Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:44][C@H:45]([O:49][C:50]1[N:58]=[C:57]2[C:53]([N:54]=[C:55]([O:59][CH3:60])[NH:56]2)=[C:52]([NH2:61])[N:51]=1)[CH2:46][CH2:47][CH3:48].Br[CH2:63][CH2:64][CH2:65][CH:66]1[CH2:71][CH2:70][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1>>[NH2:61][C:52]1[N:51]=[C:50]([O:49][C@@H:45]([CH3:44])[CH2:46][CH2:47][CH3:48])[N:58]=[C:57]2[C:53]=1[N:54]=[C:55]([O:59][CH3:60])[N:56]2[CH2:63][CH2:64][CH2:65][CH:66]1[CH2:67][CH2:68][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)=[O:73])[CH2:70][CH2:71]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt and phenylmethyl 4-(3-bromopropyl)-1-piperidinecarboxylate.
Reaction SMILES: [NH2:1][C@@H:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH2:15]([O:14][C:12]([NH:1][C@@H:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[C@H](N)C(O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution under an atmosphere of nitrogen containing 1.0 g (6.8 mmol) of 3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid in 9.5 mL of 1N NaOH and 10 mL of dioxane was added 1.43 g (8.4 mmol) of benzyl chloroformate. The pH was maintained above pH 8 with 1N NaOH as needed. The reaction mixture was allowed to stir at room temperature overnight. The reaction was diluted with water and washed with ether. The aqueous layer was acidified with 1N HCl to pH=2 and extracted with ether (2×). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo to afford 1.75 g (92%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic acid as a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 282, Found 282.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([CH:27]1[O:29][CH2:28]1)Cl.[C:30](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH:28]3[CH2:27][O:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH:9]1[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2n[nH]c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reactant: ClCC1CO1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nn(C3CO3)c3c2C(C)N(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reaction time: 72 h
Yield: 56.1 %

Procedure:
To a solution of 3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (18.26 g, 53 mmol) and epichlorohydrin (41.12 mL, 526 mmol) in DMF (100 mL) was added cesium carbonate (20.56 g, 63 mmol). The reaction mixture was allowed to stir for 72 h, diluted with EtOAc (200 mL) and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 20% acetone/CH2Cl2) to afford 3-(4-chloro-3-methyl-phenyl)-1-oxiranyl methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (12.0 g, 57%). TLC (silica, 20% acetone/CH2Cl2): Rf=0.68. MS (electrospray) m/z 491.2 (491.2, calculated for C27H31ClN6O, [M+H]+). 1H NMR (400 MHz, CDCl3) 7.55 (s, 1H), 7.36 (m, 2H), 4.61 (m, 2H), 4.38-4.47 (m, 1H), 4.11 (dd, J=14.3, 5.7 Hz, 1H), 3.67-3.79 (m, 2H), 3.34 (m, 1H), 2.83 (t, J=4.5 Hz, 1H), 2.75 (m, 2H), 2.51 (m, 1H), 2.41 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]3[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].O>C1COCC1>[CH:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[NH:26][C:27]3=[O:28])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1NC1CCN(C2CC3CCCc4cccc2c43)CC1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CC3CCCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
N-[1-(1,2,2a,3,4,5-Hexahydroacenaphthylen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.15 g) was dissolved in THF (70 ml), 1,1′-carbonyldiimidazole (0.591 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.76 g) as a white solid.
Reaction SMILES: [NH3:1].[C:2]([O:8][CH2:9][C:10]1([O:15][CH2:14][CH2:13][O:12]1)[CH3:11])(=[O:7])[CH2:3][C:4]([CH3:6])=O>CO>[NH2:1]/[C:4](/[CH3:6])=[CH:3]\[C:2]([O:8][CH2:9][C:10]1([O:15][CH2:14][CH2:13][O:12]1)[CH3:11])=[O:7]
Reactant: N
Reactant: CC(=O)CC(=O)OCC1(C)OCCO1
Solvent: CO
Product: C/C(N)=C/C(=O)OCC1(C)OCCO1
Yield: 84 %

Procedure:
Ammonia gas was passed through a mixture of 19 g of 2,2-ethylenedioxypropyl acetoacetate and 100 ml of methanol for 2.5 hours under ice-cooling while stirring. The solvent was then distilled off and the residue was distilled under reduced pressure to obtain 16 g (84% yield) of 2,2-ethylenedioxypropyl 3-aminocrotonate as a pale yellow oil having a boiling point of 120° C. (5 mmHg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[C:5]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:2].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[CH:29]1.N1CCCCC1>CO>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:9]2\[O:10][C:6]3[C:5]([CH2:14][N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]4)=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:7]=3[C:8]\2=[O:11])=[CH:29]1
Reactant: CCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of tert-butyl 4-[(6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.138 g, 0.367 mmol) in methanol (1.5 mL) was added with indole-3-carboxaldehyde (0.0553 g, 0.367 mmol) and piperidine (0.0250 g, 0.294 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.137 g, 74%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[Cl:19][C:20]1[N:24]=[C:23](Cl)[S:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[Cl:19][C:20]1[N:24]=[C:23]([N:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:18][CH:17]=3)[CH2:16][CH2:15]2)[S:22][N:21]=1
Reactant: Clc1nsc(Cl)n1
Reactant: COc1ccc(CCN2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(CCN2CCN(c3nc(Cl)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-methoxyphenethyl)piperazine dihydrochloride (1.04 g, 3.55 mmol), 3,5-dichloro-1,2,4-thiadiazole (500 mg, 3.23 mmol) and DIPEA (1.33 g, 1.8 ml, 10.3 mmol) in 23 mL EtOH was stirred for 1 h at RT. The reaction solution was concentrated in vacuo and the crude product was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield, after evaporation of the product containing fraction, 1.06 g (97%) of the title compound as white solid. MS (m/e): 339.2 (MH+).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[CH2:13][S:14][C:15](=N)N)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.ClC[CH2:23][C:24]#[N:25].[OH-].[Na+]>O.C(O)C>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[CH2:13][S:14][CH2:15][CH2:23][C:24]#[N:25])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#CCCCl
Reactant: N=C(N)SCc1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CCCSCc1cccc(CN2CCCCC2)c1
Temperature: 20 °C

Procedure:
A stirred solution of the above isothiourea (1.2 g) and 3-chloropropionitrile (0.4 ml) in a mixture of water (7 ml) and ethanol (5 ml) was treated at 0°-5° C. with 2.5N sodium hydroxide (5.3 ml). The reaction mixture was stirred at 0°-5° C. for a further hour and then allowed to warm to 20° C. The reaction mixture was extracted with ethyl acetate and the extracts washed with water, dried and evaporated to provide 3-(3-piperidinomethylbenzylthio)propionitrile as an oil.
Reaction SMILES: C1(C[CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH:11]1([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:38]([OH:40])=O)[CH:35]=4)[CH2:30]3)=[O:28])=[CH:22][CH:21]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=[O:51]>>[CH:11]1([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:38]([NH:10][CH2:9][CH2:8][OH:51])=[O:40])[CH:35]=4)[CH2:30]3)=[O:28])=[CH:22][CH:21]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: NCCCc1ccccc1
Reactant: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(C(=O)O)cc3C2)cc1
Product: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(C(=O)NCCO)cc3C2)cc1

Procedure:
The title compound was prepared as described in Example 1C, substituting 2-aminoethanol for 3-phenylpropan-1-amine and 2-({4-[(cyclopentylacetyl)amino]phenyl}carbamoyl)isoindoline-5-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.70 (s, 1H), 8.51-8.40 (m, 1H), 8.31 (s, 1H), 7.86-7.75 (m, 2H), 7.51-7.36 (m, 5H), 4.78 (bs, 4H), 4.71 (t, J=5.6 Hz, 1H), 3.58-3.46 (m, 2H), 3.39-3.28 (m, 2H), 2.32-2.13 (m, 3H), 1.82-1.68 (m, 2H), 1.67-1.44 (m, 4H), 1.27-1.10 (m, 2H); MS (ESI(+)) m/e 451 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[C:5]([C:11]([F:14])([F:13])[F:12])[N:4]=1)[CH3:2].[CH3:15][O:16][C:17](=[O:38])[CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:15][O:16][C:17](=[O:38])[CH:18]=[CH:9][C:8]1[C:3]([CH2:1][CH3:2])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:6][CH:7]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1nc(C(F)(F)F)ccc1C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc(C(F)(F)F)ccc1C=CC(=O)OC
Temperature: 110 °C
Yield: 80 %

Procedure:
To a solution of 2-ethyl-6-trifluoromethyl-pyridine-3-carbaldehyde in toluene (10 mL) was added methyl(triphenylphosphoranylidene)acetate (172 mg, 0.516 mmol). The mixture was heated at 110° C. for overnight cooled to room temperature, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (EtOAc/hexanes=1/4) to yield the 3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid methyl ester (89 mg, 80%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[CH:13]1([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCCCCC.C(OC(=O)C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37](CCN)=[CH:36][CH:35]=1>C(Cl)Cl>[CH:13]1([CH2:19][O:20][C:1]([NH:8][CH2:12][CH2:11][C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[O:2])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OCC1CCCCC1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(F)cc1)OCC1CCCCC1
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A solution of 4.87 g (30 mmol) of carbonyldiimidazole and 3.43 g (30 mmol) of cyclohexylmethanol was stirred, under nitrogen and at room temperature, for 2-4 hours or the time until the TLC (silica gel; hexane-ethylacetate, 4:1) analysis indicated a complete disappearance of cyclohexylmethanol in the mixture. To this reaction mixture, a solution of 4-fluorophenylethyl amine (4.18 g, 30 mmol) in methylene chloride (5 mL) was added and stirred overnight. The TLC analysis indicated a complete disappearence of 4-fluorophenylethyl amine. The reaction mixture was extracted with 4×50 mL of methylene chloride. The combined extracts were washed with 5% HCl (2×50 mL),water, dried over MgSO4, and concentracted under vacuum. The solid was crystallized from hexane to furnish 5.0 g of N-(Cyclohexylmethyloxycarbonyl)-4-fluorophenylethyl amine (59% yield). mp 44°-45° C.
Reaction SMILES: C1OC1.[C:4]1(=[O:10])[O:9][C:7](=[O:8])[CH:6]=[CH:5]1.[OH-:11].[Na+:12].[S:13](=[O:16])([OH:15])[O-:14].[Na+]>O>[S:13]([CH:5]([CH2:6][C:7]([O-:11])=[O:8])[C:4]([O-:9])=[O:10])([OH:15])(=[O:14])=[O:16].[Na+:12].[Na+:12]
Reactant: O=S([O-])O
Reactant: O=C1C=CC(=O)O1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1CO1
Product: O=C([O-])CC(C(=O)[O-])S(=O)(=O)O

Procedure:
Subsequently, 704 g of the resulting 10 mol ethylene oxide adduct was subjected to an esterification reaction with 100 g of maleic anhydride at 80° C. for 2 hours. Thereafter, 300 g of water was added to this reaction mixture and then neutralized with an aqueous solution of sodium hydroxide at an internal temperature of 30° C. or lower. Further, the resulting mixture was subjected to a sulfonation reaction at 70° C. for 3 hours by introduction of 120 g of sodium bisulfite to give a composition K as an example of the present invention.
Reaction SMILES: [OH:1][C:2]1([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][NH:4][CH2:3]1.[F:20][C:21]1[C:22]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](F)=[O:25].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:15]([O:14][C:13](=[O:19])[NH:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:2]1([OH:1])[CH2:3][N:4]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([F:30])=[C:21]([F:20])[C:22]=2[NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])[CH2:5]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCCCC1C1(O)CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCC1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 2-(3-hydroxyazetidin-3-yl)cyclohexylcarbamate (181 mg, 0.669 mmol) and 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl fluoride (265 mg, 0.669 mmol), prepared using procedures similar to those described in Reference 1, in tetrahydrofuran (2.2 mL) was added N,N-diisopropylethylamine (110 μL) at room temperature. After an hour, the reaction mixture was heated to 50° C. and stirred for 45 minutes, at which time it was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl-2-(1-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl)-3-hydroxyazetidin-3-yl)cyclohexylcarbamate. This crude material was taken into the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:14])[C:6]=1[NH:7]C(=O)C(F)(F)F.O.NN>O>[ClH:1].[NH2:7][C:6]1[C:5]([CH3:14])=[CH:4][S:3][C:2]=1[Cl:1]
Reactant: Cc1csc(Cl)c1NC(=O)C(F)(F)F
Agent: NN
Solvent: O
Product: Cc1csc(Cl)c1N
Product: Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
400 mg of 2-chloro-4-methyl-3-trifluoroacetylaminothiophene were admixed with 1.5 ml of hydrazine hydrate and then stirred at 50° C. for one hour. The mixture was admixed with water, the solution was extracted using ethyl acetate and the organic phase was washed once with dilute acetic acid and once more with water. After the organic phase had been dried over sodium sulfate, it was made strongly acidic using hydrogen chloride-saturated diethyl ether, and the solvent was distilled off on a Rotavapor under reduced pressure. After distilling off to a substantial extent, the mixture was admixed again with ethyl acetate and the solvent was again distilled off, in the course of which brown-colored crystals separated out. The solid was filtered off rapidly and transferred to a desiccator for drying over diphosphorus pentoxide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:13][CH2:12][C@@H:11]([O:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:14])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](CO)OCOCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)OCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.6 %

Procedure:
To a stirred solution of (2S)-2-[(benzyloxy)methoxy]propan-1-ol (Banfi, L., et al., J. Org. Chem. (1984), 49:3784-90) (11.40 g, 0.058 mol) in dichloromethane (50 mL) and pyridine (20 mL) was added p-toluenesulfonyl chloride (11.0 g, 0.057 mol) at 0° C. The reaction mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate and washed with water, 5% hydrochloric acid solution, water and brine; dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford (S)-2-(benzyloxymethoxy)propyl 4-methylbenzenesulfonate (17.10 g, 84%): 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=8.3 Hz, 2H), 7.36-7.25 (m, 7H), 4.71 (s, 2H), 4.59-4.48 (m, 2H), 4.02-3.93 (m, 3H), 2.41 (s, 3H), 1.19-1.11 (m, 3H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][N:16]=[CH:17][N:8]2[C:7]1=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>C1COCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9]3=[N:15][N:16]=[CH:17][N:8]3[C:7](=[O:18])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c(=O)n2cnnc2c2[nH]cnc21
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2cnnc2c2[nH]c(Br)nc21
Temperature: 70 °C
Yield: 6.9 %

Procedure:
To a mixture of 6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (0.12 g, 0.487 mmol) in THF (5 mL) in a microwave reaction tube was added N-bromosuccinimide (0.20 g, 1.1 mmol). The mixture was heated at 70° C. in microwave oven for 12 min. After cooling down to room temperature, it was purified using preparative LCMS to provide the product (0.011 g). LCMS calculated for C11H14BrN6O (M+H): 325.0, 327.0. found: 325.0, 327.0.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([P:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClC(Cl)(Cl)C>>[Br-:28].[CH2:29]([P+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Oc1ccc(P(c2ccccc2)c2ccc(OC(C)=O)cc2)cc1
Solvent: CC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc([P+](Cc2ccccc2)(c2ccccc2)c2ccc(OC(C)=O)cc2)cc1
Product: [Br-]

Procedure:
A mixture of 3.8 g (0.01 mol) of bis(4-acetoxyphenyl)phenylphosphine, 1.7 g (0.01 mol) of α-bromotoluene and 15 ml of 1,1,1-trichloroethane was heated to reflux at which time complete solution was achieved. Shortly thereafter, product began to precipitate from solution. After heating at reflux for 2.5 hr, the mixture was cooled, filtered and the solid was washed with ether and dried. The yield of benzylbis(4-acetoxyphenyl)phenylphosphonium bromide was 5.0 g (90.0% of theory); mp=233°-5° C.
Reaction SMILES: COC(C1(N[C:13](=[O:34])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22](O)[CH2:23][CH:24](O)[C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:15]=2)CCCCCC1)=O.Cl.[H][H].[CH2:38]([OH:40])C>[Pd]>[CH3:38][O:40][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)[CH:15]=1
Reactant: [H][H]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(C(O)CC(O)c3cccc(C)c3)c2)CCCCCC1
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: COC(=O)c1ccc(OC)c(CCCc2cccc(C)c2)c1

Procedure:
The compound of step 1 (140 mg, 0.424 mmol) was dissolved in ethanol (10 ml), 12 N hydrochloric acid (0.2 ml) and palladium on charcoal (10%) was added, and the mixture was hydrogenated at a hydrogen pressure of 6 bar at room temperature overnight. After filtration and evaporation, the residue was purified by silica gel chromatography (HEP/EA gradient) to give 80 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:25][CH2:24][CH:23]2[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH:22]12>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH:22]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH:23]3[CH2:24][CH2:25]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCNC2C1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC2CCN(c3c(Br)cnc4[nH]cc(NC(=O)c5cccnc5)c34)C2C1

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.3 mmol, Example 1, Step I) and tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (190 mg, 0.9 mmol) in n-BuOH (4 mL) were heated to 160° C. for 18 hours in a sealed tube. After concentration, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[2,3-c]pyrrole-5(1H)-carboxylate as a solid.