)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nc2c(C(=O)[O-])cccc2o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-methyl 2-(3-methylmorpholino)benzoxazole-4-carboxylate (0.58 g, 2.1 mmol) in 1,4-dioxane/CH3OH/H2O (2:2:1, 8.5 mL) containing lithium hydroxide monohydrate (150 mg, 6.30 mmol) was stirred at room temperature 24 h. The reaction mixture was concentrated under reduced pressure and residual H2O was azeotropically removed with benzene (2×100 mL) to yield lithium (S)-2-(3-methylmorpholino)benzoxazole-4-carboxylate as a white solid which was used in the next step without further isolation or purification.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([NH:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4[NH:35][C:36]3[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=CC=1.Cl.CO>C(O)(C(F)(F)F)=O.CC#N.CCOCC.C(Cl)Cl>[N:12]1[C:13]([C:17]2[C:18]([NH:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4[NH:35][C:36]3[CH:37]=[CH:38][C:39]([C:40]#[N:41])=[CH:42][CH:43]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]2[C:9]([NH:8][CH:16]=[N:15]2)=[N:10][CH:11]=1
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4Nc4c(C)ccc5c(Nc6ccc(C#N)cc6)nccc45)ncnc32)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1Nc1ncccc1-c1ncnc2[nH]cnc12
Yield: 43.3 %

Procedure:
A solution of 4-(5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile (0.37 g, 0.63 mmol) in TFA (3 mL) was stirred in a 65° C. oil bath for 4.5 h. The reaction mixture was concentrated to give a dark orange residue. The residue was dissolved in MeCN (4 mL) and added dropwise to 1 N HCl in Et2O (100 mL). The resulting precipitate was collected by suction filtration. The bright yellow solid was dissolved in MeOH (50 mL) and 2M NH3 in MeOH (50 mL) and adsorbed onto a pad of silica gel. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 1% to 10% 1 M NH3.MeOH in CH2Cl2 (over 30 min), to provide 4-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile (0.128 g, 43% yield). The orange solid was suspended in MeOH (5 mL), Et2O (100 mL), and hexane (100 mL), and stirred at reflux for 2 h. The solid was collected by suction filtration, washed with hexane and dried in vacuo at 80° C. overnight to give 4-(5-(3-(9H-purin-6-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile as an amorphous orange solid. 1H NMR (400 MHz, DMSO-d6) □ ppm 2.38 (s, 3H), 6.91 (dd, J=7.78, 4.77 Hz, 1H), 7.28 (d, J=5.52 Hz, 1H), 7.66 (d, J=8.53 Hz, 1H), 7.75 (d, J=8.53 Hz, 2H), 8.01 (d, J=5.52 Hz, 1H), 8.03-8.07 (m, 1H), 8.13 (d, J=8.53 Hz, 2H), 8.42 (d, J=9.03 Hz, 1H), 8.74 (s, 1H), 9.06 (s, 1H), 9.66 (s, 1H), 9.71-9.85 (m, 1H), 11.87 (s, 1H), 13.84 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[CH2:27]([NH2:30])[CH2:28][NH2:29]>>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:14]2[CH2:13][N:12]([C:4]3[CH:3]=[C:2]([NH:29][CH2:28][CH2:27][NH2:30])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH2:18][CH2:17][CH2:16][C:15]=2[CH:19]=1)(=[O:25])=[O:24]
Reactant: NCCN
Reactant: CS(=O)(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3ccccc3n1)C2
Product: CS(=O)(=O)c1ccc2c(c1)CCCN(c1cc(NCCN)c3ccccc3n1)C2
Temperature: 150 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
The mixture of 2-(4-chloroquinolin-2-yl)-7-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (55.6 mg, 0.144 mmol) and ethane-1,2-diamine (1 mL) was heated with stirring in a 10 mL microwave process vial for 2 hours at 150° C. under microwave irradiation. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give 27.5 mg of product as a light-yellow solid (yield was 46.5%). MS obsd. (ESI+) [(M+H)+] 411. 1H NMR (400 MHz, CD3OD) δ ppm 7.82-7.73 (m, 4 H), 7.53 (d, J=7.6 Hz, 1 H), 7.45-7.40 (m, 1 H), 7.12-7.08 (m, 1 H), 5.98 (s, 1 H), 4.96 (s, 2 H), 4.16 (s, 2 H), 3.41 (t, J=6.4 Hz, 2 H), 3.16 (brs, 2 H), 3.06 (s, 3 H), 2.97 (t, J=6.4 Hz, 2 H), 1.96 (brs, 2 H).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:29])[N:11]([CH3:28])[CH:12]=[C:13]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[C:14]=1[F:15])C1C=CC=CC=1.C(S)C.B(F)(F)F.CCOCC>C(Cl)Cl.CO>[C:18]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=[C:16]([C:13]2[C:14]([F:15])=[C:9]([OH:8])[C:10](=[O:29])[N:11]([CH3:28])[CH:12]=2)[CH:17]=1
Reactant: Cn1cc(-c2cccc(-c3ccccc3)c2)c(F)c(OCc2ccccc2)c1=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Solvent: CCS
Product: Cn1cc(-c2cccc(-c3ccccc3)c2)c(F)c(O)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77.2 %

Procedure:
To a solution of 3-(benzyloxy)-5-(biphenyl-3-yl)-4-fluoro-1-methylpyridin-2(1H)-one (22 mg, 0.057 mmol) in CH2Cl2 (0.8 mL) was added ethanethiol (53 mg, 0.856 mmol) followed by BF3.OEt2 (0.108 mL, 0.856 mmol). The resulting mixture was stirred at room temperature for 3.5 h, diluted with MeOH and concentrated. Purification by preparative HPLC (10-80% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 13 mg (77%) of 5-biphenyl-3-yl-4-fluoro-3-hydroxy-1-methylpyridin-2(1H)-one as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.61 (d, J=7.9 Hz, 4H), 7.49 (dt, J=22.1, 7.5 Hz, 3H), 7.42-7.35 (m, 2H), 6.99 (d, J=7.9 Hz, 1H), 6.40 (br, 1H), 3.69 (s, 3H). High resolution mass spec (FT/ICR) calc (M+H)+=296.1081 found 296.1081.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:17][CH2:18][O:19][Si:20]([CH:24]([CH3:25])[CH3:26])([CH:21]([CH3:23])[CH3:22])[CH:27]([CH3:28])[CH3:29]
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)[Si](OCCOc1cc(F)ccc1F)(C(C)C)C(C)C

Procedure:
The stirred mixture of 0.80 g of 2,5-difluorophenol, 0.82 g of potassium carbonate, 1.98 g of (2-iodoethoxy)triisopropylsilane and 10 ml of acetone is kept at reflux over 3 hours. The reaction mixture is cooled, poured onto water (100 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed with brine (1×80 ml) dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rt=6.63.