Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[CH2:11]O.CC(C)(O)[C:25]#[N:26].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[CH2:11][C:25]#[N:26]
Reactant: OCc1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(O)C#N
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: N#CCc1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of (4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)methanol (1.19 g, 3.31 mmol) in THF (58.6 mL) was added acetone cyanohydrin (0.454 mL, 4.97 mmol), 1,1′-(azodicarbonyl)dipiperidine (1.67 g, 6.62 mmol) and tributylphosphine (1.65 mL, 6.62 mmol) and the reaction was stirred for 3 hours at room temperature. The reaction was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→20/80) to give 551 mg (45% yield) of the title compound as a beige solid. LC/MS (FA) ES+ 368, 370. NMR (400 MHz, CDCl3) δ: 7.35 (d, 1H, J=6.0 Hz), 7.32 (d, 1H, J=2.0 Hz), 7.07 (dd, 1H, J=6.0, 2.0 Hz), 3.82 (s, 2H), 3.80-3.77 (m, 4H), 3.66 (s, 2H), 3.42-3.40 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl>[OH-].[K+]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:18][CH:19]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Temperature: 100 °C

Procedure:
Methyl 2-hydroxy-5-[2-[4-[(2-pyridinylamino)sulfonyl]phenyl]ethenyl]benzoate (12 g, 29 mmol) was dissolved in 1 M KOH (120 ml) and the solution was refluxed for 7 h. The cooled solution was acidified with an excess of 1 M hydrochloric acid. The precipitate was filtered off and washed with water (3×200 ml). The product was redissolved in a small portion of 1 M NAOH. Water and dioxane (500+500 ml) was added and the solution was heated to 100° C. The solution was acidified with an excess of 1 M HCI, and the product precipitated upon cooling. Yield 9 g (75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:37](=[O:38])[C:31]2[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=2)[C:40]1=[O:39]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3cc(-c4cc5ccccc5s4)ccc3o2)cc1N
Product: COc1ccc(-c2nc3cc(-c4cc5ccccc5s4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-4-methoxyphenyl-5-(2-benzothiophenyl)benzoxazole (120 mg, 0.32 mmol) and 1,2,4-benzenetricarboxylic anhydride (62 mg, 0.32 mmol) the title compound was obtained. (41 mg, 23%). 1H NMR (DMSO) δ 13.82(s, 1H), 8.46(dd, 1H), 8.38(d, 1H), 8.35(m, 2H), 8.18(d, 1H), 8.13(d, 1H), 8.00(d, 1H), 7.96(s, 1H), 7.85(m, 3H), 7.50(d, 1H), 7.40(m, 2H), 3.90(s, 3H). MS 547.2 m/z (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C1(C=CC(=O)C=CC2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+]>C1(C)C(C)=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Br)cc2)CC1
Reactant: c1c[nH]cn1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Product: CC(=O)N1CCN(c2ccc(-n3ccnc3)cc2)CC1
Temperature: 125 °C
Yield: 79.6 %

Procedure:
To a reaction solution prepared by dissolving 20 g of 1-acetyl-4-(4-bromophenyl)-piperazine and 7.9 g of imidazole in 120 ml of xylene, 16.9 g of 1,10-phenanthroline, 1.4 g of 1,5-diphenyl-1,4-pentadien-3-one, 28.9 g of cesium carbonate and 1.8 g of a copper (I) trifluoromethanesulfonate benzene complex, as a catalyst, were added at room temperature, followed by heating at reflux in an argon gas flow at 125° C. for 24 hours. After the completion of the reaction, the reaction solution was mixed with 300 ml of an aqueous ammonium solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:ethyl acetate=3:1→chloroform:methanol=20:1) to obtain 15.2 g of the objective 1-acetyl-4-(4-imidazol-1-ylphenyl)-piperazine (melting point: 181-182° C.).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@:11]2([CH3:19])[CH2:13][C@H:12]2[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])=O)=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:19][C@@:11]1([OH:10])[CH2:13][C@H:12]1[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]
Reactant: C=CCCC[C@@H]1C[C@@]1(C)OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCCC[C@@H]1C[C@@]1(C)O
Reaction time: 1 h

Procedure:
To a solution of 1,6-heptadiene (19.65 g, 204 mmol), in THF (341 ml) was added EtOAc (6.67 ml, 68.1 mmol), and chlorotitanium triisopropoxide (68.1 ml, 68.1 mmol). Cyclohexylmagnesium chloride (2M, 153 ml, 306 mmol) was then added slowly over 2 hours. After an additional 1 hour of stirring at RT, the reaction mixture was filtered through CELITE. The filtrate was then concentrated in vacuo and purified on SiO2 (15% EtOAc/hexanes) to yield the title compound as a mixture of enantiomers. To a solution of the enantiomers (5.5 g, 39.2 mmol) in anhydrous DCM, at 0° C. and under N2, was added Et3N (10.9 mL, 78 mmol) and 4-nitrobenzoyl chloride (8.7 g, 47.1 mmol). The reaction was stirred for 2 hours, diluted with H2O (70 mL) and extracted with DCM (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (gradient elution, 0 to 50% EtOAc in hexane) to yield (1R,2R and 1S,2S)-1-methyl-2-(pent-4-en-1-yl)cyclopropyl 4-nitrobenzoate. The benzoate enantiomers (12 g, 41.5 mmol) were separated by chiral chromatography on an AD-H column, eluting with 10% CO2 in MeOH. The desired peak fractions were concentrated to give (1R,2R)-1-methyl-2-(pent-4-en-1-yl)cyclopropyl 4-nitrobenzoate. To a solution of (1R,2R)-1-methyl-2-(pent-4-en-1-yl)cyclopropyl 4-nitrobenzoate (4.87 g, 16.83 mmol) in MeOH (67 mL) was added K2CO3 (4.65 g, 33.7 mmol). The mixture was stirred for 1 hour, filtered, and concentrated in vacuo. The material was purified on SiO2 (gradient elution, 0-50% ether/hexanes) to give the title compound. 1H NMR (500 MHz) (CDCl3) δ 5.82 (m, 1H), 4.99 (m, 2H), 2.09 (m, 2H), 1.78 (s, 1H), 1.55 (m, 2H), 1.41 (s, 3H), 1.32 (m, 1H), 1.14 (m, 1H), 0.97 (m, 1H), 0.84 (m, 1H), 0.06 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]2(O)[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:21][CH:20]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C2(O)CCN(Cc3ccccc3)CC2)cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1c(C2=CCN(Cc3ccccc3)CC2)cc2ccccc21
Yield: 85.1 %

Procedure:
A mixture of 1.4 gm (3.1 mMol) 1-phenylsulfonyl-2-(1-benzyl-4-hydroxypiperidin-4-yl)-1H-indole and 1.2 gm (6.2 mMol) p-toluenesulfonic acid in 30 mL toluene was heated at reflux for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the organic phase washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 2% methanol in dichloromethane. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 1.13 gm (84%) 1-phenylsulfonyl-2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as an off-white foam. A portion was converted to the title compound by treatment with oxalic acid.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:12]=3[C:13]=2[CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=2)[C:9]2[O:10][C:11]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:12]=3[C:13]=2[CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COCCOCc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOCc1c(C(Nc2ccc(C(=O)OC)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a mixture of cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-yl}methanone (881 mg) synthesized above, methyl 4-aminobenzoate (440 mg), triethylamine (2.93 mL) and methylene chloride (10 mL) was added a 1.0M solution (3.16 mL) of titanium (IV) chloride in methylene chloride, and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown solid. To a solution (10 mL) of the obtained solid in tetrahydrofuran were added acetic acid (301 μL) and sodium cyanoborohydride (331 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title object compound (482 mg, 39%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:29][CH3:30].C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][C@@H:18]([CH2:19][CH3:20])[C:16]([NH:15][C:12]1[CH:13]=[N:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:29][CH3:30])[CH:4]=2)=[CH:10][CH:11]=1)=[O:17]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of 1,1-dimethylethyl ((1S)-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 66, 70 mg) in dichloromethane (2.5 mL) cooled down to 0° C. TFA (0.779 mL, 10.11 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 hours and then evaporated. The residue was diluted with dichloromethane (10 mL) and neutralized with a saturated aqueous solution of NaHCO3 (15 mL). The organic phase was separated, dried over sodium sulphate, filtered and evaporated to afford the title compound as a yellow pale oil (53.1 mg).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[C@@H:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([Cl:39])[CH:3]=1.[CH3:40][N:41](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Cl:39][C:4]1[CH:3]=[C:2]([C:40]#[N:41])[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[C@@H:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1csc2c(Br)cc(Cl)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1csc2c(C#N)cc(Cl)cc12
Temperature: 80 °C

Procedure:
A degassed mixture of ethyl N-(4-{(1S)-1-[(7-bromo-5-chloro-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoyl)-β-alaninate (0.128 g, 0.198 mmol), zinc cyanide (0.046 g, 0.40 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.114 g, 0.099 mmol) in anhydrous DMF (2.9 mL) was heated at 80° C. for 2.5 hours. After cooling to room temperature, the solution was concentrated, then the residue was purified by silica gel chromatography eluting with 35% EtOAc/hexanes. The resulting material was further purified by preparative HPLC (Daicel AD-H chiral column, 2 cm×25 cm, 16% IPA/Heptane, 20 mL/min) to provide the title compound as a white solid. LC1: 4.12 min. (M+H)+ 593.
Reaction SMILES: II.[CH3:3][C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6]Br.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)#[N:11]>C1COCC1>[CH3:3][C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1)=[O:17]
Reactant: CC(C)(C)CCBr
Reactant: N#Cc1ccc(C=O)cc1
Agent: II
Solvent: C1CCOC1
Product: CC(C)(C)CCC(=O)c1ccc(C#N)cc1
Temperature: -10 °C
Yield: 62.5 %

Procedure:
Keep Mg turnings (402 mg, 15.251 mmol) in vacuo in a two-neck round bottom flask for 2 h. Purge the flask with nitrogen/vacuo several times. Add a couple crystals of iodine, anhydrous THF (60 mL) and 3,3-dimethyl-bromobutane (0.8 mL, 5.59 mmol) slowly (exothermic reaction observed). Add dropwise the remaining 3,3-dimethyl-bromobutane (1.6 mL, 11.18 mmol) and reflux the mixture overnight. Add some additional 3,3-dimethyl-bromobutane (0.24 mL, 1.67 mmol) and reflux for 30 min. Cool the mixture to −10° C. and add a solution of 4-cyanobenzaldehyde (4 g, 30.502 mmol) in anhydrous THF (40 mL). Warm the flask gradually to room temperature overnight. Quench the mixture with 0.1M aqueous HCl (100 mL) and extract twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1) to give the desired intermediate as an oil (0.752 g, 23%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][C@@H:29]1[NH:34][CH2:33][CH2:32][N:31]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:30]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:34]2[CH2:33][CH2:32][N:31]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:30][C@@H:29]2[CH3:28])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: C[C@H]1CN(c2ccc3ccccc3n2)CCN1
Product: C[C@H]1CN(c2ccc3ccccc3n2)CCN1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[(S)-3-methyl-piperazin-1-yl]-quinoline
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:32](=[O:34])[C:31]2[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:29][CH:30]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: O=C(NC1CCCC1)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 90.1 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 51 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 566 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18]Br)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: C1CNCCN1
Solvent: CCO
Product: c1ccc(-c2nc(CN3CCNCC3)oc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A mixture of 4,5-diphenyl-2-bromomethyloxazole (X; 20 g, 0.063 moles) and excess piperazine (10 mol equivalent) in 400 ml of absolute ethanol was stirred overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in 4X200 ml of methylene chloride and washed several times with water and brine. The organic layer was dried over Na2SO4, evaporated and the product was obtained as a yellow solid (19.8 g, 95%) after passing through a silica gel column and eluting with a mixture of methanol/chloroform (1:9). This procedure is amenable for large scale synthesis. MS (DCl) MH+ 320.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][N:10]=[C:5]2[NH:4][CH:3]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:1][C:2]1([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])[C:6]2=[N:7][CH:8]=[CH:9][N:10]=[C:5]2[NH:4][CH2:3]1
Reactant: Brc1c[nH]c2nccnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)C1(Br)CNc2nccnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-bromo-5H-pyrrolo[3,2-b]pyrazine (1 g, 5.05 mmol) in N,N-dimethylformamide (10 ml) was cooled at 0° C., and sodium hydride (167 mg, 5.55 mmol) was added in several portions. After stirring at 0° C. for 30 minutes, benzenesulfonyl chloride (980 mg, 5.55 mmol) was added via syringe. The mixture was allowed to warm up to room temperature and stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (30% ethyl acetate in hexane) to afford the title compound. MS (DCI/NH3) m/z 339 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.CC1([CH2+])C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37](=[O:40])[NH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O.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(O)C>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[CH:39]=[CH:38][C:37](=[O:40])[NH:36][CH:35]=4)=[CH:25][C:6]=3[N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(C#N)cc1)C[C@H]2C
Reactant: [CH2+]C1(C)OB(c2ccc(=O)[nH]c2)OC1(C)C
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)[nH]c3)cc1N(c1ccc(C#N)cc1)C[C@H]2C
Temperature: 100 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
A mixture of (R)-4-(8-bromo-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (39.3 mg, 0.1 mmol), (4,5,5-trimethyl-2-(6-oxo-1,6-dihydropyridin-3-yl)-1,3,2-dioxaborolan-4-yl) methylium (66 mg, 0.3 mmol, tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), cesium carbonate (65.2 mg, 0.2 mmol), toluene (2 mL), ethanol (1 mL) and water (3 drops) was stirred at 100° C. for 16 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with water (3*20 mL), brine (3*20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo, and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give (R)-4-(1,4-dimethyl-8-(6-oxo-1,6-dihydropyridin-3-yl)-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile as a white solid (20 mg, 49.0%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]([NH2:37])=O)=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39].N1C=CC=CC=1>O1CCOCC1.O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]#[N:37])=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)C1=C(COCC(N)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCC#N)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
A solution of trifluoroacetic anhydride (0.56 g) in dioxane (5 ml) was added dropwise over 5 minutes to a stirred, ice-cooled solution of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetamide (0.84 g) and pyridine (0.32 g) in dioxane (25 ml). The mixture was stirred at room temperature for 4 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica (10 g) eluting with dichloromethane plus 0-2% v/v methanol. Appropriate fractions were combined and evaporated to give the title compound (0.60 g), m.p. 128°-130° C.