Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[CH3:39][O:38][C:36]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:37]
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCCCCCCC(=O)OC)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to that of Example 51, by reaction of 370 mg (0.86 mmol) of ethyl 4-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro 2-naphthylselanyl)benzoate with 408 mg (1.72 mmol) of methyl 8-bromooctanoate and 238 mg of potassium carbonate in MEK (10 ml), 502 mg (99%) of a yellow oil are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3O)([OH:14])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-:25].[K+].[K+].O.[CH2:31]([O:33][C:34](=[O:39])[C:35](Br)([CH3:37])[CH3:36])[CH3:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[O:25][C:35]([CH3:37])([CH3:36])[C:34]([O:33][CH2:31][CH3:32])=[O:39])([OH:14])[CH2:10][CH2:9]2)=[O:7])=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(c1ccc(Br)cc1)N1CCC(O)(c2ccccc2O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(C2(O)CCN(C(=O)c3ccc(Br)cc3)CC2)c1
Yield: 86.4 %

Procedure:
801 mg of {1-(4-bromobenzoyl)-4-(2-hydroxyphenyl)-4-hydroxypiperidine was stirred for 9 hours at the ambient temperature of 100° C. in the presence of 1.20 g (8.68 mmol) of potassium carbonate in 4.00 g (20.5 ml) of ethylα-bromoisobutyrate. After completion of the reaction, The reaction mixture was cooled, and water was added thereto, followed by extraction with chloroform. Subsequently, the extract was dried over anhydrous sodium sulfate. Chloroform and the remained ethyl α-bromoisobutyrate was distilled off under reduced pressure to obtain 902 mg (86.4%) of ethyl 3-{1-(4-bromobenzoyl)-4-hydroxypiperidin-4-yl}α,α-dimethylphenoxyacetate.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]2[CH3:19])[CH:7]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[CH3:19][CH:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]1[NH:8][C:6]1[CH:7]=[C:2]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=[CH:4][C:5]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: C1CNCCN1
Reactant: CC1CCc2ccccc2C1Nc1cc(F)ccc1S(C)(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1CCc2ccccc2C1Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O
Yield: 92.2 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydro-2-methylnaphthalen-1-amine (63.3 mg, 0.19 mmol), piperazine (328 mg, 3.79 mmol) and N,N-diisopropylethylamine (0.34 mL, 1.99 mmol) in N,N-dimethylformamide (3 mL) was stirred at 110° C. for 16 h. The reaction mixture was cooled down, poured over 10 mL of water and extracted with diethyl ether. After evaporation of solvent the crude product was purified by silica chromatography (10% methanol in dichloromethane) to yield 70 mg (92%) of desired product. 1H NMR (400 MHz, CDCl3): δ 7.61 (d, 1H), 7.29 (m, 1H), 7.14 (m, 3H), 6.46 (d, 1H), 6.27 (dd, 1H), 12.2 (d, 1H), 4.28 (t, 1H), 3.29 (m, 1H), 3.20 (m, 4H), 3.01 (m, 1H), 2.96 (m, 4H), 2.88 (s, 3H), 2.30-1.70 (m, 4H), 1.12 (d, 3H); MS (ESI) m/z: 400.1 (M++1).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]([F:11])([F:10])[CH2:8][OH:9].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:9][CH2:8][C:7]([F:11])([F:10])[F:6])[O:4][CH3:5]
Reactant: OCC(F)(F)F
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
In a dry box, methyl chloroformate (219 mL, 268 g, 2.84 mol) was added slowly to a solution containing 2,2,2-trifluoroethanol (233.5 g, 2.335 mol), pyridine (225 g), and dichloromethane (1.2 L, anhydrous) at −10° C. to 30° C. (the dichloromethane was cooled in a freezer before use), with magnetic stirring. The reaction mixture was stirred at room temperature in the dry box overnight. The reaction mixture was then taken out of the dry box, and was washed with 5% HCl (300 mL), followed by 3 washes with 50 mL portions of 5% HCl, one wash with 5% sodium carbonate (100 mL), and 2 washes with 100 mL portions of brine. The organic phase was then dried over anhydrous sodium sulfate. Dichloromethane was removed by rotary evaporation. The residue liquid was distilled with a spinner band column, yielding 185.4 g (46% yield) of pure methyl 2,2,2-trifluoroethyl carbonate, also referred to herein as “FS-D”. NMR analysis data were consistent with literature values (U.S. Pat. No. 5,659,062).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](C=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH:13]S(O)(=O)=O.OO>>[OH:13][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: O=S(=O)(O)O
Agent: OO
Product: Oc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-Benzodioxan-6-carboxaldehyde (5.20 g) was dissolved in MeCH (60 mL) containing conc. H2SO4 (0.6 mL). At 0° C. an aqueous solution of 30% H2O2 (4.7 mL) was added to the mixture over 5 minutes. The mixture was warmed to room temperature, stirred an additional 18 h and evaporated. The residue was taken up with H2O and extracted with CH2Cl2. The extract was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 3:1) to give 6-hydroxy-1,4-benzodioxan (3.85 g). ESMS: m/z 153 MH+.
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH2:14])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[S:15]([OH:19])([OH:18])(=[O:17])=[O:16].CS[C:22](=[NH:24])[NH2:23].CN(C)C=O>O>[S:15]([OH:19])([OH:18])(=[O:17])=[O:16].[OH:1][C:2]1([CH2:13][NH:14][C:22]([NH2:24])=[NH:23])[CH2:3][O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH2:8]1
Reactant: NCC1(O)COc2ccccc2OC1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCC1(O)COc2ccccc2OC1

Procedure:
3-hydroxy-3-aminomethyl-3,4-dihydro-2H-1,5-benzodioxepin from Example 1, Step E, (1.95 g., 10 millimoles) and 2.78 g. (10 millimoles) of S-methylisothiourea sulfate in 15 mls. of dimethylformamide and 2 mls. of water is heated at 90°-100° C. for 5 hours. The solvent is evaporated in vacuo and the residue recrystallized from ethanol to give 3-hydroxy-3-guanidinomethyl-3,4-dihydro-2H-1,5-benzodioxepin sulfate.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6])#[N:2].[K+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1>[C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:6])#[N:2]
Reactant: N#Cc1ncccc1C(=O)[O-]
Reactant: CCOC(=O)CBr
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)c1cccnc1C#N
Yield: 100.3 %

Procedure:
Toluene (40 cc) containing compound 3 (4.1 g; 0.022 mol), ethyl bromoacetate (3.35 g; 0.02 mol) and TDA-1 (0.3 cc) is heated under reflux for 4 hours. The toluene is then evaporated off and the residue taken up with water and then extracted with dichloromethane. After drying, evaporating and crystallization in pentane, (ethoxycarbonyl)-methyl 2-cyanonicotinate (4.7 g; m.p. 74° C.) is obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:24]([OH:26])=[O:25])[C:15]([CH2:18][C:19]4[S:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N+]=[N-])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.C(OCC)(=O)C>[C:29]1([CH:35]([O:25][C:24]([CH:14]2[N:13]3[C:27](=[O:28])[C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C@H:12]3[S:17][CH:16]=[C:15]2[CH2:18][C:19]2[S:23][CH:22]=[CH:21][CH:20]=2)=[O:26])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(Cc3cccs3)=CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7β-phenylacetylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid in 150 ml of methanol is diluted with 200 ml of ethyl acetate, then treated with 9.70 g of diphenyldiazomethane in 20 ml of ethyl acetate. The reaction mixture is stirred at room temperature for 1 hour and evaporated to dryness under reduced pressure. The residue is crystallised from ethyl acetate and chromatographed on 400 g of silica gel. Elution with ethyl acetate yields the 7β-phenylacetylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid diphenylmethylester, which after recrystallisation from ethyl acetate melts at 166°-167°; [α]D20 = + 359° ± 2° (c = 0.490 in 95% ethanol); thin-layer chromatogram (silica gel): Rf = 0.73 (system: toluene/ethyl acetate 1:1) and Rf = 0.56 (system: toluene/acetone 4:1); ultraviolet absorption spectrum (in 95% alkanol): strong terminal absorption; infrared absorption spectrum (in mineral oil); characteristic bands at 2,97μ, 5,62μ, 5,75μ, 6,03μ and 6,54μ.
Reaction SMILES: O=[C:2]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[BH4-].[Na+].CC(C)=O.[OH-].[Na+]>CO.CCOCC>[C:13]1([CH3:17])[CH:14]=[CH:15][CH:16]=[C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:3]=[CH:2][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]4)[CH2:6][CH2:7]2)[CH:12]=1
Reactant: Cc1cccc(N2CCN(CCC(=O)c3ccc4c(c3)CCC(=O)N4)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CO
Product: Cc1cccc(N2CCN(CC=Cc3ccc4c(c3)CCC(=O)N4)CC2)c1
Reaction time: 0.5 h

Procedure:
5.0 Grams of 6-{1-oxo-3-[4-(3-tolyl)-1-piperazinyl]-propyl]-3,4-dihydrocarbostyril was suspended in 250 ml of methanol, and 2.5 g of sodium borohydride was added gradually to this solution under ice-cooling condition and the mixture was stirred for 30 minutes. Then 10 ml of acetone was added to the mixture and the reaction mixture was concentrated under a reduced pressure to dryness. To the residue thus obtained were added 10N-NaOH and ether and stirred at a room temperature for 30 minutes. The crystals thus formed were collected by filtration and were suspended in 250 ml of dioxane then added 10 ml of concentrated hydrochloric acid. The mixture was refluxed for 15 minutes then concentrated under a reduced pressure to dryness. The residue thus obtained was separated by a silica-gel chromatography and recrystallized from ethanol to obtain 6-{3-[4-(3-tolyl)-1-piperazinyl]-1-propenyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 2.9 g
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[S:7][CH:8]=1)([O-])=O.C([O-])=O.[NH4+]>CCO.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:25]([F:27])([F:28])[F:26])[C:29]([F:30])([F:31])[F:32])=[CH:20][CH:19]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[S:7][CH:8]=1
Reactant: O=[N+]([O-])c1csc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: Nc1csc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 18 h
Yield: 30.5 %

Procedure:
In a 50 mL round bottomed flask a mixture of 2-(4-(4-((4-nitro-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (80 mg, 0.154 mmol), ammonium formate (48.6 mg, 0.770 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10% Pd/C (1.639 mg, 0.015 mmol) in EtOH (10 mL) was stirring under an atmosphere of H2 (1 atm) for 18 h. Afterwards, the reaction mixture was filtered through a plug of Celite® (diatomaceous earth), and the filtrate was concentrated to give the crude product. The crude product was dissolved in CH2Cl2 and filtered through a plug of silica gel. The filtrate was concentrated to give 2-(4-(4-((4-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (23 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH2:18][CH2:19][CH2:20][OH:21])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][S:2]([O:21][CH2:20][CH2:19][CH2:18][C:7]1([CH3:6])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8]1)(=[O:4])=[O:3]
Reactant: CC1(CCCO)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(CCCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Methanesulfonyl chloride (1.4 ml, 18.09 mmol) in methylene chloride (10 ml) was added dropwise to a mixture of 2-methyl-2-(3-hydroxypropyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 38 (2.1 g, 9.24 mmol), triethylamine (2.8 g, 20.09 mmol), 4-dimethylaminopyridine (50 mg, 0.41 mmol) and methylene chloride (80 ml) with cooling on ice-bath followed by stirring at room temperature overnight. The reaction mixture was concentrated. 10% hydrochloric acid was added to the residue, and the resulting mixture was stirred for 30 minutes with cooling on ice-bath. The precipitates were filtered off and washed with water to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propyl methanesulfonate (2.6 g, yield 92%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:8]([OH:10])=O)=[CH:5][S:6][CH:7]=1.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:45]=[C:46]([NH2:53])[C:47]4[CH:48]=[N:49][NH:50][C:51]=4[CH:52]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:52]=[C:51]4[C:47]([CH:48]=[N:49][NH:50]4)=[C:46]([NH:53][C:8]([C:4]4[C:3]([O:2][CH3:1])=[CH:7][S:6][CH:5]=4)=[O:10])[CH:45]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: COc1cscc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cscc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.08 h

Procedure:
4-(Methyloxy)-3-thiophenecarboxylic acid (35 mg) was treated with N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (84 mg) in DMF (250 μl) and DIPEA (69 μl). The reaction mixture was shaken for five min prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (25 mg) in DMF (250 μl). The reaction mixture was left to stand at 22° C. for 18 h. The solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 ml) prior to application on to an aminopropyl SPE cartridge (0.5 g) that had been preconditioned with methanol and then chloroform. The product was eluted after 2 hr with ethyl acetate/methanol (1:1, 3 ml), and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method C) gave the title compound.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55](O)=[O:56])=[O:40])([CH3:37])([CH3:36])[CH3:35].[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[CH:61][C:60]=1[NH2:65].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[CH:61][C:60]=1[NH:65][C:55]([C:43]1[N:44]=[C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])[S:46][C:42]=1[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:56]
Reactant: Cn1ncc(N)c1Cl
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of PyBOP (4.08 g, 7.84 mmol) and 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (2.20 g, 6.16 mmol) in DCM (50 mL) was stirred at room temperature for 30 min. A solution of 5-chloro-1-methyl-1H-pyrazol-4-amine (737 mg, 5.60 mmol) and DIPEA (1.6 mL, 9.0 mmol) in DCM (50 mL) was then added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (3×50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-100% EtOAc/isohexane) followed by trituration with MeCN gave tert-butyl 4-(5-chloro-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate as an off-white solid (1.71 g, 65%). 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.42-7.33 (m, 1H), 7.09-7.01 (m, 2H), 3.87 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].O.S(=O)(=O)(O)O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([CH:4]([CH2:14][CH2:15][CH2:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCC(=O)CCCC(CCCCCCC(=O)O)C(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 8-acetyl-12-hydroxyheptadecanoic acid (9.85 g., 0.03 mole) in acetone (29 ml.) is cooled to 5°-10° and treated, dropwise, over 21/4 hours with a solution prepared from a mixture of chromium trioxide (2.57 g., 0.0257 mole) water (7.5 ml.) and concentrated sulfuric acid (2.1 ml.). Stirring is continued for an additional 30 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:43]
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 58.5 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (60 mg, 0.15 mmol, 1.0 equiv; Example 122) in anhydrous DMF (0.5 mL) was added N-ethyldiisopropylamine (96 mg, 129 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and ethyl bromoacetate (55.1 mg, 37 μL, 0.33 mmol, 2.2 equiv; [CAS RN 105-36-2]) and the reaction mixture heated by microwave irradiation to 100° C. for 2 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μM, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 42.7 mg (62%) of the title compound as a light yellow powder. MS (ISP): 486.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][N:18]([CH2:23][CH2:24][C:25]#[N:26])[CH2:19][CH2:20][C:21]#[N:22])[CH2:12]1)[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][N:5]([CH2:4][CH2:3][CH2:1][NH2:2])[CH2:6][CH2:7][CH2:8][NH2:9])[CH2:12]1)[CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: N#CCCN(CCC#N)CC1CCCC(CN(CCC#N)CCC#N)C1
Reactant: [H][H]
Solvent: C1COCCO1
Product: NCCCN(CCCN)CC1CCCC(CN(CCCN)CCCN)C1
Yield: 97.6 %

Procedure:
5.00 g of N,N,N′,N′-tetrakis(2-cyanoethyl)-1,3-bis(aminomethyl)cyclohexane, 0.50 g of Raney Co and 50 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 8.0 MPa at 180° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 5.10 g of the title compound as a pale red oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC=CC=1.[Mg].[S:17]([C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)C#N>C1COCC1>[C:1]1([S:17][C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: N#CSc1ccc[nH]1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Brc1ccccc1
Product: c1ccc(Sc2ccc[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of phenyl magnesium bromide (prepared from bromobenzene (0.75 ml) and magnesium chips (0.19 g, 7.8 mmol) in anhydrous THF (20 ml), cooled to 0° C., was slowly added a solution of 2-thiocyanopyrrole 11 (0.5 g, 4.0 mmol) in anhydrous THF (20 ml). After stirring at 0° C. for 30 min, the mixture was poured into crushed ice and extracted with ethyl acetate. The organic phase was washed with 20% NH4Cl, anhydrified and evaporated. The residue was purified by chromatography (35% hexane in chloroform) to give 0.6 g (93% yield) of 12 as colourless prisms: melting point 86-87° C. (hexane); IR (CHCl3) 3420 cm−1; 1H NMR (CDCl3) δ8.20 (br s, 1H), 7.25-6.85 (m, 5H), 6.92 (m, 1H), 6.55 (m, 1H), 6.31 (m, 1H). Anal. (C9H9NS): C, H, N.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[CH2:10]([Mg]Br)[CH:11]([CH3:13])[CH3:12]>C(OCC)C>[CH2:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6])[CH:11]([CH3:13])[CH3:12]
Reactant: C=Cc1cccc(Br)c1
Reactant: CC(C)C[Mg]Br
Solvent: CCOCC
Product: C=Cc1cccc(CC(C)C)c1
Temperature: 25 °C

Procedure:
In a 15-liter separable four-necked flask equipped with a stirrer and a reflux condenser were placed 3 liters of sufficiently dried diethyl ether, 915 g (5 moles) of m-bromostyrene and 31 g of bis(1,3-diphenylphosphino)propanenickel(II) chloride, and the above-mentioned diethyl ether solution of isobutylmagnesium bromide was added thereto dropwise with stirring at room temperature. After the completion of the addition, stirring was continued under the reflux of diethyl ether, until the reaction had been over. After the end of the reaction, the solution was cooled to room temperature, and was then thrown into pieces of ice in order to inactivate remaining isobutylmagnesium bromide. The resultant ether layer was separated by a separating funnel, and was washed with water until it had become a neutral state. Afterward, diethyl ether was distilled off, thereby obtaining 670 g of crude m-isobutylstyrene.