Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K:1].C([O:9][C:10]1[C:11]([N:28]2[S:32](=[O:34])(=[O:33])[NH:31][C:30](=[O:35])[CH2:29]2)=[CH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([O:20]CC1C=CC=CC=1)=[CH:15][CH:14]=2)C1C=CC=CC=1.N#N>O.[Pd]>[K:1].[OH:9][C:10]1[C:11]([N:28]2[S:32](=[O:34])(=[O:33])[NH:31][C:30](=[O:35])[CH2:29]2)=[CH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([OH:20])=[CH:15][CH:14]=2
Reactant: O=C1CN(c2cc3ccc(OCc4ccccc4)cc3cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Agent: N#N
Agent: [K]
Solvent: O
Product: O=C1CN(c2cc3ccc(O)cc3cc2O)S(=O)(=O)N1
Reaction time: 1.5 h

Procedure:
To a solution of 5-(3,6-bis-benzyloxynaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (0.129 g, 0.252 mmol) in H2O (5 mL), flushed with N2, is added 10% Pd/C (0.10 g). The mixture is flushed with N2 again and then placed under an atmosphere of H2. The mixture is stirred vigorously for 1.5 h before being judged complete by LC/MS. The reaction mixture is filtered over Celite. The filtrate is washed with EtOH and the aqueous layer is lyophilized overnight. The residual solid is redissolved in H2O and refiltered over Celite. The green filtrate is lyophilized again overnight. The residue is purified via prep HPLC. The desired fractions are concentrated and dissolved in a minimum amount of EtOH. To this solution is added a 0.5M solution of KHCO3 followed by the addition of H2O. The reaction mixture is stirred for 2 min and lyophilized overnight to afford 5-(3,6-dihydroxynaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt: 1H NMR (DMSO-d6) 9.93 (s, 1H), 9.63 (s, 1H), 7.79 (s, 1H), 7.61 (d, J=8 Hz, 1H), 7.01 (s, 1H), 6.86 (m, 2H), 4.43 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 5-nitroindoline-2,3-dione (1 g, 5.20 mmol) in DMF (20 ml) was cooled to 0° C., and NaH (60% w/w dispersion in mineral oil, 0.208 g, 5.20 mmol) was added portion wise. The mixture was stirred at 0° C. for 1 hour, and methyl 2-bromoacetate (0.483 ml, 5.20 mmol) was added. The mixture was stirred at room temperature for 4 hours, then it was portioned between ethyl acetate and 1N HCl. The organic phase was washed twice with brine and dried over sodium sulfate. The solvent was removed and the crude was purified by flash chromatography on silica gel (DCM:EtOAc=95:5) affording methyl 2-(5-nitro-2,3-dioxoindolin-1-yl)acetate (0.976 g, 3.69 mmol, 71% yield) MS/ESI+ 264.9 [MH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@@H:5]([CH2:12][C:13](OCOC)=[O:14])[C:6](OCOC)=[O:7].CSC.B.CO>O1CCCC1>[OH:7][CH2:6][C@@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:12][CH2:13][OH:14]
Reactant: COCOC(=O)C[C@H](OCOC)C(=O)OCOC
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: COCO[C@H](CO)CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
A solution of (S)-2-methoxymethoxybutanedioic acid, bis methoxymethyl ester (10 g, 37.5 mmol) in dry tetrahydrofuran (10 ml) under dry nitrogen was treated with borane dimethylsulphide (8.3 ml, 83 mmol). The solution was heated between 60° C. and 80° C. over a period of 5.5 hours and then cooled in ice and treated dropwise with methanol (50 ml). After effervescence had ceased the solution was stirred at room temperature for 18 hours and the solvent removed under vacuum. The residue was evaporated to dryness with methanol (2×50 ml) and the residue chromatographed on silica, eluting with chloroform-methanol 5:1 to give (S)-1,4-dihydroxy-2-(methoxymethoxy)butane (3.9 g, 69%); IR: υmax (film) 3400, 2940, 2890, 2820, 1470, 1440, 1410, 1380, 1300, 1210, 1150, 1100, 1030, 920 cm-1 ; 1H NMR: δH (CDCl3) 1.78 (2H, m, CH2), 2.96 (2H, s, D2O exchangeable OH's), 3.44 (3H, s, OCH3), 3.5-3.85 (5H, m, CH plus 2×CH2 's), 4.72 (1H, d, J=7 Hz, CH of CH2), 4.77 (1H, d, J=7 Hz, CH of CH2).
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.[CH3:58][N:59](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([C:58]#[N:59])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)O)ccc12
Reactant: CN(C)C=O
Agent: [Pd]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1nn(Cc2c(Cl)cccc2C#N)c2cc(CC(=O)O)ccc12

Procedure:
To a solution of the compound [97](30.1 mg) in N,N-dimethylformamide (0.9 mL) were added zinc cyanide (20.2 mg), tris(dibenzylideneacetone)dipalladium(0) (7.9 mg) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (5.1 mg) at room temperature, and then the reaction mixture was subjected to microwave irradiation at 150° C. for 2 hours. The reaction mixture was extracted with ethyl acetate, and then the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative liquid chromatography to give the titled compound (5.0 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[C:18]([C:20]1[CH:25]=[C:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cccc(C#N)c2)cc1
Yield: 63 %

Procedure:
Prepared in a similar manner to example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-cyanophenylboronic acid. Yield: 63%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (dd, 2H), 5.2 (broad, 1H), 7.45 (d, 2H), 7.55 (d, 3H), 7.65 (d, 1H), 8.2 (dd, 1H), 8.4 (d, 1H). MS (M+H, 321).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>CN(C=O)C>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCOC2CCCCO2)cc1
Temperature: 100 °C
Yield: 105.4 %

Procedure:
A mixture containing 40 g of methyl 4-hydroxybenzoate and 90.84 g of K2CO3 in 400 ml of DMF is heated to 100° C. and 71.47 g of 2-(2-bromoethoxy)tetrahydro-2H-pyran are added slowly, with continued heating for 8 hours. The inorganic material is filtered off and rinsed with DMF. The filtrate is evaporated under vacuum and then taken up in DCM, washed 3 times with water, dried over MgSO4 and then evaporated. 77.66 g of the expected compound are obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:8][CH:7]=[N:6]1)#[N:2].[OH-:24].[K+].OO>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]3[N:5]([CH2:4][CH2:3][C:1]([NH2:2])=[O:24])[N:6]=[CH:7][CH:8]=3)=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: N#CCCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Product: NC(=O)CCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Reaction of 3-dimethylamino-1-[4-(4-fluorophenoxy)phenyl]-propenone with 2-cyanoethylhydrazine as described above gave 1-(2-cyanoethyl)-5-[4-(4-fluorophenoxy)phenyl]pyrazole. Reaction of a solution of the nitrile with 10 mL of a 20% aqueous KOH solution and 4 mL of an aqueous 30% H2O2 solution at reflux gave 64 mg of the amide as a white solid, mp 118-120° C. 1H NMR (CDCl3): δ 7.54 (d, 1H, J=1.8 Hz), 7.35 (d, 2H, J=8.7 Hz), 7.10-6.98 (m, 61H), 6.26 (d, 1H, J=1.8 Hz), 6.08 (br s, 1H), 5.30 (br s, 1H), 4.39 (t, 2H, J=6.6 Hz), 2.86 (t, 3H, J=6.6 Hz).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19]Cl.O.[SH:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19][S:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1-c1ccccc1
Yield: 84.1 %

Procedure:
Prepared according to Procedure C using Intermediate 2i (400 mg, 1.05 mmol), 6-mercapto-purine monohydrate (196 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was chromatographed in MeOH/CH2Cl2 and subsequently recrystallized from EtOH to provide 439 mg of a pale yellow crystalline solid (84%), mp 222.0-222.5° C. (dec). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.55 (s, 1H); 8.45 (s, 1H); 7.73 (t, J=8.0 Hz, 1H); 7.64 (d, J=7.7 Hz, 1H); 7.50-7.59 (m, 4H); 7.41-7.48 (m, 1H); 7.25-7.38 (m, 5H); 4.41 (d, J=16 Hz, 1H); 4.16 (d, J=16 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 157.0, 153.7, 151.5, 149.7, 149.3, 143.5, 139.9, 137.8, 135.1, 134.1, 133.3, 131.5, 130.5, 130.3, 130.1, 129.1, 128.9, 128.4, 128.4, 126.9, 117.5, 32.3. MS (ES): m/z 497.0 (M+). Anal. calcd. for C26H17ClN6OS: C, 62.84; H, 3.45; Cl, 7.13; N, 16.91; S, 6.45. Found: C, 62.60; H, 3.47; Cl, 7.15; N, 16.65; S, 6.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:11])=[N:5][C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1.[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:11][C:4]2[C:3]([O:2][CH3:1])=[N:8][C:7]([CH3:9])=[C:6]([CH3:10])[N:5]=2)(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COc1nc(C)c(C)nc1N
Product: COc1nc(C)c(C)nc1NS(=O)(=O)c1ccc(Cl)s1

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5,6-dimethyl-2-pyrazinamine and 5-chloro-2-thienylsulphonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:15]([CH3:17])[CH3:16])[C:10]=2[CH:11]=[C:12]([OH:14])[CH:13]=1)=[O:4].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:15]([CH3:17])[CH3:16])[C:10]=2[CH:11]=[C:12]([O:14][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])[CH:13]=1)=[O:4]
Reactant: CN(C)CCO
Reactant: COC(=O)c1cc(O)cc2c1ccn2C(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCN(C)C)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a cooled (0° C.) mixture of 6-hydroxy-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (700 mg, 3 mmol), 2-dimethylamino-ethanol (320 mg, 3.60 mmol) and PPh3 (948 mg, 3.60 mmol) in THF (10 mL) was added DEAD (620 mg, 3.60 mmol) and stirred for 16 h at RT. Reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography by eluting with 2% MeOH in chloroform to afford the title compound (550 mg, 60%) as colorless gum. LCMS (ES+): m/z=305.36 [M+H].
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:10][C:6]1[NH:29][N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:32]([Cl:33])=[C:24]([Br:23])[CH:25]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(Cl)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Cl)c(Br)c2)[nH]1
Reaction time: 8 h

Procedure:
49 g of β-amino-β-ethoxyacrylic acid ethyl ester and 2 g of p-toluenesulphonic acid were dissolved in 225 ml of ethanol and 72 g of 3-bromo-4-chlorobenzylhydrazine were added under nitrogen. After standing overnight, the compound identified above had settled out as a precipitate and was filtered off and recrystallised twice from ethanol. Melting point: 171°-172°C, 40 g (43%).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:27])[C:7]=2[N:6]=[C:5]1[CH2:28][CH2:29][CH3:30].ClCCl.[BH4-].[Na+]>[Ni](Cl)Cl.CO>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:12]2[CH:13]=[CH:14][C:15]3[C:16]4[N:4]([CH2:3][CH:2]([CH3:31])[CH3:1])[C:5]([CH2:28][CH2:29][CH3:30])=[N:6][C:7]=4[C:8]([NH2:27])=[N:9][C:10]=3[CH:11]=2)=[CH:19][CH:20]=1
Reactant: CCCc1nc2c(N)nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(Oc4ccc(N)cc4)ccc3c2n1CC(C)C
Reaction time: 0.42 h
Yield: 59.7 %

Procedure:
Nickel(II)chloride (0.044 g, 0.34 mmol) was added to a solution of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.436 g, 1.04 mmol), prepared as described in Example 35, in 20:80 dichloromethane:methanol (30 mL). Sodium borohydride (0.300 g) was added in small portions to the resulting solution, and the reaction was stirred for 25 minutes. A solid formed in the reaction and was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, and the resulting solution was washed with water. The organic solution was stirred with AMBERLITE IRA-756 ion exchange resin for 30 minutes, and the resin was then removed by filtration. The filtrate was concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography using a 10 g silica gel cartridge (RediSep, ISCO, 230-400 mesh) attached to a gradient pump system, 254 nm UV detector and fraction collector (ISCO COMBIFLASH Sg100c system). The column was equilibrated with 1% methanol in dichloromethane and the reaction mixture was injected onto the column. The mixture was eluted at 35 mL/minute, with a linear gradient program consisting of 1% methanol/dichloromethane to 5% methanol/dichloromethane over five minutes and holding at 5% methanol/dichloromethane to elute the desired compound. Fractions were examined by TLC and those containing the desired compound were combined and concentrated. The product was then recrystallized from acetonitrile to yield 0.242 g of 7-(4-aminophenoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a tan, crystalline solid, mp 190-191° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH:33]1([CH2:38]I)[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl>C1COCC1.CN1C(=O)N(C)CCC1.CCOC(C)=O>[S:29]1[CH:30]=[CH:31][N:32]=[C:28]1[NH:27][S:24]([CH:23]([C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][CH:21]=1)[CH2:38][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)c1ccc(CS(=O)(=O)Nc2nccs2)cc1
Reactant: ICC1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)S(=O)(=O)Nc2nccs2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (1.0 mmol, 0.10 g) in 7 mL of THF and 3 mL of DMPU at 0° C. is added n-BuLi (0.61 mL, 2.5 M in hexane) and the reaction mixture is stirred for 15 min, then cooled to −78° C. The title C compound, C-(4-methane-sulfonyl-phenyl)-N-thiazol-2-yl-methanesulfonamide (0.693 mmol, 0.23 g) is added and the reaction mixture is allowed to warm to 0° C. After 1 h, the reaction is recooled to −78° C., cyclopentylmethyliodide (0.72 mmol, 0.15 g) is added and the reaction is allowed to warm to RT over 3 h. The reaction mixture is poured into aqueous 1 N HCl, and the product is taken up in EtOAc, dried and evaporated to afford an orange oil. Chromatography on silica affords 2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethanesulfonic acid thiazol-2-ylamide: 1H NMR δ 11.6 (br s, 1H), 7.84 (d, J=8, 2H), 7.58 (d, J=8, 2H), 6.67 (d, J=4.5, 1H), 6.39 (d, J=4.5, 1H); 4.27 (m, 1H), 3.03 (s, 3H), 2.04-2.2 (m, 1H), 1.12-1.61 (m, 10H); e/z (ES) 415 (M+1, 100%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15](C(OCC3C=CC=CC=3)=O)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.Cl>O>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: Cc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(Br)c12
Agent: Cl
Solvent: O
Product: Cc1nccn2c(C3CCNCC3)nc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Benzyl 4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (0.471 mmol, 202 mg) was dissolved in 37% hydrochloric acid (32.9 mmol, 2.745 ml). The reaction mixture was stirred at room temperature for one hour. Water was added and the aqueous mixture washed twice with diethyl ether. The aqueous layer was basified with aqueous sodium hydroxide and extracted twice with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to give 1-bromo-8-methyl-3-(piperidin-4-yl)imidazo[1,5-a]pyrazine (100 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:18][OH:19].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:19][NH:18][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(C)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2ncc(C(=O)NO)s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15a (125 mg, 0.518 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (360 mg, 5.18 mmol) and a freshly prepared solution of sodium methoxide in methanol (178 mg, 7.72 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16a. HPLC: (Rt=10.74 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:17][C:18]([CH3:20])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH:18]([CH3:20])[CH3:17])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(C2CCN(C(C)C)CC2)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
A mixture of 2 g (8.3 mmol) 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester, 0.67 g acetone, 1.2 ml acetic acid and 2.47 g (11.6 mmol) sodium triacetoxyborohydride in 20 ml THF was stirred at 40° C. for 18 h. After evaporation to dryness the residue was extracted with 3×250 ml ethyl acetate and the combined organic phases were washed with 2×NaHCO3, NaCl aq., dried with MgSO4 and evaporated to yield 1.9 g (83%) of the title compound of orange solid. (m/e): 283.0 (MH+; 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:41][C:42]([F:54])([F:53])[O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:32]=[CH:2][C:3]([C:47]3[CH:46]=[CH:45][C:44]([O:43][C:42]([F:41])([F:53])[F:54])=[CH:49][CH:48]=3)=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 86.9 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethoxy phenyl boronic acid (145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg) as a white solid:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(O)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:13]([CH3:18])[CH3:14])[C:5]2=[O:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)N1C(=O)c2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a suspension of 5-bromo-1H-isoindole-1,3(2H)-dione (ABCR, 5.0 g) and triphenylphosphine (8.70 g) in tetrahydrofuran (THF) (100 mL) under nitrogen at room temperature was added di-t-butyl azodicarboxylate (7.64 g). The suspension was cooled in an ice/water bath and to this was added iso-propanol (2.032 mL). The reaction mixture was allowed to warm to room temperature to give a pale yellow solution. After 60 minutes, the solvent was removed in vacuo and the residue was dissolved in DCM (30 mL). This was applied to a 750 g silica cartridge and eluted with a gradient of 0-40% ethyl acetate in cyclohexane over 8CV. The required fractions were combined and evaporated in vacuo to give the title compound (5.27 g) as a pale yellow solid.
Reaction SMILES: [OH:1][C@@H:2]([CH3:26])[C@@H:3]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=O)[N:18]=[CH:17]1)[CH2:4][S:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[NH4+:28]>COCCOC>[OH:1][C@@H:2]([CH3:26])[C@@H:3]([N:16]1[CH:20]=[C:19]([C:21]([NH2:28])=[O:23])[N:18]=[CH:17]1)[CH2:4][S:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cn([C@@H](CSc2ccc3ccccc3c2)[C@H](C)O)cn1
Agent: [OH-]
Solvent: COCCOC
Product: C[C@H](O)[C@H](CSc1ccc2ccccc2c1)n1cnc(C(N)=O)c1

Procedure:
A mixture of ethyl 1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate (0.18 g), 28% ammonium hydroxide (20 mL) and 1,2-dimethoxyethane (10 mL) was heated at 100° C. in the stainless steel bottle for 24 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (elution; 10:1 chloroform-1% ammonium hydroxide/methanol) to give the product, which was recrystallized from 3:7 n-hexane-ethyl acetate (10 mL) to give 1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamide (102) (90 mg).