Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[C:12]=1[NH:19][C:20](=[O:36])[CH2:21][CH:22]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:29][C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)(C)(=O)=O.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>CN(C)C=O.C(OCC)(=O)C>[N:37]1([CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[C:12]=2[NH:19][C:20](=[O:36])[CH2:21][CH:22]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[O:29][C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: CSc1cccc(COCCCOS(C)(=O)=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cccc(COCCCn2ccnc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 90 °C
Reaction time: 5.5 h
Yield: 68 %

Procedure:
251 mg of the crude crystals of N-{2-[3-(mesyloxy)propoxy]methyl-6-methylthiophenyl}-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (i) above] were suspended in 3 ml of dimethylformamide. 162 mg (2.39 mmol) of imidazole were added to the suspension, and the mixture was stirred for 5.5 hours at 90° C. At the end of this time, the reaction mixture was allowed to return to room temperature, after which it was diluted with ethyl acetate and washed several times with water. The solvent was then removed by distillation under reduced pressure, and the resulting residue was subjected to column chromatography through 15 g of silica gel. Fractions eluted with mixtures of methylene chloride and methanol ranging from 100:2 to 100:7 by volume were collected. Recrystallization from a mixture of methylene chloride and methanol afforded 162 mg (yield 68%) of the title compound as crystals, melting at 176.5°-177° C.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([S:22]([CH2:25][C@@H:26]([C@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)[NH:27][OH:28])(=[O:24])=[O:23])[CH2:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([S:22]([CH2:25][C@H:26]([N:27]([OH:28])[CH:1]=[O:3])[C@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)(=[O:23])=[O:24])[CH2:19]2)=[CH:14][CH:13]=1
Reactant: O=S(=O)(C[C@H](NO)[C@H]1CCCO1)N1CCc2ccc(Cl)cc2C1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CN(O)[C@@H](CS(=O)(=O)N1CCc2ccc(Cl)cc2C1)[C@H]1CCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (0.5 ml) and acetic anhydride (0.125 ml) was stirred at 0° C. for 1 hour, then a solution of (1R)-2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-N-hydroxy-1-[(2R)-tetrahydrofuran-2-yl]ethanamine (80 mg, 0.22 mmol) in anhydrous THF (5 ml) was added and the resulting mixture was stirred at RT for 1 hour. The mixture was evaporated under reduced pressure. The residue was taken up with MeOH (5 ml) and heated at 55° C. for 1 hour. The reaction mixture was evaporated under reduced pressure. After purification by crystallization in EtOAc/pentane, the title compound (22) was obtained as a white powder (37 mg, 43%). HPLC, Rt: 3.0 min (purity: 94.1%). LC/MS, M+(ESI): 389.3, M−(ESI): 387.3.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.[NH2:60][C@@H:61]([C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[CH2:62][C:63]([O:65][CH3:66])=[O:64]>CN1C(=O)CCC1.CCOC(C)=O>[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([NH:60][C@@H:61]([C:67]2[CH:68]=[CH:69][C:70]([Cl:73])=[CH:71][CH:72]=2)[CH2:62][C:63]([O:65][CH3:66])=[O:64])=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)C[C@@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 104.1 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.579 g, 1.52 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.5 g, 1.38 mmol) and DIPEA (0.503 mL, 3.04 mmol) in NMP (5 mL) at 20° C. The resulting solution was stirred at 20° C. for 5 minutes. (R)-methyl 3-amino-3-(4-chlorophenyl)propanoate (hydrochloride) (Intermediate 40) (0.346 g, 1.38 mmol) was then added to the solution and stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (50 mL), water (50 mL), and water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (R)-methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (0.800 g, 100%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].C([O-])([O-])=O.[Na+].[Na+]>>[Br:8][C:3]1[C:2]([O:1][C:9](=[O:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Oc1cccnc1Br
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)Oc1cccnc1Br
Temperature: 0 °C
Yield: 98.6 %

Procedure:
A solution of 3-hydroxy-2-bromopyridine (21.4 g, 123 mmol) in acetic anhydride (25 g, 245 mmol) was refluxed for 1 hour. After cooling, the mixture was poured into ice water, neutralized with Na2CO3 and extracted with ether. The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by ether to afford Acetic acid 2-bromo-pyridin-3-yl ester (26.2 g, 99%). 1H NMR (CDCl3, 400 mHz) δ 8.28 (m, 1H), 7.46 (m, 1H), 7.30 (m, 1H), 2.38 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: NCCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Temperature: 0 °C
Yield: 129.3 %

Procedure:
To a round-bottomed flask containing 7-bromo-4-chloro-3-nitroquinoline (60 g, 209.1 mmol) was added DMF (390 mL) and triethylamine (44 mL, 313.6 mmol) and the solution was stirred at 0° C. in an ice-bath. To this cooled solution was added 3-aminopropan-1-ol (17.6 mL, 230.0 mmol) and the reaction was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the resultant orange solid was recrystallized from ethyl acetate (800 mL). The product was separated by filtration and the solids were washed with diethyl ether and dried under reduced pressure to afford crude 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol (88.15 g) as a brown solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH:29]=[O:30])[CH2:24][CH2:23][CH2:22][CH2:21]1.[Cl-].[NH4+]>O1CCCC1>[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:29]([OH:30])[CH2:19][C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Cc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A stirred solution of diisopropylamine (14 mL) in dry tetrahydrofuran (150 mL), is treated dropwise with a solution of butyl lithium in hexanes (40 mL; 2.5 M), under nitrogen, while keeping the temperature at below −70° C. The resulting mixture is then stirred for a further period of 30 minutes at below −70° C. The stirred mixture, while it is still maintained at below −70° C., is then treated dropwise with a solution of 4-picoline (9.3 g) in dry tetrahydrofuran (20 mL). The stirred mixture is maintained at below −70° C. for a further 45 minutes. The stirred mixture, while it is still maintained at below −70° C., is then treated with a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (22.0 g) in dry tetrahydrofuran (100 mL), and it is stirred at below −70° C. for a further 30 minutes. The resulting mixture is then allowed to warm to room temperature overnight, and then treated with saturated aqueous ammonium chloride solution (200 mL). The layers are separated and the aqueous layer is further extracted with ethyl acetate (3×300 mL). The combined organic extracts are dried over magnesium sulfate and evaporated to dryness. The resulting residue is recrystallized from ethyl acetate, to give (±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (28.5 g), in the form of a cream solid, m.p. 102-103° C.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C(OCC)(OCC)OCC.C1(C)C=CC=CC=1.[C:29]([C@@H:34]([C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[OH:37])O)([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]3[O:37][C@@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[C@H:34]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:8]3)=[CH:5][C:4]=2[O:9]1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)[C@@H]1OC(c2ccc3c(c2)OCO3)O[C@H]1C(=O)OCC
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of piperonal (60 g, 0.4 mol), triethyl orthoformate (59.2 g, 0.4 mol), toluene (250 mL) and p-toluenesulfonic acid (2 g, 0.01 mol) was heated at 100°-110° C. for 0.5 h. Diethyl L-tartrate (103 g, 0.5 mol) was added to the hot solution over a 10 min. period. The mixture was then heated at reflux for 2 h. Subsequently over a 3 hour period, distillate (150 mL) was collected (pot temperature 84° C. to 110° C.). The mixture was cooled (25° C.) and washed with sodium bicarbonate solution (2×50 mL) and brine (1×50 mL). Evaporation of solvents under reduced pressure provided 130.7 g of crude product. Recrystallization from methanol provided 90 g (67% yield) of (4R,5R)-2-(3,4-methylenedioxyphenyl)-4,5-dicarboethoxy-1,3-dioxolane, mp 39°-40° C., [α]D -34.8° (c, 1.0 methanol). 1H-NMR (CDCl3) δ7.12 (1H, d, J=1.5 Hz), 7.03 (1 H, dd, J=1.5 Hz and 7.9 Hz), 6.80 (1H, d, J=7.9 Hz), 6.06 (1H, s), 5.97 (2H, s), 4.91 (1H, d, J=4.0 Hz), 4.80 (1H, d, J=4.0 Hz), 4.36-4.26 (4H, 2 q, overlapping, J=7.0 Hz), 1.38-1.30 (6H, 2 t, overlapping, J=7.0 Hz). IR (KBr) 2980, 2900, 1735, 1490, 1445, 1415 cm-1. MS m/e (% abundance) 338 (3), 265 (16), 166 (100), 149 (96), 135 (54), 121 (35), 93 (10), 65 (12), 43 (8).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:22]1([CH2:28][O:29][CH2:30][CH2:31][CH2:32][Br:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC#N>[Br-:33].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: BrCCCOCc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOCc3ccccc3)(CC1)C2
Product: [Br-]
Yield: 52.5 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (30.4 mg, 0.109 mmol) and 3-bromopropyl phenylmethyl ether (0.03 mL, 0.17 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (29.1 mg, 53%). EI-MS m/z 428 (M+) Rt (1.93 min).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:24])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH:13]1[CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]1([CH3:21])[CH3:20])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH:13]2[CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]2([CH3:21])[CH3:20])[NH:3][N:2]=1)=[O:24])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCC1C(C)CCCC1(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CCC2C(C)CCCC2(C)C)[nH]n1
Yield: 31.7 %

Procedure:
Hydrazine hydrate (0.867 mL, 17.9 mmol) was added to a stirring room temperature solution of 52 (5.2981 g, 17.9 mmol) in EtOH (17.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 97:3 Hexanes:2N NH3 in EtOH) to obtain 1.6604 g (31.8%) of 53. Partial 1H (CDCl3, 400 MHz): δ 12.45 (1H, broad s), 6.58 (1H, s), 4.32 (2H, q, J=7.1 Hz), 2.63 (2H, t, J=8.3 Hz), 1.31 (3H, t, J=7.1 Hz), 0.90 (3H, s), 0.83 (3H, s), 0.78 (3H, d, J=6.8 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 106.04, 60.66, 48.99, 34.03, 30.10, 24.89, 14.17 ppm. HPLC: 12.000 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])[C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2cccc(Cl)c2)o1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1c(Cl)cccc1Cl)n1c(=O)on(-c2cccc(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dichlorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3-chlorophenyl)-4-(2,6-dichlorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[F:26]>CC(C)=O>[F:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: NCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(NCCN2CCCCC2)c(F)c1
Temperature: 25 °C

Procedure:
To a suspension of 2-(piperidin-1-yl)ethanamine (0.90 g, 7.02 mmol) and K2CO3 (0.97 g, 7.02 mmol) in acetone (30 mL) was added 1,2-difluoro-4-nitrobenzene (1.11 g, 6.98 mmol) in one portion in an ice bath and the mixture was refluxed overnight, cooled to rt and filtered. The filtrate was concentrated in vacuo to give the crude product, which was used for next step without further purification.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[C:34]1[CH:43]=[CH:42][C:41]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][CH:6]([C:12]1[C:16]([C:34]2[CH:43]=[CH:42][C:41]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=3[CH:35]=2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Oc1ccc2c(c1)CCCC2)C(F)(F)F
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1-c1ccc2c(c1)CCCC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Under argon atmosphere, ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (50 mg, 0.12 mmol), 5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (39a) (41.4 mg, 0.15 mmol) and sodium carbonate (13.7 mg, 0.13 mmol) were dissolved in dimethylformamide (2.5 mL) and water (0.85 mL). The solution was degassed under argon for 10 minutes and Tetrakis(triphenylphosphine)palladium (28.5 mg, 0.02 mmol) was added. The reaction was heated and shaken at 100° C. for 4 hours. After cooling at room temperature, water was added and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC (cyclohexane/ethyl acetate: 9/1) to provide the desired product (39b) (40 mg, 0.1 mmol, 77%).
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11]CCNCCCCNCCCN)[CH:6]=[CH:5][C:4]=1O.[CH2:25]([N:28](C1NC=C2CCCCC=12)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27].[CH3:41]C(N(C)C)=O.CC(C)([O-])C.[K+].CI>O>[CH3:41][N:10]1[CH:11]=[C:8]2[C:7]([CH2:6][CH2:5][CH:4]([N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[CH2:3]2)=[CH:9]1
Reactant: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Reactant: CC(=O)N(C)C
Reactant: CCCN(CCC)c1[nH]cc2c1CCCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCCN(CCC)C1CCc2cn(C)cc2C1
Reaction time: 0.33 h

Procedure:
2 millimoles (680 mg) of dl-5-di(n-propyl)amino 4,5,6,7-tetrahydro-2H-benzo[c]pyrrole were dissolved in 75 ml. of dimethylacetamide (DMA). 10 millimoles (1.1 g) potassium tertiary-butoxide were added and the resulting mixture stirred for 20 minutes under nitrogen. Next, a solution of 2.1 millimoles of methyl iodide (0.13 ml) in 5 ml. of DMA was added in dropwise fashion. The resulting reaction mixture was stirred at ambient temperature for 5 hours at which time an additional 0.13 ml of methyl iodide was added and the subsequent mixture stirred for an additional 3.5 hours. The reaction mixture was then diluted with water and the aqueous layer extracted with ethyl acetate. The ethyl acetate layer was separated and washed with water followed by saturated aqueous sodium chloride. The ethyl acetate layer was then dried and the ethyl acetate removed therefrom by evaporation. An ether solution of the resulting residue was chromatographed over 35 g. of Florisil using ether as the eluant. Fractions shown by TLC to contain dl-2-methyl-5-di-n-propylamino- 4,5,6,7-2H-benzo[c]pyrrole were combined and the solvent removed therefrom in vacuo. NMR of the residue thus obtained indicated that the dl-2-methyl-5-di-n-propylamino-4,5,6,7-2H-benzo[c]pyrrole had been prepared.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10](/[CH:18]=[C:19]1/[C:20](=[O:32])[N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH2:22][CH2:23]/1)=[C:11]2[C:15]([OH:17])=[O:16])=[O:4].[Na].[SH:34][C:35]1[N:40]2[N:41]=[C:42]([C:44]3[CH:45]=[C:46]([OH:51])[C:47](=[CH:49][CH:50]=3)[OH:48])[N:43]=[C:39]2[N:38]=[C:37]([CH3:52])[CH:36]=1>CN(C)C=O>[OH:51][C:46]1[CH:45]=[C:44]([C:42]2[N:43]=[C:39]3[N:38]=[C:37]([CH3:52])[CH:36]=[C:35]([S:34][CH2:2][C:3]([NH:5][C@@H:6]4[C:13](=[O:14])[N:12]5[C@@H:7]4[S:8][CH2:9][C:10](/[CH:18]=[C:19]4/[C:20](=[O:32])[N:21]([CH2:24][C:25]6[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=6)[CH2:22][CH2:23]/4)=[C:11]5[C:15]([OH:17])=[O:16])=[O:4])[N:40]3[N:41]=2)[CH:50]=[CH:49][C:47]=1[OH:48]
Reactant: Cc1cc(S)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reactant: O=C(CBr)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4ccc(O)cc4)C3=O)CS[C@H]12
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1cc(SCC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN(Cc5ccc(O)cc5)C4=O)CS[C@H]23)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reaction time: 1 h

Procedure:
(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (see ex. C34a) (200.0 mg, 0.38 mmol) was dissolved in 4 ml N,N-dimethylformamide and 4-[7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl]pyrocatechol sodium salt (124.0 mg, 0.42 mmol) was added. After 5 h the reaction mixture was poured on diethyl ether and the suspension was filtered. The solid material was digerated with 10 ml ethyl acetate:water (1:1) for 1 h, filtered and dried in high vacuum.
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[Si:31]([O:38][CH2:39][CH2:40][CH2:41][CH2:42]I)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>O.C(COC)OC>[Si:31]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:22]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])[S:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.701 ml, 1.10 mmol) was added to a dimethoxyethane (5 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00 mmol) obtained in Example 5. The mixture was stirred at −78° C. for 1 hour and then, at room temperature for 30 minutes. The reaction mixture was cooled to −78° C., followed by the dropwise addition of 4-(t-butyldimethylsilyloxy)-1-iodobutane (0.260 ml, 1.00 mmol). While elevating the temperature of the reaction mixture to room temperature, stirring was conducted for 15 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (8% ethyl acetate-hexane), whereby the title compound (401 mg, 82%) was obtained as a colorless solid. The resulting solid was recrystallized from hexane to yield colorless needle crystals.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[NH2:11])[N:3]=[CH:2]1.[O:12]=[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=2)[N:14]1[CH2:27][C:28](O)=[O:29]>>[O:12]=[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]([F:25])([F:24])[F:26])[CH:19]=2)[N:14]1[CH2:27][C:28]([NH:11][C:10]1[CH:9]=[CH:8][S:7][C:6]=1[C:4]1[N:3]=[CH:2][S:1][CH:5]=1)=[O:29]
Reactant: Nc1ccsc1-c1cscn1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1ccsc1-c1cscn1

Procedure:
The title compound was prepared from 2-(thiazol-4-yl)thiophen-3-amine and 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid according to protocol A. Retention time (min)=6.485, method [7], MS(ESI) 436.1 (M+H); 1H NMR (300 MHz, CD3Cl) δ 11.32 (s, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.04 (d, J=5.5 Hz, 1H), 7.92 (d, J=10.2 Hz, 1H), 7.90 (s, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.22 (d, J=1.4 Hz, 1H), 7.20 (d, J=5.5 Hz, 1H), 7.03 (d, J=9.7 Hz, 1H), 5.23 (s, 2H).