Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([F:16])([F:15])[F:14])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:6]2)[CH3:2].C1COCC1.CCO.O.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([F:14])([F:15])[F:16])[C:7]([C:17]([OH:19])=[O:18])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(CC)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.2 %

Procedure:
A 15 mL single-neck round bottom flask was charged with ethyl 6-ethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.238 g, 0.932 mmole), THF:EtOH:H2O (7:2:1 by volume, 3 mL), and aqueous NaOH (0.41 mL of 2.5 N aq solution, 1.026 mmole). The reaction was stirred at RT under nitrogen for 3 days and was concentrated in vacuo (high vacuum) to yield a semi-solid. The semi-solid was dissolved in H2O, washed with diethyl ether, and sparged with nitrogen with gentle warming. The resulting organic solvent-free aqueous phase was acidified with concentrated HCl with stirring providing a slurry. The slurry was vacuum filtered yielding a white solid. The solid was dried on high vacuum yielding the title compound as a white powder (0.178 g, 70%): mp 145-149° C. LCMS m/z 273.15 (M+H). HRMS m/z 271.0600 (M−H, C13H10F3O, Cald'd 271.0577). 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.30 (d, 1H, J=2.0 Hz), 7.27 (d, 1H, J=8.3 Hz), 6.94 (d, 1H, J=8.3 Hz), 5.77 (q, 1H, J=7.0 Hz), 2.61 (q, 2H, J=7.5 Hz), 1.21 (t, 3H, J=7.5 Hz).
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[O:7]1[CH2:6][CH2:5][S:1][CH2:2][CH2:3][O:4][C:16]1=[O:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCSCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCCSCCO1

Procedure:
The procedure of Example 1 was followed using 2,2′-thiodiethanol (10.2 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding only oligomeric compounds.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3]>[C].[Pd].CC(O)C>[CH3:12][O:11][C:1]1[CH:10]=[C:6]([CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][C:2]=1[OH:3]
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: [Pd]
Solvent: CC(C)O
Product: CCCc1ccc(O)c(OC)c1

Procedure:
Palladium-carbon (5 mass %, 54 mg) was added to a 2-propanol (2.5 mL) solution of eugenol (CAS No. 97-53-0, 500 mg) under an argon atmosphere. The resultant mixture was vigorously stirred at an external temperature of 50° C. under a hydrogen flow for about 4.5 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated, to thereby obtain the title compound (447 mg) having the following physical properties.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:43])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:20][CH:19]2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+]>O.CO>[C:39]([O:38][C:36]([CH:19]1[CH2:20][CH:21]([C:29]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)=[O:30])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:43])[NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([OH:5])=[O:3])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N3CCCC3)C2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CC(C(=O)N2CCCC2)C(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 43.1 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.85 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbonyl)phenyl)ureido]acetyl}-5-phenyl-4-(1-pyrrolidinylcarbonyl)pyrrolidine-2-carboxylate and 0.18 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 50 cm3 of methanol. After treatment, there is obtained 0.76 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-4-(1-pyrrolidinylcarbonyl)-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid [Rf =0.17; eluent: methylene chloride/methanol (97.5/2.5)].
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.O([Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:14]1([S:11]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([NH2:1])[C:3]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([O:27][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:25][CH2:26]4)=[C:4]3[CH:10]=[CH:9]2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol (5.00 g, 13.0 mmol) was dissolved in DCM (50 mL) and 2,6-lutidine (6.0 mL, 51.8 mmol) was added. The mixture was cooled to 0° C. and tert-butyldimethylsilyl triflate (8.90 mL, 38.9 mmol) was added dropwise. The mixture was allowed to return to room temperature and stirred for 16 h. The mixture was concentrated under vacuum, then the residue was dissolved in methanol (10 mL). This mixture was stirred at room temperature for 90 min, then concentrated. The residue was suspended in water and extracted with DCM (×3). The combined organic extracts were washed sequentially with 10% aqueous citric acid, saturated aqueous NaHCO3 and brine, then dried (Na2SO4) and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: DCM to 25% ethyl acetate in DCM) gave 3.09 g (48%) of trans 1-benzenesulfonyl-N*4*-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4,5-diamine. LCMS (Method B, ESI): RT=3.99 min, m+H=501.1; NMR (400 MHz, CDCl3) δ: 8.14 (d, 2H), 7.84 (s, 1H), 7.54 (m, 1H), 7.45 (m, 3H), 6.55 (d, 1H), 3.70 (m, 2H), 2.35-1.85 (m, 6H), 1.46 (m, 2H), 1.30 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:19])[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(CCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c1
Yield: 19.7 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3-methoxyphenethyl)-1-piperidine-carboxamide formate (0.398 g, 0.899 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.290 g, 0.71 mmol) according to Procedure G to yield (eluant: 20:1 chloroform-methanol) the title compound (0.110 g, 0.14 mmol)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([Cl:17])[C:13]([O:18][CH3:19])=[CH:12][CH:11]=2)=[O:7])[CH3:4].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:24][C:23]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=2)[C:10]2[C:15]([CH:16]=1)=[C:14]([Cl:17])[C:13]([O:18][CH3:19])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2c(Cl)c(OC)ccc2[nH]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)c(OC)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
Sodium hydride (60 mg) was added to a solution of ethyl-4-chloro-5-methoxyindole-2-carboxylate (250 mg), 3,4-dichlorobenzylchloride (0.21 ml) and tetrabutylammoniumiodide (3 mg) in DMF at ambient temperature under an inert atmosphere. The reaction was stirred at ambient temperature for 18 hours then partitioned between ethylacetate (30 ml) and water(30 ml). The organic phase was dried (MgSO4), concentrated under vacuo and the residue purified by column chromatography using isohexane-15% ethylacetate as eluent to yield the product as a white solid (196 mg,48%) NMR: δ (CDCl3) 1.39 (t, 3H), 3.93 (s, 3H), 4.32 (q, 2H), 5.73(s, 2H), 6.84 (dd, iH), 7.06-7.16 (m, 3H), 7.31 (d, 1H), 7.42 (s, 1H)
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.Cl.[CH3:12][N:13]([CH3:32])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30].I.[NH2:34][C:35]1[C:36]([C:43]([NH:45][C:46](=[NH:49])SC)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1>C(O)C>[CH3:32][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:46]([NH2:49])=[N:45][C:43]([C:36]1[C:35]([NH2:34])=[N:40][C:39]([NH2:41])=[C:38]([Cl:42])[N:37]=1)=[O:44]
Reactant: CN(C)CCCNC(=O)CCCCCCCCCCCN
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCNC(=O)CCCCCCCCCCCNC(N)=NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
Diisopropylethylamine (0.23 mL, 1.31 mmol) was added to a suspension of 12-amino-dodecanoic acid (3-dimethylaminopropyl)amide dihydrochloride (5) (0.081 g, 0.22 mmol) in absolute ethanol (5 mL). The mixture became homogeneous. It was stirred at 70° C. (oil bath) for 5 min and then 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.093 g, 0.24 mmol) was added in one portion. The reaction mixture was stirred at this temperature for 3 hours and cooled to room temperature. The solvent was then removed by rotary evaporation, the residue dissolved in small volume of methanol, and this solution passed through an ion exchange resin column (Dowex 550A OH type). The resin was rinsed with methanol and the methanol solution was concentrated in vacuo. The resulting residue was purified by Biotage silica gel column chromatography, eluting with a gradient of 1% to 10% of 9:1 methanol/ammonium hydroxide in dichloromethane, to give 12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]dodecanoic acid (3-dimethylaminopropyl)amide 6 (0.070 g, 63%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.25 (m, 14H), 1.50 (m, 6H), 2.01 (t, 2H), 2.11 (s, 6H), 2.20 (t, 2H), 3.02 (m, 2H), 3.12 (t, 2H), 6.80 (br, 3H), 7.75 (m, 1H). m/z (ESI) 512 [C23H42ClN9O2+H]+. mp 82-84° C.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([C:46]([NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl.[OH-].[Na+]>O1CCOCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:46]([NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH:43]=[CH:44][CH:45]=2)=[N:20][CH:19]=[N:18]1
Reactant: O=C(NCc1ccccc1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 18.1 %

Procedure:
To a stirred solution of (3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-N-benzylcarboxamide (0.232 g, 0.322 mmol) was added dioxane (10.0 mL) and aqueous 6 N hydrochloric acid (10.0 mL) and the mixture heated at 50° C. for 24 h. The mixture was cooled and aqueous 6 N sodium hydroxide (20 mL). Neutralization of the aqueous layer to pH=7 with aqueous 6 N hydrochloric acid followed by extraction with ethyl acetate, drying of the organic extracts over anhydrous sodium sulfate, filtration and evaporation gave crude product. Purification by preparative HPLC (15–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0230 g, 18% yield). 1H NMR (CD3OD) δ 8.78 (s, 1H), 8.49 (t, 1H), 8.21 (dt, 1H), 8.11 (br d, 1H), 7.93 (dt, 1H), 7.69 (t, 1H), 7.65 (d, 1H), 7.40 (dd, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 4.64 (s, 2H). ES-MS (m/z) 395 [M+1]+
Reaction SMILES: O[C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:3]([CH3:7])[C:4]([OH:6])=[O:5].C1(S(Cl)(=O)=O)C=CC=CC=1>N1C=CC=CC=1>[CH3:7][C@H:3]1[C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:5][C:4]1=[O:6]
Reactant: C[C@H](C(=O)O)[C@@H](O)CCCCc1ccccc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[C@@H]1C(=O)O[C@H]1CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
A solution of (-)-(2S,3S)-3-hydroxy-2-methyl-7-phenylheptanoic acid (0.79 g, 3.3 mmol) in pyridine (30 mL) is cooled to 0° C. and benzenesulfonyl chloride (0.85 mL, 6.7 mmol) is added over 1 minute. The reaction is stirred in ice for 5 minutes, at room temperature for 2 hours and then at 0° C. for 16 hours. The reaction is poured into ice (40 mL) and extracted with ether (100 mL). The organic phase is washed with NaHCO3 (30 mL), 1N HCl (2×20 mL) and water (2×30 mL). The organic phase is dried over MgSO4 and concentrated in vacuo. The crude product is purified by column chromatography (silica, 25% ether in petroleum ether) to give (3S,4S)-3-Methyl-4-(4-phenylbutyl)oxetan-2-one (0.28 g, 39%): 1H NMR (300 MHz, CDCl3) δ 7.31-7.21 (m, 2H), 7.19-7.15 (m, 3H), 4.19-4.13 (m, 1H), 3.25-3.16 (m, 1H), 2.64 (t, J=7.6 Hz, 2H), 1.95-1.64 (m, 4H), 1.55-1.40 (m, 2H), 1.36 (d, J=7.8 Hz, 3H); MS (EI) m/e 218 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[C:20]1(C)C=C(C)C=C(C)C=1Cl>CN(C=O)C>[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:19])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:20][O:1]2)=[CH:4][CH:5]=1
Reactant: Cc1cc(C)c(Cl)c(C)c1
Reactant: COc1ccccc1CC(=O)c1ccc(O)cc1O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1coc2cc(O)ccc2c1=O
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
BF3—OEt2 complex (14 ml, 112 mmol) was gradually added to a solution of 1-(2,4-dihydroxy-phenyl)-2-(2-methoxy-phenyl)-ethanone (7.2 gm, 28 mmol) in DMF at 0° C. The resulting solution was stirred for 30 min. Mesityl chloride (6.5 ml, 84 mmol) was then gradually added to it at 50° C. The solution was then heated up to 110° C. for 5 hours. The mixture was then concentrated. The residue was treated with ice and the solid obtained was purified with silica gel column chromatography using hexane-chloroform as the eluent to give 7-hydroxy-3-(2-methoxy-phenyl)-chromen-4-one (5.6 gm, 75%) as white solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:13])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:2][CH:1]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:13]
Reactant: O=CC1CCc2ccccc2C1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC=C1CCc2ccccc2C1=O

Procedure:
The 2-formyl-1-tetralone derivative of formula (3) is converted to the corresponding 2-enol ether of formula (4) by reacting a compound of formula (3) with an alcohol, preferably methanol, in the presence of a catalytic amount of a strong acid, preferably concentrated sulfuric acid. The reaction is preferably carried out at a temperature of about the reflux temperature of the alcohol, for about 5 minutes to 2 hours, preferably about 15 minutes. The product of formula (4), a 2-methoxymethylene-1-tetralone derivative, is isolated by conventional means, preferably by precipitation and filtration, and is reacted in the next step without any further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:37][CH2:36][N:35]([C:41]4[CH:42]=[CH:43][C:44]([C:45]#[N:46])=[CH:47][CH:48]=4)[CH2:40][CH2:39]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][S:15][CH2:16][C@@H:8]12
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (80.0 mg, 0.318 mmol) was suspended in propionitrile (0.8 mL) and (cyanomethyl)trimethylphosphonium iodide (93.0 mg, 0.382 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (167 ul, 0.955 mmol). To the stirred mixture was then added 4-(piperazin-1-yl)benzonitrile (59.6 mg, 0.318 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature and left to sit 48 h. The precipitate was filtered off, washed with ethanol (5 mL) and dried in vacuum to afford the title compound (36.0 mg, 26.9%) as a white solid. 1H NMR(CHLOROFORM-d) δ (ppm): 8.26 (br. s., 1H), 7.79 (d, J=1.8 Hz, 1H), 7.44-7.60 (m, 2H), 6.96 (br. s., 1H), 6.76-6.91 (m, 2H), 5.05 (dt, J=13.6, 2.7 Hz, 1H), 4.43 (dd, J=10.7, 3.2 Hz, 1H), 3.27-3.63 (m, 6H), 3.15 (td, J=12.8, 2.3 Hz, 1H), 3.00 (td, J=12.8, 2.7 Hz, 1H), 2.77-2.93 (m, 2H), 2.59 (br. s., 4H), 2.34-2.45 (m, 1H). [M+H] calc'd for C22H24N6OS, 421; found, 421.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[K+].[Br-]>>[N:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc3cccnc23)CC1
Agent: [Br-]
Agent: [K+]
Product: c1cnc2c(N3CCCNCC3)cccc2c1
Yield: 100 %

Procedure:
The title compound was prepared according to the procedure of Example 1, Step 6 except that 4-quinolin-8-yl-[1,4]diazepane-1-carboxylic acid tert-butyl ester was used in place of 4-(2-methoxy-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester. Yield: 100%; 1H NMR (300 MHz, CDCl3): δ2.05 (pent, J=6.2 Hz, 2H), 3.11 (t, J=5.7, Hz, 2H), 3.31 (t, J=5.6 Hz, 2H), 3.68 (t, J=6.0 Hz, 2H), 3.75 (t, J=6.0 Hz, 2H), 4.47 (brs, 1H), 7.09 (dd, J=1.4, 7.4 Hz, 1H), 7.28-7.39 (m, 3H), 8.02 (dd, J=1.5, 7,5 Hz, 1H), 8.78 (d, J=1.4 Hz, 1H); IR (KBr, cm−1): 3309w; MS (ES) m/z (relative intensity): 228 (M++H, 60).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[S:37]([NH-:40])(=[O:39])=[O:38].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC(O)=O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3/[CH:27]=[CH:28]/[C:29]([NH:40][S:37]([C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)(=[O:39])=[O:38])=[O:30])[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C/c1ccccc1-c1cccc(-c2ccccc2OCc2ccccc2)c1
Reactant: [NH-]S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccccc1-c1cccc(-c2ccccc2OCc2ccccc2)c1)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.1 %

Procedure:
To (E)-3-(2-{3-[2-(Phenylmethoxy)phenyl]phenyl}phenyl)prop-2-enoic acid (210 mg, 0.52 mmol) of Example 2 (step 2), 2-thiophenesulfonylamide (121 mg, 0.74 mmol) and DMAP (250 mg, 2.04 mmol) in CH2Cl2 (3 mL) was added EDCI (142 mg, 0.74 mmol). After stirring at r.t. for 2 days, the reaction mixture was poured into 1N HCl (or aqueous AcOH) and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Purification by flash chromatography (Tol:EtOAc:AcOH, 1:0:0 to 20:1:0.1) and recrystallization (Hex:CH2Cl2) provided the desired material as a white solid (161 mg, 56%). 1H NMR (acetone-d6) δ 5.13 (2H, s), 6.72 (1H, d), 7.04 (1H, td), 7.1-7.2 (2H, m), 7.2-7.4 (8H, m), 7.4-7.5 (4H, m), 7.55 (1H, t), 7.62 (1H, dt), 7.7-7.8 (3H, m) and 7.92 (1H, dd).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:6]2[CH:25]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[SH:50].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([CH:25]=[C:3]([CH2:2][S:50][C:41]4[CH:42]=[CH:43][C:44]5[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=5)[N:40]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)=[CH:8][N:9]=2)[CH2:12][CH2:13]1
Reactant: Sc1ccc2ccccc2n1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CO)cn23)cn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CSc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 75b (70.2 mg, 0.209 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (10 mL) and DIEA (72.7 μL, 0.417 mmol) were added. MsCl (24.3 μL, 0.313 mmol) was added, and then the reaction was stirred at rt for 3 days. Additional MsCl (24.3 μL, 0.313 mmol) and DIEA (72.7 μL, 0.417 mmol) were added and the reaction was stirred for 2 h. The solvent was removed under reduced pressure. The crude material was placed in a 50 mL round bottom flask equipped with a stir bar, followed by addition of ACN (25 mL). 2-Quinolinethiol (38.2 mg, 0.230 mmol) and K2CO3 (43.3 mg, 0.313 mmol) were added and then the reaction was stirred at rt for 1 h. The temperature was increased to 80° C. and the reaction was stirred for 18 h. The reaction was cooled to rt, diluted with DCM (20 mL), and filtered. The solvent was removed under reduced pressure. The crude produced was purified by flash column chromatography on silica gel (25-g SiO2 pre-packed column, 0-100% EtOAc/heptanes) to afford compound 75c. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.84 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.81-7.89 (m, 2H), 7.78 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.46-7.53 (m, 1H), 7.35 (s, 1H), 7.21 (d, J=8.6 Hz, 1H), 4.69 (s, 2H), 4.30-4.43 (m, 4H), 3.82-3.91 (m, J=4.5, 4.5 Hz, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H21N7OS: 480.2 (M+H). found: 480.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]2[CH3:30])=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[CH3:30])=[CH:4][CH:3]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1CC1=C(c2ccc(Cl)cc2)CC(C)(C)CC1
Agent: Cl
Product: CC1CNCCN1CC1=C(c2ccc(Cl)cc2)CC(C)(C)CC1

Procedure:
A solution of EXAMPLE 290C (0.298 g) and HCl (4.0M in dioxane, 2 mL) were stirred for 1 hour. The reaction was concentrated and partioned between dichloromethane (100 mL) and NaHCO3 (100 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to provide the title compound.