Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C[O:12][C:13](=[O:42])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3Br)[CH:24]=2)=[CH:18][C:17]=1[CH3:41]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:31]1[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:30]=1[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:42])=[O:12])=[C:17]([CH3:41])[CH:18]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccc3F)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 2-fluorophenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 132 mg (68%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H22O4F4 510, found 511 (M+1, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12](Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[NH:17][NH2:18]>C(O)CCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:18][NH:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)NN
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccc(C#N)cc2)nn1
Temperature: 25 °C

Procedure:
A mixture of 0.40 g. of 6-(p-cyanophenyl)-3-chloropyridazine and 0.70 g. of 97% ethyl carbazate in 25 ml. of n-butanol is prepared. The solution is stirred and heated at reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and the product precipitated from solution. The product is filtered, washed with n-butanol, water, dried and recrystallized from ethanol giving a crystalline material, m.p. 235° C.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=O)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][NH:36][CH2:35]2>CN(C=O)C>[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][N:36]([C:9]([C:8]1[CH:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]([O:15][CH3:16])=[CH:6][C:7]=1[O:13][CH3:14])=[O:11])[CH2:35]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: COc1cc(OC)c(C(C)C)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(OC)c(C(C)C)cc1C(=O)N1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2.45 g, 10.9 mmol), HOBt (1.61 g, 11.9 mmol) and EDC (1.85 g, 11.9 mmol) in anhydrous DMF (33 ml) under N2 was added 5-bromo-2,3-dihydro-1H-isoindole (1.97 g, 9.95 mmol) and stirred at room temperature overnight. The reaction was quenched by diluting with NaOH (1M, aq.) and extracting the product with EtOAc (×2). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a brown oil. The product was purified by flash column chromatography using gradient elution (ether/petrol) to yield (5-bromo-1,3-dihydro-isoindol-2-yl)-(5-isopropyl-2,4-dimethoxyphenyl)methanone as a beige solid (3 g). 1H NMR (Me-d3-OD) 7.60-7.13 (3H, m), 7.14 (1H, s), 6.71 (1H, s), 4.89 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.90 (3H, s), 3.27 (1H, sept), 1.20 (6H, d). MS: [M+H]+ 404/406.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C)C=O.O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:8][C:5]2[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2coc(CO)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a suspension of kojic acid (50 g: 0.32 Mol.) in dimethylformamide (300 ml) are added potassium carbonate (63 g: 1.42 Eq.) and p-methoxybenzyl bromide (92 g: 1.42 Eq.), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with water (1liter) to give 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone (74.5 g). Yield: 81%. mp. 124°~130° C.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:9](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccnc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 86.7 %

Procedure:
To a solution of 2-nitro-1H-imidazole (500 mg, 4.4 mmol) in DMF (50 mL) is added cesium carbonate (1.7 g, 5.3 mmol) and the mixture is heated to 50° C. for 30 minutes. The resulting suspension is cooled to room temperature and MeI (0.33 mL, 5.3 mmol) is added. The reaction is heated to 50° C. for 2 hours is then cooled to room temperature and filtered through a bed of Celite. The filtrate is poured over ice water and extracted ethyl acetate. The organic layer is washed with water, brine, dried (Na2SO4) and concentrated to afford the title compound (485 mg, 86%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[N:6][N:5]2[CH:17]=1.[CH3:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:17]=[C:2]([C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[C:24]([N+:25]([O-:27])=[O:26])[CH:23]=3)[N:3]=2)[N:6]=1
Reactant: Fc1ccccc1-c1ccc2nc(Cl)cn2n1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ncc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 11.4 %

Procedure:
To a mixture of 2-chloro-6-(2-fluorophenyl)imidazo[1,2-b]pyridazine (0.100 g, 0.403 mmol), 2-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.605 mmol), Na2CO3 (2.01 mmol) in 2-propanol (3.75 mL) and water (1.25 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(0.0403) mmol). The mixture is heated at 80° C. for 12 hours, then cooled, concentrated under reduced pressure, added sat. aqueous NaHCO3 (20 mL) and extracted with EtOAc (3×20 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford the title compound (0.016 g, 11%) as a white solid: Rf 0.38 (1:1 EtOAc:hexanes); LCMS (m/z)=350.3 [M+H]+, tR=2.71 min.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:37]=2)[C:32]([C:48]2[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=2)=[N:31]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[C:33]4[C:38](=[CH:37][CH:36]=3)[N:30]([CH3:29])[N:31]=[C:32]4[C:48]3[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1nc(-c2ccncc2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3ccncc3)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.207 mmol), 1-methyl-3-(pyridin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (53 mg, 0.16 mmol), Pd(PPh3)4 (18 mg, 16 μmol), and K2CO3 (66 mg, 0.47 mmol). De-gassed dioxane (2 mL) and water (0.5 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 75% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J=5.9 Hz, 2H), 8.64 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.94 (d, J=5.9 Hz, 2H), 7.89 (s, 1H), 7.61-7.39 (m, 5H), 5.21 (s, 1H), 4.18 (s, 3H), 3.75 (s, 3H), 2.60 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:3][CH2:4][CH:5]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:37])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[CH:24]([NH2:35])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]=[N+:33]=[N-:34])=[CH:28][CH:27]=3)=[CH:12][CH:11]=2)[CH:6]1[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1.[C:52](C1CC(=O)N(O)C1=O)(=[O:66])[CH2:53][CH2:54][CH2:55][CH2:56][C@H:57]1[C@@H:65]2[C@@H:60]([NH:61][C:62]([NH:64]2)=[O:63])[CH2:59][S:58]1>CN(C)C=O>[N:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH:24]([NH:35][C:52](=[O:66])[CH2:53][CH2:54][CH2:55][CH2:56][CH:57]2[CH:65]3[NH:64][C:62](=[O:63])[NH:61][CH:60]3[CH2:59][S:58]2)[C:23](=[O:36])[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17](=[O:37])[NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[C:8](=[O:9])[CH:5]([CH2:4][CH2:3][CH:2]([OH:1])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:6]3[C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)=[CH:15][CH:14]=2)=[CH:27][CH:28]=1)=[N+:33]=[N-:34]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)C2CC(=O)N(O)C2=O)N1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(N)Cc3ccc(N=[N+]=[N-])cc3)cc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(Cc3ccc(N=[N+]=[N-])cc3)NC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Yield: 54.6 %

Procedure:
40 mg (0.058 mmol) of compound 12 and 60 mg of D-biotinyl-N-hydroxysuccinimide 13 (Bachem) are solved in 0.5 ml DMF (dimethylformamide). It is evaporated after 1 h at room temperature. The residue is purified by flash chromatography (methylenchloride/methanol/conc. ammonia 30:5:1). 29 mg (55%) of compound 14 is obtained in form of an amorphic solid compound: C49H57N9O7S (912.12) MS (ESI+) 916.6 (M+H+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:23]1([CH2:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)[C:18]([OH:20])=[O:19])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 43.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (58.5 mL of a 0.93M stock solution, 53.2 mmol) cooled to −78° C. was treated with (4-methoxy-phenyl)-acetic acid (4.21 g, 25.35 mmol) in tetrahydrofuran/ 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (5.85 g, 27.8 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at −78° C. for 45 min and at 0° C. for 1 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methoxy-phenyl)-propionic acid (2.76 g, 43.8%) as a yellow solid: mp 119-121° C.; EI-HRMS m/e calcd for C15H20O3(M+) 248.1412 found 248.1415.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(C=O)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
6-Bromoindole-3-carboxaldehyde, 23 (5.0 g, 22.3 mmol) is dissolved in methylene chloride (40 mL), then cooled to 0° C. and tert-butylchloroformate (3.40 g, 25.0 mmol) and triethyl amine (2.50 g, 25.0 mmol) are added over 5 minutes. The reaction is maintained at reflux, under inert atmosphere for 3 hours. The reaction is cooled, filtered and the solvent removed in vacuo. The residue composed primarily of compound 24 is used in the Example 18 without purification. (See, e.g., G. Wille and W. Steglich, Synthesis, 2001, 759-762 for a related procedure.)
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([NH:16][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:15][C:9]=3[N:8]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1ccc2[nH]c(-c3ccc(C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
To a solution of 2-p-tolyl-1H-benzo[d]imidazol-5-amine (150 mg, 0.67 mmol) in pyridine (10 mL) at room temperature was added butyryl chloride (77 μL, 0.74 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed twice with saturated aqueous copper sulfate, followed by sodium bicarbonate and brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 56 mg (28%) of the title compound (LCMS RT=6.96 min, MH+ 294.0)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1.[CH2:23]([O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:23]([O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[N:5]=[C:6]([S:8][CH3:9])[N:7]=2)[CH:28]=1)[CH3:24]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: COc1ccc(CCNc2cc(Cl)nc(SC)n2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Oc2cc(NCCc3ccc(OC)c(OC)c3)nc(SC)n2)c1
Temperature: 90 °C
Yield: 83.5 %

Procedure:
A mixture of (6-dhloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine [250 mg, 0.74 mmol, Intermediate (31)], 3-hydroxy-benzoic acid ethyl ester (0.18 g, 1.1 mmol), and Cs2CO3 (0.48 g, 1.48 mmol) in DMF (4 mL) is heated to 90° C. for 15 h. The mixture is diluted with water, and extracted with EtOAc. The extracts are washed (water), dried (MgSO4), filtered, concentrated, and chromatographed (silica gel, 30% EtOAc in Heptane) to afford 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methylsulfanyl-pyrimidin-4-yloxy}-benzoic acid ethyl ester [0.29 g 83%, Intermediate (71)]. LCMS: RT=3.7 minutes, MS: 470 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(Br)cc21

Procedure:
Reaction Scheme 9 discloses the preferred method of synthesis of a starting material from which certain examples for compounds of the invention within the scope of Formula 6 are preferably made. In accordance with this scheme 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) is reacted with t-butylmagnesium chloride in tetrahydrofuran in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(H)-pyrimidinone (DMPU). Thereafter, the resulting intermediate tertiary alcohol is heated in the presence of acid (p-toluenesulfonic acid) to give 7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene (Compound C42). Compound C42 is reacted with 1-ethoxyvinyltributyltin (EVTB) in the presence of Pal(0) catalyst to yield after acidic work-up 7-acetyl-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene (Compound C43). Compound C43 is subjected to a sequence of reactions of the type described above in connection with Reaction Scheme 8, starting with a Horner Emmons reaction with diethyl cyanomethylphosphonate, to eventually provide ethyl 7-[4,4-dimethyl-3,4-dihydro-1-(1,1-dimethylethyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (Compound C46). Compound C46 of the invention is within the scope of Formula 6. ##STR24##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH2:31])=[N:23]1>C(O)C>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])[N:3]=2)=[N:23]1
Reactant: Nc1n[nH]c2ccccc12
Reactant: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Cl)n1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Nc2n[nH]c3ccccc23)n1
Reaction time: 18 h
Yield: 26.5 %

Procedure:
A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (100 mg, 0.326 mmol) and 1H-indazol-3-ylamine (86 mg, 0.651 mmol) in ethanol (3 mL) was heated at 160 C. and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160 C. for 18 hours under nitrogen. The resulting melt was dissolved in 5% methanol:dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1×25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography (25% to 50% hexane:ethyl acetate) afforded V-2 as a yellow solid (35 mg, 27%). 1H NMR (500 MHz, d6-DMSO) δ 9.78 (br s, 1H), 8.62 (d, 1H), 7.9-7.85 (m, 1H), 7.78-7.72 (m, 1H), 7.70-7.68 (m, 1H), 7.65-7.62 (m, 1H), 7.60-7.55 (m, 1H), 7.52-7.45 (m, 3H), 7.41-7.38 (m, 1H), 7.28-7.25 (m, 1H), 7.18 (s, 1H), 6.95-6.92 (m, 1H), 5.76 (s, 1H); LC-MS (ES+) m/e=405.18 (M+H); HPLC-Method D Rt 2.74 min.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6].CCN(S(F)(F)[F:36])CC>C(Cl)Cl.C1COCC1>[F:36][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCF)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (120 mg, 0.28 mmol) in methylene chloride (10 mL) and THF (6 mL) under nitrogen at −78° C. was added DAST (89 mg, 0.56 mmol) and the reaction mixture was stirred at −78° C. for 2 h and warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/hexanes gradient). The resulting crude residue was triturated in methylene chloride and filtered to afford the desired product (90 mg, 75%) as a off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.10 (t, J=5.9 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.76 (d, J=5.4 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.43 (d, J=9.2 Hz, 1H), 5.75 (d, J=5.4 Hz, 1H), 4.51 (t, J=4.9 Hz, 1H), 4.42 (t, J=4.9 Hz, 1H), 3.71 (s, 3H), 3.24 (q, J=5.2 Hz, 1H), 3.19 (q, J=5.2 Hz, 1H); ESI MS m/z 433 [C20H17FN2O4S2+H]+; HPLC 93.4% (AUC), tR=15.64 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH:29]([C:63]2[CH:68]=[C:67]([CH2:69][CH3:70])[CH:66]=[C:65]([OH:71])[C:64]=2[F:72])[C:30]2[N:31]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:32]=[C:33]([C:35]3[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=3[C:37]([NH2:39])=[O:38])[N:34]=2)=[CH:24][CH:23]=1)#[N:21].O[C@@H:74]1[CH2:78][CH2:77][O:76][CH2:75]1>C1COCC1>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH:29]([C:63]2[CH:68]=[C:67]([CH2:69][CH3:70])[CH:66]=[C:65]([O:71][C@H:74]3[CH2:78][CH2:77][O:76][CH2:75]3)[C:64]=2[F:72])[C:30]2[N:31]([C:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:32]=[C:33]([C:35]3[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=3[C:37]([NH2:39])=[O:38])[N:34]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: CCc1cc(O)c(F)c(C(Nc2ccc(C#N)cc2)c2nc(-c3ccccc3C(N)=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O[C@@H]1CCOC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(O[C@H]2CCOC2)c(F)c(C(Nc2ccc(C#N)cc2)c2nc(-c3ccccc3C(N)=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
To a solution of triphenylphosphine (40.6 mg, 0.155 mmol) in 1 mL THF at 0° C., was added diethyl azidodicarboxylate (24.5 μL, 0.155 mmol), dropwise. The mixture was stirred at 0° C. for 20 min, then a solution of Intermediate 188.6 (36 mg, 0.052 mmol) and (R)-3-hydroxytetrahydrofuran (8.3 μL, 0.103 mmol) in 1 mL THF was added dropwise. The mixture was stirred at 0° C. for 15 min and at rt for 14 h, then was concentrated. The crude residue was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 40.5 mg of Intermediate 204.1, contaminated with triphenylphosphine. LCMS (2 min gradient) RT=2.00 min, 768.25 (M+H)+.