Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1.[CH2:20](OCCOCC)[CH3:21]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[F:18][C:13]1[CH:12]=[C:11]([C:8]2[O:9][C:10]3[C:2]([CH:20]=[CH2:21])=[CH:3][C:4]([OH:19])=[CH:5][C:6]=3[N:7]=2)[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: CCOCCOCC
Reactant: Oc1cc(Br)c2oc(-c3ccc(O)c(F)c3)nc2c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 115 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (0.87 g, 1.1 mmol) was added into a mixture of 7-bromo-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol (7.16 g, 22.1 mmol) tributyl(vinyl)tin (10.5 g, 33.25 mmol) and ethylene glycol diethyl ether (65 mL). The reaction mixture was stirred at 115° C. for 48 h, cooled to room temperature and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography, on acidic silica gel (hexanes/EtOAc/CH2Cl2 1/1/1), gave a white solid (4.35 g, 72% yield, m.p. 250-252° C.); MS m/e 272 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[N:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:15][C:16]1[N:21]=[C:20]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:14])[N:19]=[C:18]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1H-benzimidazole (0.99 g, 5 mmol), tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (Eur. J. Org. Chem. 2001, 2825-2839) (2.0 g, 6 mmol), and 3.5 g (25 mmol) powdered K2CO3 in 40 mL DMF was stirred at room temperature for 1 hr. Water was added and the product was collected by filtration and washed successively with water and cold ethanol to give 2.14 g (86% yield) of tert-butyl 4-{4-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate: mp (CH2Cl2/EtOH)>300° C.; 1H NMR (CDCl3) δ7.99 (d, J=8.3 Hz, 1H), 7.48 (t, JHF=53.4 Hz, 1H), 7.41 (t, J=8.3 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 4.06 (s, 3H), 3.95 (m, 4H), 3.58 (m, 4H), 1.50 (s, 9H); Anal. Calcd. for C21H24ClF2N7O3: C, 50.9; H, 4.9; N, 19.8. Found: C, 51.1; H, 4.9; N, 19.95%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])[CH3:3].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1)=[O:15].CCOCC>N1C=CC=CC=1C([O-])=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH:8][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:21][CH:20]=2)=[O:23])[CH:9]=[CH:10][CH:11]=1)[CH3:1]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])c1ccccn1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(=O)Nc2cccc(CN(C)C)c2)cc1
Yield: 73 %

Procedure:
Equimolar amounts of 3 -(N,N-dimethylaminomethyl)aniline (XVI; R=H) (Stedman, E. J. Chem. Soc. 1927, 1902) and 4-(methoxycarbonyl) benzenecarbonyl chloride (XvII; Z=H) were reacted together in pyridineat 0 ° C., to give methyl 4-[3 -(N,N-dimethylaminomethyl)phenyl]carbamoylbenzene-carboxylate (IX; R=Z=H) (73%), mp (dilsopropyl ether) 108°-109 ° C. 1H NMR (CD3SOCD3) 10.42 (s, 1 H, CONH), 8.13 (s, 4 H, H-2',H-3'), 7.75 (s, 1H, H-2), 7.70 (d, J=8.2 Hz, 1 H, H-6), 7.30 (t, J=8.2 Hz, 1 H, H-3), 7.04 (d, J=8.2 Hz, 1 H, H-4), 3.97 (s, 3H, COOCH3), 3.40 (s, 2 H, CH2), 2.18 (s , 6 H, N (CH3)2).Anal.(C18H 20 N2O3) C, H, N.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[CH:14]3[CH2:15][CH2:16][CH:10]2[CH2:11][C:12](=[O:17])[CH2:13]3)=[CH:6][CH:5]=1>CO.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH:14]3[CH2:15][CH2:16][CH:10]2[CH2:11][CH:12]([OH:17])[CH2:13]3)=[CH:18][CH:19]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1CC2CCC(C1)N2Cc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium borohydride (95 mg, 1.50 mmol) was added to a solution of 8-(4-bromobenzyl)-8-azabicyclo-[3.2.1]octan-3-one (0.22 g, 0.75 mmol) in methanol (10 mL) and the reaction mixture was stirred for 30 minutes. The reaction was diluted with water (10 mL) and extracted into DCM (3×20 mL). The combined organic layer was washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as an off-white solid (200 mg, 90%). 1H NMR (CDCl3, 300 MHz): 7.43 (dd, J=8.3, 2.0 Hz, 3H), 7.29-7.23 (m, 2H), 3.60-3.45 (m, 2H), 3.23-3.10 (m, 2H), 2.16-1.40 (m, 8H). LCMS (Method B): RT=1.90 min, M+H+=296/298.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][C:56]=3[O:65][CH3:66])=[N:49][C:50]([CH3:54])=[N:51]2)=[CH:46][CH:45]=1.CCN(C(C)C)C(C)C.[CH2:76]([SH:83])[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:76]([S:83][C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][C:56]=3[O:65][CH3:66])=[N:49][C:50]([CH3:54])=[N:51]2)=[CH:46][CH:45]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: SCc1ccccc1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nc(C)nc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)ccc1-c1nc(C)nc2cc(SCc3ccccc3)ccc12
Reaction time: 1 h

Procedure:
A solution of Pd2(dba)3 (0.046 g, 0.050 mmol), Xantphos (0.058 g, 0.100 mmol), 7-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylquinazoline (0.797 g, 2.007 mmol), and n,n-diisopropylethylamine (1.051 ml, 6.02 mmol) in 10 mL dioxane was heated to 60° C. and was treated with benzyl mercaptan (0.237 ml, 2.007 mmol). After stirring for one hour, LC/MS showed mostly product, so the reaction mixture was concentrated. This material was carried on to step 3 without purification. (M+H)+=441.0.
Reaction SMILES: Br[C:2]1[C:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][S:4][CH:3]=1.[C:14](C1C(Br)=CSC=1)(=[O:16])[CH3:15]>>[C:14]([C:2]1[C:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][S:4][CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1cscc1Br
Reactant: Brc1cscc1Sc1ccccc1
Product: CC(=O)c1cscc1Sc1ccccc1
Yield: 66 %

Procedure:
Prepared from 3-bromo-4-phenylsulfanyl-thiophene in 66% yield according to the procedure for the preparation of 4-acetyl-3-bromo-thiophene. 1H NMR (300 MHz, CDCl3) δ8.09 (d, 1H, J=3.3 Hz), 7.57 (d, 2 H, J=7.2 Hz), 7.38-7.42 (m, 3H), 6.31 (d, 1H, J=3.3 Hz), 2.57 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2>CCCCCC.C(OCC)(=O)C>[N:27]1[C:28]2[C:23](=[C:22]([NH:21][CH2:12][C:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:9][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:19][CH3:20])([CH3:18])[CH3:17])[CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc2ncccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2ncccc12)C(F)(F)F
Yield: 27.7 %

Procedure:
Analogously to Example 1, 200 mg (0.48 mmol) of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)oxirane is reacted with 99 mg (0.68 mmol) of 5-aminoquinoline. After chromatography on silica gel with hexane-ethyl acetate (0–70%), 58 mg of the product is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:56]=[C:57]2[C:62](=[CH:63][CH:64]=1)[CH:61]=[C:60]([C:65]1[CH:66]=[C:67]([NH2:71])[CH:68]=[CH:69][CH:70]=1)[CH:59]=[CH:58]2>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:56]=[C:57]2[C:62](=[CH:63][CH:64]=1)[CH:61]=[C:60]([C:65]1[CH:66]=[C:67]([NH:71][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:68]=[CH:69][CH:70]=1)[CH:59]=[CH:58]2
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(OC(F)(F)F)c5oc4=O)c3)ccc2c1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
DIEA (0.0115 mL, 0.067 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.016 g, 0.06 mmol) and HATU (0.025 g, 0.067 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-naphthalen-2-yl)-phenylamine (0.015 g, 0.06 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.015 g of product in 49% yield: LCMS (ESI) m/z 506 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C(OC(C1C=CNC=1C)=O)C.[F:37]C1C=CC=CC=1CBr>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:37])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: Fc1ccccc1CBr
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: CCOC(=O)c1cc[nH]c1C
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1F

Procedure:
Prepared similarly according to a reaction sequence in Example 117 steps (a), (b), (c) and (d) for the synthesis of 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, 2-fluorobenzyl bromide. The title compound, ESI MS (m/z): 471 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[CH3:32][N:33](C)C=O>O>[C:32]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1)#[N:33]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(-c2cc(-c3ccc([N+](=O)[O-])cc3)cc(-c3ccccn3)n2)n1
Temperature: 160 °C
Reaction time: 4.5 h

Procedure:
A mixture of 6-bromo-4'-(4-nitrophenyl)-2,2':6',2"-terpyridine (5.63 g), cuprous cyanide (4.66 g), sodium cyanide (2.55 g), and dimethylformamide (35 ml) was heated under argon with stirring to 160° C. for 4.5 hours, cooled to room temperature, and treated with 175 of water. After 15 min, the resulting slurry was filtered, the dark brown paste so obtained was placed in water (85 ml) containing sodium cyanide (3.2 g), and the reaction mixture was stirred for 15 minutes. The solid product was isolated by filtration, washed with water and dried under vacuum. Yield: 4.38 g.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].Cl>CN(C)C=O>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]([CH3:12])[CH2:10][OH:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(CO)NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CO)N(CC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 19.5 h

Procedure:
To a mixture of an optically-active compound of 2-benzylaminopropan-1-ol (111.2 g), potassium carbonate (111.6 g) and N,N-dimethylformamide (556 ml) cooled to 0° C. was added dropwise bromoacetic acid tert-butyl ester (109 ml) over 20 minutes, and the mixture was stirred at room temperature for 19.5 hours. The mixture was acidified by the addition of 2M aqueous hydrochloric acid solution and 6M aqueous hydrochloric acid solution to pH 2, and washed with toluene (1000 ml). The separated organic layer was extracted with 0.1M aqueous hydrochloric acid solution (300 ml). The combined aqueous layer was adjusted to pH 10 by 4M aqueous sodium hydroxide solution, and extracted with ethyl acetate (700 ml). The organic layer was sequentially washed with water (900 ml) and saturated aqueous sodium chloride solution (500 ml). The separated aqueous layer was extracted with ethyl acetate (400 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the titled compound (160.0 g).
Reaction SMILES: CN([CH2:4][CH2:5]N(C)C)C.C([Li])(CC)C.[C:14]([Si:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27]C=[C:25]([F:29])[C:24]=1[F:30])([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].CI>C1COCC1>[C:14]([Si:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:4]([CH3:5])=[C:25]([F:29])[C:24]=1[F:30])([CH3:20])[CH3:19])([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(F)c1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(CO[Si](C)(C)C(C)(C)C)c(F)c1F
Reaction time: 0.33 h
Yield: 105.3 %

Procedure:
To a solution of TMEDA (3.9 mL, 3.0 g, 26 mmol) in THF (33 mL) at −78° C. was added sec butyllithium (20 mL, 1.3 M in hexane, 26 mmol). After stirring for 20 minutes, a solution of tert-butyl-(2,3-difluoro-benzyloxy)-dimethyl-silane (6.0 g, 23 mmol) in 17 mL of THF was added dropwise. After stirring for 1 hour, the solution was added dropwise to a solution of methyl iodide (8 mL) in THF (40 mL) at −20° C. After stirring for 18 hours, the mixture was quenched with saturated aqueous NH4Cl, extracted 3× into ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo, giving 6.6 g of tert-butyl-(2,3-difluoro-4-methyl-benzyloxy)-dimethyl-silane as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.07 (app. t, 1H, J=7.2 Hz), 6.89 (app. t, 1H, d=7.3 Hz), 4.74 (s, 2H), 2.26 (d, 3H, J=1.9 Hz), 0.87 (s, 9H), 0.07 (s, 6H) ppm.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][CH:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[O:9]=[C:7]([NH:17][CH:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)SC/C(=C/c1ccccc1)C(=O)O
Reactant: COC(=O)CC(C)N
Product: COC(=O)CC(C)NC(=O)/C(=C\c1ccccc1)CSC(C)=O

Procedure:
The (E)-2-acetylthiomethyl-3-phenylpropenoic acid described in Example 1 (step C) is coupled with methyl 3-(RS)-aminobutanoate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:21])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)N3CCCCC3)ccc2n1C

Procedure:
An amount of 0.5 g (1.4 m mole) of 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5yloxy]-2-methyl-propanoic acid was dissolved in 25 ml of tetrahydrofurane and heated for four hours with 0.24 g (1.4 m mole) of N,N'-carbonyldiimidazole on a steam bath. Subsequently, 0.24 g (2.8 m mole) of piperidine were added, and the mixture was refluxed for 12 hours. After evaporation the residue was mixed with dilute hydrochloric acid and extracted with ether. The evaporated ether residue was purified by column chromatography with toluene/ethyl acetate (8:2) on silicagel.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cc1
Yield: 5.2 %

Procedure:
2-Chloro-5-(4-trifluoromethoxyphenyl)-pyrimidine (4.22 mmol), 4-formylphenyl boronic acid (5.1 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol), 2 M potassium carbonate (4.2 mL) and dioxane (21 mL) were combined in a vial and irradiated by microwave for 20 min at 150° C. The organic layer from the reaction mixture was loaded directly onto silica and dried in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (75 mg) as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 9.06 (s, 2H), 8.68 (d, J=8.8 Hz, 2H), 8.03 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.7 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][N:8]4[CH3:11])=[C:4]([C:12]4[O:13][C:14]([CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]5)=[N:15][N:16]=4)[CH:3]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: CC(C)N1CCN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CCN(Cc2nnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4C)o2)CC1
Temperature: 110 °C
Yield: 41 %

Procedure:
6-Bromo-1-methyl-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazole (45 mg, 0.107 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (26.1 mg, 0.107 mmol), sodium carbonate (34.1 mg, 0.322 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (7.85 mg, 10.73 μmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified firstly by silica (20 g) cartridge using a gradient of ethyl acetate and cyclohexane then by Mass Directed Automated Preparative HPLC (Method B). The solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (20 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:25][CH:24]2[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:20]([CH2:21][C:22]([C:50]3[S:54][C:53]([O:55][CH2:56][CH2:57]O)=[N:52][CH:51]=3)=[C:23]2[C:34](=[O:49])[N:35]([CH:46]2[CH2:48][CH2:47]2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[CH3:45])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.CCOCC>[C:11]([O:15][C:16]([N:18]1[CH2:25][CH:24]2[N:26]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH:20]([CH2:21][C:22]([C:50]3[S:54][C:53]([O:55][CH2:56][CH2:57][O:8][C:7]4[C:2]([Cl:1])=[CH:3][C:4]([CH3:10])=[CH:5][C:6]=4[Cl:9])=[N:52][CH:51]=3)=[C:23]2[C:34](=[O:49])[N:35]([CH:46]2[CH2:47][CH2:48]2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[CH3:45])[CH2:19]1)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Reactant: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCOc4c(Cl)cc(C)cc4Cl)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A sol. of 2,6-dichloro-p-cresol (0.55 mmol; 97 mg) in toluene (4.8 mL) was treated with compound E9 (0.37 mmol; 250 mg) followed by azodicarboxylic dipiperidide (0.73 mmol; 184 mg) and PBu3 (1.28 mmol; 0.27 mL). The reaction mixture was stirred at 80° C. After 1 h, the reaction mixture was allowed to cool to rt, diluted with Et2O (50 mL), filtrated, and the filtrate was washed with NaOH 1M (50 mL) and brine (50 mL). The org. extract was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30:70) yielded the title compound (0.23 g, 76%). LC-MS: tR=1.25 min; ES+: 843.29.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].O[CH2:14][CH:15]([CH2:17]O)O.N.C>S(=O)(=O)(O)O.O.II>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[CH:17][CH:15]=[CH:14][C:3]=2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: OCC(O)CO
Agent: II
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C(=O)O)c2cccnc12
Yield: 69.3 %

Procedure:
A of 3-amino-4-methoxybenzoic acid (5.0 g), glycerol (4.16 g), and iodine (135 mg) in concentrated sulphuric acid (5 ml) was heated at 180° C. for 2 hours. The reaction was allowed to cool, diluted with water (170 ml), made basic to pH8/9 with 0.88 ammonia and stirred with activated charcoal (2.0 g). The mixture was filtered through Celite and the filtrate acidified to pH4/5 with acetic acid. The precipitate was obtained by filtration and dried in a dessicator to yield the desired product (4.21 g) as a tan solid.