Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 84.2 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]-triazin-4-ylamine (2.62 g, 5.68 mmol), pyrrolidine (808 mg, 11.36 mmol, 2.0 eq), triethylamine (575 mg, 5.68 mmol, 1.0 eq); and sodium iodide (85 mg, 0.56 mmol, 0.1 eq) in anhydrous DMF (28 mL) was stirred at 55° C. for 17 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with 50% aq. brine (3×), dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude was triturated from MeOH, filtered, and washed with cold MeOH and ether to provide 2.16 g (84.2%) of the desired product as a white solid. 1H-NMR (DMSO-d6) 8.54 (s, 1H), 7.89 (s, 1H), 7.80 (d, 1H), 7.58 (s, 1H), 7.36 to 7.30 (m, 5H), 7.14 (d, 1H), 6.59 (s, 1H), 5.65 (s, 2H), 2.90 (t, 2H), 2.48 to 2.39 (m, 6H), 1.87 to 1.83 (m, 2H), 1.67 to 1.64 (m, 4H); LC-MS [M+H]+=452, RT=2.14 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(N(CC)CC)C>N1C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1n(-c2ccc(Cl)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Yield: 7.6 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1 and 4-chlorophenyboronic acid (44 mg, 0.28 mmol) in pyridine (1.5 mL) was added copper (II) acetate (51 mg, 0.28 mmol) followed by triethylamine (0.04 mL, 0.28 mmol) and 3 Å molecular sieves (100 mg) under argon. The reaction mixture was stirred at reflux for 6 h. After this time, the reaction mixture was cooled to RT and diluted with water (5 mL). The resultant mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) and saturated aqueous NaCl (2×5 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to give 2,7,8-tris(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (5 mg, 8%) as yellow lyophilate. HPLC: 4.35 min; M+H=467; 1H NMR (CDCl3) δ 8.22 (1H, s), 8.10 (2H, d, J=10.0 Hz), 7.43 (2H, d, J=10.0 Hz), 7.35-7.38 (6H, m), 7.15 (2H, d, J=10.0 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2.O[CH2:20]C1C=C2C(=CC=1)C=C(C(C)C(O)=O)C=C2.[H-].[Na+].CI.Cl>C1C=CC=CC=1>[CH3:20][O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)C(C)c1ccc2cc(CO)ccc2c1
Reactant: CC(C(=O)O)c1ccc2cc(CO)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: c1ccccc1
Product: COCc1ccc2cc(C(C)C(=O)OC)ccc2c1
Reaction time: 2 h

Procedure:
To a mixture of 24.4 g. of methyl 6-hydroxymethyl-2-naphthyl-α-methylacetate (prepared from 6-hydroxymethyl-2-naphthyl-α-methylacetic acid by esterifying the latter by means of the procedure described in Part A of this example) and 500 ml. of benzene are added 2.4 g. of sodium hydride. The resulting mixture is stirred for 2 hours; then 12.2 g. of methyliodide are added. The resulting mixture is next neutralized by the addition of aqueous 1N hydrochloric acid after it has been allowed to stand for one hour; the mixture is then washed with water, dried over sodium sulfate, and evaporated to give methyl 6-methoxymethyl-2-naphthyl-α-methylacetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:42])[C@@H:9]([CH3:41])[C:10]([NH:12][C@H:13]1[CH2:19][O:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:24][C:25]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29]([C:37]([OH:39])=O)=[CH:30]3)[C:14]1=[O:40])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][NH:44][CH2:45][CH2:46][OH:47].C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[OH:47][CH2:46][CH2:45][N:44]([CH3:43])[C:37]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[C:25]([CH2:24][N:15]1[C:14](=[O:40])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:42])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH3:41])[CH2:19][O:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]1=3)=[C:34]([O:35][CH3:36])[CH:33]=[CH:32]2)=[O:39]
Reactant: CNCCO
Reactant: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(C(=O)N(C)CCO)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2ccccc21
Yield: 85.6 %

Procedure:
A mixture of 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoic acid (100 mg, 173 μmol, Eq: 1.00), 2-(methylamino)ethanol (26.0 mg, 27.8 μl, 346 μmol, Eq: 2.00), HOBT.H2O (31.8 mg, 208 μmol, Eq: 1.20), HBTU (78.8 mg, 208 μmol, Eq: 1.2), DIEA (67.1 mg, 90.5 μl, 519 μmol, Eq: 3.00) in DMF was stirred at 0° C. for 2 h. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford tert-butyl (S)-1-((S)-5-((6-((2-hydroxyethyl)(methyl)carbamoyl)-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (94 mg, 85% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:16](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH3:16])[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(-c2ccco2)cc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a solution of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220 mg) in N,N-dimethylformamide (2.5 mL) were added potassium carbonate (139 mg) and methyl iodide (0.25 mL) and the mixture was stirred at room temperature for 8 hrs. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→0:1) to give the title compound (94 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[Cl-].[OH:16][NH3+:17].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N:17][OH:16]
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 80 °C
Yield: 57.5 %

Procedure:
118.5 g (0.58 mol) of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone are dissolved in 470 ml of ethanol and heated at 80° C. To the solution are added 42.4 g (0.61 mol) of hydroxylammonium chloride and 80.9 g (0.99 mol) of sodium acetate dissolved in 240 ml of water. The reaction mixture is refluxed for 5 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into 500 ml of water, and a white solid is precipitated. The solid is isolated by filtration and rinsed with water, and purified by recrystallization from toluene, yielding 73.1 g of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone oxime as a white solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 3.84 (s, 3H), 6.99 (d, 2H), 7.55 (d, 2H), 9.11 (br s, 1H). The spectrum indicates the compound is a single isomer, which is tentatively assigned as Z-conformation.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26](Br)=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:32][C:33]1[C:38]([CH:39]([CH3:41])[CH3:40])=[CH:37][C:36](B(O)O)=[C:35]([O:45][CH3:46])[CH:34]=1>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:36]4[CH:37]=[C:38]([CH:39]([CH3:41])[CH3:40])[C:33]([F:32])=[CH:34][C:35]=4[O:45][CH3:46])=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C

Procedure:
A mixture of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 2, 49 mg, 0-092 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Intermediate 6, 21 mg, 0.101 mmol) and 1,1-bis(ditbutylphosphino)ferrocene palladium dichloride (6 mg, 0.0092 mmol) in aqueous potassium carbonate/THF (3 mL, 3 mL) was heated at reflux for 2 h under N2. After cooling to room temperature, the aqueous phase was separated and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (0-15% EtOAc in hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a colorless oil. LCMS=619.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.88 (br s, 2H), 7.84 (s, 1H), 7.68 (brs, 2H), 7.49 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.28 (br s, 1H), 6.71 (d, J=12.1 Hz, 1H), 5.88 (brs, 1H), 5.25 (br d, J=16.7 Hz, 1H), 4.21 (br m, 2H), 3.95 (br m, 2H), 3.81 (s, 3H), 3.21 (m, 1H), 2.39 (m, 2H), 1.92 (m, 1H), 2.11 (3H, s), 1.29 (br d, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:7]=2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:12]1([C:10]2[NH:9][C:8]3[CH:18]=[CH:19][C:5]([CH2:3][OH:2])=[CH:6][C:7]=3[N:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc2[nH]c(-c3ccccc3)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2[nH]c(-c3ccccc3)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
2-Phenyl-1H-benzoimidazole-5-carboxylic acid methyl ester (1.178 g, 4.67 mmol) was dissolved in 20 mL THF. Cooled to 0° C. and then added LAH (886 mg, 23.35 mmol). The mixture was heated to 50° C. overnight. Added 0.9 mL water, 0.9 mL 15% NaOH aqu. solution then 3 mL water. Stirred at RT for 30 mins. Filtered through celite and washed the celite with ethyl acetate. Washed the filtrate with brine. Dried over Na2SO4. Filtered and removed solvent in vacuo. Obtained 783 mg (74.8%) of (2-Phenyl-1H-benzoimidazol-5-yl)-methanol as an off white foam.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[Br:23][C:24]1[C:25]([CH:34]=O)=[CH:26][C:27]2[O:32][CH2:31][CH2:30][O:29][C:28]=2[CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:23][C:24]1[C:25]([CH2:34][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:26][C:27]2[O:32][CH2:31][CH2:30][O:29][C:28]=2[CH:33]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cc1Br)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cc4Br)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To 10 mL of a chloroform solution containing 130 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 109 mg of 7-bromo-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde, 25 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 140 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=10:1] to give 113 mg of 1-(2-(4-((7-bromo-2,3-dihydro-1,4-benzodioxin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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.COCCOC>[CH2:26]1[O:27][C:21]2[CH:20]=[CH:19][C:24]([C:2]3[CH:3]=[CH:4][C:5]4[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:23][C:22]=2[O:25]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCO2
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: COCCOC
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a mixture of methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (0.57 g), 3,4-methlenedioxyphenyl borate (0.47 g) and sodium carbonate (0.42 g) were added water (2 ml) and 1,2-dimethoxyethane (12 ml). Under argon atmosphere, the mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (0.16 g). The mixture was stirred at 80° C. for 14 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give methyl 7-(3,4-methlenedioxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (0.43 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]([CH3:21])[C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[OH:17]>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[CH:12]=[C:13]([CH:18]([CH3:21])[C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C#N)c1ccc(O)c(NC(=O)c2ccccc2)c1
Temperature: 100 °C

Procedure:
Benzoyl chloride (27.09 g., 0.19 mole.) was added, with cooling, during 20 minutes to a stirred solution of 2-(3-amino-4-hydroxyphenyl) propionitrile (28.35 g., 0.175 mole.) in dry pyridine (200 ml.) at 0°-3° C. After addition was complete, the mixture was heated at 100° C., for 1 hour. It was then evaporated under reduced pressure to yield crude 2-(3-benzamido-4-hydroxyphenyl) propionitrile as an oil.
Reaction SMILES: [K].[CH:2]1([S:5]([N:8]2[C:12]3[C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]([F:21])=[C:19]([F:20])[C:11]=3[N:10]([C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])C2=O)(=[O:7])=[O:6])[CH2:4][CH2:3]1.C(OCC)(=O)C>C1COCC1.CCCCCC>[F:21][C:18]1[C:14]2[N:15]=[CH:16][O:17][C:13]=2[C:12]([NH:8][S:5]([CH:2]2[CH2:4][CH2:3]2)(=[O:7])=[O:6])=[C:11]([NH:10][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:19]=1[F:20]
Reactant: O=c1n(-c2ccc(I)cc2F)c2c(F)c(F)c3ncoc3c2n1S(=O)(=O)C1CC1
Agent: [K]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
Potassium trimethylsilonolate (29 mg, 0.182 mmol) was added to a solution of 8-cyclopropanesulfonyl-4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-19a: 65 mg, 0.121 mmol) in THF (5 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was concentrated and the concentrate was dissolved in water, acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (25-35% ethyl acetate in hexane) afforded 18 mg of the product (29.5% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:34](=[O:39])[NH:35][CH2:36][CH2:37][NH2:38])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:38]4[CH2:37][CH2:36][NH:35][C:34]4=[O:39])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCNC4=O)ccc23)CC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (458 mg, 1.38 mmol), which was prepared as described in Example 12b, and (2-amino-ethyl)-carbamic acid benzyl ester hydrochloride (446 mg, 1.93 mmol) in DMSO (1.0 mL) was added K2CO3 (1.52 g, 11.04 mmol). The mixture was stirred at 115° C. overnight and subsequently partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography on silica gel (EtOAc as eluent) to afford the desired product as a white solid (400 mg, 73%). 1H NMR (CDCl3) δ 9.13 (s, 1H), 8.69 (dd, J=9.40 and 2.35 Hz, 1H), 8.08 (d, J=9.53 Hz, 1H), 7.42 (d, J=2.33 Hz, 1H), 5.25 (br, 1H), 4.31 (m, 2H), 4.09 (t, J=8.21 Hz, 2H), 3.69 (t, J=8.14 Hz, 2H), 3.63 (m, 1H), 2.95 (m, 2H), 1.77-2.04 (4H), 1.48 (s, 9H). Calcd for C21H28N5O3 (MH+) 398.3, found 398.3.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[CH:22]1[O:26][CH2:25][CH2:24][O:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH2:11][O:12][CH3:13])=[CH:17][C:16]=1[CH:22]1[O:23][CH2:24][CH2:25][O:26]1
Reactant: COCOc1cc(C#N)ccc1F
Reactant: Oc1ccc(Br)c(C2OCCO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)ccc1Oc1ccc(Br)c(C2OCCO2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A mixture of 4-fluoro-3-methoxymethoxybenzonitrile (33.0 g, 182 mmol), 4-bromo-3-(1,3-dioxolan-2-yl)phenol (44.6 g, 182 mmol), and potassium carbonate (30.1 g, 218 mmol) in N,N-dimethylformamide (370 mL) was stirred at 100° C. under nitrogen atmosphere overnight. The mixture was poured into ethyl acetate/water. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was passed silica gel short column (3:1 hexane/ethyl acetate) followed by trituration with hexane/ethyl acetate to give 4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-methoxymethoxybenzonitrile (32.6 g, 44%),
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[Si](C)(C)C.BrN1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+].[NH:39]1[CH:43]=[CH:42][CH:41]=[N:40]1>C1COCC1.O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([N:39]1[CH:43]=[CH:42][CH:41]=[N:40]1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: c1cn[nH]c1
Reactant: COCCCC(=O)OC
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COCCC(C(=O)OC)n1cccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
To a stirred, cooled (−78° C.) solution of 1.32 g (10.0 mmol) of methyl 4-methoxybutanoate in 15 mL of anhydrous THF under an atmosphere of nitrogen was added 10.5 mL (10.5 mmol) of a 1.0 M solution of LiHMDS in tetrahydrofuran. The resulting mixture was stirred for 1 h, then 1.09 g (10 mmol) of chlorotrimethylsilane was added. After stirring for 20 min, 1.78 g (10.0 mmol) of solid N-bromosuccinimide was added and the mixture was stirred for 2 h at −78° C., then slowly warmed to ambient temperature over 40 min. The reaction was quenched with a saturated aqueous ammonium chloride solution and then the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was dissolved in 15 mL of DMF and 5.5 g (40 mmol) of potassium carbonate followed by 3.4 g (50 mmol) of 1H-pyrazole were added. The resulting mixture was heated to 80° C. for 40 min, then cooled to ambient temperature. The reaction was diluted with 75 mL of water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-75% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to yield the title compound (0.26 g, 13%). LC-MS: m/z (ES) 199 (MH)+.