Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[O:9])[CH:5]([C:10]([O:12]CC)=[O:11])[CH2:4]1)[CH3:2].[Li+].[OH-].C(Cl)Cl>C1COCC1.O>[CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[O:9])[CH:5]([C:10]([OH:12])=[O:11])[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C1CN(CC)C(=O)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCN1CC(C(=O)O)C(=O)C1=O
Yield: 71.5 %

Procedure:
A solution of ethyl 1-ethyl-4,5-dioxopyrrolidine-3-carboxylate (150 mg, 0.753 mmol) and LiOH (43.3 mg, 1.81 mmol) in THF (0.5 mL) and H2O (0.5 mL) was heated at 80° C. for 1 h using microwave irradiation. The reaction solution was concentrated under reduced pressure and acidified with 1 N aqueous HCl, whereupon a precipitate formed. CH2Cl2 was added to the suspension and the precipitate was collected by filtration and dried in vacuo to provide Intermediate 8 (92.1 mg, 71.4% yield). HPLC/MS (Method D) RT=0.48 min, [M+H]+ 172.1; 1H NMR (400 MHz, Solvent) (δ ppm): 1.11-1.24 (m, 3H), 3.53 (q, J=7.28 Hz, 2H), 3.84 (s, 0.47H), 4.04 (s, 1.53H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH:9]=[CH:8][C:7]3[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14][NH:15][C:6]=3[C:5]=2[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31].O>CN(C)C=O>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][N:15]1[C:6]2[C:5]3[N:4]=[C:3]([S:2][CH3:1])[N:12]=[CH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14]1
Reactant: CCOC(=O)c1n[nH]c2c1ccc1cnc(SC)nc12
Reactant: CN(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CCN(C)C)c2c1ccc1cnc(SC)nc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (150 mg, 0.52 mmol) in dry dimethylformamide (4 ml) was added cesium carbonate (339 mg 1.04 mmol) followed by 2-bromo-N,N-dimethylethanamine (135 mg 0.88 mmol). The heterogeneous mixture was stirred at room temperature for 24 hours. The mixture was treated with water and extracted with EtOAc. The organic layer washed with brine, dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography eluting with EtOAc/Ethanol 85/15 to give ethyl 1-[2-(dimethylamino)ethyl]-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate as the major isomer (60 mg 32%) 1H NMR (401 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.16 (d, J=8.67 Hz, 1H), 7.83 (d, J=8.79 Hz, 1H), 5.29 (t, J=6.59 Hz, 1H), 4.32-4.49 (m, 2H), 2.94 (br. s., 2H), 2.71 (s, 3H), 2.24 (br. s., 6H), 1.41 (t, J=7.08 Hz, 3H); and
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[Cl:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.Cl>CS(C)=O.O>[ClH:15].[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1nc2ccccc2s1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)[C@H](Cc1ccccc1)Nc1nc2ccccc2s1
Temperature: 95 °C

Procedure:
11.8 g phenylalanine (73.4 mmol) was added in portions to a suspension of 5.7 g powdered NaOH (143 mmol) in 50 mL DMSO, and stirred under nitrogen. 2-Chlorobenzothiazole (11 g, 65 mmol) was added over fifteen minutes at room temperature. The reaction was heated on an oil bath at about 95° C. for 4 hours. The reaction mixture was then cooled, poured into 200 mL ice and water, and the pH of the resulting mixture was adjusted to about 1-2 by addition of 10N HCl.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To the product from Example 186 (1.3 mg, 0.0023 mole) in H2O (15 mL) and CH3CN (15 mL) was added LiOH (290 mg, 0.0069 mole). The reaction mixture was stirred at room temperature for 1 hour. The pH was lowered to ~2.5 with TFA and the product was isolated by RPHPLC to yield the title compound (1.1 g after lyophilization) as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11](=[O:13])[CH:10](C(OC)=O)[C:9](=[O:18])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(#N)C>[OH:18][C:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:12][C:11](=[O:13])[CH:10]=1
Reactant: COC(=O)C1C(=O)CC(c2ccccc2)NC1=O
Solvent: CC#N
Product: O=C1C=C(O)CC(c2ccccc2)N1

Procedure:
The title compound was prepared by decarboxylation of methyl 6-phenyl-2-,4-dioxopiperidine-3-carboxylate (prepared as per Ashton et al., Heterocycles 28: (2) 1015 (1989)) by refluxing in acetonitrile (as per Toda et al., J. Antibiotics 23: (2) 173 (1980)). Removal of the solvent gave a solid (m.p. 166°-169° C,). 1H NMR (CDCl3) δ 2.77 (dd, 1 H), 2.90 (dd, 1 H), 3.38 (s, 2 H), 4.80 (dd, 1 H), 6.40 (s, 1 H), 7.32-7.46 (m, 5 H).
Reaction SMILES: [CH2:1]=[O:2].[CH2:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[BrH:12]>C(Cl)(Cl)Cl>[Br:12][CH2:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=O
Reactant: CCCCCCCCO
Reactant: Br
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOCBr

Procedure:
30 g (1 mole) of paraformaldehyde, 107 ml of 1-octanol (1 mole) are stirred in 100 ml chloroform at 0°-5° C., by passing HBr gas. After the reaction completion, indicated by the complete dissolution of the solid, the organic layer is washed with water several times, and dried over anhydrous sodium sulphate. The residue is diluted in chloroform, to give a 3M solution. The product boiled at 150°-155° C. (1 torr) and has a singlet (2 hydrogens) at 5.8 ppm from TMS. The product is kept refrigerated.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>CC#N.[Bi](Br)(Br)Br>[CH2:19]([CH:11]1[CH2:10][CH:9]([O:8][CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[CH2:13][CH:12]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20]
Reactant: CCOC(=O)C1CC(O[Si](C)(C)C(C)(C)C)CC1CC
Reactant: O=C1CCOCC1
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CC(OC2CCOCC2)CC1CC
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 281 %

Procedure:
To a solution of ethyl 4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (0.100 g, 0.333 mmol) in MeCN (2.2 mL) was added triethylsilane (0.080 mL, 0.499 mmol) and bismuth(III) bromide (0.010 g, 0.022 mmol). The reaction mixture was stirred at ambient temperature for about 1 min followed by dropwise addition of dihydro-2H-pyran-4(3H)-one (0.050 g, 0.499 mmol). The reaction mixture was stirred at ambient temperature for about 15 min. The reaction was filtered through an Acrodisc® and the solvent was removed under reduced pressure. To a solution of ethyl 4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (0.200 g, 0.666 mmol) in MeCN (4.5 mL) was added triethylsilane (0.160 mL, 1.00 mmol) and bismuth(III) bromide (0.020 g, 0.045 mmol). The reaction mixture was stirred at ambient temperature for about 1 min followed by dropwise addition of dihydro-2H-pyran-4(3H)-one (0.100 g, 0.998 mmol). The reaction mixture was stirred at ambient temperature for about 15 min. The reaction was filtered through an Acrodisc® and the solvent was removed under reduced pressure. The residues were dissolved in DCM (2 mL) each, combined, and the crude material was purified by silica gel chromatography using a gradient of 10-100% EtOAc in heptane to give ethyl 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate (0.253 g, 98%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.13 (q, J=7.1, 2H), 4.05-3.98 (m, 1H), 3.98-3.88 (m, 2H), 3.58-3.47 (m, 1H), 3.46-3.36 (m, 2H), 2.80 (q, J=8.5, 1H), 2.16 (dt, J=13.3, 7.7, 1H), 2.09-1.93 (m, 3H), 1.90-1.81 (m, 2H), 1.62-1.49 (m, 3H), 1.43 (ddd, J=11.1, 7.4, 5.2, 1H), 1.33-1.22 (m, 4H), 0.92-0.83 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[CH:4]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26].[Li]CCCC>C1COCC1.CCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[CH:4]=1
Reactant: COc1cc(C)nc(N(C)C)c1
Reactant: COCOCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCOCCCCCCCCCCc1cc(OC)cc(N(C)C)n1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution containing 156 mg (0.94 mmol) of 4-methoxy-N,N,6-trimethylpyridin-2-amine in 5 mL of anhydrous THF were added 252 mg (0.94 mmol) of 1-bromo-9-(methoxymethoxy)nonane followed by 650 μL (1.04 mmol) of 1.6M n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 15 min. The reaction was quenched with satd. aq. ammonium chloride and poured into 50 mL of water. The mixture was extracted with two 50-mL portions of ethyl acetate. The combined organic solution was washed with a 50-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (3×10 cm). Elution with 1:1 hexanes-ethyl acetate afforded the expected product as yellowish oil: yield 235 mg (70%); silica gel TLC Rf 0.47 (1:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.24 (br m, 12H), 1.55 (quint, 2H, J=6.4 Hz), 1.68 (quint, 2H, J=7.6 Hz), 2.55 (dd, 2H, J=7.6, 7.6 Hz), 3.03 (s, 6H), 3.46 (s, 3H), 3.49 (t, 2H, J=6.8 Hz), 3.76 (s, 3H), 4.59 (s, 2H), 5.77 (s, 1H) and 6.01 (s, 1H); 13C NMR (CDCl3) δ 26.17, 29.25, 29.39, 29.48, 29.50, 29.55, 29.60, 29.62, 29.72, 37.96, 37.96, 54.63, 55.01, 67.85, 87.44, 96.36, 97.86, 160.77, 162.05 and 167.41; mass spectrum (APCI), m/z (M+H)+353.2808 (C20H37N2O3 requires 353.2804).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2O)[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[N:4]=2)[N:9]=[CH:8][C:7]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cnc2ccc(CC)nc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(CC)nc2c1Cl

Procedure:
A mixture of ethyl 6-ethyl-4-hydroxy-1,5-naphthyridine-3-carboxylate (3.0 g) and phosphorus oxychloride (25 ml) was stirred and heated at 40°-50° C. for 1 hour. The mixture was then cooled and then worked up as described in Example B1 to give ethyl 4-chloro-6-ethyl-1,5-naphthyridine-3-carboxylate, m.p. 94°-96° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:8](=[O:10])[CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)CC1=CCCCC1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CC1=CCCCC1

Procedure:
Following General Procedure U and using cyclohex-1-enylacetic acid (Alfa) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=139-142° C.). The reaction was monitored by tlc (Rf=0.27 in 1:1 EtOAc/hexanes).
Reaction SMILES: C(O)C.[C:4]1([C:10]2[CH:11]=[CH:12][C:13]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[O:21])=[C:14]([CH:18]=2)[C:15]([OH:17])=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1>[Pd].CN(C=O)C>[CH:4]1([C:10]2[CH:11]=[CH:12][C:13]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[O:21])=[C:14]([CH:18]=2)[C:15]([OH:17])=[O:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Nc1ccc(C2=CCCCC2)cc1C(=O)O)c1ccc(C2CCCCC2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(Nc1ccc(C2CCCCC2)cc1C(=O)O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
22 mg of 10% Pd—C was added to an ethanol (11 mL)/DMF (1 mL) solution comprising 216 mg (0.54 mmol) of 5-(cyclohex-1-en-1-yl)-2-{[(4-cyclohexylphenyl)carbonyl]amino}benzoic acid obtained in Example 81, and the mixture was stirred under hydrogen atmosphere at room temperature for 72 hours. The reaction mixture was filtered using filter paper, and the filtrate was condensed, thereby giving 195 mg of the target 5-cyclohexyl-2-{[(4-cyclohexylphenyl)carbonyl]amino}benzoic acid (yield: 90%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([C:11](O)=O)=[N:2]1.[Br:14][C:15]1[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]2[NH:21][C:11]([C:3]3[CH2:4][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[O:1][N:2]=3)=[N:22][C:17]=2[CH:16]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Product: Brc1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1

Procedure:
The title compound was prepared from 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (283 mg, 1.55 mmol, as prepared in Example 1, step B) and 4-bromobenzene-1,2-diamine (1.3 eq., 377 mg, 2.02 mmol) in 68% overall yield (299 mg) according to the procedures described in Example 1, steps F and G. 1H-NMR (400 MHz, d4-MeOH) δ: 7.74 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.6, 1.8 Hz, 1H), 3.25 (s, 2H), 1.69-1.88 (m, 6H), 1.43-1.63 (m, 4H).
Reaction SMILES: P(CCCC)(CCCC)CCCC.CCN(CC)CC.[CH2:21]([OH:26])[CH:22]([OH:25])[CH:23]=[CH2:24].Br[C:28]1[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1>CN(C=O)C.O>[OH:26][CH2:21][C:22](=[O:25])[CH2:23][CH2:24][C:32]1[CH:31]=[C:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28][CH:33]=1
Reactant: C=CC(O)CO
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CCC(=O)CO)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a stirred solution of Pd (OAc)2 (75 mg, 0.34 mmol), nBu3P (136 mg, 0.67 mmol), and Et3N (442 mg, 4.37 mmol) in DMF (10 ml) was added 3-butene-1,2-diol (296 mg, 3.36 mmol) followed by methyl 3-bromophenylacetate (1.0 g, 4.37 mmol), and the reaction mixture was stirred at 100° C. for 5 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by silica gel (25 g) column chromatography eluting with toluene/ethyl acetate (20:1) to give methyl 3-(4-hydroxy-3-oxobutyl)phenylacetate (193 mg, 24.4%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH2:11])[CH:3]=1.[CH3:12][C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:14]=1.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>CN(C=O)C>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH:11][C:19]([C:18]2[C:13]([CH3:12])=[N:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=2)=[O:20])[CH:3]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Cc1cn(N)c2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2ncccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methyl-pyrrolo[3,2-b]pyridin-1-yl amine (839 mg, <5.71 mmol), 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (1.32 g, 6.13 mmol), HATU (2.6 g, 6.85 mmol), DIPEA (2.21 g 17.1 mmol) in DMF (17 mL) is stirred at 150° C. for 1 h. The reaction is quenched with water and ether. The water layer is concentrated in vacuo. The residue is chromatographed through silica gel eluting with a mixture of DCM, MeOH and triethylamine (9.5:0.5:0.05) to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (134 mg). MS: 345 345 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.22 (s, 1H), 8.79 (d, 1H), 8.64 (d, 1H), 8.40(d, 1H), 8.05 (t, 1H), 7.87 (d, 1H), 7.60 (t, 1H), 7.49 (s, 1H) 7.30 (dd, 1H), 2.87 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [Li][CH2:2]CCC.CCN(C(C)C)C(C)C.[C:15]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CI>C1COCC1>[CH3:2][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:15]1=[O:22]
Reactant: [Li]CCCC
Reactant: O=C1CCCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
n-BuLi (2M solution) (35.86 mmol, 17.93 mL) was slowly added at 0° C. to a solution of DIPEA (5 mL, 35.86 mmol) in THF (45 mL). After stirred for 30 min at 0° C. the solution was cooled to −78° C. Cycloheptanone (4.0 gms, 4.2 mL, 35.66 mmol, 1.0 eqv) was added drop wise and the resulting mixture was stirred for 30 min at −78° C. before adding methyl iodide (2.96 mL, 47.4 mmol, 1.33 eq). The cooling bath was removed and the solution was allowed to reach ambient temperature and stirred at RT for 15 hours before being quenched with aqueous saturated NH4Cl. The mixture was extracted with DCM. The organic layer was washed with 0.1 M aqueous HCl and aqueous saturated NaHCO3, dried over Na2SO4, filtered, and evaporated. The residue was purified by short path distillation to give 2.8 g of 2-methyl-cycloheptanone (62% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C@H:16]3[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C([C@](C([O-])=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C([O-])=O)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[NH4+:63].[NH4+].[ClH:65]>C(O)C>[ClH:65].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C@H:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C@H:16]3[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)(=[NH:63])[NH2:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C[C@@H]1CN(CC(=O)OCC)CC[C@@H]1N1CCN(c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: O=C([O-])[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)[O-])C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CN(CC(=O)OCC)CC[C@@H]1N1CCN(c2ccc(C(=N)N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
660 mg of (+)-cis-diethyl 4-[4-(4-cyanophenyl)-1-piperazinyl]-1,3-piperidinediacetate-(+)-dibenzoyl-D-tartrate was dissolved in 20 ml of ethanol, into which hydrogen chloride was bubbled at from -10° C. to -20° C. until saturation. This was heated up to room temperature and stirred overnight, and thereafter the solvent was removed by distillation. The residue thus obtained was dissolved in 20 ml of ethanol, and 1.0 g of ammonium carbonate was added thereto and stirred at room temperature overnight. The solvent was removed from the reaction mixture by distillation, and the resulting residue was purified by silica gel column chromatography (using an eluent of chloroform/methanol=10/1) to obtain 300 mg of (+)-cis-diethyl 4-[4-(4-amidinophenyl)-1-piperazinyl]-1,3-piperidinediacetate hydrochloride.
Reaction SMILES: N1C=CC=CC=1.F.C(#N)C.[C:11]([O:16][C:17]1[CH2:30][C@@H:29]([O:31][Si](C(C)(C)C)(C)C)[C@H:28](/[CH:39]=[CH:40]/[C@@H:41]([O:47][Si](C(C)(C)C)(C)C)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:18]=1[S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=O)(=[O:15])[CH2:12][CH2:13][CH3:14].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.N1C=CC=CC=1>[C:11]([O:16][C:17]1[CH2:30][C@@H:29]([OH:31])[C@H:28](/[CH:39]=[CH:40]/[C@@H:41]([OH:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:18]=1[S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)O)=C(OC(=O)CCC)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCSC1=C(OC(=O)CCC)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)CCCCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
A hydrogen fluoride-pyridine solution (0.1 ml) was added to a solution of ice-cooled acetonitrile (1 ml) and pyridine (0.1 ml), then a pyridine (0.1 ml) solution of (11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dienoic acid (79 mg) was added. The ice bath was detached, then the solution was stirred for 20 hours while raising it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated sodium hydrogencarbonate. The target substance was extracted from the mixture by ethyl acetate. The extract was washed with saturated sodium chloride solution, then was dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure, then was purified by a preparative TLC (Merck TLC plate silica gel 60 F254, 20×20 cm, layer thickness 0.25 mm, 2 pieces, ethyl acetate:hexane 4:1) to obtain (11R,12S,13E,15S)-9-butyryloxy-11,15-dihydroxy-7-thiaprosta-8,13-diene acid (17 mg, 33%).
Reaction SMILES: [N:1]([C@@:4]1([OH:20])[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].[CH3:21]OC(OC)N(C)C>C(Cl)(Cl)Cl>[CH3:21][N:14]1[C:15](=[O:16])[C:17]([CH3:18])=[CH:19][N:11]([C@@H:6]2[O:7][C@H:8]([CH2:9][OH:10])[C@@:4]([N:1]=[N+:2]=[N-:3])([OH:20])[CH2:5]2)[C:12]1=[O:13]
Reactant: Cc1cn([C@H]2C[C@@](O)(N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cn([C@H]2C[C@@](O)(N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(C)c1=O

Procedure:
3'-Azidothymidine (0.5 g; 1.9 mMol) and N,N-dimethylformamide dimethylacetal (Zemlicksa, Coll. Czech. Chem. Comm. 35, 3572 (1972)) (0.9 mL; 7.5 mMol) were refluxed to 20 mL CHCl3 for 48 hours. The solvent was removed in vacuo and the material placed on a silica column. Elution with EtOAc/CHCl3 (1:1 v/v) resulted in pure material as a viscous oil: 0.26 g (0.9 mMol, 47%).
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:27])[CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:8](=[O:27])[CH2:9][C:10]2[N:14]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:31][CH:30]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Sc2ccccn2)cc1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2ccc(Cl)cc2)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-thioacetic acid S-pyridin-2-yl ester 1c and 4-chlorophenylmagnesium bromide using a similar procedure described above. 1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 2.38 (s, 3H), 4.61 (s, 2H), 7.02 (d, J=9.8 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.51 (t, J=9.1 Hz, 3H), 7.65 (s, 1H), 7.84 (d, J=8.4 Hz, 2H). Mass spectrum m/e 375 (M+).