Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][C@@:7]2([C:16]3[C:11](=[CH:12][C:13]([Cl:26])=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=4)[CH:15]=3)[CH2:10][O:9]2)[C@H:6]([OH:27])[C@@H:5]([OH:28])[C@@H:4]1[OH:29].N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:26][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[C@:7]1([C@H:6]([OH:27])[C@@H:5]([OH:28])[C@H:4]([OH:29])[C@@H:3]([CH2:2][NH:1][C:36](=[O:38])[CH3:37])[O:8]1)[O:9][CH2:10]2
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CNC(C)=O)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a stirred solution of (1S,3′R,4′S,5′S,6′R)-6′-(aminomethyl)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (20 mg, 0.047 mmol) and 0.04 mL of pyridine in 1 mL of dichloromethane, was added acetic anhydride (45 μL, 0.048 mmol) and 3 mg of 4-dimethylaminopyridine. After being stirred for 2 h at ambient temperature, the reaction mixture was diluted with 20 mL of dichloromethane, washed with 1 M hydrochloric acid and concentrated. The residue was dissolved in 1 mL of methanol and cooled in an ice bath. After addition of 0.3 mL of 4 M potassium hydroxide solution, the mixture was stirred for 2 h at ambient temperature. The reaction mixture was then neutralized with 1 M hydrochloric acid and concentrated. The residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated and dried over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 5 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.25 (s, 1H), 7.11 (s, 1H), 6.99 (s, 4H), 5.00 (d, J=12.6 Hz, 1H), 4.95 (d, J=12.6 Hz, 1H), 4.00 (d, J=15.4 Hz, 1H), 3.95 (d, J=15.4 Hz, 1H), 3.71-3.57 (m, 3H), 3.45 (dd, J=14.4, 2.8 Hz, 1H), 3.17-3.11 (m, 2H), 2.48 (q, J=7.6 Hz, 2H), 1.09 (t, J=7.6 Hz, 3H); MS ESI (m/z) 484 (M+Na)+, calc. 461.
Reaction SMILES: Cl.[CH2:2]1[C:5]2([CH2:9][CH2:8][CH2:7][O:6]2)[CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30]([N:32]3[CH2:35][CH:34]([O:36][C:37]4[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=4)[CH2:33]3)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:4]1[C:5]2([CH2:9][CH2:8][CH2:7][O:6]2)[CH2:2][N:3]1[CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH:34]2[CH2:35][N:32]([C:30]([C:28]3[O:29][C:25]([C:22]4[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)=[N:26][N:27]=3)=[O:31])[CH2:33]2)=[CH:44][CH:43]=1
Reactant: C1COC2(C1)CNC2
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CC6(CCCO6)C5)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
5-Oxa-2-azaspiro[3.4]octane HCl salt (0.052 g, 0.35 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.052 ml, 0.38 mmol) was added, followed by 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.11 g, 0.29 mmol) and finally sodium triacetoxyhydroborate (0.123 g, 0.58 mmol). The reaction was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane (10 ml) and subsequently shaken with NaHCO3 (sat. 2 ml). The two phases were separated using a phase separator. The organic phase was evaporated. The product was purified by preparative reverse-phase HPLC at pH 10 to give 23 mg (17%) of the desired product as a solid. 1H NMR (500 MHz, CDCl3): δ 1.90 (p, 2H), 2.13 (t, 2H), 3.16 (d, 2H), 3.37 (d, 2H), 3.62 (s, 2H), 3.80 (t, 2H), 3.91 (s, 3H), 4.33 (dd, 1H), 4.62-4.7 (m, 1H), 4.73-4.78 (m, 1H), 5.03-5.16 (m, 2H), 6.74 (d, 2H), 7.04 (d, 2H), 7.25 (d, 2H), 8.11 (d, 2H). MS (APCI+) m/z 477.3 [M+H]+, LC purity: 97%
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccnc(-c2ccccn2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with [2,2′-bipyridine]-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.59 min.; [M+H]+: 403.97 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:13].C(N(CC)CC)C>CC(C)=O>[CH3:18][O:17][C:15]([CH2:14][C:12]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])=[O:13])=[O:16]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1cnccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)CC(=O)Nc1cnccc1C(=O)O

Procedure:
A solution of 3-aminopyridine-4-carboxylic acid (1.0 eq), methyl 2-(chlorocarbonyl)acetate (1.1 eq), and triethylamine (2.0 eq) in acetone was stirred overnight at room temperature. The solvent was removed in vacuo. The product was used without further purification. LC/MS m/z 239.2 (MH+), Rt 1.40 minutes.
Reaction SMILES: CC(O)(C)C.[CH:6]1([CH:9]=[O:10])[CH2:8][CH2:7]1.[N+:11]([CH3:14])([O-:13])=[O:12].CC([O-])(C)C.[K+]>C1COCC1.[NH4+].[Cl-]>[CH:6]1([CH:9]([OH:10])[CH2:14][N+:11]([O-:13])=[O:12])[CH2:8][CH2:7]1
Reactant: O=CC1CC1
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)C1CC1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A mixture of THF (10 ml) and t-BuOH (10.00 ml) was cooled to 0° C. To this was added cyclopropanecarboxaldehyde (1.1 ml, 14.60 mmol) and nitromethane (1.18 ml, 21.88 mmol). After stirring 5 minutes 1M KOtBu (2.92 ml, 2.92 mmol) in THF was added slowly. During the addition a white solid formed. The mixture was allowed to warm as the bath warmed to rt overnight. The mixture was diluted with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated (no heat) to afford 1-cyclopropyl-2-nitroethanol (4-10, 1.9 g, 99%) as a clear oil which was sufficiently pure for use in the next step. 1H NMR (399 MHz, CDCl3): δ 4.56-4.52 (m, 2H); 3.72-3.64 (m, 1H); 2.42 (d, J=3.9 Hz, 1H); 0.99-0.90 (m, 1H); 0.68-0.59 (m, 2H); 0.52-0.44 (m, 1H); 0.39-0.32 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=[C:13]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:11][N:8]1[C:7]([CH:12]=[C:13]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:33]1[C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=[C:32]1[CH2:30][CH3:31])=[N:3][C:4]=2[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 140 °C
Yield: 82.5 %

Procedure:
A mixture of tert-butyl 3-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methylene)azetidine-1-carboxylate (0.88 g, 2.9 mmol), 2-ethylbenzimidazole (0.40 g, 2.74 mmol), Xphos (0.10 g, 0.21 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol) and cesium carbonate (1.4 g, 4.2 mmol) in DMF (4.0 mL) was heated in a Biotage microwave at 140° C. for 30 minutes. The reaction mixture was then filtered through paper and then partitioned between brine and EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-10% MeOH in DCM) to give the title compound (1.2 g, quant.). LCMS m/z: 531.2 (MH+).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[NH:8][N:7]=[C:6]([O:9][CH2:10][CH2:11][OH:12])[C:5]=1C(OCC)=O>C(O)C>[NH2:3][C:4]1[NH:8][N:7]=[C:6]([O:9][CH2:10][CH2:11][OH:12])[CH:5]=1
Reactant: CCOC(=O)c1c(OCCO)n[nH]c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(OCCO)n[nH]1

Procedure:
1M NaOH (46.5 mL, 46.5 mmol) was added to a solution of ethyl 5-amino-3-(2-hydroxyethoxy)-1H-pyrazole-4-carboxylate (2.00 g, 9.29 mmol, prepared as described in Neidlein, Richard, et al. “Heterocyclic Compounds from 2-(Alkoxycarbonylcyanomethylene)-1,3-dioxolanes.” J. Het. Chem. Vol. 26 (1989): pp. 1335-1340) in ethanol (30 mL), and the mixture was refluxed overnight. The solution was washed with DCM with 25% IPA, then acidified to a pH of 3 with concentrated HCl. Gas evolution was observed. The solution was washed with DCM with 25% IPA, and the aqueous layer was evaporated. The residue was treated with methanol, filtered, and the filtrate was evaporated to yield crude 2-(5-amino-1H-pyrazol-3-yloxy)ethanol (3.28 g) along with inorganic salts.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]2)=[CH:4][C:3]=1[O:16][CH3:17].C(O)(=O)C>C(Cl)Cl.C1(C)C=CC=CC=1.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(-n2ccc([N+](=O)[O-])n2)ccc1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(-n2ccc(N)n2)ccc1Br
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a mixture of 1-(4-bromo-3-methoxyphenyl)-3-nitro-1H-pyrazole (2.3 g, 7.72 mmol) in DCM (24 mL) and acetic acid (6.18 mL, 108 mmol) was added zinc dust (2.52 g, 38.6 mmol) at 0° C. The reaction mixture was stirred at 0° C. to RT overnight. The reaction mixture was filtered through celite, rinsed with EtOAc and concentrated in vacuo. The residue was purified by silica chromatography (EtOAc/heptane=10:90 to 50:50) to give a white foam which was dissolved in 6 mL of toluene, concentrated and dried to give 1.9 g of 1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-amine as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:29][C:25]1([CH3:30])[CH2:24][NH:23][CH2:28][CH2:27][N:26]1[C:13]([C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]=1)=[O:15]
Reactant: O=C(O)c1nnn(-c2cccc(F)c2)n1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1C(=O)c1nnn(-c2cccc(F)c2)n1

Procedure:
This intermediate was prepared from 2-(3-fluoro-phenyl)-2H-tetrazole-5-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[C:5](=[O:19])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+].[C:61]([N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62]>C(O)(C)(C)C.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]>[C:64]([O:63][C:61]([N:68]1[CH2:73][CH2:72][N:71]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4](=[O:20])[C:5](=[O:19])[N:6]3[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:70][CH2:69]1)=[O:62])([CH3:67])([CH3:65])[CH3:66]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1C(=O)N(Cc2cccc(F)c2)c2cccc(Br)c21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C(=O)C(=O)N3Cc2cccc(F)c2)CC1
Temperature: 120 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
4-Bromo-1-(3-fluoro-benzyl)-1H-indole-2,3-dione (3.05 g) was dissolved in 45 mL of tert-butanol and Boc-piperazine (2.04 g), Pd2(dba)3 (164 mg), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (217 mg), and potassium carbonate (1.84 g) were added. The mixture was stirred at 120° C. for 4 hours and then cooled to room temperature. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography to afford 1.80 g of 4-[1-(3-fluoro-benzyl)-2,3-dioxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS: 340 (M−Boc+H)+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:4].CCOCC.[Li+].[OH-].Cl>O.CO>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3]([OH:4])=[O:2])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H]1CCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
To a solution of (2S)-methyl-1-(benzyloxycarbonyl)azetidine-2-carboxylate (0.78 g, 3.12 mmol) in a 1:1 mixture of ether:methanol (25.0 mL) was added 1N LiOH in water (5.8 mL) at about 0° C. The mixture was stirred under argon at about 0° C. for about 30 minutes and then at about room temperature overnight. The pH was adjusted to about pH 1 by adding 1N HCl, then the mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 0.78 g (99% yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 2.45-2.63 (br, 2H); 4.00 (t, 2H, J=7.7); 4.77-4.90 (br, 1H); 5.16 (s, 2H); 7.37 (s, 5H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[N:21]1[C:29]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]=2[S:23][CH:22]=1>>[N:21]1[C:29]2[CH2:28][CH2:27][N:26]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:25][C:24]=2[S:23][CH:22]=1
Reactant: c1nc2c(s1)CNCC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4ncsc4C3)n2)c1

Procedure:
B45 was prepared following the general procedure reported for B10 using A1 and 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride. The title compound (B45) was purified by column chromatography (silica gel, DCM/MeOH gradient 100:0 to 85:15); yield: 28.9 mg (7%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.84-2.94 (m, 2H), 4.13 (t, J=5.8 Hz, 2H), 4.23 (s, 2H), 5.03 (s, 2H), 6.83 (s, 2H), 7.00 (d, J=7.1 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.42-7.63 (bm, 1H), 7.82-7.93 (bm, 1H), 8.28 (s, 1H), 8.96 (s, 1H), 9.77 (s, 1H). MS (ES) C16H17N7O2S2 requires: 403. found: 404 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[CH2:26][OH:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C@H:13]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COc2ccccc2)C1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A solution of tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(hydroxymethyl)cyclohexylcarbamate (120 mg) in tetrahydrofuran (3 mL) was treated with phenol (45 mg) and triphenylphosphine (125 mg). The mixture was stirred at rt and treated dropwise over about 3 minutes with diethyl azodicarboxylate (74 μL). The mixture was stirred for 3.5 h, then was concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with 1:5 v/v ethyl acetate/hexane, to provide tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(phenoxymethyl)cyclohexylcarbamate as a white glassy foam (110 mg). MS found: (M+H)+=455.3.
Reaction SMILES: N[C:2]1[C:3]([Br:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.N([O-])=O.[Na+].C(=O)([O-])O.[Na+].[H+].[B-](F)(F)(F)[F:21]>O>[Br:9][C:3]1[C:2]([F:21])=[CH:7][C:6]([Br:8])=[CH:5][N:4]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1cc(Br)cnc1Br
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: Fc1cc(Br)cnc1Br
Temperature: -10 °C

Procedure:
37.00 g (146.87 mmol) of 3-amino-2,5-dibromopyridine are diazotized in 50 ml of aqueous HBF4 (35% strength) at -10° C. using 11.10 g (160.87 mmol) of sodium nitrite in 20 ml of water. After the reaction mixture has been stirred for a further half an hour at -10° C., it is heated at 50° C. for 30 minutes, poured into ice water, neutralized using sodium hydrogencarbonate and extracted three times with dichloromethane. The organic phase is washed twice with water, dried over sodium sulfate, filtered and freed from solvent. Chromatographic purification (silica gel/dichloromethane) gives 11.10 g of 2,5-dibromo-3-fluoropyridine. ##STR13##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2.C([Sn](CCCC)(CCCC)[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)CCC>COCCOC.CO.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>[Cl:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[CH:11][CH:10]=2
Reactant: Clc1cc2cc(Br)ccc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: COCCOC
Product: Clc1cc2cc(-c3cncs3)ccc2cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A suspension of 6-bromo-3-chloroisoquinoline (39 mg, 0.16 mmol), 5-(tributylstannyl)-thiazole (72 mg, 0.19 mmol) and Pd(PPh3)4 (18.6 mg, 0.016 mmol) in DME/MeOH (3/1 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction mixture was filtered and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with 25% EtOAc in cyclohexane to afford the title compound (11 mg, 28%).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Cc1ccc(N)c(Cl)c1
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(C)cc1Cl
Yield: 35 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (15.0 g, 72.4 mmol) and 2-chloro-4-methylaniline (20.5 g, 144.7 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (8.37 g, 35%) was obtained.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10]>O.[OH-].[Na+]>[NH2:10][C:9]1[CH:8]=[C:7]([Cl:6])[CH:13]=[CH:12][C:11]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: Nc1cccc(Cl)c1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)ccc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 48.2 %

Procedure:
Concentrated sulphuric acid (specific gravity. 1.84) (13.9 ml, 250 mmol) was diluted with 100 ml of water. 3-Chloro-aniline (31.9 g, 250 mmol) was added over 30 minutes while temperature was kept at 85° C. During the addition some precipitation occurred. The suspension was allowed to cool to room temperature and heavy precipitation was formed. The solid is filtered with suction to yield white crystalline solid. The solid was heated slowly to 200° C. under vacuum (water pump) and fitted with a water trap. The solid was kept at 200° C. for 7 hours. Water was lost from the crystalline material. The solid was allowed to cool and then dissolved in dilute aqueous NaOH and precipitated with hydrochloric acid. Yielded 25 g (48%) of the title compound as a white crystalline solid (m.p. >250° C.).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]4([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:25])[CH:10]=2)=CC=1.FC(F)(F)C(O)=O>ClCCCl>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:17][C:18](=[O:19])[C:12]2=[C:11]([CH3:25])[CH:10]=1
Reactant: COc1ccc(COc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(O)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6′-((4-Methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3, 3.3 g, 8.59 mmol) was dissolved in 1,2-dichloroethane (25 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at 50° C. for 2 h. After completion, solvent was evaporated under reduced pressure. Obtained crude was washed with water (50 mL) followed by n-pentane and dried under reduced pressure to afford 6′-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (4) as yellow solid. Yield: 0.85 g, 90%; MS (ESI) m/z 249.07 [M+1]+.