Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22]([C:29](OCC5C=CC=CC=5)=[O:30])=[N:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C([NH2:44])=O>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22]([C:29]([NH2:44])=[O:30])=[N:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC=O
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4nc(C(=O)OCc5ccccc5)c5ccccc54)ccc3o2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4nc(C(N)=O)c5ccccc54)ccc3o2)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-1H-indazole-3-carboxylate (0.35 g), sodium methoxide (0.1 g) and formamide (4 ml) in tetrahydrofuran (2 ml) was stirred at 100° C. for 2 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure. Water was added to the residue and the resulting precipitates were collected by filtration and washed with a mixture of n-hexane and diisopropyl ether to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-1H-indazole-3-carboxamide. (0.22 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:10]=1)=[O:4].[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:8]=[C:9]([N:11]([CH2:26][CH3:27])[C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(C)cc2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)C(C)C)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
5-Isobutyrylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (0.786 g, 2.32 mmol) and NaH (6.2 g, 2.55 mmol) were added to DMF (20 mL), and the mixture was stirred for 30 minutes at room temperature, then cooled to 0° C. Ethyl iodide (1.181 g, 11.6 mmol) was added, and the reaction mixture was stirred for five days at room temperature. The reaction was quenched by addition of saturated aqueous NH4Cl and water, and the mixture was extracted with diethyl ether. The combined organic layers were separated, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to give 0.461 g of 5-(ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](CC#N)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O:23]CC)(=[O:22])[CH3:21]>O.S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:21][C:20]([OH:23])=[O:22])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: N#CCc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc2[nH]nc(-c3cccc(F)c3)c2c1

Procedure:
50 mg of 2-[3-(3-fluorophenyl)-1H-5-indazolyl]acetonitrile was suspended in 0.5 ml of water and 0.4 ml of concentrated sulfuric acid, and the suspension was stirred at 95° C. for 2 hours. The reaction mixture was added with 20 ml of ethyl acetate, sequentially washed with water (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 48 mg of the title compound as pale red crystals.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].BrBr.BrC(Br)=O.CC([O-])=O.[Na+].[NH2:24][C:25]([NH2:27])=[S:26]>CC(O)=O.C(O)C>[NH2:27][C:25]1[S:26][CH:2]=[C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[N:24]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: O=C(Br)Br
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 4-acetyl-benzoic acid (10 g, 61 mmol), in HOAc (400 mL) at 55° C. was treated with bromine (1 eq., 3.12 mL) dropwise over 10 minutes. After 90 minutes the reaction was cooled, the acetic acid was removed, ethyl acetate (50 mL) was added and then removed to get rid of the remainder of the acetic acid. The crude bromo ketone was then dissolved in ethanol (200 mL) with NaOAc (12 g) and thiourea (1 eq. 4.4 g) was added. The suspension was stirred at room temperature for 15 hours. The solvents were removed and the solids washed with water (3×100 mL) then ether:ethanol (4:1, 3×100 mL) and dried to give the product as a tan solid. MS: 221.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].Cl.[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29]Cl)[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:19][CH3:20])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1
Reactant: COc1cc(CCl)cc(Cl)n1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2cc3ncnc(Oc4ccccc4)c3cc2OC)cc(Cl)n1
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.1 g, 4.1 mmol), (prepared as described for the starting material in Example 13), 2-chloro-4-chloromethyl-6-methoxypyridine hydrochloride (0.88 g, 3.9 mmol) and potassium carbonate (2.0 g, 14 mmol) in DMF (20 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool, diluted with water and the precipitated product collected by filtration, washed with water and dried to give 7-((2chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (1.38 g, 79%). 1H NMR Spectrum: (CDCl3) 3.95(s, 3H); 4.04(s, 3H); 5.20(s, 2H); 6.70(s, 1H); 6.95(s, 1H) 7.18(m, 3H); 7.30(t, 1H); 7.40(t, 2H); 7.58(s, 1H); 8.52(s, 1H) MS-ESI: 424 [MH]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([OH:28])=O)[N:20]=1.[CH:32]([N:35](CC)[CH:36](C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CNC.C1COCC1>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([N:35]([CH3:36])[CH3:32])=[O:28])[N:20]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)O)n4)n3Cc3cccc(Cl)c3)n12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)N(C)C)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.03 h

Procedure:
To a solution of 3-{3-[6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl]-1H-pyrazol-1-yl}propanoic acid (8.0 mg, 0.018 mmol, from Step 6) in DMF (0.25 mL) was added N,N-diisopropylethylamine (13 μL, 0.074 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (12 mg, 0.033 mmol, Aldrich). After 2 minutes, 2.0 M dimethylamine in THF (0.074 mL, 0.15 mmol, Aldrich) was added. After 15 minutes, the reaction was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (5.5 mg, 65%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][N+:18]([CH3:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]>>[CH3:17][N:18]([CH3:27])[CH:19]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: Cc1ccccc1C=[N+](C)C
Agent: [Cl-]
Product: Cc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and dimethyl-(2-methyl-benzylidene)-ammonium chloride.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]2[C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[O:18][CH:19]([CH2:20][CH3:21])[C:13]=2[CH:12]=1.O>O1CCOCC1>[CH2:20]([CH:19]1[C:13]2[CH:12]=[C:11]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=[CH:15][C:14]=2[C:17](=[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=3)[NH:24][C:23]2=[O:32])[O:18]1)[CH3:21]
Reactant: NCCN1CCOCC1
Reactant: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)cc21
Solvent: O
Solvent: C1COCCO1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(NCCN3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (177 mg, 1.51 mmol) in 3 mL of dioxane is treated with 3-(6-Chloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-5-fluoro-1,3-dihydro-indol-2-one (100 mg, 0.30 mmol) in one portion. The reaction mixture is heated at 100° C. until no starting material remained. The reaction mixture is treated with water (10 mL) and heating is continued for 1 hr. The precipitate which formed is collected by filtration and washed with small amounts of water, EtOAc and ether. The solid obtained is dried under vacuum to give the title compound as a yellow solid (18 mg, 14%).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[N:1]1([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:21])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1=CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CC=CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Into a solution of 1,2,3,6-tetrahydropyridine (1.00 g, 12.0 mmol) and triethylamine (3 mL) in CH2Cl2 (30 mL), benzoyl chloride (1.69 g, 12.0 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hrs and washed with saturated Na2CO3 (20 mL×3) and brine solution (20 mL), dried over Na2SO4 and concentrated under vacuum to afford crude product. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (10/3, v/v) to afford target product as a colorless oil (2.27 g, 100%). 1H NMR (CDCl3): δ 2.16-2.25 (m, 2H), 3.46-4.20 (m, 4H), 5.53-5.91 (m, 2H), 7.29-7.53 (m, 5H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C[O:30][C:31](=[O:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH2:39][CH2:40]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH:23]4[CH2:28][CH2:27][N:26]([CH2:40][CH2:39][O:38][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[C:31]([OH:42])=[O:30])[CH2:25][CH2:24]4)=[CH:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCCOc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccccc1OCCCl
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCCOc3ccc4c(c3)OCO4)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D), starting with 8.1 mmol of 1-[3-(benzo[1,3]dioxol-5-yloxy)-propyl]-3-piperidin-4-yl-1H-indole and 2.3 g (11 mmol) of of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After the standard work-up, 2.68 g of the corresponding acid was obtained. The crude mixture was purified by flash chromatography over silica gel affording 1.15 g (26% of yield) of the expected acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[CH2:30](B1OC(C)(C)C(C)(C)O1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Cc4ccccc4)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 11, Step 1, using the following starting materials: 3-(1-benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and benzylboronic acid pinacol ester.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1F
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
40% Methanolic Triton B (0.51 mL, 1.12 mM) was added to a solution of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (303 mg, 0.86 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (270 mg, 1.72 mM) was added and the resultant mixture stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 295 mg (80%) of the {9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.5-7.3 (m, 5H), 7.05 (d, 1H, J=8 Hz), 6.8 (m, 1H), 6.6 (d, 1H, J=8 Hz), 6.4 (t, 1H, J=8 Hz), 6.2 (br s, 1H), 6.0 (br s, 1H), 5.6 (s, 2H), 4.9 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3432, 3180, 1774, 1766, and 1674. MS (ES) m/e 425.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(S(C)(=O)=O)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure of Examples 44 and 60 and General Procedure C, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-methylsulfonylphenyl boronic acid were reacted to give 146. MS: (ESI+) 524.1
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][C:7](=[O:17])[C:8](CC)(CC)P(O)(O)=O)C.[CH2:18](/[C:20](=[CH:23]\[CH2:24][CH3:25])/[CH:21]=O)[CH3:19].O>CO>[CH2:18](/[C:20](=[CH:23]\[CH2:24][CH3:25])/[CH:21]=[CH:8]/[C:7]([O:6][CH3:4])=[O:17])[CH3:19]
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Reactant: CC/C=C(/C=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC/C=C(/C=C/C(=O)OC)CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a 28 wt % solution of sodium methoxide in methanol (25.7 g) at 10° C. were added dropwise diethyl phosphonoacetic acid ethyl ester (25.3 g) and (E)-2-ethyl-2-pentenal (11.5 g) successively under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours, poured into chilled water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (dichloromethane) to give 13.4 g of methyl (E,E)-4-ethyl-2,4-heptadienoate as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][Cl:24]>CC(CC(C)C)=O>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:22][CH2:23][Cl:24])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCBr
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)OC(=O)c1ccc(OCCCl)cc1
Yield: 93.1 %

Procedure:
A mixture containing 0.79 g (4.1 mmol) of 4-hydroxy-benzoic acid tert-butyl ester, 1.13 g (8.14 mmol) of K2CO3 and 1.6 mL (16.3 mmol) of 1-bromo-2-chloro-ethane in 10 mL of isobutyl methyl ketone was refluxed for 5 hours. After filtering, the solvent was removed under reduced pressure affording 0.98 g (94% yield) of 4-(2-chloro-ethoxy)-benzoic acid tert-butyl ester.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH2:19][CH2:18]3)[CH2:12][C:11](=[O:24])[C:10]=1[C:25](=O)[CH2:26][CH3:27]>C(O)C>[CH2:2]([O:4][N:5]=[C:25]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH2:19][CH2:18]3)[CH2:12][C:11]=1[OH:24])[CH2:26][CH3:27])[CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
Ethoxyamine hydrochloride (0.42 g; 4.1 mmole) and then aqueous 1% sodium hydroxide (17.0 ml) were added to a solution of 3-hydroxy-5-(5-indanyl)-2-propionylcyclohex-2-en-one (1.10 g; 3.87 mmole) in anhydrous absolute ethanol (200 ml). The mixture was stirred at room temperature for a period of 4 hours and then the ethanol was removed by evaporation under reduced pressure using a rotary evaporator. The residue was treated with dichloromethane and the organic phase was washed twice with dilute aqueous hydrochloric acid and twice with water. The organic phase was dried over anhydrous sodium sulphate and the solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(5-indanyl)-cyclohex-2-en-1-one (1.20 g; 94.8%) as a pale yellow oil.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16](=[NH:20])OCC)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH2:26])[CH3:22]>C(O)C>[ClH:1].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH:26][C:16]([C:14]1[O:15][C:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)=[NH:20])[CH3:22]
Reactant: CCOC(CN)OCC
Reactant: CCOC(=N)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: Cl
Solvent: CCO
Product: CCOC(CNC(=N)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1)OCC
Reaction time: 48 h
Yield: 30 %

Procedure:
A solution of 98 g (0.33 mole) of ethyl 5-(4-nitrophenyl)-2-furimidate hydrochloride and 48 g (0.36 mole) of aminoacetaldehyde diethyl acetal in 1500 ml of absolute ethanol was heated under reflux for 4 hr. After standing in a refrigerator for 2 days, the solid which was deposited was collected by filtration and washed with anhydrous ether to give 38 g (30%) of N-(2,2-diethoxyethyl)-5-(4-nitrophenyl)-2-furamidine hydrochloride. The filtrate was concentrated on a rotary evaporator. The solid which was deposited was collected by filtration and washed with anhydrous ether to give 34 g (57% total yield) of additional product, m.p. 220°-280° (dec.)
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][F:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>N1CCCCC1.C(#N)C.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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]#[C:28][C@:26]([C:23]4[N:22]=[C:21]([CH3:20])[O:25][N:24]=4)([OH:30])[CH3:27])[CH:10]=3)[C:6]([CH2:18][F:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: Nc1nccc(-n2nc(CF)c3ccc(Br)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(CF)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 66 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (70 mg, 0.21 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.02 mmol), copper(I) iodide (3 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (90 mg, 0.41 mmol). The reaction mixture was warmed to 66° C. for 2 hr, re-treated with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (45 mg, 0.20 mmol) and warming continued at 66° C. for a further 1 hr. Following cooling to RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a brown oil which was suspended in acetonitrile and concentrated in vacuo. The residue was slurried in diethyl ether (0.5 mL) to which was introduced acetonitrile until a fine cream precipitate resulted. Filtration furnished the title compound as a cream solid: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 2.62 (3H, s), 5.85 (2H, d, J=47.45 Hz), 6.82 (1H, s), 6.95-7.23 (3H, m), 7.43 (1H, dd, J=8.28, 1.18 Hz), 7.98 (1H, d, J=8.20 Hz), 8.33 (1H, d, J=5.36 Hz), 8.94 (1H, s); LC-MS: m/z=+394.00 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]=[C:18]([Br:31])[CH:17]=2)=[CH:8][C:7]=1[CH3:32]>C(O)C.[OH-].[Na+]>[Br:31][C:18]1[CH:17]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]([CH3:32])[CH:8]=2)[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH:19]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)ccc1OCC(=O)O

Procedure:
A solution of (4-{3-[3-bromo-5-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (45 mg, 0.088 mmol) in ethanol (5 ml) and 1N NaOH (0.5 ml) was stirred at 75° C. for 30 min. The reaction mixture was evaporated and the residue dissolved in water (2 ml). Aqueous 1N HCl (0.5 ml) was added and the mixture was extracted with methylene chloride (3×15 ml). The combined organic phases were dried and evaporated to give the title compound in 36 mg (88%) yield.