Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].C([O-])(=O)C.[NH4+:33].[OH-].[NH4+]>CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)/[CH:3]=[C:4](\[NH2:33])/[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: O=C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CO
Product: N/C(=C\C(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A 5 L round-bottom flask was charged with methanol (100 mL), the ketoamide 2-3 (200 g), and ammonium acetate (110.4 g). Methanol (180 mL) and 28% aqueous ammonium hydroxide (58.6 ml) were then added keeping the temperature below 30° C. during the addition. Additional methanol (100 mL) was added to the reaction mixture. The mixture was heated at reflux temperature and aged for 2 h. The reaction was cooled to room temperature and then to about 5° C. in an ice-bath. After 30 min, the solid was filtered and dried to afford 2-4 as a solid (180 g); m.p. 271.2° C.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH2:15](Br)[CH3:16]>>[CH2:15]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)[CH3:16]
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: CCBr
Product: CCn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano [3,2-b]-indol- 4(5H)-one is alkylated with ethyl bromide to give 4.8 g of product, mp 103°-104°C, after recrystallization from methylene chloride-hexane.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[F:1][C:2]1[C:3]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
To 3-fluoro-2-pyridinecarboxylic acid (available from Fluorochem, 63 mg, 0.44 mmol) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (172 mg, 0.45 mmol), DIPEA (0.106 ml) and DMF (1 ml). The reaction was stirred for 20 mins at 25° C. 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the reaction was stirred for a further 20 h at 25° C. The solvent was dried under a stream of nitrogen to give the crude product. This sample in DMF was loaded onto an aminopropyl cartridge (5 g) and after standing for 3 h, the column was washed with 10% methanol in dichloromethane. The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product which was purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was dried under a stream of nitrogen to give the title compound (23 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)OCc3ccccc3)c(Cl)cc2F)c1=O
Temperature: 90 °C
Yield: 34.8 %

Procedure:
A mixture of 0.60 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 7-7], 0.13 g of sodium carbonate, 0.39 g of benzyl alcohol and 2.4 ml of toluene was heated at 90° C. for 2 hours, then under reflux for 2 hours. It was cooled to room temperature, then, the solvent was distilled off under reduced pressure, and the resulted residue was subjected to silica gel chromatography to obtain 0.24 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(benzyloxycarbonyl)methoxypyridine [present compound 7-82].
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=1[O:40][CH3:41]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=4[O:40][CH3:41])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCCC(=O)Cc1ccc(OCCCBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC(=O)Cc1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone (3.7 g, 11.3 mmol) acetonitrile (140 ml) was heated at reflux for 4 hours. At the end of the reaction, the mixture was cooled and filtered. The filtrate was concentrated to an oil. Purification was performed by flash chromatography over a silica gel column (SiO2, 55 g; eluted with 1% methanol in dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 400 ml). The fractions containing pure product were pooled and concentrated to a solid (4.3 g, 91%). Recrystallization from ethanol (10 ml) gave a powdery solid of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-pentanone (3.22 g), m.p.=79°-80° C.
Reaction SMILES: Cl[CH2:2][Si:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>CN(C)C=O>[CH3:13][C:12]([CH3:15])([O:11][Si:3]([CH3:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH3:14]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)O[Si](C)(CCl)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)O[Si](C)(Cn1cncn1)c1ccccc1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
A mixture of 3.6 g (0.015 mol) of chloromethyl(1,1-dimethylethoxy)methyl(phenyl)silane and 1.3 g (0.015 mol) of 1,2,4-triazole sodium salt in 8 ml of dimethylformamide was stirred at 80° for 2 hours, cooled, and poured onto water. The resulting mixture was extracted with ether, and the ether extracts were washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.7 g of a yellow oil. Chromatography on silica gel, eluting with 50:50 ethyl acetate-hexanes, provided 1.5 g (36%) of the title compound as a pale yellow oil: nD21 1.5134; ir (neat) 3120, 3070, 3045, 2975, 2925, 1500, 1425, 1380, 1365, 1270, 1255, 1240, 1190, 1140, 1115, 1050, 1020, 1010, 830, 810, 790, 740, 700, 680 cm-1 ; nmr (CDCl3): 0.6 (3H, s), 1.3 (9H, s), 3.9 (2H, s), 7.3-7.7 (5H, m), 7.9 (1H, s) and 8.0 (1 H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].O.[NH2:16][NH2:17]>C(O)C>[NH:16]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12])[NH2:17]
Reactant: NN
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Solvent: O
Product: NNc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
2-Chloro-5-nitrobenzenesulphonamide (3.35 g, 14.2 mmole) was dissolved in ethanol (75 ml) with heating and hydrazine hydrate (5 ml. 100 mmole) added. The mixture was refluxed for 45 minutes and then allowed to cool to room temperature. The product cystallised in long needles, 2.4 g. A second crop was obtained on cooling the filtrate in an ice bath, 0.5 g. The combined crops were recrystallised from water (120 ml) to afford pure 2-hydrazino-5-nitrobenzenesulphonamide, m.p. 209°-210° C., 1.85 gm, 60% as orange-yellow needles. TLC analysis (EtOAc:petrol, 1:1) showed one spot (Rf =0.3). Spectroscopic data was consistent with the product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[CH3:32])=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (300 mg, 0.676 mmol) in pyridine (6.0 mL) was added cyclopropanecarbonyl chloride (80 μL, 0.879 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (200 mL), washed with 5% aqueous sodium hydrogen carbonate solution (200 mL), water (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (234 mg, 68%) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1)=[CH:3][C:2]([C:37]1[CH:36]=[C:35]([F:48])[C:34]([OH:49])=[C:33]([Cl:32])[CH:38]=1)=[CH:11][CH:10]=2)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl (trans-4-((6-bromo-3-butyrylquinolin-4-yl)amino)cyclohexyl)carbamate (49 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (36 mg, 64%) as a yellow-brown solid. ESI MS m/z 556 [C30H35ClFN3O4+H]+
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[Cl-].[NH4+]>O1CCCC1.CO.[Zn]>[F:1][C:2]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3cccc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)pyrrolo[2,1-f][1,2,4]triazine (4.25 g, 15.5 mmol) in 40 mL of tetrahydrofuran and 60 mL of methanol at 0° C. was added zinc dust (3.04 g, 46.5 mmol, <10 micron) followed by ammonium chloride (2.49 g, 46.5 mmol). The mixture was stirred at room temperature overnight. Additional zinc dust (6.08 g, 93 mmol) and ammonium chloride (5.0 g, 93 mmol) were added and the reaction was allowed to stir at room temperature for 4 h. The heterogeneous mixture was filtered through a thin pad of Celite® with methanol and the filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (SiO2, EtOAc/Hexane 1:1) gave the title compound (3.5 g, 92%) as a yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].O1[CH2:38][CH2:37]OCC1>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.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:37]=[CH:16][CH:15]=[CH:14][N:11]=3)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cc(-c3ccccn3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-[4-bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (100 mg, 0.209 mmol) produced in Example (99a), 2-(tributyltin)pyridine (0.08 mL, 0.25 mmol), cesium fluoride (68 mg, 0.448 mmol) and dioxane (15 mL) was added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol), followed by stirring for 3 hours at an external temperature of 90° C. under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 43 mg of the title compound as light yellow crystals.
Reaction SMILES: [Cl-].[C:2]([O:13][CH2:14][CH3:15])(=[O:12])[C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([O-:8])=O)[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:20]([O:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[CH2:33][C:34]#[N:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl>C(Cl)Cl>[C:34]([CH2:33][C:32]1[CH:36]=[C:37]([CH:38]=[CH:39][C:31]=1[O:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]([C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[C:2]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])#[N:35]
Reactant: CCCCCCCCCCOc1ccccc1CC#N
Reactant: CCOC(=O)c1cccc(C(=O)[O-])c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CC#N
Temperature: 0 °C
Yield: 38.6 %

Procedure:
To a solution of 1.45 g of isophthalic acid, monoethyl ester monochloride in 25 ml of methylene chloride cooled to 0° C. by means of an external ice bath were added to 2.73 g aluminum chloride. After stirring for an hour, 1.87 g of 2-decyloxybenzyl cyanide were added. The reaction was stirred at 0° C. for 4 hours and then poured into ice water containing hydrochloric acid. After stirring for 1 hour, the layers were separated. The organic layer was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by chromatography over silica gel eluting with a 5-30% ethyl acetate in hexane gradient. The appropriate fractions were pooled and concentrated in vacuo to provide 1.1 g of the title product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(OCC)C>ClCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:19][CH:18]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: OB(O)c1ccc(F)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Reaction time: 8 h

Procedure:
2-Methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (II-1) (200 mg, 1.01 mmol) was dissolved in 10 mL dichloromethane. Powdered molecular sieves (3 Å, 200 mg), 4-fluorobenzene boronic acid (284 mg, 2.02 mmol) and [Cu(OH)TMEDA]2Cl2 (47 mg, 0.10 mmol) were added. Oxygen was bubbled through the reaction mixture for 5 min and stirring was continued at RT overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 ml water, dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→85:15 gradient) and a mixture of 2 regioisomers was isolated. The desired compound was obtained by recrystallization from diethylether as a white solid (151 mg, 51%), mp=151° C., MS: m/e=292.1 (M+H+).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH3:34][N:35]([CH3:41])[S:36]([CH:39]=[CH2:40])(=[O:38])=[O:37]>>[CH3:34][N:35]([CH3:41])[S:36]([CH2:39][CH2:40][N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)(=[O:38])=[O:37]
Reactant: C=CS(=O)(=O)N(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(=O)(=O)N(C)C)C3)ccc1-2
Yield: 75 %

Procedure:
Following the procedure for 320, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and ethenesulfonic acid dimethylamide were reacted. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 2% MeOH in DCM) to give 443 as a beige solid (117 mg, 75%). LCMS: RT=7.69 min, [M+H]+=503. 1H NMR δ (ppm) (CDCl3): 8.31 (1 H, d, J=8.17 Hz), 7.89 (1 H, s), 7.08 (1 H, dd, J=8.21, 1.86 Hz), 6.99-6.96 (1 H, m), 5.92-5.83 (1 H, m), 4.38 (2 H, t, J=5.05 Hz), 3.77 (2 H, t, J=6.90 Hz), 3.74-3.64 (1 H, m), 3.39 (2 H, t, J=5.06 Hz), 3.23 (2 H, t, J=6.67 Hz), 3.00-2.92 (4 H, m), 2.87 (6 H, s), 1.60 (6 H, d, J=6.64 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:25][OH:26])[CH:5]=[CH:4][C:3]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1)[O:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[N:12][C:11]=1[CH:25]=[O:26]
Reactant: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CO)cc2F)no1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1004.3 %

Procedure:
To a mixture of 20 mg of 3-{2-fluoro-4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one in 10 mL of chloroform was added 23 mg of manganese dioxide. After stirring at room temperature overnight, the reaction mixture was filtered through celite and washed with dichloromethane/methanol. The filtrate was concentrated under reduced pressure to give 200 mg of 5-[3-fluoro-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](OC(C)(C)C)=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].C(O)(C(F)(F)F)=O.C1(=O)[O:41][C:39](=[O:40])[CH2:38][CH2:37]1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](=[O:22])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
To a solution of (R)-4-biphenyl-4-yl-3-tert-butoxycarbonylamino-butyric acid ethyl ester (400 mg, 1.04 mmol) in DCM (10 mL) at room temperature is added TFA (2.009 mL, 26.1 mmol) and the mixture is stirred at room temperature for 1 hour. The mixture is concentrated under reduced pressure. To the obtained TFA salt in DCM (10 mL) at ice bath temperature is added succinic anhydride (125 mg, 1.25 mmol) and followed by TEA (0.363 mL, 2.61 mmol). The reaction is stirred at room temperature for 16 hours. The mixture is concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 2% to 5% EtOH/DCM) give (R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl ester (200 mg). HPLC retention time=1.53 minutes (condition C); MS=384 (m+1).