Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH2:7]O)=[CH:3][CH:4]=[CH:5][CH:6]=1.S(=O)(=O)(O)O.[BrH:20]>>[Br:20][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br
Reactant: OCc1ccccc1-c1ccccc1
Agent: O=S(=O)(O)O
Product: BrCc1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A stirred solution of 58.9 g (0.319 mole) of 2-biphenylmethanol and 6 ml of concentrated sulfuric acid in 67 ml of aqueous 48% hydrobromic acid was heated under reflux for 5 hours. The reaction mixture was cooled to ambient temperature, poured into ice-water, and the resulting mixture extracted with three portions of 100 ml each of diethyl ether. The combined extracts were washed with 50 ml of a saturated aqueous solution of sodium bicarbonate, then with 50 ml of water. The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give 76.8 g of 2-(bromomethyl)biphenyl as a residual oil. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:10]#[N:11])=[C:5](SC)[S:6][CH3:7].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1>C(O)C>[OH:2][C:3]1[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=[C:5]([S:6][CH3:7])[C:4]=1[C:10]#[N:11]
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)C(C#N)=C(SC)SC
Solvent: CCO
Product: CSc1nc2ccnn2c(O)c1C#N
Temperature: 25 °C
Yield: 67 %

Procedure:
Under nitrogen gas atmosphere, 2-cyano-3,3-bismethylthio-2-propenoic methyl ester (6 g, 29.5 mmol) was added to ethanol (40 mL) along with 3-aminopyrazole (2.6 g, 31 mmol) and the mixture was refluxed for 2.5 hours. The reaction was then cooled to room temperature and precipitate was collected by filtration under vacuum. The solid was washed with ethanol and dried under vacuum to give 7-hydroxy-5-(methylthio)pyrazolo[1,5-a]pyrimidine-6-carbonitrile in 67% yield (4.1 g). This material was used for the next step without further purification. LCMS (M+1=207)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[C:13]=1[F:22])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[C:14]([F:21])[C:13]=1[F:22])[CH3:10]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(-c2ccc(Br)cc2)c(F)c1F
Temperature: 25 °C
Yield: 94 %

Procedure:
4-Bromoiodobenzene (1) (20.0 g), 4-ethoxy-2,3-difluorophenylboronic acid (2) (14.4 g), potassium carbonate (29.3 g), Pd(Ph3P)2Cl2 (1.49 g), toluene (100 ml), Solmix A-11 (100 ml), and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25° C., and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from Solmix A-11 and dried, giving 20.8 g of 4-ethoxy-4′-bromo-2,3-difluoro-1,1′-biphenyl (3). The yield based on the compound (1) was 94.0%.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]([CH3:31])[CH:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=2)[CH:14]=[C:13]1C(OCC)=O)[CH3:11])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)C>[CH3:31][C@H:9]1[C@H:10]([CH3:11])[N:12]2[C:20]3[CH:19]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]2[C:6](=[O:7])[NH:8]1.[CH3:31][C@H:9]1[C@@H:10]([CH3:11])[N:12]2[C:20]3[CH:19]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]2[C:6](=[O:7])[NH:8]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)NC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc2cc3n(c2c1)[C@@H](C)[C@H](C)NC3=O
Product: CCOC(=O)c1ccc2cc3n(c2c1)[C@H](C)[C@H](C)NC3=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %
Yield: 45 %

Procedure:
To a solution of the crude diethyl 1-{3-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H-indole-2,6-dicarboxylate from the preceding reaction in CH2Cl2 (10 mL) is added TFA (10 mL). The mixture is stirred for 1 h at room temperature. The solvent is removed and the residue is dried in vacuo for 1 h. To a solution of the residue in ethanol (100 mL) is added K2CO3 (6.2 g, 44.8 mmol). The reaction mixture is refluxed for 1 h. After cooling to room temperature, the solvent is removed under vacuum and the residue is partitioned between EtOAc and water. The organic layer is separated, washed with brine, dried (MgSO4) and concentrated to afford the crude compound which is purified by flash column chromatography using EtOAc in heptane to afford ethyl trans-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-α]indole-7-carboxylate (870 mg, 20% for 2 steps) and ethyl cis-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate (1.9 g, 45% for 2 steps).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:23][O:24][C:25](=[O:73])[C@@H:26]([NH:42][C:43]([C@@H:45]1[CH2:54][C:53]2[CH:52]=[C:51]3[O:55][CH2:56][C@H:57]([C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH:67]5[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]5)[CH:60]=4)[O:58][C:50]3=[CH:49][C:48]=2[CH2:47][NH:46]1)=[O:44])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[C:35]=2[CH3:41])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C.CO>[CH3:23][O:24][C:25](=[O:73])[C@@H:26]([NH:42][C:43]([C@@H:45]1[CH2:54][C:53]2[CH:52]=[C:51]3[O:55][CH2:56][C@H:57]([C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH:67]5[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]5)[CH:60]=4)[O:58][C:50]3=[CH:49][C:48]=2[CH2:47][N:46]1[C:7]([C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[CH3:10])=[O:9])=[O:44])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[C:35]=2[CH3:41])=[CH:30][CH:29]=1
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1cccc(OCC2CCCCC2)c1)CO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1cccc(OCC2CCCCC2)c1)CO3
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
2,5-Dimethyl-oxazole-4-carboxylic acid (6 mg) was taken in 1 mL of anhydrous DCM and EDCI (9 mg), HOBT (7 mg) and (S)-2-{[(3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg) and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and DIEA (25 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was loaded onto a silica gel column (1:3 EtOAc/hexanes to 4% MeOH in 1:1 EtOAc/hexanes) to get pure (S)-2-{[(3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (22 mg). This product was hydrolyzed according to General Procedure B to the title compound (17 mg). LCMS (m/z): 800.
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:2][C:1]([NH:9][S:20]([CH:19]=[CH2:18])(=[O:22])=[O:21])([CH3:3])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Temperature: -18 °C
Yield: 90 %

Procedure:
Tert-octylamine (1.47 mol, 236.3 ml), triethylamine (0.49 mol, 68.3 ml) and dichloromethane (400 ml) were placed in a 3 neck flask under nitrogen and cooled to −18° C. A solution of 2-chloro-1-ethane sulfonyl chloride in dichloromethane (400 ml) was added in a dropwise fashion over 2 hours, the reaction temperature was maintained between −18 and −9° C. during the addition. The reaction was allowed to warm to room temperature (RT) over 1 hour then washed with 1N HCl (400 ml) followed by distilled water (2×200 ml). The organic layer was dried with MgSO4 then concentrated to give a pale yellow oil. The oil was dried under vacuum at 50° C. to give ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide, 96.0 g (90% yield) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[NH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]([NH:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:19])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Reactant: NCCN1CCOCC1
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C(=O)NCCN2CCOCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 12.9 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-l-yl]-2-phenylbutanoic acid (3.544 g, 10 mmole), triethylamine (2.024 g, 20 mmole), and N,N-bis(2-oxo-3oxazolidinyl)phosphoramidic chloride (2.545 g. 10 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which 4-(2-aminoethyl)morpholine (1.302 g, 10 mmole) was added. The reaction mixture was stirred at room temperature for 14 hours, washed with water (100 ml), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by crystallization from ethanol/diethyl ether with addition of ethanolic HCl gave 0.6 g of the title compound as the dihydrochloride, 2.5 hydrate, 0.2 CHCl3 solvate, m.p. 60°-5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C>O1CCCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccccc1
Reaction time: 3 h
Yield: 21.4 %

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine (2.0 g; 7.5 mmole) and phenyl isocyanate (1.6 g; 13.4 mmole) in tetrahydrofuran (5 ml) was stirred at room temperature for 30 minutes. Ethanol (5 ml) was added, and the reaction mixture was stirred for 3 hours and then concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide crude product (2.7 g). Recrystallization from the same solvent yielded the title compound as colorless crystals (0.62 g; 21% yield), m.p. 135°-137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].[Br:12][C:13]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[S:15][C:14]=1[Cl:22].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O>[Br:12][C:13]1[CH:17]=[C:16]([S:18]([NH:1][C:2]2[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])(=[O:20])=[O:19])[S:15][C:14]=1[Cl:22]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: Nc1cccc(C(=O)O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cccc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1O
Yield: 53 %

Procedure:
A solution of 3-aminosalicylic acid (0.17 g, 1.11 mmol) and 3-bromo-2-chlorothiophene-5-sulfonyl chloride (0.33 g, 1.11 mmol) in aqueous dioxane (20 mL, 95:5 dioxane/water) was stirred at room temperature for 4 weeks. The pH of the reaction mixture was adjusted to about 9 using 1M Na2CO3 and then EtOAc (200 mL) and water (100 mL) were added. The organic phase was removed and the aqueous phase washed with more EtOAc. The pH of the aqueous phase was adjusted to about 3 with concentrated phosphoric acid and EtOAc (200 mL) was added. The aqueous phase was removed and the organic phase was washed with 1 M HCl and brine, dried over MgSO4, filtered and concentrated. The brown residue was recrystallized from aqueous MeOH at 60° C. The precipitate was collected by filtration and dried over night. The title compound was obtained in 53% yield (0.24 g). 1H NMR (500 MHz, MeOH-d4) δ ppm 6.92 (t, J=7.93 Hz, 1 H) 7.34 (s, 1 H) 7.65 (dd, J=7.93, 1.59 Hz, 1 H) 7.75 (dd, J=7.93, 1.59 Hz, 1 H). MS (ESI+) m/z 412 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23]N(O)C(N)=O.ClC1C=C(C=CC=1)[C:33](OO)=[O:34].[OH-:40].[Ca+2].[OH-:42].CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])(=[O:40])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([O:34][CH3:33])=[O:42]
Reactant: CC1=C(CCN(O)C(N)=O)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CC1=C(C)/C(=C/c2ccc(S(C)(=O)=O)cc2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (Z)-5-fluoro-2-methyl-1-(4-methylsulfinyl benzylidene)inden-3-yl acetate from Example 7 (3.7 g, 10 mmol) in methylene chloride (100 mL) there was added 85% m-chloroperoxy benzoic acid (2.54 g, 12.5 mmol) and the mixture was stirred at room temperature for 1 hour. There was added more methylene chloride (100 mL) then calcium hydroxide (5.5 g) and after 10 minutes, the suspension was filtered. The residue obtained by evaporation of the filtrate was stirred with ether (100 mL) at room temperature for 5 hours, then filtered to afford the title compound as a fluffy yellow solid, mp 162-164° C.
Reaction SMILES: N1[CH2:6][CH2:5][O:4]CC1.[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]1(CCC=O)[CH:19]=CC=[CH:16][CH:15]=1.[OH-].[K+]>CO.C(O)(=O)C>[CH2:13]([CH:15]1[CH2:16][CH2:6][C:5](=[O:4])[CH:19]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CCCc1ccccc1
Reactant: C1COCCN1
Reactant: Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1C=CC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A 1-liter four-necked flask equipped with a Dean-Stark trap and a thermometer was charged with 71 g of morpholine and 400 ml of toluene, and 100 g of 3-phenylpropionaldehyde were added dropwise thereto while chilling with ice water, followed by azeotropic dehydration for 1 hour. After cooling the reaction mixture, excess morpholine was distilled off with toluene. The residue was dissolved in 400 ml of toluene. In a 1-liter four-necked flask equipped with a thermometer and a condenser, 70 g of methyl vinyl ketone were added dropwise under reflux to the solution over 1 hour. After aging under reflux for 1 hour, the reaction mixture was cooled, and 10% sulfuric acid was added dropwise to the reaction mixture until the pH of the reaction mixture reached 3. The thus-acidified reaction mixture was then stirred at room temperature for 1.5 hours. After separating the resulting lower water layer, the residual organic layer was neutralized, washed with water, dried and concentrated, thereby obtaining 137 g of a crude product. Dissolved in 500 ml of methanol were 137 g of the crude product, and 4 ml of 4.5 mol/liter aqueous KOH were added dropwise to the solution at room temperature, followed by stirring for 3 hours at the same temperature. After neutralizing the resultant mixture with acetic acid, methanol was distilled off. After the residue was charged into a 1-liter four-necked flask equipped with a Dean-Stark trap and a thermometer to dissolve it in 500 ml of toluene, 2 g of p-toluenesulfonic acid were added to the solution, followed by azeotropic dehydration for 3 hours. After cooling, the residue was neutralized and washed with water, and the resultant organic layer was dried and concentrated, thereby obtaining 119 g of a crude product. This product was purified by column chromatography to obtain 41 g (yield: 30%) of 4-benzyl-2-cyclohexen-1-one.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[Br:62][C:63]1[CH:64]=[C:65]([CH2:71]N)[CH:66]=[CH:67][C:68]=1[O:69][CH3:70]>C(Cl)Cl>[Br:62][C:63]1[CH:64]=[C:65]([CH2:71][N:20]([CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:29][CH3:30])[C:21]([C:23]2([C:26]([NH2:32])=[O:27])[CH2:24][CH2:25]2)=[O:22])[CH:66]=[CH:67][C:68]=1[O:69][CH3:70]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Reactant: COc1ccc(CN)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(OC)c(Br)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (600 mg, 1.444 mmol), HBTU (657 mg, 1.733 mmol), Et3N (1006 μL, 7.22 mmol) and {[3-bromo-4-(methyloxy)phenyl]-methyl}amine (343 mg, 1.589 mmol) in DCM was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[3-bromo-4-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (100 mg, 11.29%). LC-MS m/z 613 M+, 0.83 min (ret time).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH2:13][C:14](=[O:20])[O:15]C(C)(C)C)(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[ClH:29]>O1CCOCC1>[ClH:29].[CH3:7][O:6][C:4](=[O:5])/[CH:3]=[CH:2]/[C:1]([O:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]([OH:20])=[O:15])[CH2:21][C:22]([OH:24])=[O:23])=[O:8]
Reactant: COC(=O)/C=C/C(=O)OCCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)/C=C/C(=O)OCCN(CC(=O)O)CC(=O)O
Reaction time: 90 h

Procedure:
To a solution of 2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)ethyl methyl fumarate (2.52 g, 6.2 mmol) in dioxane (25 ml) was added 2M HCl in dioxane (30 ml) and the mixture stirred for 90 hours. The precipitate was filtered, washed with diethyl ether and dried in a vacuum oven at 55° C. for 18 hours to give (E)-2,2′-((2-((4-methoxy-4-oxobut-2-enoyl)oxy)ethyl)azanediyl)diacetic acid hydrochloride, a white solid (1.31 g, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][NH:6][C:7]1[C:8]([NH2:25])=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:11][CH:12]=1.[C:29]1(=[O:39])[C:33]2([CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:32][C:31](=O)[O:30]1.[Si](C=[N+]=[N-])(C)(C)[CH3:41]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:9][C:8]=2[N:25]=[C:41]1[CH2:32][C:33]1([C:29]([O:30][CH3:31])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C1CC2(CCCC2)C(=O)O1
Reactant: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1cccc(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Product: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)CCCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution of N1-(3-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine (1.0 g, 2.4 mmol) in acetonitrile (20 mL) was added 2-oxaspiro[4.4]nonane-1,3-dione (420 mg, 2.7 mmol) and the solution heated to 80° C. for 8 h. The solution was cooled to RT and concentrated to dryness. To this residue was added acetic acid (15 mL) and the resulting solution was heated to 80° C. for 3 h. The solution was cooled, concentrated to dryness and the resulting residue was taken up in toluene/MeOH (15 mL; 3:1). The solution was treated with TMSCHN2 (1.5 mL, 3 mmol, 2 M in hexanes) dropwise (bubbling observed). The mixture was stirred at RT for 30 min and then concentrated to dryness. The residue was purified using FCC to provide 1.12 g of the title compound. MS (ESI): mass calcd. for C32H30BrN3O3, 583.15; m/z found, 584.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.5, 1H), 8.09 (d, J=8.7, 1H), 7.82 (d, J=8.2, 1H), 7.75-7.69 (m, 2H), 7.56-7.52 (m, 1H), 7.40 (d, J=7.9, 1H), 7.35 (d, J=2.2, 1H), 7.20 (s, 1H), 7.18-7.14 (m, 1H), 7.05-7.02 (m, 1H), 6.99-6.96 (m, 1H), 6.89-6.86 (m, 1H), 5.42 (s, 2H), 5.33 (s, 2H), 3.62 (s, 3H), 3.08 (s, 2H), 2.26-2.20 (m, 2H), 1.87-1.80 (m, 2H), 1.77-1.64 (m, 4H); 584.0 (M+H) m/z
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:35][O:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([OH:41])=O.CCN(C(C)C)C(C)C.O[NH:56][C:57](=[NH:71])[CH2:58][S:59][C:60]1[N:64]([CH3:65])[C:63]([C:66]2[S:67][CH:68]=[CH:69][CH:70]=2)=[N:62][N:61]=1>CN(C=O)C.O>[CH3:35][O:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]1[O:41][N:71]=[C:57]([CH2:58][S:59][C:60]2[N:64]([CH3:65])[C:63]([C:66]3[S:67][CH:68]=[CH:69][CH:70]=3)=[N:62][N:61]=2)[N:56]=1
Reactant: COc1ccccc1C(=O)O
Reactant: Cn1c(SCC(=N)NO)nnc1-c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccccc1-c1nc(CSc2nnc(-c3cccs3)n2C)no1
Temperature: 25 °C
Reaction time: 7 h
Yield: 1.3 %

Procedure:
HBTU (171 mg, 0.45 mmol) and HOBT (8 mg, 0.06 mmol) were added to a solution of 2-methoxy benzoic acid (68 mg, 0.45 mmol) and DIPEA (192 ml, 1.11 mmol) in DMF (3 ml). After 10 min N-hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamidine (100 mg, 0.37 mmol) was added. The reaction mixture was stirred at RT for 7 h and then at 110° C. over night. After cooling the reaction mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried and concentrated. Flash chromatography (heptane/EtOAc 1:2) afforded 1.9 mg (11%) of the desired product.