Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](O)=[O:4].[C:7]([O:11][C:12](=[O:19])[NH:13][C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:7]([O:11][C:12](=[O:19])[NH:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:3](=[O:4])[C@H:2]([OH:1])[CH3:6])[CH2:15]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C[C@@H](O)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 96.9 %

Procedure:
[(R)-1-((R)-2-Hydroxy-propionyl)-pyrrolidin-3-yl]carbamic acid tert-butyl ester (500 mg) was prepared by following General Procedure F starting from (R)-2-hydroxy-propionic acid (200 mg), (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (372 mg), HBTU (800 mg), and DIEA (400 uL) in DMF (4 mL).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([F:18])[C:5]([N:19](S(CCC)(=O)=O)[S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])=[CH:4][CH:3]=1.Cl>C1COCC1.[OH-].[K+]>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:18])[C:5]([NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)N(c1ccc(Cl)c(C(=O)OCc2ccccc2)c1F)S(=O)(=O)CCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Temperature: 25 °C
Yield: 67.8 %

Procedure:
Benzyl 6-chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (5.4 g, 10.98 mmol) was dissolved in THF (100 mL) and 1M aqueous KOH (100 mL). This mixture was refluxed for 16 hours and then allowed to cool to room temperature. The mixture was then acidified to a pH of 2 with 2M aqueous HCl and extracted with EtOAc (2 X). The extracts were washed with water, dried over sodium sulfate and concentrated to a solid that was triturated with hexanes/ether to give 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (2.2 g, 68%) as a solid. NMR (DMSO-d6, 400 MHz) δ 9.93 (s, 1H), 7.49 (t, 1H, J=8), 7.38 (dd, 1H, J=8, 2), 3.11-3.16 (m, 2H), 1.68-1.78 (m, 2H), 0.97 (t, 3H, J=8).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1.C[CH2:19][OH:20]>[Ni]>[Cl:1][C:2]1[C:7]([NH:8][CH:19]=[O:20])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCO
Agent: [Ni]
Product: CC(C)C(=O)Nc1nc(Cl)c(NC=O)c(Cl)n1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
The title compound of Example 24 (6.77 g, 24.26 mmol) was placed in a Parr bottle containing 220 ml absolute EtOH and 10.0 g (wet) Raney nickel catalyst that had been previously shaken under hydrogen (40 psi) for 10 minutes. The mixture was shaken under hydrogen (40 psi) for an hour, filtered over celite, and the filtrate was concentrated to a yellow-white solid that was dried under vacuum overnight. This solid was stirred in 1,2-dichloroethane (250 ml) at 0° C. Acetic anhydride (30 ml) was added, followed by formic acid (30 ml), dropwise under nitrogen. The resulting mixture was stirred at room temperature for 2 hours, concentrated to half the original vlume; and azeotroped with toluene to remove residual formic/acetic acid. The crude solid was triturated with methanol to give the title compound (4.92 g, 73%) as an off-white solid; m.p. 206°-209° C. (dec); 1H-NMR (DMSO-d6) δ 1.08 (d, J=6.8 Hz, 6.0 (CH3)2CH), 2.74 (m, J=6.8 Hz, 1.0 (CH3)2CH), 8.18 (d, J=10.3 Hz) and 10.26 (br s) [total 1.0, NHCHO from two conformers], 11.17 br s, 1.0).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[O:11][C:10]([C:12]([O:14]CCCC)=O)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[NH3:19]>>[CH2:1]([N:3]([CH2:6][C:7]1[O:11][C:10]([C:12]([NH2:19])=[O:14])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: N
Reactant: CCCCOC(=O)c1ccc(CN(CC)CC)o1
Product: CCN(CC)Cc1ccc(C(N)=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 25.3 g (0.1 mole) of n-butyl 5-(N,N-diethylaminomethyl)-2-furoate is added to 50 ml of liquid ammonia in a pressure vessel. The mixture is held at 180° C. and 2000 pounds per square inch gage pressure for 8 hours. The mixture is cooled to ambient temperature and evaporated to dryness giving 5-(N,N-diethylaminomethyl)-2-furamide (m.p. 164°-165° C.).
Reaction SMILES: C=O.[C:3](O)(=O)C.[NH:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:8]1>CO>[CH3:3][N:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:8]1
Reactant: CC(=O)O
Reactant: Oc1ccc(C2CNCCO2)cc1
Agent: C=O
Solvent: CO
Product: CN1CCOC(c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
A 36% aqueous formaldehyde solution (20.1 mg, 2.51 mmol), 0.029 ml (0.502 mmol) of acetic acid, and 53.2 mg (0.251 mmol) of triacetoxysodium borohydride were successively added to a solution of 15 mg (0.084 mmol) of the title compound produced in step (iv) of Reference Example 12 in methanol (0.7 ml), and the mixture was stirred at room temperature for 15 min. Thereafter, the reaction solution was purified by preparative thin layer chromatography (chloroform:methanol:28% aqueous ammonia=9:2:0.2) to give 15 mg (yield 93%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[CH:46][C:47]([N:50]3[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]3)=[N:48][CH:49]=2)O1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(=O)([O-])[O-].[Na+].[Na+]>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[C:15]([CH3:16])=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:44]4[CH:45]=[CH:46][C:47]([N:50]5[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]5)=[N:48][CH:49]=4)[CH:3]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[CH:9]=2)[C:12]([CH3:25])=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 83.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Step-i of example-14) (200 mg, 0.361 mmol) was coupled with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (intermediate 69C) (140 mg, 0.361 mmol) using Pd(dppf)Cl2 (14 mg, 0.018 mmol) and sodium carbonate (114, 0.018 mmol) in DME/water (25/5 ml). This afforded 221 mg (83% yield) of the titled compound. MS: m/z=736.2 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:10][C:9]=2[F:27])=[CH:4][CH2:3]1.C(=O)(O)[O-].[Na+].[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>CC(C)=O.O>[C:33]([O:36][CH2:37][C:38]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:9]([F:27])=[CH:10][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:12][C:13]=2[F:14])=[CH:4][CH2:3]1)=[O:39])(=[O:35])[CH3:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCNCC2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCC(=O)N1CC=C(c2c(F)cc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.1 %

Procedure:
A solution of (5R)-3-(4-(1,2,5,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (650 mg, 1.64 mM) in acetone (20 ml) and water (10 ml), was treated with sodium bicarbonate (1.38 g, 16.4 mM) and the mixture cooled to 0–4°. Acetoxyacetyl chloride (448 mg, 3.28 mM) was added dropwise and the reaction mixture stirred at 0–4° for 20 minutes before allowing to warm to ambient temperature. After dilution with water the mixture was extracted well with ethyl acetate. The organic phase was separated, dried (sodium sulfate), solvent evaporated, and the residue triturated with diethyl ether to give the desired product (702 mg).
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH:6]=1.C(O)(=O)C.[C-:14]#[N:15].[K+]>CO>[CH3:7][C:4]1([CH3:8])[CH2:5][C:6]([C:14]#[N:15])=[CH:2][C:3]1=[O:9]
Reactant: [C-]#N
Reactant: CC1(C)CC=C(Br)C1=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CC(C#N)=CC1=O
Temperature: 27.5 °C
Reaction time: 4.5 h

Procedure:
To a stirred solution of 2-bromo-5,5-dimethylcyclopent-2-enone (prepared according to procedure reported in Organic Letters 2002, 4, 71-74, 17 g, 90 mmol) in methanol (200 ml) was added acetic acid, (5.15 ml, 90 mmol) at 25-30° C. Solid potassium cyanide (11.71 g, 180 mmol) was added and continued stirring the reaction mass for 4-5 h at 25-30° C. The progress of reaction was monitored by TLC. After completion of reaction, filtered the reaction mass through cotton filter and then filtrate was concentrated under reduced pressure. A crude oily compound was dissolved in Ethyl acetate (500 ml) and washed with water (100 ml) to remove the unreacted potassium cyanide. Organic layer was dried over sodium sulphate and concentrated under reduced pressure till dryness. Crude compound was purified over silica gel (100-200 mesh) by using 10% ethylacetated in hexane as eluent to obtain title produced (7.1 g)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].ClCCl>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: CCN(CC)Cc1ccc(Cl)c(C(=O)OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
To a solution of methyl 2-chloro-5-[(diethylamino)methyl]benzoate (3.97 g, 15.5 mmol) in anhydrous THF (100 mL) was added a solution of diisobutylaluminum hydride (1 M in toluene, 35 mL, 35 mmol). The reaction mixture was stirred at room temperature for 90 minutes. A Rochelle's salt solution (200 mL) and dichloromethane (200 mL) were added. The resultant mixture was stirred at room temperature for 2 hours. The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording {2-chloro-5-[(diethylamino)methyl]phenyl}methanol (3.0 mg, 85% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:19])=[O:20])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30])([CH3:34])[CH3:33]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Reactant: Cn1c(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2Cl)n1C
Yield: 45 %

Procedure:
3-Benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-03) (250.0 mg, 45.0%) was synthesized as a brown solid from 3-benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-03) (500.0 mg, 1.08 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([I:26])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:9]2=[O:25])=O.S(Cl)(Cl)=O>CN(C=O)C>[C:2]([C:4]1[CH:5]=[C:6]([I:26])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:9]2=[O:25])#[N:1]
Reactant: COC(=O)c1ccc(C)c(-n2cnc3c(C(N)=O)cc(I)cc3c2=O)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2cnc3c(C#N)cc(I)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 3-[8-(aminocarbonyl)-6-iodo-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate in DMF (15 ml) was added thionyl chloride (1.79 ml). The reaction mixture was stirred at room temperature for 30 minutes and ice-water added. The resultant mixture was extracted with methylene chloride (×2) and the combined organic layers washed with water, saturated NaHCO3 solution, dried (magnesium sulphate) and concentrated to yield methyl 3-(8-cyano-6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate as a white solid (2.04 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.88 (s, 3H), 7.61 (d, 1H), 8.03 (m, 2H), 8.53 (s, 1H), 8.67 (d, 1H), 8.74 (d, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][N:10]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH2:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[F:39])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12])(C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:10]([CH2:9][CH2:8][CH2:7][OH:6])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)(=[O:13])=[O:12])=[C:25]([CH2:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[CH:26]=1
Reactant: COc1ccc(S(=O)(=O)N(CCCO[Si](C)(C)C(C)(C)C)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCCO)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 0.67 h
Yield: 50.2 %

Procedure:
To 8 g of N-(3-{[tertbutyl(dimethyl)silyl]oxy}propyl)-N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide in 80 ml of tetrahydrofuran at 0° C. are added 2.98 g of tetrabutylammonium fluoride trihydrate. After 40 minutes at 25° C., the reaction medium is concentrated and then chromatographed on a column of silica gel, eluting with dichloromethane, to give 3.28 g of the expected product.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([NH:13][NH2:14])=O)[CH:8]=2)[NH:3]1.[C:15](#[N:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.CO>CCCCO.CN(C=O)C>[C:16]1([C:15]2[N:22]=[C:11]([C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH2:10]4)[NH:13][N:14]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccccc1
Reactant: NNC(=O)c1ccc2c(c1)CC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Cc2cc(-c3nc(-c4ccccc4)n[nH]3)ccc2N1
Temperature: 150 °C
Yield: 5.2 %

Procedure:
To a solution of 2-oxoindoline-5-carbohydrazide (200 mg, 1.05 mmol) in n-BuOH/DMF (6 ml/2 ml) was added benzonitrile (324 mg, 3.14 mmol) and potassium carbonate (29 mg, 0.21 mmol). The mixture was heated at 150° C. for 3 hours under microwave irradiation. CHCl3/MeOH (20 ml/1 ml) was added to the mixture and insoluble solid was removed by filtration. The filtrate was concentrated. H2O was added to the residue and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (CHCl3/MeOH) gave 5-(3-phenyl-1H-1,2,4-triazol-5-yl)indolin-2-one (15 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:32].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:7][CH:8]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:32])=[O:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C=O)cc2)cc1)NC(=O)OC(C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 91.4 %

Procedure:
Amide compound 10 (2.0 g, 4.85 mmol) was dissolved in THF (50 mL) and the solution stirred at 70° C. Potassium permanganate (3.06 g, 19.4 mmol) dissolved in water (50 mL) was added slowly through a dropping funnel (5 mL/min) over 2 hours. After addition was complete, reaction mixture was stirred at 70° C. for 30 min and cooled to room temperature. The brown precipitate was filtered over a Celite® bed and the filtrate was concentrated under reduced pressure. The residual oil was taken up in EtOAc (100 mL) and acidified with 2.0 M HCl. The organic layer was separated and washed with water (1×50 mL) and brine (1×50 mL), dried, and concentrated under reduced pressure to yield the desired acid compound 11 (1.9 g, 91%). 1H NMR (DMSO-d6): 12.7 (br, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.56 (ddd, J=13.6, 9.2, and 6.0 Hz, 1H), 2.93 (s, 3H), 2.74-2.91 (m, 5H), 1.31 (s, 9H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([O:11][C:12]([C:14]1([O:18]/[N:19]=[C:20](/[C:24]2[N:25]=[C:26]([NH:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[S:27][CH:28]=2)\[C:21]([OH:23])=O)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl.[NH2:50][CH:51]1[C:76](=[O:77])[N:53]2[C:54]([C:60]([O:62][CH:63]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:61])=[C:55]([CH2:58][Cl:59])[CH2:56][S:57][C@H:52]12>C(Cl)Cl>[C:7]([O:11][C:12]([C:14]1([O:18]/[N:19]=[C:20](/[C:24]2[N:25]=[C:26]([NH:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[S:27][CH:28]=2)\[C:21]([NH:50][CH:51]2[C:76](=[O:77])[N:53]3[C:54]([C:60]([O:62][CH:63]([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[O:61])=[C:55]([CH2:58][Cl:59])[CH2:56][S:57][C@H:52]23)=[O:23])[CH2:15][CH2:16][CH2:17]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (1.46 g, 7 mmoles) was added to a suspension of (Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid [IV-5'] (4.09 g, 7 mmoles) in 70 mL of dry methylene chloride, and the mixture was stirred for 1 hour at room temperature. The acid chloride solution was added at -20° C. to a solution of silylated 7-ACA ester, which was prepared by adding BSA (5.6 mL, 21 mmoles) to a stirred suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride [V] (3.16 g, 7 mmoles) in dry methylene chloride (70 mL). The mixture was stirred for 20 minutes at -10° C. and then at room temperature for 40 minutes. The reaction mixture was evaporated and diluted with ethyl acetate (300 mL), and the organic layer was washed with 5% aqueous sodium bicarbonate, water and a saturated sodium chloride solution. After drying over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (Wako gel C-200, 60 g); elution with chloroform. The fractions containing the desired product were combined and evaporated to obtain 5.88 g (86%) of VI-5' as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:28][C:29]([OH:31])=O)[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[N:6][CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:28][C:29]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:31])[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[N:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1CC(=O)O
Reactant: CS(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1CC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
To a solution of N-[(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-acetic acid (0.045 g, 0.10 mmol) in dichloromethane (2 mL) was added 4-dimethylaminopyridine (0.018 g, 0.15 mmol), and 1,3-dicyclohexylcarbodiimide (0.023 g, 0.11 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes, and then treated with methanesulfonamide (0.011 g, 0.12 mmol). The reaction was stirred at ambient temperature for 18 hours, filtered through a pad of celite and the resulting filter cake was washed with dichloromethane. The combined organics were concentrated in vacuo and purified by silica gel chromatography followed by trituration with dichloromethane to give the title compound (0.037 g, LRMS: 525.3, 527.2).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([C:21]2[C:30]3[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[S:33][C:29]=3[C:28]([Br:38])=[C:27]3[C:22]=2[CH:23]=[CH:24][CH:25]=[CH:26]3)[CH:18]=[C:17]([Br:39])[C:3]=1[O:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](OC)=[O:7].[H-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-]>C1COCC1>[Br:38][C:28]1[C:29]2[S:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[C:30]=2[C:21]([C:19]2[CH:18]=[C:17]([Br:39])[C:3]([O:4][C@@H:5]([CH2:6][OH:7])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:2]([Br:1])[CH:20]=2)=[C:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2
Reactant: COC(=O)C(Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OC[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of R)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenoxy]-3-phenyl-propionic acid, methyl ester (0.30 g, 0.414 mmol) in THF (4.2 mL) was added dropwise to a -78 ° C., stirred solution of mixed hydride (0.435 mL, 0.414 mmol) of lithium aluminum hydride/aluminum chloride (1.0 M solution in THF) in THF (3 mL) under a dry nitrogen atmosphere over a period of 5 min. After 1 h., the solution was allowed to warm to ambient temperature. After 2 h. the reaction mixture was quenched carefully with methanol (3 mL) and further diluted with water (80 mL). Aqueous mixture was extracted with ethyl acetate (2×80 mL). The ethyl acetate extracts were washed with water, dried with brine and anhydrous MgSO4, and concentrated to provide the title compound as a white solid (0.28 g, 97%): mp 83-85: MS (EI): [M+], 3 bromine isotope pattern, 694, 696, 698, 700.