Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:7]=1[C:8]([NH:10][C:11]1[C:12]([CH3:17])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])=O.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:8](=[O:9])[C:7]2[C:6](=[CH:21][CH:20]=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=2)[N:5]=1
Reactant: Cc1ccccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Temperature: 0 °C
Yield: 99 %

Procedure:
16.5 g(0.05 mol) of N-(2-fluoroacetamido-5-nitrobenzoyl)-o-toluidine and 25.5 g(0.25 mol) of acetic acid anhydride are dissolved in 250 ml of glacial acetic acid. The solution is refluxed for 2 hours under heating. Then, the reaction solution is evaporated to remove solvent. The residue thus obtained is poured into ice-water, and the aqueous mixture is adjusted to pH 9 with potassium carbonate. The crystalline precipitate is collected by filtration. 15.5 g of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-quinazolinone are obtained.
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[CH:9]=[C:10]([C:14]3[O:15][C:16]4[CH:32]=[CH:31][C:30]([NH:33][C:34](=[NH:36])[CH3:35])=[CH:29][C:17]=4[C:18](=[O:28])[C:19]=3[O:20]CC3C=CC=CC=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.C(Cl)(Cl)[Cl:38].CO.N>>[ClH:38].[ClH:1].[N:3]1([C:8]2[CH:9]=[C:10]([C:14]3[O:15][C:16]4[CH:32]=[CH:31][C:30]([NH:33][C:34](=[NH:36])[CH3:35])=[CH:29][C:17]=4[C:18](=[O:28])[C:19]=3[OH:20])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CC(=N)Nc1ccc2oc(-c3cccc(-n4ccnc4)c3)c(OCc3ccccc3)c(=O)c2c1
Reactant: ClC(Cl)Cl
Agent: Cl
Agent: N
Solvent: CO
Product: CC(=N)Nc1ccc2oc(-c3cccc(-n4ccnc4)c3)c(O)c(=O)c2c1
Yield: 90 %

Procedure:
Prepared analogously to Example 5, starting from 2-[(3-(imidazol-1-yl)-phenyl]-3-benzyloxy-6-[(1-iminoethyl)amino]-4H-1-benzopyran-4-one dihydrochloride. Yield: 90%; m.p.: 281.0-281.5° C. TLC (80/20/2 Chloroform/Methanol/Ammonia) Rf: 0.32; Elem. anal.: C20H16N4O3.2HCl, Theory: C, 55.44; H, 4.19; N, 12.93. Found: C, 53.05; H, 4.34; N, 12.18. 1H-NMR (d6-DMSO): 11.83 (s broad, 1H), 10.30 (s, 1H), 9.75 (m, 2H), 8.73 (s broad, 1H), 8.46 (m, 2H), 8.38 (m, 1H), 8.07-7.75 (m, 6H), 2.41 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[C:32](O)(=[O:36])[CH2:33][CH2:34][CH3:35]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[CH2:28][CH2:27]2)[N:10]=1
Reactant: CCCC(=O)O
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 20 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt Example 11, and butyric acid (Aldrich), to give 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-butan-1-one. HRMS, observed: 398.2189; Calcd for (M+H)+: 398.2187.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.[Li+:14].[OH-:15]>>[Li+:14].[F:12][C:2]([F:1])([F:13])[C:3]1[N:8]=[C:7]([C:9]2[O:11][CH:3]=[N:8][C:7]=2[C:9]([O-:11])=[O:15])[CH:6]=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Agent: [Li+]
Product: O=C([O-])c1ncoc1-c1cccc(C(F)(F)F)n1

Procedure:
Prepared starting from 6-trifluoromethyl-pyridine-2-carboxylic acid following sequentially general procedures M and E (using LiOH). LC-MS-conditions 02: tR=0.80 min; [M+H]+=259.12.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([OH:10])[CH2:9][C@H:2]12.C(N(CC)CC)C.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>ClCCl>[F:31][C:19]([F:18])([F:30])[C:20]1[CH:21]=[C:22]([S:26]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@@H:8]([OH:10])[CH2:9][C@@H:2]3[CH2:1]2)(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O[C@H]1C[C@@H]2CNCCN2C1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@@H](O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (7S,8aR)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 17D, 5 g, 21.52 mmol) and solvent 2,2,2-trifluoroethanol (50 mL) were added to 20% palladium hydroxide on carbon, wet (0.500 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of the above crude (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.0 g, 7 mmol) and triethylamine (1.13 g, 11.2 mmol) in dichloromethane (40 mL) was slowly added a solution of 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.712 g, 7 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature for 4 hours. The solution was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.58 (m, 2H), 1.97 (m, 2H), 2.10-2.35 (m, 3H), 2.90 (m, 1H), 3.20 (m, 1H), 3.62 (m, 1H), 3.77 (m, 1H), 4.14 (m, 1H), 4.80 (m, 1H), 7.92 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:46]([O:50][C:51](=[O:61])[NH:52][C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[C:55]([NH2:60])[CH:54]=1)([CH3:49])([CH3:48])[CH3:47].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:59][C:56]1[CH:57]=[CH:58][C:53]([NH:52][C:51](=[O:61])[O:50][C:46]([CH3:47])([CH3:49])[CH3:48])=[CH:54][C:55]=1[NH:60][C:10]([C:8]1[S:7][C:3]2=[N:4][CH:5]=[CH:6][N:1]=[C:2]2[CH:9]=1)=[O:12]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Reactant: O=C(O)c1cc2nccnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (1.01 g, 5.61 mmol), HATU (1.8 g, 5.61 mmol) and DIPEA (1.953 mL, 11.21 mmol) in DMF (8 mL) was stirred for 15 min. (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl 27 (1.246 g, 5.61 mmol), DIPEA (1 eq) in DMF (8 mL) were added and stirred overnight at rt. Citric acid solution (3%) was added and extracted with EtOAc. Organic layer was washed with NaHCO3 solution, brine, dried and evaporated. Purification by chromatography (0-20% EtOAc in CH2Cl2) gave tert-butyl 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)phenylcarbamate 28 (1.43 g, 66.4%). (m/z)=385 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([NH:18][C:19]1[C:20](=[O:39])[N:21]([C:25]2[CH:26]=[C:27]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:28]([NH:30][CH:31]2[CH2:33][CH2:32]2)=[O:29])[CH:22]=[CH:23][N:24]=1)([CH3:17])[CH3:16]>>[CH:31]1([NH:30][C:28](=[O:29])[C:27]2[CH:26]=[C:25]([N:21]3[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][CH2:7][CH2:6][NH:4][CH2:3][CH2:1][OH:2])([CH3:17])[CH3:16])[C:20]3=[O:39])[C:36]([CH3:37])=[C:35]([F:38])[CH:34]=2)[CH2:32][CH2:33]1
Reactant: NCCO
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCCl)c1=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCNCCO)c1=O

Procedure:
The title compound was prepared from ethanolamine and 3-{3-[(1-{2-[(2-chloroethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 321a) using a similar method to that described for Example 2521. The crude product was purified by preparative HPLC (X-Bridge column eluting with 95-5% gradient of aqueous 0.2% ammonia in acetonitrile) to give the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21]Br>CN(C=O)C>[O:1]1[C:2]2[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:5]=[CH:6][C:7]=2[O:8][CH2:21][CH2:20]1
Reactant: BrCCBr
Reactant: COC(=O)c1cc(O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(cn1)OCCO2
Temperature: 115 °C
Yield: 86.6 %

Procedure:
To a stirred solution of methyl 4,5-dihydroxypyridine-2-carboxylate (348 mg, 2.06 mmol) in DMF (20 mL) is added solid K2CO3 (3.1 g, 22 mmol) and 1,2-dibromoethane (386 μL, 4.5 mmol). The mixture is heated at 115° C. for 2 h. DMF is removed in vacuo, the residue is partitioned between water and EtOAc. The aqueous layer is again extracted with EtOAc. The combined organic layers are dried (MgSO4) and concentrated in vacuo to give a yellow solid for methyl 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carboxylate (348 mg, 86%): 1H NMR (400 MHz, CDCl3) δ 8.29, 7.71, 4.39, 3.99.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[O:7][C:8]=1[CH3:9])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>O.C1COCC1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:6]2[O:7][C:8]([CH3:9])=[C:4]([CH2:1][CH2:2][CH2:3][OH:27])[N:5]=2)=[CH:15][CH:14]=1
Reactant: C=CCc1nc(-c2ccc(OC)cc2)oc1C
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(CCCO)c(C)o2)cc1
Reaction time: 2 h

Procedure:
The above prepared 4-allyl-2-(4-methoxy-phenyl)-5-methyl-oxazole (4.51 g, 19.7 mmol) was dissolved in 60 ml of abs. THF and and treated at 0° with 100 ml of 9-BBN-solution (0.5 M hexane). Hydroboration was allowed to proceed for 2 h at RT. Afterwards, 56 ml of 3N NaOH and 114.5 ml of 30% H2O2 was added simultaneously, whereby the internal temperature rose to 45°. After 1 h, the heterogeneous mixture was diluted with ice and water, extracted twice with AcOEt, washed water, and dried over natrium sulfate. Evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=1/3) yielded 4.54 g of the title compound as colorless oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]([CH2:14]P(=O)(OC)OC)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1/[CH:26]=[CH:14]/[C:13]1[CH:21]=[CH:22][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: O=Cc1ccccc1F
Reactant: COP(=O)(Cc1ccc(S(=O)(=O)c2ccccc2)cc1)OC
Product: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccccc2F)cc1

Procedure:
The title compound was prepared from dimethyl [4-(phenylsulfonyl)benzyl]phosphonate (Step 2) and 2-fluorobenzaldehyde according to the method of Example 46 Step 5. δH (500 MHz, CDCl3): 7.97–7.92 (4H, m), 7.63–7.55 (4H, m), 7.52–7.49 (2H, m), 7.35 (1H, d, J=16.5 Hz), 7.30–7.25 (1H, m), 7.18–7.14 (2H, m), 7.10–7.06 (1H, m).
Reaction SMILES: [NH:1]1[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O.[C:10]1([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[Na+].C1C=CC=CC=1>[C:10]1([CH2:16][CH2:17][CH2:18][C:19]([N:1]2[CH2:8][S:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)[C@@H]1CSCN1C(=O)CCCc1ccccc1
Yield: 81.9 %

Procedure:
Dissolved in 100 ml of 1N sodium hydroxide were 6.65 g of L-thioproline, and 50 ml of water were further added to the solution. A solution of 9.10 g of 4-phenylbutanoyl chloride in 50 ml of benzene was added dropwise to the solution under stirring. Thereafter, 50 ml of 1N sodium hydroxide were further added, and the mixture was stirred for 24 hours. A benzene layer was removed, and a water layer was washed twice with 70 ml of ether. After 7% hydrochloric acid was further added to the water layer to acidify it, the water layer was extracted three times with 70 ml of ethyl acetate. The resulting extract was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the resultant oily residue was subjected to column chromatography on silica gel, thereby obtaining 11.4 g of N-(4-phenylbutanoyl)-L-thioproline as colorless crystals from a chloroform-methanol fraction.
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7].C(NCC)C.[C:15]1([O:21][C:22]([N:24]2[CH:37]([C:38]#[CH:39])[C:36]34[O:40][C:31]3([C:32](=[O:41])[CH2:33][CH2:34][CH2:35]4)[C:30]3[CH:29]=[CH:28][C:27]([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:26][C:25]2=3)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.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.[Cu]I>[C:15]1([O:21][C:22]([N:24]2[CH:37]([C:38]#[C:39]/[CH:2]=[CH:3]\[C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[C:36]34[O:40][C:31]3([C:32](=[O:41])[CH2:33][CH2:34][CH2:35]4)[C:30]3[CH:29]=[CH:28][C:27]([O:42][C:43](=[O:48])[C:44]([CH3:46])([CH3:45])[CH3:47])=[CH:26][C:25]2=3)=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2cc(OC(=O)C(C)(C)C)ccc2C23OC12CCCC3=O
Reactant: C[Si](C)(C)C#CC=CCl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(=O)C21O3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
A mixture of Pd(PPh3)4 (185 mg, 0.16 mmol), 1-chloro-4-(trimethylsilyl)-but-1-en-3-yne (0.776 g, 4.89 mmol), and diethylamine (0.51 mL, 4.93 mmol) in degassed benzene (5 mL) was stirred at 25° C. for 15 minutes. The resultant solution was added to a mixture of Compound 230 (1.50 g, 3.26 mmol) and CuI (124 mg, 0.65 mmol) in degassed benzene (15 mL) via a syringe followed by stirring at 25° C. for one hour. The reaction mixture was quenched by saturated aqueous NH4Cl, extracted with ethyl ether (80 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 25 percent ethyl ether in petroleum ether) provided a solid product Compound 231 (0.606 g, 32 percent): Rf =0.43 (silica, 50 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2964, 1721, 1494, 1378, 1305, 1270, 1253, 1202, 1181, 1122, 846 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=8.7 Hz, 1 H, H1), 7.44-7.10 (m, 6 H, H4 and aromatic), 6.99 (dd, J=8.7, 2.4 Hz, 1 H, H2), 5.98 (d, J=1.5 Hz, 1 H, H6), 5.84 (d, J=11.1 Hz, 1 H, olefinic), 5.69 (br d, J=11.1 Hz, 1 H, olefinic), 2.81-2.66 (m, 2 H, H9), 2.41-2.26 (m, 2 H, H7), 2.10-1.86 (m, 2 H, H8), 1.33 (s, 9 H, COC(CH3)3), 0.22 (s, 9 H, SiC(CH3)3); MS (FAB+) m/e (rel intensity) 582 (M+H, 100), 525 (13), 460 (48), 406 (8), 360 (6), 320 (8), 279 (25), 246 (5);HRMS for C34H36NO6Si (M+H), calcd 582.2312, found 582.2322.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]2=[N:6][C:7]=1Cl.B(O)(O)[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([C:2]2[N:3]=[C:4]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]3=[N:6][C:7]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1CCc2nc(Br)c(Cl)nc2N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Temperature: 80 °C
Reaction time: 66 h

Procedure:
To a stirrred suspension of 2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (Intermediate J) (10 g, 38.1 mmol), p-tolylboronic acid (11.39 g, 84 mmol) in MeCN (400 ml) and water (100 ml) under N2 supply, was added solid K2CO3 (fine mesh) (7.90 g, 57.1 mmol) followed by Pd(PPh3)2Cl2 (1.337 g, 1.905 mmol). The yellow RM was heated to 80° C. and was left stirring for 66 hours. The RM was allowed to cool slowly to RT and then placed in the fridge for 3-4 hours. The fine yellow needles were filtered off under suction and were washed with small quantity of acetonitrile, followed by water. After air drying for 10 min, the solid was transferred, dried in vacuo at 40° C. for 2 hours, to afford the title compound as fine crystalline needles;
Reaction SMILES: CI.[NH:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][N:5]=[N:4]1.[CH2:18](N(CC)CC)C>C(#N)C>[CH3:18][N:6]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[N:3][N:4]=[N:5]1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(Cc2nnn[nH]2)cc1
Solvent: CI
Solvent: CC#N
Product: Cn1nnnc1Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of methyl iodide (34.1 ml, 0.5 mol) in acetonitrile (100 ml) was added dropwise, over lh, to a solution of 4-(1H-tetrazol-5-ylmethyl)nitrobenzene (20.5 g, 0.1 mmol), and triethylamine (18.7 ml, 0.25 mol), in acetonitrile (500 ml), at room temperature. The mixture was stirred for 3h, the solvent removed under vacuum and residue dissolved in EtOAc (500 ml). The solution was washed with water (2x) and brine (1x) and the solvent evaporated. The crude product was chromatographed through silica-gel eluting with EtOAc/hexane (1:1)→EtOAc (100%) to give 2 components. The more polar product (7.9 g) was identified as the desired 1-methyl substituted tetrazole. The less polar product (7.0 g) was identified as being the 2-substitution product; 5 (360 MHz, CDCl3, more polar isomer) 3.94 (3H, s, CH3), 4.40 (2H, s, CH2), 7.42 (2H, d, J=8.7 Hz, Ar--H), 8.21 (2H, d, J=8.7Hz, Ar--H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([OH:24])[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[O:24]1[CH2:12][C@H:11]1[C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:10][CH:9]=1
Reactant: CC(=O)Nc1ccc([C@@H](O)COS(=O)(=O)c2ccc(C)cc2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc([C@@H]2CO2)cn1
Reaction time: 0.67 h

Procedure:
A solution of (R)-toluene-4-sulfonic acid 2-(6-acetylamino-pyridin-3-yl)-2-hydroxy-ethyl ester (200 g, 0.57 mol) in THF (2.4 L) was cooled to −15° C. and potassium t-butoxide (542 ml, 0.542 mol, 1M in THF) was added slowly at −15° C. to −10° C. over a two hour period. Stirring was continued at −15° C. for an additional 40 minutes. The reaction mixture was filtered with the aid of Celite®. The filtration was done through cloth precoated with Celite®. The filter cake was washed with tetrahydrofuran. The filtrate was concentrated under vacuum to afford 300 ml of an oil. The oil was diluted with 1.2 liters of hexanes which resulted in the formation of a solid. The suspension was stirred at room temperature for one hour to granulate the solid. The suspension was filtered and the filtrate was washed with hexanes to afford 80.0 g (78.8%) of the title product as a solid. mp 96-98° C. 1H NMR (CDCl3): δ=8.70 (br, 1 H); 8.21 (m, 2 H); 7.57 (d of d, 1 H); 3.86 (m, 1 H); 3.17 (m, 1 H); 2.83 (m, 1 H); 2.19 (s, 3 H). MS (Cl): m/z=179 (M+H+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[N:7]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)=[N+:2]=[N-:3].[S:40]1[CH2:44][C:43](=[O:45])[NH:42][C:41]1=[O:46].N1CCCCC1>CCO>[N:1]([CH2:4][CH2:5][C:6]1[N:7]([CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:44]3[S:40][C:41](=[O:46])[NH:42][C:43]3=[O:45])=[CH:20][CH:19]=1)=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCc1c(CCOc2ccc(C=O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: [N-]=[N+]=NCCc1c(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 87 %

Procedure:
The mixture of 4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzaldehyde (1.29 g, 2.41 mmole, 1.0 equiv.), 2,4-thiazolidine dione (0.41 g, 3.13 mmole, 1.3 equiv.) and piperidine (0.12 ml, 1.21 mmole, 0.5 equiv.) in EtOH (125 ml) was refluxed overnight. EtOH was removed on vacuo. The residue was diluted in EtOAc and washed with water, then brine. The organic layer was dried over MgSO4 and concentrated, and the residue was chromatographed with 30-35% EtOAc/hexane to obtain 5-(4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzylidene)-thiazolidine-2,4-dione (1.33 g, 87%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CCO>[C:10]1([CH3:13])[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[S:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2nsc(Cl)n2)cc1
Reactant: C1CNCCN1
Solvent: CCO
Product: Cc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-3-p-tolyl-1,2,4-thiadiazole (900 mg, 4.27 mmol) and piperazine (1.84 g, 21.4 mmol) in 25 mL EtOH were heated to reflux and stirred for 1 h at this temperature. The resulting yellow solution was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica eluting with a gradient formed from DCM, MeOH and NEt3 to yield after evaporation of the product containing fractions 1.1 g (99%) of the title compound as light yellow solid. MS (m/e): 261.3 (MH+).
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Br[CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18]([OH:20])=[O:19]>C(N(CC)CC)C>[O:15]=[C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([S:4][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=[O:19])[NH:14]1
Reactant: O=c1[nH]c(S)nc2ccccc12
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(Sc1nc2ccccc2c(=O)[nH]1)c1ccccc1
Yield: 31 %

Procedure:
A methylene chloride solution of 8.9 g (0.05M) of 2-mercapto-4(3H)-quinazolinone, α-bromophenylacetic acid and triethylamine is heated to gentle reflux for 48 hours. A small amount of insoluble material is filtered off and then the solvent is removed. The oily residue is dissolved in water and insoluble material filtered off. The aqueous filtrate is acidified with a dilute HCl solution and the gummy solid is extracted with methylene chloride. The methylene chloride solution is dried over anhydrous magnesium sulfate. After the solvent is removed the residual solid is dissolved in 500 ml hot acetonitrile, and upon cooling the solid is filtered. The filtrate, upon standing, gives 5.0 g (31% yield) of product which has a melting point of 184°-5° C. dec.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([C:2]2[CH:15]=[CH:14][C:5]([C:6]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: O=C(c1ccncc1)c1ccc(F)cc1
Product: O=C(c1ccncc1)c1ccc(N2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 4.76 g of 4-(4-fluorobenzoyl)pyridine and 9.8 ml of piperidine was stirred at 100° C. for 24 hours and the reaction mixture was then worked up in the same manner as Example 3 to give 5.3 g of the title compound as a yellow oil.