Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][C:4]#[C:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[F:25])[N:8](C(OC(C)(C)C)=O)[CH:7]=1.[NH4+].[Cl-]>C1COCC1.CO.CCOC(C)=O.[Zn]>[CH3:33][N:2]([CH3:1])[CH2:3][C:4]#[C:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=2[F:25])[NH:8][CH:7]=1
Reactant: CN(C)CC#Cc1cn(C(=O)OC(C)(C)C)c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CC#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a mixture of tert-butyl 3-(3-(dimethylamino)prop-1-ynyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (170 mg, 0.374 mmol) in THF (10 mL) and MeOH (10 mL), was added Zn powder (<10 micron, 500 mg) and NH4Cl (500 mg). The reaction mixture was stirred at rt for 2 h, diluted with EtOAc, and filtered through a pad of Celite®. The filtrate was washed with sat. aq. KH2PO4 solution, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (110 mg, 90%) as a yellow solid. LC/MS(ESI+) m/z 325 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32]Cl)[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CO>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32][S:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Sc1ncccn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(CCCSc1ncccn1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 92.7 %

Procedure:
2.78 g of 2-mercaptopyrimidine were added to a solution of 1.95 g of 85% potassium hydroxide and 9.03 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) in 140 ml of methanol, and the resulting mixture was heated under reflux for 15 hours. At the end of this time, the reaction mixture was cooled, and the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 9:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 10.1 g (yield 92%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.Cl.[O:38]([NH2:40])[CH3:39].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][O:38][CH3:39])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:35][CH2:36]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: CON
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(5-chloro-1H-indol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent Mass: 536.18 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH:11]([CH2:18][CH2:19]OS(C)(=O)=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH2:19][N:36]2[CH2:37][CH2:38][C:33]([OH:39])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:34][CH2:35]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccc(Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccccc1)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 40.3 %

Procedure:
N-(4-Chlorophenyl)-beta-(2-methanesulfonyloxyethyl)-N-methyl-benzenepropanamide (1.44 g) in DMF (10 mL) was treated with 4-phenyl-4-hydroxypiperidine (1.61 g) and the mixture heated at 80° C. for 2 hours. The cooled reaction mixture was diluted the EtOAc (50 mL) and water (50 mL) and the aqueous phase removed. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts, washed with water (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 10% MeOH:CH2Cl2 gave the title compound (0.7 g). Mass spectrum (FAB): 477.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: NCCCCCCNc1ccc(Cl)cc1
Product: O=c1c(NCCCCCCNc2ccc(Cl)cc2)c(Nc2cccnc2)c1=O
Yield: 86 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and N-(4-chlorophenyl)-hexane-1,6-diamine.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[C:10]([Cl:22])[CH:9]=2)=[O:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[Cl:22])[N:7]=[C:6]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1c(Cl)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1
Product: O=C(O)c1c(N2CCCC2)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 25 step D from 2,6,7-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 25 step C) and pyrrolidine. Brown solid. MS (ESI): 387.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:9]([CH2:12][CH3:13])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.S(=O)(O)[O-].[Na+].[C-:32]#[N:33].[K+]>O>[CH2:14]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:12][CH3:13])[C@H:10]([OH:11])[C:32]#[N:33])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@@H]([C@H](O)C#N)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of argon, (S)-2-(dibenzylamino)butanal (8.55 g, 32.0 mmol, Eq: 1.00) was combined with dioxane (70 ml) to give a light yellow solution. The reaction was stirred for 10 min at 0° C. Then sodium bisulfite in water (40%, 26.5 ml) was added. The reaction was stirred for another 10 min at 0° C. Then potassium cyanide (8.33 g, 128 mmol, Eq: 4), diluted in water (35 ml) was added. The reaction was stirred overnight at RT. The reaction mixture was poured into water (75 ml) and extracted with ethyl acetate (2×75 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% ethyl acetate in heptane). The title compound was obtained as a light yellow oil (6.49 g, 68.9%, MS (m/e)=295.3 [M+H+]).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.C(N(CC)CC)C.[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[CH:18]>CN(C)C=O.O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:8][C:4]1[C:3]([C:18]#[C:17][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ncnc(Cl)c1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2c(N)ncnc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a degassed solution of Example 1A (400 mg, 1.6 mmol) in N,N-dimethylformamide (6 mL) was added copper (I) iodide (120 mg, 0.63 mmol) and triethylamine (2 mL, 14.33 mmol). The mixture was degassed for 5 minutes and tert-butyl 4-ethynylpiperidine-1-carboxylate (1.67 g, 7.98 mmol) and bis(triphenylphosphine) palladium(II)chloride (220 mg, 0.31 mmol) were added. The mixture was stirred at room temperature for 3 hours and diluted with water and extracted with ethyl acetate. The ethyl acetate layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound. LCMS: 337.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[N:15]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Reactant: BrCCOc1ccccc1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(CCOc3ccccc3)c2=O)cn1
Yield: 20 %

Procedure:
Prepared as in Example 10-65 from 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (example 10-64) and (2-bromoethoxy)benzene. Yield: 20%. 1H NMR (DMSO-d6, 400 MHz): δ2.13 (s, 3H), 2.40 (s, 3H), 3.15 (s, 3H), 3.99 (t, J=4.4 Hz, 2H), 4.13 (t, J=4.8 Hz, 2H), 5.20 (s, 2H), 6.80 (d, J=8 Hz, 2H), 6.90 (t, J=7.1 Hz, 1H), 7.22 (t, J=8 Hz, 2H), 7.75 (s, 1H), 8.17 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.031 μM.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][NH:29][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(Nc1ncc(CNC2CCCC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 37.1 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg, 0.30 mmol), cyclopentylamine (45 μL, 0.45 mmol) and sodium triacetoxyborohydride (102 mg, 0.48 mmol) to afford 45 mg (37%) of the desired product after purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1.ClC(Cl)(Cl)C#N.C(N(CC)CC)C.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:21]([NH:49][C:46]5[CH:47]=[CH:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=5)=[O:22])=[CH:24][CH:25]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1
Reactant: O=C1Cc2cnc(Nc3ccc(C(=O)O)cc3)nc2-c2ccc(Cl)cc2N1
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1ccc(NC(=O)c2ccc(Nc3ncc4c(n3)-c3ccc(Cl)cc3NC(=O)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a pre swelled PL-TPP resin [200 mg, 0.3 mmol, (Polymer labs, 1.5 mmol/gram loading)] in DMA (1.0 mL) was added a mixture of 4-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic acid (I-3) (25 mg 0.066 mmol), DMA (1.5 mL) and trichloroacetonitrile (0.53 mmol). After agitating for three hours at room temperature, triethylamine (46 μL, 0.33 mmol) was added, followed by p-anisidine (8.1 mg, 0.066 mmol). The reaction mixture was stirred at 22° C. overnight. The reaction mixture was filtered and the resin was washed with DMF, DMA, and MeOH (1×1 mL). The combined organic layers were concentrated and the crude product was purified by RP-HPLC using an Agilent HPLC equipped with a SunFire™ column (Waters Corporation), Method Formic Acid, to give I-555 (22 mg, 69%). 1H NMR (DMSO): δ 10.38 (s, 1H), 10.32 (s, 1H), 9.93 (s, 1H), 8.59 (s, 1H), 8.10 (d, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.64 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.29 (s, 1H), 6.89 (d, J=8.5 Hz, 1H), 3.73 (s, 2H), 3.43 (s, 1H), 3.32 (s, 3H); MS Rt=2.70 min (m/z) 466 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:25][CH2:24]2)[N:18]=1.Cl.[Cl:27]CC1C=CC=C(C(C)C)N=1>>[Cl:27][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]3[CH2:24][CH2:25]3)[N:18]=2)[N:3]=1
Reactant: ClCc1cccc(C2CC2)n1
Reactant: CC(C)c1cccc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: Cl
Product: O=[N+]([O-])c1cccc2c1c(Cl)nn2Cc1cccc(C2CC2)n1
Yield: 72 %

Procedure:
Prepared according to Preparation D, Step D, substituting 3-chloro-4-nitro-1H-indazole for 3-bromo-4-nitro-1H-indazole and 2-(chloromethyl)-6-cyclopropylpyridine hydrochloride for 2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the title compound (72%).
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[CH:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([O:15][CH:16]2[O:21][CH:20]([CH2:22][OH:23])[CH:19]([OH:24])[CH:18]([OH:25])[CH:17]2[OH:26])[CH:7]=1.NCC(O)=O.[OH-].[Na+]>>[CH:10]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:6][CH:7]=[C:8]([O:15][C@@H:16]2[O:21][C@H:20]([C:22]([OH:3])=[O:23])[C@@H:19]([OH:24])[C@H:18]([OH:25])[C@H:17]2[OH:26])[CH:9]=1
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(OC2OC(CO)C(O)C(O)C2O)cc1
Agent: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
The reagent solutions were: NaAc buffer: 200 mM sodium acetate buffer pH 4.5; Substrate: 50 mM p-nitrophenyl-α-D-glucopyranoside (Sigma N-1377) in NaAc buffer (0.3 g/20 ml) and stop solution: 800 mM glycine-NaOH buffer pH 10. 30 μl filtered supernatant was placed in a fresh 96-well flat bottom MTP. To each well 50 μl NaAc buffer and 120 μl substrate was added and incubated for 30 minutes at 50° C. (Thermolab systems iEMS Incubator/shaker HT). The reaction was terminated by adding 100 μl stop solution. The absorbance was measured at 405 nm in a MTP-reader (Molecular Devices Spectramax 384 plus) and the activity was calculated using a molar extinction coefficient of 0.011 μM/cm.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].Cl[C:11]1[NH:16][C:15](=[O:17])[C:14]([F:18])=[CH:13][N:12]=1>C1(C)C=CC=CC=1>[CH2:1]([O:7][C:11]1[NH:16][C:15](=[O:17])[C:14]([F:18])=[CH:13][N:12]=1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: OCC1CCCO1
Reactant: O=c1[nH]c(Cl)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(OCC2CCCO2)ncc1F
Reaction time: 15 h
Yield: 72 %

Procedure:
A 40 g quantity of tetrahydrofurfuryl alcohol and 7.2 g of sodium hydride are added to 200 ml of absolute toluene, and the mixture is stirred at 75°-80° C for 15 hours. Subsequently 14.9 g of 2-chloro-5-fluoropyrimidin-4-one is added to the reaction mixture, and the resulting mixture is heated in a sealed tube at 148° to 150° C for 5 hours for reaction. The resulting reaction mixture is treated in the same manner as in Example 6 to give 15.4 g of white crystalline 2-tetrahydrofurfuryloxy-5-fluoropyrimidin-4-one in a yield of 72.0%, m.p. 89°-91° C.
Reaction SMILES: [NH:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[C:4](=[O:26])[NH:3]1.[CH:27]1(N)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CC(N(C)C)=O>[CH:27]1([NH:1][C:2]2[C:6]3([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]3)[N:5]([C:19]3[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=3)[C:4](=[O:26])[N:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=N)NC(=O)N2c1ccc(I)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1ccc(I)cc1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-imino-1-(4-iodophenyl)-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (10 g, 21.3 mmol) in cyclohexylamine (97 mL, 852 mmol) and DMA (100 mL) was stirred at 140° C. for 3 days, sealed, under argon. The reaction mixture was cooled to rt, poured onto ice/water (1000 mL), filtered to afford the desired product as a white solid, after washing with water and drying. LRMS (M+1)=553.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1.C([Li])CCC.Cl[C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=1>CCCCCC.C1COCC1>[CH3:1][C:2]1([CH3:16])[CH2:3][CH2:4][C:5]([CH3:15])([CH3:14])[C:6]2[CH:7]=[C:8]([C:12]#[C:13][C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=3)[CH:9]=[CH:10][C:11]1=2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free argon or nitrogen atmosphere. To a solution of 417.6 mg (1.9667 mmol) of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-6-ethynylnapthalene in 3 ml of dry tetrahydrofuron (THF) at 0° C. was added dropwise 1.3 ml of 1.6M (2.32 mmol) n-butyllithium in hexane. This mixture was stirred at 0° C. for 10 minutes and at room temperature for 15 minutes, cooled again to 0° C. and then treated by double-ended needle with a solution of 290 mg (2.1279 mmol) of fused zinc chloride in 4 ml dry THF. The mixture was stirred at 0° C. for 45 minutes and at room temperature for 15 minutes. A solution of 361.1 mg (1.9455 mmol) of ethyl 6-chloronicotinoate in 4 ml dry THF was transferred by double ended needle into a suspension of 420 mg (0.3635 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry THF, the resultant mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynyl zinc prepared above. The reaction mixture was stirred at room temperature for 70 hours and then quenched with ice and 30 ml of 3N HCl. The resultant mixture was extracted with 3×50 ml of ether, the ether extracts combined and washed successively with saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). The ether solution was filtered and concentrated in-vacuo. The resultant crude product was purified by flash chromatography (silica, 10% ethyl acetate in hexanes) followed by recrystallization from a mixture of ethylacetate in hexane to give the title compound as a pale cream solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][C:13]3[C:14]4[CH2:15][C:16]5[N:21]6[CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=[C:20]6[C:19](=[O:30])[NH:18][C:17]=5[C:31]=4[CH:32]=[CH:33][CH:34]=3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][C:13]3[C:14]4[CH2:15][C:16]5[N:21]6[CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=[C:20]6[C:19](=[O:30])[NH:18][C:17]=5[C:31]=4[CH:32]=[CH:33][CH:34]=3)[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(Cc2nc(-c4ccccc4)c[nH]2)c1C3
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(Cc2nc(-c4ccccc4)c[nH]2)c1C3
Yield: 61.3 %

Procedure:
A mixture of 0.4 g of ethyl 9-(4-phenyl-1H-imidazol-2-ylmethyl)-4,5-dihydro-4-oxo-10 H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate and 12.5 ml of acetic acid and 2.5 ml of 6 N hydrochloric acid is heated for 24 hours at a temperature close to 100° C. The reaction medium is filtered while hot on sintered glass and the solid residue obtained is washed with three times water and then dried under reduced pressure at 60° C. 0.23 g of 9-(4-phenyl-1H-imidazol-2-ylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid is thus obtained in the form of a white solid melting at a temperature greater than 260° C. (Analysis: C24H17N5O3, 3.96 H2O, 0.91 C2H4O2 : % calculated C: 68.07, H: 4.05, N: 16.54, % found C: 68.1, H: 4.1, N:16.5).
Reaction SMILES: O.O.[Br-:3].[Ca+2].[Br-].CC1C=CC(S(O[C:17]2[CH2:21][CH:20]([C:22](=[O:39])[NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[C:31](=[O:38])[NH:32][CH:33]([CH:35]3[CH2:37][CH2:36]3)[CH3:34])[N:19]([C:40]3[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[N:18]=2)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>O>[Br:3][C:17]1[CH2:21][CH:20]([C:22]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[C:31](=[O:38])[NH:32][CH:33]([CH:35]2[CH2:37][CH2:36]2)[CH3:34])=[O:39])[N:19]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=2)[N:18]=1
Reactant: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Ca+2]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Temperature: 90 °C
Yield: 172.5 %

Procedure:
0.25 g of calcium bromide dihydrate was added to a mixed liquid comprising 1.0 g of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl 4-methylbenzenesulfonate and 10 ml of toluene, followed by heating at about 90° C. for 6.5 hours. After the reaction liquid was stood to cool, 0.41 g of sodium hydrogen carbonate and 10 ml of water were added to the reaction liquid, followed by stirring. After liquid-liquid separation, the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.96 g of the crude desired product.