Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[O:39][CH3:40])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:41])[C@@H:7]([O:42][C@@H:43]2[O:48][C@H:47]([CH3:49])[C@@H:46]([N:50](C)[CH3:51])[CH2:45][CH2:44]2)[CH2:6][CH2:5][CH2:4]1.O.O.O.C([O-])(=O)C.[Na+].II.[OH-].[Na+].[OH-].[NH4+]>CO.O.O>[C:24]([O-:26])(=[O:25])[CH3:23].[NH4+:50].[CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[O:39][CH3:40])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:41])[C@@H:7]([O:42][C@@H:43]2[O:48][C@H:47]([CH3:49])[C@@H:46]([NH:50][CH3:51])[CH2:45][CH2:44]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC[C@H]1CCC[C@H](O[C@H]2CC[C@H](N(C)C)[C@@H](C)O2)[C@@H](C)C(=O)C2=C[C@@H]3[C@@H](C=C[C@@H]4C[C@@H](O[C@@H]5O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]5OC)C[C@@H]34)[C@@H]2CC(=O)O1
Agent: CC(=O)[O-]
Agent: II
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC[C@H]1CCC[C@H](O[C@H]2CC[C@H](NC)[C@@H](C)O2)[C@@H](C)C(=O)C2=C[C@@H]3[C@@H](C=C[C@@H]4C[C@@H](O[C@@H]5O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]5OC)C[C@@H]34)[C@@H]2CC(=O)O1
Temperature: 47 °C
Yield: 136.8 %

Procedure:
A suspension of Spinosyn A (5.0 gms, 5.13 mmol) and sodium acetate trihydrate (4.68 gms, 34.4 mmol) in 80% methanol/water (125 ml) was heated to 47° C. under nitrogen. The pH dropped from 10 to 8 on addition of iodine (1.75 gms, 68.0 mmol) as a solid in one portion, giving a brown color. The pH was maintained at 8-9 by periodic addition of 1N sodium hydroxide. The reaction was heated for 2.75 h (during which time the color faded to pale yellow), and was then cooled to ambient temperature. The solution was poured into a solution of water (250 ml) and ammonium hydroxide (50 ml), and extracted with diethyl ether. The ether extract was washed with brine, dried (K2CO3), and evaporated at ambient temperature under vacuum. The crude product was purified by reversed phase HPLC on a C18 column, eluting with methanol:acetonitrile:0.05% ammonium acetate (45:45:10) giving Spinosyn B (2.52 gms) which was identical (MS, 1H NMR, 13C NMR, IR, and OR) to a naturally produced sample of Spinosyn B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:26]=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1.CCCCCC>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:38])[F:37])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 70 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol) was dissolved in pyridine (3.0 mL), 1-isocyanato-4-(trifluoromethoxy)benzene (99 μL, 0.66 mmol) was added, and the mixture was stirred at 70° C. for 2 hr. 1-Isocyanato-4-(trifluoromethoxy)benzene (20 μL, 0.13 mmol) was added to the reaction mixture, and the mixture was further stirred at 70° C. for 3 hr. The obtained suspension was cooled to room temperature, and diluted with ethyl acetate (5 mL), tetrahydrofuran (1 mL) and n-hexane (5 mL). The precipitated resultant product was collected by filtration to give the title compound (177 mg, 74%) as a colorless powder.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:9]#[N:10])[S:7][CH:8]=1.[O-:11]S([O-])(=O)=O.[Na+].[Na+].C>CCOC(C)=O.CCO.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:9]([NH2:10])=[O:11])[S:7][CH:8]=1
Reactant: N#Cc1cc(Cl)cs1
Reactant: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: NC(=O)c1cc(Cl)cs1
Temperature: 28 °C
Reaction time: 1.25 h
Yield: 31 %

Procedure:
Equip a 12-L reaction flask with a cooling bath, air stirrer, and thermometer probe and charge with KOH (288.6 g, 5.143 moles) and water (6.04 L) to form a solution that exotherms to about 31° C. Allow the solution to cool to about 28° C., and charge the mixture with 4-chloro-2-thiophene carbonitrile (671.3 g, 4.675 moles) (a small amount of solids are undissolved). Add EtOH (675 mL), at which time a gradual exotherm occurs and continues over 1-1.5 h to about 38° C. Stir the reaction at ambient temperature overnight. Filter the reaction mixture under vacuum, wash with water, and dry to give crude product. Dissolve the solids in EtOAc (10.0 L), treat with Na2SO4 and activated charcoal for 1-2 h, then filter and wash with EtOAc. Concentrate the filtrate on a rotary evaporator at 45° C. until solids begin to precipitate out. Release the vacuum and increase the temperature to 60-65° C. to redissolve the solids. With stirring at 60° C., add heptane (3.5 L) slowly to precipitate solids. Stir for 15-20 min at 60° C., then cool the mixture to 30-40° C. and filter. Wash the solids with heptane (2×0.75 L), and dry to give the title compound as a white solid (235.4 g, 31%). Obtain a second crop (67.8 g, 9%) from the filtrate.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50]>O1CCCC1.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:19])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
A solution of 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid (0.43 g, 1.31 mmol) and carbonyldiimidazole (0.42 g, 2.62 mmol) in anhydrous tetrahydrofuran (22 mL) was refluxed under nitrogen for 30 min. The reaction mixture was cooled to ambient temperature and treated with 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.59 mL, 3.93 mmol) and methylsulfonamide (0.54 g, 3.93 mmol). The resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ethyl acetate (60 mL), washed with 1 M aqueous hydrochloric acid (2×30 mL) and brine (50 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 30% ethyl acetate (containing 0.2% acetic acid) in hexanes to afford the title compound as a white solid (0.31 g, 58%); 1H NMR (300 MHz, DMSO-d6) δ 12.01 (br s, 1H), 8.47 (d, J=2.5 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 3.93 (s, 2H), 3.33 (s, 3H), 2.07-1.98 (m, 1H), 1.97-1.90 (m, 3H), 1.72-1.56 (m, 12H), 0.98-0.90 (m, 2H), 0.76-0.70 (m, 2H); MS (ES+) m/z: 405.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]3)=[N:23][N:24]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:42]2[CH:50]=[CH:49][CH:48]=[C:47]3[C:43]=2[CH:44]=[CH:45][NH:46]3)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:33][C:28]1([CH3:32])[O:29][CH2:30][CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:42]4[CH:50]=[CH:49][CH:48]=[C:47]5[C:43]=4[CH:44]=[CH:45][NH:46]5)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][N:23]=2)[CH2:27]1
Reactant: CC1(C)CN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CCO1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CN(Cc2nnc(-c3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)o2)CCO1
Temperature: 100 °C
Yield: 24.3 %

Procedure:
To a solution of 6-bromo-4-{5-[(2,2-dimethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazole (176 mg, 0.298 mmol) in dioxane (2.5 ml) and water (0.25 ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (102 mg, 0.420 mmol, available from Frontier Scientific Europe), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (43.5 mg, 0.060 mmol) and potassium phosphate tribasic (198 mg, 0.933 mmol). The mixture was heated under microwave irradiation at 100° C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The crude residue was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC. The product-containing fractions were blown down under a stream of nitrogen to give a yellow solid. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 3 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen to give a brown solid (31 mg) that was dissolved in DMSO (750 μL) and purified by Mass Directed Automated Preparative HPLC. The solvent was removed under a stream of nitrogen. The appropriate fraction was blown down under a stream of nitrogen to give the title compound as a pale yellow gum (2.4 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[S:21]1[CH:25]=[CH:24][C:23]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)=[CH:22]1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: OB(O)c1ccsc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(-c3ccsc3)cc2N1
Temperature: 100 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
To a warm, stirred solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) dissolved in 60 mL toluene and 60 mL ethanol was added tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.9 mmol) followed by 2M aqueous sodium carbonate (50 mL, 100 mmol) and thiophene-3-boronic acid (4.3 g, 33.6 mmol). The mixture was stirred at 100° C. in an oil bath for 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 mL), washed with IN hydrochloric acid (200 mL), water (200 mL), saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to give a black solid. The solid was triturated with methylene chloride to give 2.02 g (36%) of 6-thiophen-3-yl-1,3-dihydroindol-2-one as a purple-gray solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Br:10]C1CC(C(C)C)CCC1=O>>[Br:10][CH:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: CC1(C)CCCCC1=O
Product: CC1(C)CCCC(Br)C1=O

Procedure:
The bromination of 2,2-dimethyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:42](O)[CH2:43][OH:44].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29][CH2:42][CH2:43][OH:44])=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC1=C(C(=O)OCCO)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg (0.1 mmol) of the compound of Example 47 in 0.3 ml dry dimethylformamide are added 48.6 mg (0.3 mmol) N,N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour, the reaction mixture is diluted with water and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is evaporated off in vacuo. To the residue are added 0.5 ml (555 mg, 8.95 mol) ethylene glycol and 10 μl (0.07 mmol) triethylamine. The reaction mixture is stirred at 100° C. for one hour. Then the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=3)[C:25]([N:27]3[CH2:38][CH2:37][CH2:36][C@H:28]3[C:29]([O:31]C(C)(C)C)=[O:30])=[O:26])=[CH:16][CH:15]=2)[CH:5]=[C:6]([O:9][CH2:10][C:11](=[O:13])[CH3:12])[C:7]=1[F:8].[BH4-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=3)[C:25]([N:27]3[CH2:38][CH2:37][CH2:36][C@H:28]3[C:29]([OH:31])=[O:30])=[O:26])=[CH:18][CH:19]=2)[CH:5]=[C:6]([O:9][CH2:10][CH:11]([OH:13])[CH3:12])[C:7]=1[F:8]
Reactant: CC(=O)COc1cc(-c2ccc(OCc3cccc(C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c3)cc2)cc(F)c1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)COc1cc(-c2ccc(OCc3cccc(C(=O)N4CCC[C@H]4C(=O)O)c3)cc2)cc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution (1.5 mL) of the compound (66.0 mg, 0.117 mmol) of Step 1 of Example 49 in methanol, sodium borohydride (5.3 mg, 0.14 mmol) was added, and stirred at room temperature for 1 hour. After a saturated aqueous ammonium chloride solution was added to the reaction solution, the mixture was concentrated under reduced pressure, and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The resulting residue was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added thereto, and stirred at room temperature for 1 hour. The solvent was distilled away under reduced pressure. The resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1, to thus obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: Oc1cnc(-c2ccc(Cl)cc2)cn1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)cn2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 5-(4-chloro-phenyl)-pyrazin-2-ol (Preparation 25) and 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) to afford the racemate as a pale yellow solid (42 mg, 20%)
Reaction SMILES: [F:1][C:2]([F:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.C([Li])CCC.B(OC(C)C)(OC(C)C)OC(C)C.Br[C:38]1[CH:53]=[CH:52][C:41]([CH2:42][N:43]2[CH2:46][CH:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44]2)=[CH:40][C:39]=1[F:54].FC(F)(C1C=CC=CC=1)C1C=CC2OC(B(O)O)=CC=2C=1>C1COCC1>[F:18][C:2]([F:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:38]3[CH:53]=[CH:52][C:41]([CH2:42][N:43]4[CH2:46][CH:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44]4)=[CH:40][C:39]=3[F:54])=[CH:8][C:7]=2[CH:11]=1
Reactant: FC(F)(c1ccccc1)c1ccc2occc2c1
Reactant: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: OB(O)c1cc2cc(C(F)(F)c3ccccc3)ccc2o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CN(Cc2ccc(-c3cc4cc(C(F)(F)c5ccccc5)ccc4o3)c(F)c2)C1
Reaction time: 0.5 h

Procedure:
To a solution of 5-(difluoro(phenyl)methyl)benzofuran (0.684 g, 2.8 mmol) in 28 mL THF at −78° C. under nitrogen was added butyllithium, 2.5M solution in hexanes (1.3 mL, 3.4 mmol) dropwise. The clear solution was allowed to stir for 30 min, at which point triisopropyl borate (0.97 mL, 4.2 mmol) was added. After 30 min, the bath was removed and the reaction allowed reaching ambient temperature. After 30 min, 28 mL 2N HCl was added, and the reaction was diluted with MTBE. The organic layer was washed with brine and dried with anhyd sodium sulfate, filtered, and concentrated to a ] clear oil. Hexanes was added to give a white solid, which was collected by filtration. A portion of the unpurified material was carried forward as follows: ethyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (0.150 g, 0.474 mmol) and 5-(difluoro(phenyl)methyl)benzofuran-2-ylboronic acid (0.273 g, 0.949 mmol) were reacted according to Scheme B2 and general procedure F to give ethyl 1-((4-(5-(difluoro(phenyl)methyl)benzofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (t, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.45-7.60 (m, 6H), 7.38 (d, J=3.0 Hz, 1H), 7.26-7.33 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 3.43-3.51 (m, 2H), 3.20-3.38 (m, 3H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: CN(C=O)C.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[N:24]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[N:22][N:21]=2)=[CH:10][CH:9]=1.[CH2:44]([C:48]1[NH:52][C:51]([CH:53]=[O:54])=[C:50]([Cl:55])[N:49]=1)[CH2:45][CH2:46][CH3:47].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH2:44]([C:48]1[N:52]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[N:24]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]=[N:22][N:21]=3)=[CH:10][CH:9]=2)[C:51]([CH:53]=[O:54])=[C:50]([Cl:55])[N:49]=1)[CH2:45][CH2:46][CH3:47]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF (150 mL) solution of 5-(4′-bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole (30 g, 53.8 mmol) was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (10 g, 53.8 mmol) and K2CO3 (7.4 g, 53.8 mmol). The mixture was stirred at room temperature overnight. EtOAc (500 mL) was added and the organic was washed three times with a NaHCO3 solution (200 mL) followed by saturated aqueous NaCl (200 mL). Solvent was removed and purification was achieved by silica gel chromatography (50:50 EtOAc:hexanes) using an isocratic gradient to provide intermediate (11a) a white solid (41 g). MS m/z: [M+H+] calcd for C41H35ClN6O, 663.26; found 663.4. 1H-NMR (d4-MeOH): 0.83 (m, 3H), 1.26 (m, 2H), 1.53 (m, 2H), 2.53 (m, 2H), 5.56 (s, 2H), 6.87-6.96 (m, 8H), 7.05 (m, 2H), 7.25-7.43 (m, 10H), 7.53-7.58 (m, 2H), 7.84 (d, 1H), 9.73 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[N:12]=[C:11]([S:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH:10]=[N:9][CH:8]=1.ClC(OCC)=O.[NH3:29].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>C1COCC1.CCOC(C)=O.CCO.C(N(CC)CC)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[N:12]=[C:11]([S:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:29])=[O:18])[CH:10]=[N:9][CH:8]=1
Reactant: NC(=NCC(F)(F)F)Nc1cncc(SCCCC(=O)O)n1
Reactant: N
Agent: CCOC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)CCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a suspension of 4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrazin-2-ylthio]butyric acid (0.25 g.) in THF (10 ml) at 0° was added triethylamine (0.082 g.), followed by ethyl chloroformate (0.088 g.) and the mixture was stirred for 30 minutes. A solution of ammonia in THF (5 ml.) was added and the mixture stirred again for 30 minutes, the temperature being allowed to rise to room temperature. The mixture was evaporated in vacuo, aqueous solution bicarbonate (5 ml.) was added and the mixture extracted with EtOAc (2×25 ml.) After drying (MgSO4) the solution was filtered and evaporated in vacuo to give a pale yellow solid. This was purified by medium pressure liquid chromatography on silica eluted with MeOH/CH2Cl2 (1:10 v/v) to give a solid. This was dissolved in EtOAc containing a trace of EtOH and excess of a solution of maleic acid in EtOAc was added. The resulting precipitate was collected by filtration and recrystallised from EtOH to give 4-[ 6-(2-[2,2,2-trifluoroethyl]guanidino)pyrazin-2-ylthio]butyramide maleate, m.p. 171°-172° (30% yield).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C4CCCCO4)=[CH:19][CH:18]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)[CH2:31][CH3:32]>>[C:34]1([C:30]([CH2:31][CH3:32])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[C:12]2[CH:13]=[N:14][C:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(CCCN2CCCC2)nc1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(CCCN2CCCC2)nc1)c1ccccc1
Yield: 18 %

Procedure:
Following the general procedure of McMurry reaction as described in example 1, step B, (6-(3-(pyrrolidin-1-yl)propyl)pyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yl-oxy)phenyl)methanone (1.0 g, 2.5 mmol) was reacted with propiophenone (1.0 g, 7.6 mmol) to give 186 mg desired product (17.8% yield, Z/E=3/1). m/z=413[M+1]+.