Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[C:11]([C:34]([C:36]3[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)=[O:35])[CH:12]=[C:13]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH:17]=[CH:18][N:19]4[Si](C(C)C)(C(C)C)C(C)C)[CH:14]=2)=CC=1.B(F)(F)F.CCOC(C)=O.C([O-])(O)=O.[Na+]>CSC>[OH:8][C:9]1[CH:10]=[C:11]([C:34]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[O:35])[CH:12]=[C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][NH:19]3)[CH:14]=1
Reactant: COc1ccc(COc2cc(C(=O)c3ccc(OC)nc3)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2cc(O)cc(-c3cccc4[nH]ccc34)c2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To compound [3-(4-methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-(6-methoxy-pyridin-3-yl)-methanone in dimethylsulfide (2 mL) at 0° C. was added excess BF3 etherate. The resulting reaction mixture was stirred at 0° C. for 20 min. TLC indicated that the disappearance of the starting material. EtOAc was added to dilute the reaction mixture and sat. NaHCO3 was added to adjust the pH of the aqueous phase to 6-7. The aqueous phase was then extracted with EtOAc three times. The combined organic phases were dried over Na2SO4 and concentrated. The crude product was again dissolved in THF (1 mL) and treated with TBAF (1M in THF, 1 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature. At the end of the reaction, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water three times. The organic phase was then dried and concentrated to afford the crude product which was further purified by preparative SFC to afford [3-hydroxy-5-(1H-indol-4-yl)-phenyl]-(6-methoxy-pyridin-3-yl)-methanone (29 mg, 75%). 1H NMR (400 MHz, CD3OD): δ 8.57 (d, J=2.3 Hz, 1H), 8.04 (dd, J=8.6, 2.3 Hz, 1H), 7.42 (d, J=1.2 Hz, 1H), 7.36-7.30 (m, 2H), 7.17 (d, J=3.1 Hz, 1H), 7.12-7.08 (m, 2H), 7.03 (d, J=7.2 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.5 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9]2[CH:10]=[N:11][N:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:7].[OH-:30].[K+].OO.O>C(O)C.O>[C:28]([C:26]1[CH:25]=[CH:24][C:3]([CH2:4][NH:5][C:6]([C:8]2[C:9]3[CH:10]=[N:11][N:12]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:13]=3[CH:14]=[CH:15][CH:16]=2)=[O:7])=[C:2]([Cl:1])[CH:27]=1)(=[O:30])[NH2:29]
Reactant: N#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c(Cl)c1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c(Cl)c1

Procedure:
To a suspension of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 2-chloro-4-cyano-benzylamide in a 1:1 mixture of EtOH—H2O (2.0 mL) was added KOH (0.018 g, 0.32 mmol) and a 30% solution of H2O2 in H2O (0.13 mL, 1.1 mmol). The suspension was sealed and heated briefly to dissolve the mixture. The resultant solution was stirred at room temperature for 16 hours, during which time a solid precipitated. The mixture was diluted with H2O (10 mL) and the solid was collected by filtration and dried to afford the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:22].[Na+].OO>C1COCC1.CCOCC.O>[C:7]1([CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][OH:22])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: C=CCOCCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled (0° C.) solution of 2-allyloxyethylbenzene (5. g; 30.8 mmol) dissolved in THF (75 ml) is slowly added a 0.5M THF solution of 9-BBN [9-borabicyclo [3.3.1]nonane] (68 ml; 34 mmol) and the reaction mixture warmed to room temperature and stirred for 4 hours. The reaction mixture is then cooled to 0° C. and 5 ml H2O is added followed by slow addition of 6N NaOH (30 ml; 7.2 g/30 ml). After stirring for 5 minutes, 30% H2O2 (20 ml) is added over 15 min. The reaction mixture warms significantly but is kept from refluxing. After addition is complete, it is stirred for 15 minutes allowing the mixture to come to room temperature. It is then diluted with Et2O, washed with H2O 2x, Na2S2O3 2x, NaHCO3 and brine, dried (MgSO4) and concentrated to dryness. The residue is purified by column chromatography using Et2O to obtain 3-(2-phenylethoxy)-1-propanol which is used directly in Step C.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH:12]4[CH2:16][CH:15]([C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[NH:14][CH2:13]4.[CH3:17][C:18]1[N:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1>>[CH3:17][C:18]1[N:23]=[CH:22][C:21]([C:2]2[C:10]3[NH:9][C:8]4[CH2:11][CH:12]5[CH2:16][CH:15]([C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[NH:14][CH2:13]5)=[CH:20][CH:19]=1
Reactant: Brc1cccc2c3c([nH]c12)CC1CNC3C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ccc(-c2cccc3c4c([nH]c23)CC2CNC4C2)cn1

Procedure:
The product of Example 30A (55 mg, 0.20 mmol) and 6-methylpyridine-3-boronic acid pinacol ester (44 mg, 0.20 mmol; Synthonix) were processed as described in Example 11 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.99-2.05 (m, 1H), 2.09-2.17 (m, 1H), 2.60 (s, 3H), 2.88 (dd, J=17.1, 2.4 Hz, 1H), 3.12-3.20 (m, 2H), 3.23-3.28 (m, 1H), 3.57 (t, J=3.4 Hz, 1H), 4.05 (dt, J=5.5, 2.7 Hz, 1H), 7.01-7.05 (m, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.50 (dd, J=7.8, 1.1 Hz, 1H), 7.94 (dd, J=7.9, 2.1 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H); MS (ESI+) m/z 290 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8](Br)[CH2:9][CH2:10][Cl:11])=O)=[CH:4][CH:3]=1.[S-:15][C:16]#[N:17].[K+].C([OH:21])C>O>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[NH:17][C:16](=[O:21])[S:15][C:8]=2[CH2:9][CH2:10][Cl:11])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(c1ccc(F)cc1)C(Br)CCCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Product: O=c1[nH]c(-c2ccc(F)cc2)c(CCCl)s1
Reaction time: 4 h

Procedure:
The 4-p-fluorophenyl-5-β-chloroethyl-4-thiazolin-2-one is prepared in the following manner: A mixture of 30 g of 1-p-fluorobenzoyl-1-bromo-3-chloropropane (prepared in accordance with our Italian Patent Application No. 23444 A/72 filed 22.4.1972), 11.5 g of potassium thiocyanate, 120 cc of ethanol and 6 cc of water is boiled under reflux for 4 hours. The precipitated solid is filtered while hot and 1-p-fluorobenzoyl-1-thiocyano-3-chloropropane precipitates from the filtrate on cooling. 22.1 g of the latter, 66 cc of glacial acetic acid and 11 cc of concentrated H2SO4 are boiled under relux for 4 hours. The acetic acid is removed from the reacting mass under reduced pressure and the residue is extracted while hot with chloroform. The chloroform solution is evaporated to dryness under reduced pressure and the residue recrystallised. M.P. = 138° C (from isopropyl alcohol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([F:26])[CH:18]=1>C(#N)C>[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([F:26])[C:18]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Yield: 47.4 %

Procedure:
To a solution of 1.468 g of morpholine and 3.0 mL of diisopropylethylamine in 80 mL of acetonitrile was added a solution of 5.019 g of 2,6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate in 10 mL of acetonitrile. The mixture was heated to reflux for 5 hours, then cooled and concentrated in vacuo. The residue was purified on a silica gel column (3 cm tall, 10 cm diam), eluting with 25% ethyl acetate/hexanes (v/v) and then 2% acetic acid/25% ethyl acetate/hexanes to give 1.95 g of an orange oil. This was washed with 5% ethyl acetate/hexanes, and the bright yellow solids air dried, mp 91°-920° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16]2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.Cl>O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Temperature: 130 °C
Yield: 67.1 %

Procedure:
In a 10 L 3-necked round bottom flask equipped with reflux condenser, mechanical stirrer and a stopper, a mixture of crude N-(4-bromophenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (108.29 g, 63% purity, 167 mmol) and potassium carbonate (115 g, 833 mmol) in water (6 L) was stirred at reflux (variac heating mantle ˜130° C.) for 18 h. The variac heating was turned off and the flask was removed from the mantle and allowed to cool to ˜70° C. White solid settled to the bottom of the flask during this time. The liquid layer was siphoned into 2 L Erlenmeyer flasks using gravity and tygon tubing initially filled with water. When no more liquid could be siphoned, the remaining slurry was filtered. The filtrate was added to an Erlenmeyer flask and all the contents of these flasks were concentrated in vacuo using a large Buchi rotovap. LCMS analysis of the filtered white solid showed that it contained desired product. The filtered solid was added to the solid obtained from rotovapping. Ethyl acetate (2 L) and water (500 mL) were added to the contents of the flask and the mixture was acidified to pH˜5.5 using 6N aq HCl solution. The aqueous layer was extracted with ethyl acetate (5×500 mL). Then the aqueous layer was divided into 3 smaller portions and each was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a white solid. Trituration of the solid with dichloromethane (50 mL) followed by vacuum suction drying provided the title compound as a white solid (59.27 g, 74% pure, 112 mmol, 67% yield). MS(ES)+ m/e 391.1, 393.3 [M+H]+. The filtrate was concentrated in vacuo, dissolved in minimal dichloromethane and loaded directly onto a silica gel column. Purification by silica gel chromatography (Analogix IF280, 0-100% 10% MeOH in CH2Cl2/CH2Cl2 (effectively 0-10% MeOH/CH2Cl2), SF65-400 g, 60 min) provided another batch of the title compound as a white solid (9.5 g, 90% pure, 22 mmol, 13%). Impure product could be further purified by silica gel chromatography (Analogix IF280, 0-5% MeOH/CH2Cl2 over 30 min, then 5-10% MeOH/CH2Cl2 over 15 min) to afford clean desired product as a white solid. Purified material was used in subsequent reactions. MS(ES)+ m/e 391.1, 392.8 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:15])=[N:10]2)=[O:4].[CH:21]1([C:24](=[O:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[C:17]([NH:16][C:8]1[C:9]([CH3:15])=[N:10][C:11]2[C:6]([N:7]=1)=[C:5]([C:3](=[O:4])[CH2:2][CH:25]([C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:30])[C:26]([O:28][CH3:29])=[O:27])[CH:14]=[CH:13][CH:12]=2)([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (0.27 g, 0.803 mmol), methyl 3-cyclopropyl-3-oxopropanoate (Accela ChemBio, 0.114 mL, 0.803 mmol), K2CO3 (EMD, 0.333 g, 2.409 mmol), in DMF (3.21 ml) was combined and stirred overnight at RT. Reaction mixture was diluted with DCM and water. The aqueous layer was acidified with 1 N HCl solution and back extracted with DCM. The organic layers were combined and washed with water and brine to remove DMF. Volatile solvents were removed by rotovap. The product methyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-(cyclopropanecarbonyl)-4-oxobutanoate (418a) was advanced to next step. m/z (ESI, +ve) 398.1 (M+H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH:34]=[CH:35][CH:36]=1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([C:37]([N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[O:38])[CH:34]=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1cccc(C(=O)N2CCOCC2)c1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(C(=O)N4CCOCC4)c3)nn12
Yield: 12 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and (3-Amino-phenyl)-morpholin-4-yl-methanone (0.179 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 22.40 mg of {3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-morpholin-4-yl-methanone as a lyophilized powder. (M+H)=430.8. 1H NMR (400 MHz, DMSO, d6) δ 9.58 (s, 1H), 8.95 (s, 1H), 7.78 (m, 2H), 7.71 (m, 1H), 7.48 (m, 1H), 7.26 (m, 1H), 7.18 (m, 1H), 7.07 (t, 1H, J=7.48 Hz), 6.94 (m, 2H), 6.89 (m, 1H), 3.96 (s, 3H), 3.73 (m, 2H), 3.36 (m, 4H), 3.17 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([O:19][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 74.1 %

Procedure:
A solution of 2.30 g (5.77 mmol) of (R)-3-(2-benzyloxycarbonylaminoethylsulfanyl)-2-tert-butoxycarbonylaminopropionic acid, 0.60 ml (0.62 g, 5.77 mmol) of benzyl alcohol, 0.07 g (0.58 mmol) of 4-dimethylaminopyridine and 1.33 g (6.93 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in 30 ml of dichloromethane was stirred at RT overnight. The reaction mixture was washed successively with 1N hydrochloric acid, 1N sodium bicarbonate solution and with water. After drying over sodium sulfate, filtering and concentrating, the residue was chromatographed on silica gel. 2.09 g of the title compound were obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Br:20])=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1cc(CCBr)ccc1OCc1ccccc1
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol (1.0 g, 4.0 mmol) and CBr4 (1.5 g, 4.5 mmol) in CH2Cl2 (10 mL), was PPh3 (1.2 g, 4.5 mmol) added portionwise at 0° C. The reaction mixture stirred for 2 hours at the same temperature. The reaction was concentrated under vacuum and the residue was stirred in ether (10 mmol). The solid, mainly triphenylphosphine oxide, was filtrated off and the filtrate was concentrated under vacuum. The residue was purified over SiO2 to afford the desired compound (1.15 g, 93.5%) as a white crystal. 1H NMR (400 MHz, DMSO-d6) δ 7.36-7.49 (m, 5H), 7.17-7.23 (m, 2H), 7.03-7.05 (m, 1H), 5.18 (s, 2H), 3.72 (t, 2H), 3.08 (t, 2H). LCMS 273.4 [MH+].
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[O:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[O:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28]([O:4][CH2:1][CH:2]=[CH2:3])=[O:29])=[CH:24][CH:23]=1
Reactant: CC(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)Cl
Reactant: C=CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.2 g allyl alcohol and 1.6 g pyridine in 50 cc methylene chloride, add 6.6 g of 2-[4-(2-quinoxalinyloxy)phenoxy]propionyl chloride in 60 cc methylene chloride. Stir the mixture at room temperature overnight. Wash the methylene chloride solution with water and dry the solution over magnesium sulfate concentrate under vacuum to give allyl 2-[4-(2-quinoxalinyloxy)phenoxy]propanoate.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[O:18]([NH2:20])[CH3:19]>C(O)C.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:19][O:18][N:20]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CON=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 99.4 %

Procedure:
A solution of 4,4′-difluorobenzophenone (3.00 g, 13.75 mmol) in a mixture of ethanol (10 ml) and pyridine (10 ml) was treated with methoxylamine hydrochloride (1.8 g, 21.7 mmol) and the resulting mixture was heated under reflux for 1 h. The cooled reaction mixture was diluted with ethyl acetate, washed successively with water, 1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulphate, evaporation of the solvent yielded 3.38 g (99% yield) of the title oxime ether as a clear syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.94 (3H, s, OCH3), 7.04 (2H, m, aromatics), 7.12 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.45 (2H, m, aromatics).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:20]2[CH:25]=[CH:24][C:23](F)=[C:22](F)[CH:21]=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][CH:12]=[C:13](CC(O)=O)[N:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.NC1C=C([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])C=CC=1.C1(C=O)CCCC1.C([O:50][C:51](=[O:60])[CH2:52][S:53]C1SC(N)=NC=1)C>>[CH:1]1([CH2:6][N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:21]=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][C:12]([S:53][CH2:52][C:51]([OH:60])=[O:50])=[CH:13][N:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1cccc(N)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Agent: O=CC1CCCC1
Product: CC(C)C(=O)Nc1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-isobuturylamino-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-Amino-phenyl)-isobutyramide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].Cl>C1COCC1>[F:16][C:17]([F:24])([F:23])[C:18]([C:15]1[C:10]([F:9])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:19]
Reactant: Fc1ccccn1
Reactant: CCOC(=O)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cccnc1F)C(F)(F)F
Temperature: -78 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
Lithium diisopropylamide (8.2 mL, 14.8 mmol, 1.8M in heptane) was added to THF (20 mL) cooled to −78° C. in a dry ice/acetone bath. 2-Fluoropyridine (1.07 mL, 12.4 mmol) was added dropwise, and the resulting mixture was stirred at −78° C. for 3 hours. Ethyl trifluoroacetate (2.06 mL, 17.2 mmol) was added to the suspension dropwise. The reaction mixture was allowed to slowly warm to room temperature. After 1 hour, the mixture was poured into 1M hydrochloric acid (35 mL) and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield the hydrate of 2,2,2-trifluoro-1-(2-fluoropyridin-3-yl)ethanone (1.9 g, 90%) as a semisolid.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6](Br)[N:7]=1.[C:21]1([C@H:27]([CH3:30])[CH2:28][NH2:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.C1([Mg]Br)CCCC1>O1CCCC1>[CH:31]1([NH:34][C:12](=[O:14])[C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:29][CH2:28][C@H:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:30])[C:3]3=[O:20])[CH:10]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: C[C@H](CN)c1ccccc1
Agent: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC[C@@H](C)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 0.1 g), N,N-diisopropylethylamnie (0.1 mL), (S)-2-phenyl-1-propylamine (0.05 mL) and tetrahydrofuran (1 mL) was stirred at room temperature overnight. Cyclopropylamine (0.2 mL) was added followed by the addition of cyclopentylmagnesium bromide (2M in diethyl ether, 0.8 mL). The mixture was stirred for 10 min., quenched with sat. NH4Cl and extracted into ethyl acetate. The organic phase concentrated in vacuo. The residue was treated with ethanol (5 mL), wet 10% palladium on carbon (45 mg) was added followed by N,N-diisopropylethylamnie (0.1 mL) and ammonium formate (0.4 g). The mixture was stirred under nitrogen atmosphere at 70° C. for 30 min. The mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (64 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.N1C=CC=CC=1.C1C=CC=CC=1>O>[Cl:18][C:4]1[N:3]=[C:2]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[C:6]([C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1nc(Cl)c2ccccc2c1-c1ccccc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Clc1nc(-n2ccnc2)c2ccccc2c1-c1ccccc1

Procedure:
2.74 g (10 mmoles) of 1,3-dichloro-4-phenylisoquinoline, 1.02 g (15 mmoles) of imidazole and 5 ml of pyridine were heated for 8 hours under reflux and, after cooling, distributed between benzene and water. The residue which remained behind after evaporation of the organic phase was chromagtographed on silica-gel. As solvent, a mixture of chloroform and methanol 95:5 was found to be suitable.