Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)[C:9]=2[F:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)[C:32]([OH:34])=[O:33]>ClCCl>[C:4]([O:34][C:32]([N:26]1[CH2:27][CH2:28][N:23]([C:19]2[CH:18]=[C:17]([CH2:16][C:10]3[C:9]([F:29])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=3)[CH:22]=[CH:21][N:20]=2)[CH2:24][CH2:25]1)=[O:33])([CH3:8])([CH3:5])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cc2ccnc(N3CCNCC3)c2)c(F)c1-c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(Cc2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Synthesis of 1-[4-(3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-piperazine (P-515) In a 40 mL vial equipped with a stir bar was placed I-274 (360 mg, 0.703 mmol) and dichlormethane (2.3 mL). The solution was cooled in an ice-water bath for 10 minutes and then trifluoroacetic acid (522 μL, 7.03 mmol) was added. The solution was stirred at room temperature for 3 hours and then concentrated by a stream of nitrogen. To the oil was added water (50 mL), a saturated sodium bicarbonate solution (till pH 8) followed by extractions with dichloromethane (2×75 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated. The residue was purified by column utilizing 10%, 15% and then 20% methanol/dichloromethane as the eluent to produce 120 mg of P-515 as an off-white solid in 41% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.80 (t, J=5 Hz, 4H), 3.39 (t, J=5 Hz, 4H), 3.73 (s, 3H), 3.84 (s, 2H), 6.46 (d, J=5 Hz, 1H), 6.69 (s, 1H), 6.94 (d, J=8 Hz, 1H), 7.28 (bd, J=7 Hz, 1H), 7.32 (t, J=9 Hz, 1H), 7.36 (s, 1H), 7.41-7.47 (m, 2H), 7.98 (d, J=5 Hz, 1H) ppm. MS (APCI+): 412.1 (M+1); LC-MS: >99%.
Reaction SMILES: [C:1]([C:5]1(C([O-])=O)[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH3:12])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[K+].[OH-].[K+]>>[C:1]([C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=CC=C(O)C(C(=O)[O-])(C(C)(C)C)C1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(O)c(C(C)(C)C)c1
Yield: 122.8 %

Procedure:
By operating according to Example 1, starting from 9.85 g of potassium 2-t-butyl-p-cresolate, obtained "in situ" by salification of 8 g of 2-t-butyl-p-cresol with KOH, and from 5.9 g of acetophenone (molar ratio = 1:1), 1.13 g of benzoylacetic acid were obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[C:17][CH2:18][OH:19])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]>[Pd].CCOC(C)=O>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12](/[CH:16]=[CH:17]\[CH2:18][OH:19])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C#CCO)cc(C)c1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(/C=C\CO)cc(C)c1OC(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of methyl 2-(acetyloxy)-5-(3-hydroxyprop-1-yn-1-yl)-3-methylbenzoate (0.417 g, 1.590 mmol) and palladium on carbon (170 mg, 1.597 mmol) in EtOAc (20 mL) was stirred at room temperature under a balloon atmosphere of H2 for 3 days. The reaction mixture was filtered through a plug of Celite and washed through with EtOAc (3×30 mL). The filtrate was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 0-20% EtOAc in hexanes over 40 min) to afford methyl 2-(acetyloxy)-5-[(1Z)-3-hydroxyprop-1-en-1-yl]-3-methylbenzoate, as a pale yellow oil. 1H NMR (500 MHz, CHCl3): δ 7.69 (s, 1 H); 7.29 (s, 1 H); 6.53 (d, J=12 Hz, 1 H); 5.94 (m, 1 H); 4.44 (d, J=6.4 Hz, 2 H); 3.88 (s, 3 H); 2.40 (s, 3 H); 2.25 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:18]([CH3:19])[C:17](=O)[O:16][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:14]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[F:8].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:18]([CH3:19])[C:17](=[S:35])[O:16][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:14]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(F)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCC1(CC)OC(=S)N(C)c2ccc(Nc3ccc(F)c(F)c3)cc21
Yield: 36 %

Procedure:
To a stirred solution of 6-[(3,4-difluorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.10 g, 0.29 mmol) in toluene (5 mL) was added Lawesson's reagent (0.09 g, 0.23 mmol). The reaction mixture was heated to reflux overnight and partitioned between ammonium chloride solution (sat.) and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation using 20% ethyl acetate/hexane followed by trituration with ether gave 6-[(3,4-difluorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione as a white solid (0.03 g, 31%). 1H NMR (DMSO-d6): δ 8.44 (s, 1H), 7.32 (q, J=9.1 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.12 (dd, J=8.8, 2.4 Hz, 1H), 6.97 (m, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.81 (m, 1H), 3.75 (s, 3H), 1.99 (m, 4H), 0.85 (t, J=7.3 Hz, 6H); MS (ESI) m/z 363 ([M+H]+); MS (ESI) m/z 361 ([M−H]−); Anal. calcd for C19H20F2N2OS: C, 62.96; H, 5.56; N, 7.73. Found: C, 62.15; H, 5.65 N, 7.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]([OH:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:33]([F:34])([F:36])[F:35]
Reactant: COCN(c1cc(Cl)cnc1C(O)c1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
A mixture of 4-chloro-N-{5-chloro-2-[hydroxy-(2-nitro-phenyl)-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (˜1.0 g) and Dess-Martin periodinane (1.50 g, 3.54 mmol) in CH2Cl2 (20 mL) at room temperature was stirred for 2-4 h. A mixture of 10% aqueous Na2S2O3 (10 mL) and saturated aqueous NaHCO3 (10 mL) was then added and the biphasic mixture vigorously stirred for 30 min. The phases were then separated and the aqueous portion extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaHCO3, then brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue purified by flash column chromatography over silica gel (EtOAc/hexanes, 1:4, then 2:3) to provide 4-Chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. Mass spectrum m/z: 586.3 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].Cl.[CH:16]([NH:19][OH:20])([CH3:18])[CH3:17].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([N:19]([OH:20])[CH:16]([CH3:18])[CH3:17])=[O:5]
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Reactant: CC(C)NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)N(O)C(=O)c1c(Cl)cccc1[Si](C)(C)C

Procedure:
The title compound was prepared by reaction of the compound of Example b and the i-propylhydroxylamine hydrochloride in dioxane in the presence of two equivalents of triethylamine using the amination methods described above. m.p. 175°-179° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([S:19][CH2:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)C([O-])=O.[NH2:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36](/[CH:44]=[C:45]1/[C:46](=[O:69])[N:47]([CH2:50][C:51]3[CH:56]=[CH:55][N+:54]([CH2:57][C:58](=[O:68])[NH:59][C:60]4[CH:65]=[CH:64][C:63]([OH:66])=[C:62]([F:67])[CH:61]=4)=[CH:53][CH:52]=3)[CH2:48][CH2:49]/1)=[C:37]2[C:41]([OH:43])=[O:42]>CN(C)C(=O)C>[F:67][C:62]1[CH:61]=[C:60]([NH:59][C:58]([CH2:57][N+:54]2[CH:55]=[CH:56][C:51]([CH2:50][N:47]3[CH2:48][CH2:49]/[C:45](=[CH:44]\[C:36]4[CH2:35][S:34][C@H:33]5[N:38]([C:39](=[O:40])[C@H:32]5[NH:31][C:21](=[O:23])[CH2:20][S:19][C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:37]=4[C:41]([O-:43])=[O:42])/[C:46]3=[O:69])=[CH:52][CH:53]=2)=[O:68])[CH:65]=[CH:64][C:63]=1[OH:66]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1ccccc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccccc5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1

Procedure:
With 175.0 mg (1.08 mmol) 1,1′-carbonyldiimidazole, 182.0 mg (1.08 mmol) 2-(phenylthio)acetic acid and 500.0 mg (0.75 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml N,N-dimethylacetamide. The resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=1.[F:22][C:23]1[CH:31]=[C:30]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=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.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:28])=[C:30]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[CH:31]=1
Reactant: CN(C)c1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Reactant: O=C(O)c1ccc(F)cc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)c1cc(N2CC3CN(C(=O)c4ccc(F)cc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
A mixture of [6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine (50 mg, 0.17 mmol), 4-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (42.0 mg, 51.6%). MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found [M+H]+. 1H NMR (CDCl3): 7.90-7.65 (m, 3H), 7.57-7.35 (m, 1H), 7.18-7.02 (m, 1H), 5.23-5.05 (m, 1H), 4.02-3.20 (m, 7H), 3.16-2.84 (m, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH2:41][CH3:42])[C:3]([O:5][CH:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][CH:13]([CH3:35])[CH:14]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([O:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:21][C:20](=[O:34])[O:19]2)[CH2:9][CH:8]([O:36]C(C)(C)C)[CH2:7]1)=[O:4].C1C=CN=CC=1.F>C(#N)C.C(OCC)(=O)C>[CH3:1][CH:2]([CH2:41][CH3:42])[C:3]([O:5][CH:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][CH:13]([CH3:35])[CH:14]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([O:24][CH2:25][O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:21][C:20](=[O:34])[O:19]2)[CH2:9][CH:8]([OH:36])[CH2:7]1)=[O:4]
Reactant: CCC(C)C(=O)OC1CC(OC(C)(C)C)CC2CCC(C)C(CCC3CC(OCOCc4ccccc4)CC(=O)O3)C21
Agent: F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CCC(C)C(=O)OC1CC(O)CC2CCC(C)C(CCC3CC(OCOCc4ccccc4)CC(=O)O3)C21
Temperature: 0 °C
Yield: 9.3 %

Procedure:
A solution of 28.8 g (44.7 mmol) of intermediate 3B in 400 ml of acetonitrile was cooled at -20° C. under argon and treated with three 10 ml portions of HF-pyridine over 2 hours, with warming to 0° C. after 1.5 hours. The reaction mixture was diluted with 500 ml of ethyl acetate and washed sequentially with saturated copper sulfate (aqueous 2×150 ml), brine (1×250, 200 and 150 ml) and saturated sodium bicarbonate (aqueous, 2×250 ml, 1×200 ml). After drying the ethyl acetate solution with sodium sulfate and concentrating, the crude product was purified by silica gel chromatography, eluting with 40% hexanes in ethyl acetate to yield 2.2 g (93.7%) of intermediate 3C as a clear, colorless oil.
Reaction SMILES: [BH4-].[Na+].[OH:3][CH2:4][C:5]1[C:9](O)([CH3:10])[O:8][C:7](=[O:12])[C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>COCCOC>[OH:3][CH2:4][C:5]1[CH:9]([CH3:10])[O:8][C:7](=[O:12])[C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(O)OC(=O)C(c2ccccc2)=C1CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1OC(=O)C(c2ccccc2)=C1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To NaBH4 (147 mg, 3.88 mmol) suspended in anhydrous ethylene glycol dimethyl ether (20 mL) at 0° C. under argon was added 4-hydroxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 6) in ethylene glycol dimethyl ether (20 mL) dropwise. After stirring for 3 hours the solution was acidified to pH2 with 6N HCl, warmed to ambient temperature and stirred an additional 1 hour. The solution was concentrated to 10 mL volume and the organics were extracted into ethyl acetate. The combined organic fractions were washed with a saturated solution of aqueous sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 30% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1C=CC=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]I.C(Cl)Cl.C1C[O:25]CC1>[Cu]I>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:25])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: C1CCOC1
Agent: [Cu]I
Agent: C[Mg]I
Solvent: ClCCl
Product: CC[C@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a mixture of the benzyl ether above (44 g, 0.268 mol) and CuI (51 g, 0.268 mol) in anhydrous THF (1 L) was slowly added MeMgI (270 mL of a 3 M THF solution, 0.810 mol) at -78° C. The mixture was stirred at -78° C. for 4 hours and was warmed to room temperature. After aqueous work-up (CH2Cl2) and chromatography, 47.0 g of the title compound was obtained: [α]25D +8.2° (c 1.2, CHCl3). IR: 3428. 1H NMR (CDCl3): δ0.94 (3H, t, J=7.5), 1.47 (2H, m), 2.38 (1H, br), 3.32 (1H, dd, J=8.0, 9.3), 3.50 (1H, dd, J=2.9, 9.3), 3.73 (1H, m), 4.54 (2H, s), 7.26-7.36 (5H, m). 13C NMR (CDCl3): δ9.8, 26.1, 71.7, 73.3, 74.3, 127.7, 127.7, 128.4, 138.0. HRMS (EI) calcd for C11H16O2 180.1150, found 180.1145.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=N)[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][N:25](C=O)C>>[CH2:1]([C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[CH:24][NH2:25])[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2sccc2c(=N)n1CCC
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCC1=Nc2sccc2C(=CN)N1CCC

Procedure:
In a sulfonation flask 3.74 g (0.015 mol) 2-butyl-3-propyl-3H-thieno [2,3-d]pyrimidine-4-ylideneamine, 2.84 g (0.03 mol) Mel, 4.15 g (0.03 mol) powdered sodium carbonate and 50 ml abs. DMF are stirred for 4 hours at an internal temperature of 70° C. Then DMF is distilled off in vacuum and the residue taken up in ethylacetate. The organic phase is washed with water and after drying the organic phase over Na2SO4 the solvent is removed in a water jet vacuum. The raw material is purified by column chromatography over silica gel (eluant: hexane/THF 1:1). Yield: 2.7 g of (2-butyl-3-propyl-3H-thieno [2,3-d]pyrimidin-4-ylidene) methylamine in the form of yellow crystals, m.p. 45-47° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12](=[O:16])[C:13](Cl)=[O:14].CCN(CC)CC.[CH2:24]([OH:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12](=[O:16])[C:13]([O:26][CH2:24][CH3:25])=[O:14]
Reactant: CCO
Reactant: COc1ccc2[nH]cc(C(=O)C(=O)Cl)c2c1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)c1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride (14.78 g, 62.20 mmol) in ethanol (144 mL), Et3N (10.40 mL, 74.63 mmol) was added at 0° C. and the resulting yellow suspension was stirred at rt for 1 h. The percipitate was filtered off, washed with cold ethanol and diethylether to yield ethyl 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetate as an orange oil. LC-MS conditions B: tR=0.63 min, [M+H]+=248.13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Yield: 45 %

Procedure:
A solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (130.8 mg, 0.37 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 5 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 57.4 mg (45%) of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5 (m, 2H), 7.3 (m, 2H), 7.15-7.0 (m, 2H), 6.95 (d, 1H, J=8 Hz), 6.85 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (CHCl3, cm−1) 3431, 3200 (br), 1628, 1614, 1600, 1580, 1546, 1488, 1448, 1329, 1261, and 776. MS (ES) m/e 333, 335.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:49])[NH:18][C:19]3[S:20][C:21]4[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=4[C:23]=3[C:24](=[O:44])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)=[CH:28][CH:27]=3)[CH:12]=2)[CH2:6][C:7](O)=[O:8])[CH2:4][CH2:3]1.Cl.[CH3:51][NH:52][CH2:53][C:54]([O:56][CH3:57])=[O:55].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.C(N(CC)CC)C.ClCCl>[CH:2]1([N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:49])[NH:18][C:19]3[S:20][C:21]4[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=4[C:23]=3[C:24](=[O:44])[NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)=[CH:30][CH:31]=3)[CH:12]=2)[CH2:6][C:7]([N:52]([CH3:51])[CH2:53][C:54]([O:56][CH3:57])=[O:55])=[O:8])[CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN(CC(=O)O)C5CC5)c4)sc4c3CCCC4)cc2)cc1
Reactant: CNCC(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)CN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.5 %

Procedure:
To a mixture of 306 mg of N-cyclopropyl-N-[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl]glycine hydrochloride and 5.0 mL of dichloromethane were added 0.182 mL of triethylamine, 91 mg of methyl N-methylglycinate hydrochloride, 125 mg of WSC.hydrochloride and 88 mg of HOBt, followed by stirring for 15 hours at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 152 mg of methyl N-cyclopropyl-N-[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl]glycyl-N-methylglycinate.
Reaction SMILES: COC(=O)C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=NC=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.CC1(C)C(C)(C)OB([C:63]2[CH:64]=[N:65][NH:66][CH:67]=2)O1>>[CH3:44][C:28]1[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])=[N:30][C:25]([C:63]2[CH:64]=[N:65][NH:66][CH:67]=2)=[C:26]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[CH:27]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cn[nH]c2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give the title compound as colorless amorphous solid. MS: 484.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(O)cc(C(=O)O)c1
Product: CC(=O)Oc1cc(C(=O)O)cc(C(=O)O)c1

Procedure:
5-hydroxyisophthalic acid (45.5 grams, 0.25 mole) was heated in acetic acid anhydride (102 grams, 1 mole) to reflux for one-half hour until dissolved. Refluxing was continued for a total time of 5 hours. Excess acetic acid anhydride was removed in vacuum and white product was recrystallized twice from a chloroform/toluene (50/50 weight/weight) mixture. Yield was 48 grams, which was 86% of theoretical yield. A melting point was determined, as in all of the preparations and examples using a Thomas-Hoover melting point apparatus, which indicated onset of decomposition, and apparent release of acetic acid, at a temperature of about 235° C. Nuclear magnetic resonance (NMR) performed on a 300 MHz GE instrument using deuterated dimethylsulfoxide (DMSO-d6) gave the following peaks (in parts per million (ppm)): 2.25 (s,3H), 7.8 (s,2H), 8.3 (s,1H),13.4 (broad, 2H, COOH).