Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[CH:23]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=S(=O)(NCCCCCO)c1ccc(-c2ccc(F)c(F)c2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 3,4-difluorophenyl boronic acid were reacted to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 22.7, 29.3, 31.9, 43.1, 62.5, 116.4 (d, J 17.6), 118.0 (d, J 17.6), 123.5 (d, J 4.9), 127.6, 127.8, 136.4 (m), 139.2, 143.3, 150.5 (d, J 250.0) and 150.7 (d, J 250.0).
Reaction SMILES: COP([CH:7]([CH:13]([CH3:15])[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(OC)=O.C([Li])CCC.[CH3:21][C:22](=[CH:24][CH2:25][CH2:26]/[C:27](=[CH:29]/[CH:30]=O)/[CH3:28])[CH3:23].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:14][CH:13]([C:7](=[CH:30][CH:29]=[C:27]([CH3:28])[CH2:26][CH2:25][CH:24]=[C:22]([CH3:23])[CH3:21])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:15]
Reactant: CCOC(=O)C(C(C)C)P(=O)(OC)OC
Reactant: CC(C)=CCC/C(C)=C/C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=CC=C(C)CCC=C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
To a solution of ethyl 2-(dimethylphosphono)-3-methylbutyrate (11.0 g, 41.3 mmol) in tetrahydrofuran (50 ml) chilled at -68° C. was dropwise added 1.62M solution of n-butyllithium in hexane (21.6 ml, 35.0 mmol) with stirring in 15 minutes under argon atmosphere. After stirring at -72° C. for 15 minutes, the mixture was mixed with geranial (4.0 g, 26.3 mmol), warmed up to room temperature in 30 minutes and stirred for 5 hours. The reaction mixture was chilled on an ice bath and mixed with saturated aqueous ammonium chloride (100 ml) and hexane (100 ml). The organic layer was separated, washed with saturated aqueous sodium chloride (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting residue was chromatographed on a silica gel column (Eluent: n-hexane:ether=30:1) to give ethyl 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienate (3,07 g, 48%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][C:12]4[NH:13][C:14]5[C:19]([C:20]=4[CH:21]=3)=[CH:18][CH:17]=[CH:16][CH:15]=5)[O:6][N:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][N:13]1[C:12]2[CH:11]=[N:10][C:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2
Reactant: ClCCCBr
Reactant: c1ccc2c(c1)[nH]c1cnc(-c3nc(C4CC4)no3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCn1c2ccccc2c2cc(-c3nc(C4CC4)no3)ncc21
Yield: 63 %

Procedure:
The compound was synthesized by mixing (Compound 5) (1.0 g, 3.6 mmol), NaH (0.22 g, 4.3 mmol) and 1-bromo-3-chloropropane (0.68 g, 4.3 mmol)in DMF, in the same manner as illustrated in example 3, to give the title compound (0.76 g, 63%) as a white solid. M.p. 165°-169° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-]>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: c1cocn1
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ncco2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C., stirred solution of oxazole (190 μL, 3.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (2.6 mL of a 1.6 M solution in hexanes, 4.2 mmol). After 30 min, zinc chloride (11.5 mL of a 1.0 M solution in diethyl ether, 11.5 mmol) is added. The reaction mixture is warmed to 0° C. and methyl 4-iodobenzoate (1 g, 3.8 mmol) and palladium(0)tetrakis(triphenylphosphine) (530 mg, 0.4 mmol) are added. The reaction mixture is heated at 70° C. for 20 h under argon, cooled to room temperature, and then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) yields the title compound. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 4H), 8.07-8.05 (m, 1H), 7.36-7.35 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: ClC1C=C(C(OCC)=O)C=CC=1C1C=C(OC)C=CC=1F.CC1(C)C(B2OC(C)(C)C(C)(C)O2)=CCC1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:75][C:76]1([CH3:101])[C:80]([C:81]2[CH:86]=[C:85]([C:87](OCC)=[O:88])[CH:84]=[CH:83][C:82]=2[C:92]2[CH:97]=[C:96]([O:98][CH3:99])[CH:95]=[CH:94][C:93]=2[F:100])=[CH:79][CH2:78][CH2:77]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>CN(C=O)C.O.C1COCC1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:75][C:76]1([CH3:101])[C:80]([C:81]2[CH:86]=[C:85]([CH2:87][OH:88])[CH:84]=[CH:83][C:82]=2[C:92]2[CH:97]=[C:96]([O:98][CH3:99])[CH:95]=[CH:94][C:93]=2[F:100])=[CH:79][CH2:78][CH2:77]1
Reactant: CCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCCC2(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CCC=C1B1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of compound T2.5 (1.80 g, 5.80 mmol), 2-(5,5-dimethylcyclopent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (T2.2)(1.40 g, 6.4 mmol), S-Phos (0.48 g, 1.20 mmol), tripotassium phosphate (3.10 g, 15.0 mmol) and palladium acetate (0.13 g, 0.58 mmol) in DMF (10.0 mL) and water (1.0 mL), was purged with N2 three times. The resulting mixture was heated at 100° C. overnight. EtOAc (120 mL) was added, and the mixture was washed with brine (25×2 mL). The organic layer was dried with MgSO4. The residue was purified by CombiFlash® silica gel column chromatography, eluting with hexane/EtOAc, 9/1 to give the Suzuki coupling product as an intermediate, ethyl 2-(5,5-dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-carboxylate. MS ESI (pos.) m/e: 369.1 (M+H)+. To a solution of ethyl 2-(5,5-dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-carboxylate (1.00 g, 3.0 mmol) in THF (10.0 mL), was slowly added LAH, (1.0M solution in diethyl ether, 4.0 mL, 4.0 mmol) at 0° C. After the addition, the reaction mixture was stirred at 40° C. for 1.5 hours, and then at room temperature for 2 hours. A mixture of water (0.22 mL) in THF (2.0 mL) was slowly added and then 15% sodium hydroxide (0.22 mL) was added at 0° C. Finally, water (0.65 mL) was added at room temperature. The solid was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by CombiFlash® silica gel column chromatography, eluting with hexane/EtOAc, 90/10 to 70/30) to give the title compound T2.6. 1H NMR (400 MHz, CDCl3) δ ppm. 7.24 (s, 2H), 7.09-7.21 (m, 1H), 6.84-6.96 (m, 1H), 6.68-6.72 (m, 2H), 5.43 (s, 1H), 4.65 (s, 2H), 3.66 (s, 3H), 2.17 (td, 2H), 1.77 (b, 1H), 1.58 (t, 2H), 0.78 (s, 6H). MS ESI (pos.) m/e: 309.1 (M−HO)+, 345.2 (M+H3O)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(OC)ccc2n1Cc1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared from ethyl 5-methoxy-1H-indole-2-carboxylate and 4-(tert-butyl) benzyl bromide in substantially the same manner, as described in step 1 of Example 1. The product was obtained as a solid. Mass spectrum (ESI, [M−H]−) m/z 364. 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, 1H, J=9.20 Hz), 7.27 (s, 1H), 7.24 (d, 2H, J=7.18 Hz), 7.16 (d, 1H, J=2.44 Hz), 6.96-6.92 (m, 3H), 5.77 (s, 2H), 4.28 (q, 2H), 3.76 (s, 3H), 1.28 (s, 3H), and 1.20 ppm (s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[CH:19][CH:18]=2)[C:13]1=[O:32].Cl>O1CCCC1.ClCCl.O.C(N(CC)CC)C>[F:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH2:15][CH2:16][C@@H:12]([NH:11][CH:1]=[O:3])[C:13]2=[O:32])=[CH:22][CH:21]=1
Reactant: N[C@@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CN[C@@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
A mixture of 188 mg (18 mmol) of acetic anhydride and 107 mg (23 mmol) of formic acid is prepared at 0° C., thereafter, heated to 60° C. for 2 hours. After cooling to RT, the mixture is diluted with 1 ml of tetrahydrofurane and a solution of 213 mg (7 mmol) of (R)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one in 2 ml of dichloromethane, beforehand prepared from the corresponding hydrochloride by treatment with triethylamine, is added. After the addition a white suspension is formed which is stirred at RT for 1 hour. For the working-up, the reaction mixture is treated with dichloromethane and water, then, the organic layer is separated, dried over sodium sulfate and evaporated. There are obtained 215 mg (92% of theory) of (R)-N-{1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-formamide as a white solid; MS: m/e=329 (M+H)+.
Reaction SMILES: N1CCCCC1.[CH:7]1([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=2[O:23][CH3:24])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([CH2:28][C:29]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])=[O:30])(O)=O.Cl>C1(C)C=CC=CC=1.CCO.O>[CH:7]1([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18](/[CH:19]=[CH:28]/[C:29]([NH:31][C:32]3[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=3[C:34]([OH:36])=[O:35])=[O:30])=[CH:17][C:16]=2[O:23][CH3:24])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1cc(C=O)ccc1OCC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OCC1CCCCC1
Yield: 52.3 %

Procedure:
Piperidine (0.24 mL, 2.4 mmol) was added to a suspension of 4-cyclohexylmethoxy-3-methoxybenzaldehyde (0.59 g, 2.4 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.48 g, 2.1 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recystallised from EtOH/water providing (E)-2-{[3-(4-cyclohexylmethoxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (0.45 g, 51%) as a colourless crystalline solid; mp 207-210° C.; δH (400 MHz, DMSO-d6) 1.03 (m, 2H, CH2), 1.20 (m, 4H, CH2), 1.63-1.82 (m, 5H, CH2, CH), 3.79 (d, J=6.4 Hz, 1H, OCH2), 3.83 (s, 3H, OCH3), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 6.96 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.18 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.21 (d, J5′,6′=8.4 Hz, J2′,6′=1.8 Hz, 1H, H6′), 7.36 (s, J2′,6′=1.8 Hz, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 25.2, 26.0, 29.2, 37.0, 55.8, 73.3, 110.7, 112.6, 116.6, 119.7, 120.3, 122.6, 127.1, 131.1, 134.0, 141.0, 141.6, 149.1, 150.2, 164.2, 169.4; HRMS (ESI) calculated for C23H25NO5 [M+Na]+ 432.1781. found 432.1781; vmax 759, 1142, 1504, 1581, 1667, 2925, 3123 cm−1.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])(=[O:6])=[O:5].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.N12CCCCC1C=NCCC2.Cl>C(#N)C.O>[CH3:1][N:2]([CH3:17])[NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:25]([NH:26][C:27]1[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=1)=[O:24])(=[O:15])=[O:14])(=[O:6])=[O:5]
Reactant: CN(C)NS(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)NN(C)C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
To a solution of 0.14 g of the product of Example 1 and 0.15 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate in 2 mL of dry acetonitrile was added 0.1 mL of 1,5-diazabicyclo[5.4.0]undec-5-ene. The solution was stirred for 15 minutes at room temperature, diluted with 2 mL of water and acidified with 5% hydrochloric acid to a pH of 4. The precipitated product was collected by filtration, washed thoroughly with water, washed with 1-chlorbutane, and dried in vacuo at 40° C. to afford 0.02 g of the subject compound, m.p. 127°-128° C. (dec).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2].Cl.[NH2:22][OH:23].C([O-])(O)=O.[Na+]>CO>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NO
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(C#N)cccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(C)(C)Cn1ncc2c(C(=N)NO)cccc21
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
Ethyl 3-(4-cyano-1H-indazol-1-yl)-2,2-dimethylpropanoate (D102) (348 mg, 1.28 mmol), hydroxylamine hydrochloride (1.087 g, 10.26 mmol), NaHCO3 (1.078 g, 12.83 mmol) in MeOH (20 ml) was heated at 65° C. for 24 h then at room temperature over the weekend. The mixture was filtered, concentrated, treated with water and vigorously stirred for 10 mins, filtered and dried to give a colourless solid, dried overnight in vacuo at 45° C. to give the title compound (373 mg, 90%). MS (ES) C15H20N4O3 requires 304, found 305 [M+H]+
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([N:58]5[CH2:63][CH2:62][NH:61][C:60](=[O:64])[CH2:59]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([N:58]5[CH2:63][CH2:62][NH:61][C:60](=[O:64])[CH2:59]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCNC(=O)C5)cccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCNC(=O)C5)cccc4c3=O)cc2)CCC1
Yield: 28 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{-4-[4-oxo-8-(3-oxo-piperazin-1-yl)-2-phenyl-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (8 mg, 28%). 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.69 (dd, J=7.4, 1.7 Hz, 1H), 7.41-7.26 (m, 9H), 7.09 (d, J=8.0 Hz, 2H), 3.71 (s, 2H), 3.40 (t, J=5.4 Hz, 2H), 3.35-2.99 (m, 4H), 2.36-2.27 (m, 2H), 2.07-1.87 (m, 3H), 1.65-1.53 (m, 1H). LCMS (Method E): RT=2.79 min, [M+H]+=466.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:17][CH2:18][CH3:19])=[CH:8][C:9]2[O:14][C:13](=[O:15])[CH:12]=[CH:11][C:10]=2[CH:16]=1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH2:18]([O:17][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[CH:16][C:10]2[CH:11]=[CH:12][C:13](=[O:15])[O:14][C:9]=2[CH:8]=1)[CH3:19]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOc1cc2oc(=O)ccc2cc1OCCCCl
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)O
Product: CCOc1cc2oc(=O)ccc2cc1OCCCN1CCN(c2ccccc2OC)CC1
Yield: 49 %

Procedure:
Method A (48 h at 60° C.); starting materials: 6-(3-chloropropoxy)-7-ethoxy-2H-1-benzopyran-2-one (example 70) and 1(2-methoxyphenyl)piperazine hydrochloride; yield 49%; fusion point 78°-80° C. (from isopropanol). Fumarate: method E; yield 82%; fusion point 149°-150° C. (from ethanol).
Reaction SMILES: [CH:1]1([C:4]2[N:14]=[C:7]3[N:8]=[C:9]([CH3:13])[CH:10]=[C:11](O)[N:6]3[N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:17])=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:17][C:11]1[N:6]2[N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:14]=[C:7]2[N:8]=[C:9]([CH3:13])[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(C3CC3)nc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)n2nc(C3CC3)nc2n1

Procedure:
A suspension of Intermediate 19 (0.15 g, 0.789 mmol) in phosphorous oxychloride (ALDRICH, 1 ml, 10.73 mmol) was heated under reflux for 1 h. The reaction mixture was added dropwise into iced water, neutralized with solid Na2CO3 and product was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The crude mixture was purified by flash chromatography (Si, eluting with Hexane:EtOAc mixtures from 100:0 to 40:60%) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C:11]3=[CH:12][CH2:13]2)[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C@H:11]3[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[C@]12CC=C3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(C)(C)C
Yield: 122.3 %

Procedure:
A mixture of lg (2.82 mmoles) of (+)-17β-tert.butoxy- 13β-ethyl-3-methoxygona-1,3,5(10),9(11)-tetraene, 0.25 g of 5% palladium on carbon and 25 ml of ethyl acetate was stirred in an atmosphere of hydrogen for 1 hr during which time a total of 74 ml of hydrogen was absorbed (70.5 ml theory). The catalyst was filtered with suction on Celite and the filter cake was washed well with ethyl acetate. Concentration of the combined filtrate and washes in vacuo gave 1.23 g of colorless solid. This material was chromatographed on 50 g of silica gel. Elution with 19:1 hexane:ether gave 0.925 g of colorless solid which recrystallized ethanol. This afforded 0.67 g of colorless plates, m.p. 121°-123°. [α]D25 + 44.69°(c 1.016, CHCl3); uv max (95% EtOH) 278 nm (ε 2020), 287 (1860); ir (CHCl3) 1610, 1580, 1500, 1360 cm-1 ; nmr (CDCl3)δ 7.18 (m, 1), 6.68 (m, 2), 3.74 (s, 3), 3.51 (t, 1, J = Hz), 1.15 ppm (s); ms m/e 356 (M+).
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[C:13]([S:21][CH:22]([CH3:24])[CH3:23])[CH:12]=2)=[CH:7][CH:6]=1.[Br:25]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:25][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[C:13]([S:21][CH:22]([CH3:24])[CH3:23])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(-c2ccc(OCCO)cc2)cc1SC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OCCBr)cc2)cc1SC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of methyl 4′-(2-hydroxyethoxy)-3-(isopropylthio)-4-biphenylcarboxylate (124 mg) and tetrabromomethane (285 mg) in tetrahydrofuran (1.86 ml) was added triphenylphosphine (207 mg) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified with silica gel column chromatography to give methyl 4′-(2-bromoethoxy)-3-(isopropylthio)-4-biphenylcarboxylate (142 mg).
Reaction SMILES: NC1SC=C(C(=O)C(N[C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:36])[NH2:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=O)N=1.NOC(C)(C)C(NNC(C1NC=C(O)C(=O)C=1)=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[C:34]([C:32]1[N:33]=[C:29]2[N:28]=[C:27]([CH3:37])[CH:26]=[C:25]([S:24][CH2:23][C:15]3[CH2:14][S:13][CH:12]4[N:17]([C:18](=[O:19])[CH2:11]4)[C:16]=3[C:20]([OH:22])=[O:21])[N:30]2[N:31]=1)(=[O:36])[NH2:35]
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Agent: CC(C)(ON)C(=O)NNC(=O)c1cc(=O)c(O)c[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)CC3SC2)n2nc(C(N)=O)nc2n1
Reaction time: 0.25 h

Procedure:
0.228 g (0.4 mmol) of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(2-carbamoyl -5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid was dissolved in 2 ml of dimethylacetamide. 0.140 g (0.52 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridyl) carbonyl]hydrazine and 0.100 g (0.52 mmol) of p-toluenesulfonic acid hydrate were added. After stirring for 20 hours at room temperature the dimethylacetamide was evaporated off at strongly reduced pressure and the residue was taken up in water and stirred for 15 minutes in order to completely precipitate the product. The product was filtered off, washed well with water and dried under strongly reduced pressure at room temperature. (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1,4-dihydro-5-hydroxy -4-oxo-2-pyridyl)carbonyl]carbazoyl]-1-methylethoxy]imino] -acetamido]-3-[[[2-carbamoyl-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl) thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was obtained as beige-colored powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][S:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.[Na].[Cl-].[NH4+].[NH4+]>O.C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CSCCN)C(=O)O
Yield: 76.1 %

Procedure:
N-t-Butoxycarbonyl-S-(2-carbobenzoxyaminoethyl)-L-cysteine (9.9 g) in 500 ml of liquid ammonia is treated with sodium metal until reaction is complete, as indicated by the persistence of a blue color. Ammonium chloride (1 g) is added, followed by ethanol (50 ml). Excess ammonia is let evaporate away. The residue is dissolved in a minimal amount of water, and extracted with ether. The aqueous layer is again taken to dryness, and the residue extracted with ethanol containing 6 ml of ammonium hydroxide. Upon removal of the ethanol the residue obtained is redissolved in 15 ml of water, and passed through 10 ml of Dowex-50 resin on the ammonium cycle. The resin is washed with 30 ml of water. The product (5.0 g) is obtained upon lyophilization of the eluent. The NMR spectrum (in D2O and NaOD) of such a sample shows a multiplet at 4.1, complex absorption between 2.6 and 3.0, and a singlet at 1.4.