Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]2[C@H:14]([C:18]([O:20]C(C)(C)C)=[O:19])[CH2:15][CH2:16][CH2:17][N:10]2[C:9](=[O:25])[CH2:8][CH2:7]1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]2[C@H:14]([C:18]([OH:20])=[O:19])[CH2:15][CH2:16][CH2:17][N:10]2[C:9](=[O:25])[CH2:8][CH2:7]1)=[O:4]
Reactant: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)OC(C)(C)C)N2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1S,9S)-tert-butyl 9-(methoxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (1.25 g, 3.52 mmol) dissolved into methylene chloride (10 mL) was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 1 h and concentrated in vacuo. Toluene (5 mL) was added and the reaction concentrated in vacuo to afford (1S,9S)-9-(methoxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid as a white solid, (587 mg, 68%): ESI-LRMS m/e calcd for C12H17N3O6[M+] 299. found 300 [M+H+].
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:18][CH:13](OC(=O)C)[C@H:12]([O:19][C:20](=[O:22])[CH3:21])[C@@H:11]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[F:40][C:41]1[C:42](=[O:48])[NH:43][C:44](=[O:47])[NH:45][CH:46]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>ClCCCl>[C:20]([O:19][C@@H:12]1[C@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@:10]([C:9]#[C:8][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])([CH2:11][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:18][C@H:13]1[N:45]1[CH:46]=[C:41]([F:40])[C:42](=[O:48])[NH:43][C:44]1=[O:47])(=[O:22])[CH3:21]
Reactant: CC[Si](C#C[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 6 (2.00 g, 3.62 mmol) was dissolved in 1,2-dichloroethane (60.0 ml), and 5-fluorouracil (0.71 g, 5.46 mmol) and N,O-bis(trimethylsilyl)acetamide (5.37 ml, 21.7 mmol) were added to the solution, followed by refluxing for one hour. After the reaction mixture was allowed to cool to room temperature, trimethylsilyl trifluoromethanesulfonate (0.85 ml, 4.70 mmol) was added thereto, followed by stirring overnight at 50° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and after stirring, the organic layer was dried over anhydrous magnesium sulfate. The residue was purified by means of silica gel column chromatography (silica gel 300 ml, eluent; n-hexane:ethyl acetate=3:1), to thereby yield a colorless viscous compound (Compound 31; 0.80 g, 1.28 mmol, 35.4%).
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C:13]([CH3:17])([CH3:16])[CH2:14][O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:16][C:13]1([CH3:17])[C:12]2[CH:18]=[CH:19][C:9]([OH:8])=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: [H][H]
Reactant: CC1(C)COc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)COc2cc(O)ccc21
Yield: 73.8 %

Procedure:
To a solution of 6-(benzyloxy)-3,3-dimethyl-2,3-dihydrobenzofuran (3.48 g, 13.7 mmol) in methanol (200 mL) was added Pd/C (1.45 g) and the mixture was hydrogenated under 40 psi of hydrogen overnight. The reaction mixture was filtered through celite, washed with methanol. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/7) to give the title compound (1.66 g, 74%): MS (ES+) m/z 165.4 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[N:7][CH:6]=[N:5]1.Cl[C:12]1[C:13]([N:27]2[CH2:32][CH:31]=[CH:30][CH2:29][CH2:28]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[N:17]=1.O>CN(C=O)C>[N:27]1([C:13]2[C:12]([O:10][CH2:9][C:8]3[N:4]([CH3:3])[N:5]=[CH:6][N:7]=3)=[N:17][N:16]3[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=[C:15]3[CH:14]=2)[CH2:28][CH:29]=[CH:30][CH2:31][CH2:32]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1N1CC=CCC1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1N1CC=CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 23 mg, 0.58 mmol) was added to a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (EP-A-421210) (57 mg, 0.53 mmol) in dry DMF (2 ml) at room temperature under nitrogen. After 1 hour at room temperature a solution of 6-chloro-7-(3,6-dihydro-2H-pyridin-1-yl)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (150 mg) in dry DMF (2 ml) was added via syringe. The mixture was stirred at room temperature for 16 hours. Water (20 ml) was added and the solid filtered and dried in vacuo. Recrystallisation from ethyl acetate/petroleum ether afforded the title pyridaziite as a white solid (131 mg, 70%). 1H NMR (250 MHz, CDCl3) 8.29 (2H, m), 7.94 (1H, s), 7.52 (3H, m), 7.23 (1H, s), 5.91 (1H, m), 5.80 (1H, m), 5.63 (2H, s), 3.96 (3H, s), 3.71 (2H, m), 3.40 (2H, m), 2.23 (2H, m). MS (ES+) 389 [MH]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CS(C)=O.[O:17]=[C:18]1[NH:26][CH:25]=[N:24][C:23]2[N:22]([CH2:27][CH2:28][C:29](OC3C=CC([N+]([O-])=O)=CC=3)=[O:30])[CH:21]=[N:20][C:19]1=2>CC(C)=O>[O:17]=[C:18]1[NH:26][CH:25]=[N:24][C:23]2[N:22]([CH2:27][CH2:28][C:29]([NH:1][CH2:2][CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][CH:5]=3)=[O:30])[CH:21]=[N:20][C:19]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
0.700 g (4.37 mmol) of tryptamine were placed into a 50 ml round bottom flask equipped with a magnetic stirring bar. Then 5.0 ml of dimethylsulfoxide were added to dissolve the tryptamine. After all the tryptamine had gone into solution, 1.0 g (3.04 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) was added and the flask was sealed with a ground glass stopper. The mixture was stirred at room temperature for five hours. The reaction mixture was poured into 60 ml of acetone. The product was filtered, washed twice with 10 ml of acetone and air dried. The yield of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(1H-indol-3-yl)ethyl]-propanamide (AIT-0072) was 0.813 g. Yield: 48% (Purity 99.3%). mp: 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH2:25])([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH:25][S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
Powdered 1-chloro-isoquinoline-5-sulfonyl chloride (10.0 g, 38.2 mmol) is added in portions to a stirred solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (7.33 g, 45.8 mmol) and NEt3 (10.7 mL, 76.4 mmol) in anhydrous CH2Cl2 (200 mL) at 0° C. under nitrogen. The resultant mixture is allowed to stir at ambient temperature for 4 hours. The mixture is concentrated and chromatographed on silica gel (gradient 0-5% CH3OH in CH2Cl2) to give 13.8 g (35.8 mmol, 94% yield) of the title compound as foam. ESIMS: m/z 386 [(M+H)+, 35Cl], 388 [(M+H)+, 37Cl]. Analysis for C16H20ClN3O4S: calcd: C, 49.80; H, 5.22; N, 10.89; found: C, 49.70; H, 5.22; N, 10.72.
Reaction SMILES: [CH2:1]([O:11][C:12]1[N:17]=[C:16]([F:18])[C:15](B(O)O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:26][N:27]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:11][C:12]1[N:17]=[C:16]([F:18])[C:15]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(B(O)O)c(F)n1
Reactant: Brc1nnc(-c2ccccc2)s1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1ccc(-c2nnc(-c3ccccc3)s2)c(F)n1
Yield: 81.6 %

Procedure:
(6-Decyloxy-2-fluoropyrid-3-yl)boronic acid (3.7 g, 12.4 mmol) and 2-bromo-5-phenyl-1,3,4-thiadiazole (1.0 g, 4.15 mmol) are refluxed for 6 hours in a mixture of sodium carbonate (3.95 g), toluene (50 ml), ethanol (25 ml) and water (25 ml) and tetrakis(triphenylphosphine)palladium(0) (5 mol %) as catalyst. Aqueous work-up and column chromatography (SiO2, CH2C12) give 1.4 g (82% of theory) of 2-(6-decyloxy-2-fluoropyrid-3-yl)-5-phenyl-1,3,4-thiadiazole.
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH:4]([NH:7][NH2:8])[CH2:3]1.C[O-].[Na+].C(O[C:15](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[CH3:16])C>C(O)C>[O:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:20]([NH2:21])=[C:17]([C:18]#[N:19])[C:15]([CH3:16])=[N:8]2)[CH2:3]1
Reactant: CCOC(C)=C(C#N)C#N
Reactant: NNC1CCOC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C2CCOC2)c(N)c1C#N
Temperature: 25 °C
Reaction time: 21 h
Yield: 54.3 %

Procedure:
A mixture of 3-tetrahydrofuranylhydrazine hydrochloride (6.2 g, 0.045 mol), sodium methoxide (2.4 g, 0.045 mol) and ethanol (70 ml) was refluxed under argon for 10 minutes. The reaction mixture was cooled to room temperature and 1-ethoxyethylidene malononitrile (6.1 g, 0.045 mol) was added. The reaction mixture was heated to reflux and stirred for 21 hours. The reaction was cooled and the solvent was removed in vacuo. The residue was recrystallized from water to afford 4.7 g (54%) of 1-(3-tetrahydrofuranyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as yellow crystals, m.p. 134°-135° C. when dried at 90° C. in high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:42]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([S:49]([CH2:48][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)(=[O:51])=[O:50])[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(S(=O)(=O)Cc4ccccc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.5 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added pyridine (0.02 ml), 4-dimethylaminopyridine (12 mg) and α-toluenesulfonyl chloride (43 mg), and the mixture was stirred at room temperature for 12 hours and then at 50° C. for 6 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=3:1) and dried under reduced pressure to give the title compound (48 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.B(OC)(OC)[O:19]C.C(OO)(=O)C>O1CCCC1>[Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:19])[C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(Cl)ccc1Br
Agent: CC(=O)OO
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-2-fluorobenzene (5 g, 23.87 mmol) in tetrahydrofuran (40 mL) cooled to −78° C. was added LDA (14.92 mL, 29.8 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 min. then allowed to warm to −20° C. and stirred for 30 min. The reaction was then cooled to −78° C. and trimethyl borate (3.47 mL, 31.0 mmol) dissolved in THF (5 mL) was added dropwise. The reaction mixture was warmed to −20° C. and stirred for 1 h. The reaction mixture was then cooled to −78° C. and peracetic acid (16 mL, 84 mmol) as slowly added dropwise. The mixture was allowed to warm to rt and stirred for 12 h. The reaction mixture was again cooled to 0° C. and quenched with 5% ammonium chloride The solution was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-bromo-6-chloro-2-fluorophenol (4.99 g, 18.25 mmol, 76% crude yield) as a yellow oil. The material was carried forward without further purification. LC/MS (ESI) m/e 225.1 [(M+H)+, calcd for C6H4BrClFO 224.9]; LC/MS retention time (method E): tR=0.87 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.[CH3:22][N:23](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:22]#[N:23]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2cc(F)c[n+]3[O-])cc1
Agent: C[Si](C)(C)C#N
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(F)cc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a solution of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine 4-oxide (2.4 g, 7.84 mmol) in 1,2-dichloroethane (60 mL) was added dimethylcarbamic chloride (1.3 g, 11.76 mmol), followed by addition of trimethylsilyl cyanide (1.2 g, 11.76 mmol). The mixture was stirred under nitrogen at 80° C. overnight. The resulting mixture was quenched by addition of a sat'd aq. NaHCO3 solution. The organic layer was washed with H2O (50 mL×3) and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (4:1) as eluent to afford 1.1 g (44.5%) of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile. MS (ESI) m/z: 316.1 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:11])(=[O:10])[NH2:9].Br[CH2:13][C:14]([NH2:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:13][C:14]([NH2:16])=[O:15])(=[O:11])(=[O:10])[NH2:9]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)COc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.1 %

Procedure:
To a solution of crude 1-(hydroxy)-2-sulfamoylbenzene (400 mg, 2.4 mmol.) in 60 mL of acetonitrile was added 2-bromoacetamide (332 mg, 2.4 mmol.), K2CO3 (662 mg, 4.8 mmol.) and KI (400 mg, 2.4 mmol.). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered, concentrated and purified by prep-TLC to afford 2-(2-sulfamoylphenoxy)acetamide (260 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C@@H:6]([CH2:10][CH2:11][C@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C[C@@H](CC[C@H](Cc2cccc(Cl)c2)C(=O)O)C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)[C@H](CC[C@H](Cc1cccc(Cl)c1)C(=O)O)Cc1ccc(O)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
To a round bottom flask was added (2R,5R)-2-(3-Chlorobenzyl)-5-(4-methoxybenzyl)hexanedioic acid (24 mg, 0.061 mmol) and pyridine hydrochloride (71 mg, 0.61 mmol). The reaction was stirred at 160° C. for 10 min. After cooling to rt, the reaction was diluted with water and extracted with EtOAc (2×5 mL). The combined EtOAc extracts were concentrated in vacuum. The resulting residue was purified using RP prep-HPLC (Method B) to give (2R,5R)-2-(3-chlorobenzyl)-5-(4-hydroxybenzyl)hexanedioic acid (14 mg, 0.037 mmol, 61% yield) as white solid. Anal. Calcd. for C20H21ClO5 m/z 376.3. found: 375.2 (M−H)+.
Reaction SMILES: I[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:15][C:14]([NH2:16])=[N:13][N:12]=3)=[CH:9][CH:10]=[C:5]2[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:15][C:14]([NH2:16])=[N:13][N:12]=3)=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4nnc(N)o4)ccc32)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: Nc1nnc(-c2ccc3[nH]cc(-c4ccccc4F)c3n2)o1
Temperature: 140 °C
Yield: 16.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)-1,3,4-oxadiazol-2-amine (0.050 g, 0.104 mmol), 2-fluorophenylboronic acid (0.020 g, 0.145 mmol, Sigma-Aldrich), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.68 mg, 5.19 μmol) and K3PO4 (0.066 g, 0.312 mmol) in 70% i-PrOH in water (1.00 mL). The mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. The layers were separated and the reaction vessel washed with MeOH. The organic washes were combined, filtered and purified by RP-HPLC (5-100% MeCN in H2O with 0.1% TFA over 20 min). Saturated NaHCO3 (aq.) was added to the tubes that contained the desired product. The mixture was extracted with 3/1 CHCl3/i-PrOH and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 5-(3-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)-1,3,4-oxadiazol-2-amine (0.005 g, 0.017 mmol, 16.30%). MS (ESI, pos. ion) m/z: 296.1 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 7.02-7.10 (m, 1H), 7.11-7.19 (m, 2H), 7.77-7.86 (m, 2H), 7.99 (d, J=2.93 Hz, 1H), 8.81-8.91 (m, 1H).
Reaction SMILES: [C:1]1([C:7]([C@H:9]2[CH2:13][N:12]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[O:22])[CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[OH:8][CH:7]([C@H:9]1[CH2:13][N:12]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:11](=[O:22])[CH2:10]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccccc2)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](c1ccccc1)N1C[C@H](C(O)c2ccccc2)CC1=O
Reaction time: 1 h

Procedure:
To an absolute ethanol (40 ml) solution of 4-(R)-phenylcarbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2.17 g, 7.40 mmol) was added sodium borohydride (280 mg) under ice cooling, followed by stirring at the same temperature for 1 hour. To the reaction solution was added 10% citric acid (50 ml) under ice cooling, and then the ethanol was removed under reduced pressure. The residue was extracted with chloroform (80 ml×2) and, after washing with saturated saline (100 ml), the organic layer was dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. Elution with eluents of n-hexane/ethyl acetate (1/3) to ethyl acetate (100%) afforded the low polar title compound having low polarity [F1] (892 mg, 41%) and the title compound having high polarity [F2] (1.163 g, 53%) as pale yellow oils.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]2[N:16]=[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28][C:22]=4[CH:21]=3)[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40].[I-].[Na+]>C(#N)C.C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]2[N:16]=[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]4[CH2:24][CH2:25][N:26]([CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH2:27][CH2:28][C:22]=4[CH:21]=3)[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1
Reactant: COCc1ccccc1-c1cccc2nc(Nc3ccc4c(c3)CCNCC4)nn12
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COCc1ccccc1-c1cccc2nc(Nc3ccc4c(c3)CCN(CC(=O)N(C)C)CC4)nn12
Temperature: 70 °C
Yield: 32.1 %

Procedure:
To a solution of [5-(2-Methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amine (70.0 mg, 0.18 mmol) in acetonitrile (5 mL) was added potassium carbonate (0.0484 g, 0.350 mmol), 2-chloro-N,N-dimethyl-acetamide (0.0270 mL, 0.263 mmol), followed by sodium iodide (0.0263 g, 0.175 mmol) and the reaction was heated at 70° C. for 2.5 hours and cooled to room temperature. The reaction was diluted with chloroform, washed with water then brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography utilizing an ISCO automated purification apparatus (basic alumina column and 0%→10% methanol in dichloromethane). Product was isolated as a yellow foam (0.028 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.64 (d, J=7.7 Hz, 1H), 7.59-7.42 (m, 5H), 7.27 (m, 1H), 7.23-7.19 (m, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.93 (s, 1H), 6.91-6.87 (m, 1H), 4.35 (br s, 2H), 3.26 (s, 2H), 3.20 (s, 3H), 3.14 (s, 3H), 2.97 (s, 3H), 2.88-2.83 (m, 4H), 2.69-2.63 (m, 4H). MS=485 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O>>[NH2:10][C:11]1[CH:12]=[C:13]([C:14]2[O:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: Nc1cccc(C(=O)O)c1
Product: Cc1ccc2nc(-c3cccc(N)c3)oc2c1

Procedure:
Prepared by the method of Example 1a), from 2-amino-5-methylphenol (448 mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitle compound was obtained, 97 mg (12%). 1H NMR (CDCl3) δ 7.55(d, J=8.2 Hz, 2H), 7.49(t, J=1.9 Hz, 1H), 7.30(s, 1H), 7.22(t, J=7.5 Hz, 1H), 7.08(dd, J=1.1, 8.2 Hz, 1H), 6.76(dd, J=2.3, 7.9 Hz, 1H), 2.43(s, 3H). MS 225 m/z (M+H)+.