Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].CN1CCOCC1.[F:22][CH2:23][CH2:24][CH:25]=[O:26].Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:22][CH2:23][CH2:24][C@H:25]([OH:26])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: O=CCCF
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@@H](O)CCF
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
Titanium tetrachloride (15.8 mL, 144 mmol) was added over 5 minutes to a vigorously stirred solution of N-propionyl-2-benzoxazolone (25.0 g, 131 mmol) in anhydrous CH2Cl2 (250 mL) cooled on ice and maintained under inert atmosphere. After 10 minutes, the yellow slurry was treated with N-methylmorpholine (15.8 mL, 144 mmol) over 5 minutes, and stirring was continued for an additional 45 minutes. A 0.48 M solution of 3-fluoropropanal (310 mL, 150 mmol) was added to the dark red solution over 30 minutes, such that the internal temperature remained below 10° C. After addition was complete, the mixture was stirred for an additional 30 minutes on ice, then at warm to ambient temperature an additional 1 hour. The reaction was treated with 250 mL of 2 N HCl with vigorous mixing, and the phases were separated, discarding the aqueous phase. The organic phase was filtered through a pad of silica gel (10 g), which was subsequently washed with 100 mL of methyl tert-butyl ether (MTBE). The combined eluates were evaporated to dryness. The resulting solid mass was triturated with MTBE, allowed to stand for 1 hour, then collected by vacuum filtration, yielding 26 gm of crystalline product. 1H-NMR: δ 8.07-8.02 (m, 1H), 7.29-7.18 (m, 3H), 4.77-4.05 (m, 2H), 4.31 (m, 1H), 3.96 (dq, J=7, 3 Hz, 1H), 2.00-1.79 (m, 2H), 1.34 (d, J=7 Hz, 3H). 13C-NMR: δ 176.1, 151.1, 142.2, 127.7, 125.6, 125.0, 116.2, 110.0, 82.0, 80.4, 68.0, 43.8, 34.7, 34.5, 10.4.
Reaction SMILES: CC1(C)C2C=CC(C#CC3C=CC(C(O)=O)=CC=3)=CC=2C(C(C)(C)C)=CC1.[CH3:28][C:29]1([CH3:57])[C:38]2[CH:37]=[CH:36][C:35]([C:39]#[C:40][C:41]3[CH:51]=[CH:50][C:44]([C:45]([O:47]CC)=[O:46])=[CH:43][CH:42]=3)=[CH:34][C:33]=2[C:32]([C:52]#[C:53][CH2:54][CH2:55][CH3:56])=[CH:31][CH2:30]1>>[CH3:28][C:29]1([CH3:57])[C:38]2[CH:37]=[CH:36][C:35]([C:39]#[C:40][C:41]3[CH:42]=[CH:43][C:44]([C:45]([OH:47])=[O:46])=[CH:50][CH:51]=3)=[CH:34][C:33]=2[C:32]([C:52]#[C:53][CH2:54][CH2:55][CH3:56])=[CH:31][CH2:30]1
Reactant: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Agent: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoic acid (Compound 80), 42.0 mg (0.106 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75) was converted into the title compound (colorless solid) using 11.1 mg (0.27 mmol) of LiOH in H2O in 3 mL of THF/water (3:1, v/v, flushed with argon).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:21]=[C:20]2[N:8]([CH2:9][C:10]3[C:11]2=[N:12][C:13]2[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:22])[C:6]=1[CH3:23])[CH2:3][CH3:4].[CH3:24][C:25]([CH3:45])([O:27][C:28]([NH:30][CH2:31][CH2:32][C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34])=[O:29])[CH3:26].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCCl>[CH3:23][C:6]1[C:7](=[O:22])[N:8]2[C:20](=[CH:21][C:5]=1[CH:2]([O:1][C:33](=[O:34])[CH2:32][CH2:31][NH:30][C:28]([O:27][C:25]([CH3:26])([CH3:24])[CH3:45])=[O:29])[CH2:3][CH3:4])[C:11]1=[N:12][C:13]3[C:18]([CH:19]=[C:10]1[CH2:9]2)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CC(C)(C)OC(=O)NCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCC(OC(=O)CCNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reaction time: 312 h

Procedure:
A mixture containing (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (61.2 mg, 0.20 mmol), 4-dimethylaminopyridine (7.4 mg, 0.06 mmol), 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) in 1,2-dichloroethane (5 mL) under an argon atmosphere was heated at reflux for 5 d. Thin layer chromatographic analysis at this time indicated that the reaction was incomplete, so the mixture was transferred to a pressure bottle and heated at 90°-95° C. for 1 d. Afterwards, additional 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) were added, and heating was continued for 13 d. The mixture was then purified by flash chromatography eluting with a solvent gradient of 0-3% MeOH/CH2Cl2. The material that was isolated was recrystallized from Et2O and dried in vacuo to afford the title compound, mp 155°-8° C. 1H NMR (CDCl3) d 8.35 (s, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.81 (m, 1H), 7.63 (m, 1H), 7.32 (s, 1H), 5.90 (dd, J=7.7, 6.1 Hz, 1H), 5.26 (s, 2H), 5.02 (br s, 1H), 3.44 (m, 2H), 2.66 (q, J=5.8 Hz, 2H), 2.02-1.80 (m, 2H), 1.38 (s, 9H), 0.98 (t, J=7.4 Hz, 3H). Anal. Calcd for C27H31N3O5.1/5 H2O: C, 67.40; H, 6.58; N, 8.73. Found: C, 67.78; H, 6.48; N, 8.35.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]5[C:20]6[N:34](C7CCCCO7)[N:33]=[CH:32][C:21]=6[C:22](=[O:31])[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[C:24]=5[CH:25]=4)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C1(N2CCN(C3C(C4C=CC5C6NN(C7CCCCO7)CC=6C(=O)N(CC(F)(F)F)C=5C=4)=CC=CN=3)CC2)CC1.[ClH:81]>>[ClH:81].[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]5[C:20]6[NH:34][N:33]=[CH:32][C:21]=6[C:22](=[O:31])[N:23]([CH2:26][C:27]([F:28])([F:29])[F:30])[C:24]=5[CH:25]=4)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=c1c2cnn(C3CCCCO3)c2c2ccc(-c3cccnc3N3CCN(C4CC4)CC3)cc2n1CC(F)(F)F
Agent: Cl
Agent: O=c1c2c(c3ccc(-c4cccnc4N4CCN(C5CC5)CC4)cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Product: O=c1c2cn[nH]c2c2ccc(-c3cccnc3N3CCN(C4CC4)CC3)cc2n1CC(F)(F)F
Yield: 70 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. starting with 7-[2-(4-cyclopropylpiperazin-1-yl)pyrid-3-yl]-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-[2-(4-cyclopropyl-piperazin-1-yl)pyrid-3-yl]-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one, in the form of a white powder (3 hydrochloride, 3H2O; yield 70%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(O)=O.[NH2:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]2[N:16]=[C:15]([N:32]2[CH2:38][CH2:37][C:36](=[O:39])[NH:35][CH2:34][CH2:33]2)[CH:14]=1>CC#N>[NH2:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]2[N:16]=[C:15]([N:32]2[CH2:38][CH2:37][C:36](=[O:39])[NH:35][CH2:34][CH2:33]2)[C:14]=1[Br:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(N2CCNC(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CC#N
Solvent: O=CO
Product: Nc1c(Br)c(N2CCNC(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.9 %

Procedure:
A solution of NBS (14.6 mg, 0.082 mmoL) in CH3CN (0.5 mL) was added to a mixture of 1-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,4-diazepan-5-one formic acid salt (32.3 mg, 0.077 mmoL) in CH3CN (3 mL). After stirring at room temperature for 10 min, the solvent was evaporated and the residue was purified by prep-LC to afford titled compound (22.6 mg, 59%). LCMS tR=2.78 Min. Mass calculated for, M+ 451.0, observed LC/MS m/z 452.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(CCO)C=CC=CC=1.O>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccs1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCc1ccccc1
Product: O=C(O)c1cc2cc(-c3cccs3)ccc2n1Cc1ccccc1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a sealed tube containing 2-[5-bromo-1-benzyl-1H-indole-2carboxylic acid (100 mg, 0.303 mmol) and 2-thiopheneboronic acid (116 mg, 0.909 mmol), (C6H5)4Pd (42 mg, 0.036 mmol), Na2CO3 (2,42 mmol) in a mixture of benzene-ethanol-H2O (5/1/2=v/v, 4.5 mL) was heated at 100° C. for 23 h. The mixture was poured onto diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The organic layer was washed with NaH2PO4, dried over MgSO4 and evaporated to give the crude product which was purified on silica gel column (15% EtOAc in hexane with 1% HCOOH) to give 65 mg of the product.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:24]([O:21][CH2:20][CH:19]([OH:22])[CH2:18][O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:23])[CH3:1])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)CCCCCCCCCCCCCCOCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.3 %

Procedure:
A mixture of 2.0 g (6.06 mmole) of 1-(15-methylhexadecyloxy)-2,3-propanediol, 2.54 g (9.09 mmole) of trityl chloride and 20 ml of pyridine was stirred at room temperature for 2 days, and then pyridine was distilled off. To the residue was added 50 ml of ethyl acetate and the ethyl acetate solution was washed with 1N hydrochloric acid, water and saturated sodium bicarbonate solution, in order, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (100 g) and eluted with hexane-ethyl acetate (20:1) to give 2.3 g of crude 1-(trityloxy)-3-(15-methylhexadecyloxy)-2-propanol. This product was treated by following the procedure of that of Reference Example 12 to give 1.0 g (yield: 39%) of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:9][C:10](OCC)=O)[CH:2]=1.[Cl:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]2[N:24]=[N:25][C:26]([NH:29][NH2:30])=[CH:27][CH:28]=2)[CH:19]=[CH:20][CH:21]=1>CS(C)=O.Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:9][C:10]2[N:25]3[N:24]=[C:23]([NH:22][C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=4)[CH:28]=[CH:27][C:26]3=[N:29][N:30]=2)[CH:2]=1
Reactant: CCOC(=O)COCc1cccnc1
Reactant: NNc1ccc(Nc2cccc(Cl)c2)nn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Product: Clc1cccc(Nc2ccc3nnc(COCc4cccnc4)n3n2)c1

Procedure:
(Step 4-ii) Ethyl 2-((pyridin-3-yl)methoxy)acetate (65 mg, 0.33 mmol) and N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine (60 mg, 0.25 mmol) were combined in a 16×100 mm test tube and placed into a 160° C. oil bath for 15 min. The residue was dissolved in 1 mL DMSO and purified by reversed-phase HPLC. Fractions containing pure product were concentrated in vacuo to yield a solid, dissolved in HCl/methanol, and concentrated in vacuo to give the yellow solid product, 3-(((pyridin-3-yl)methoxy)methyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine, as an HCl salt (22 mg, 0.055 mmol, 22% yield). 1H-NMR (500 MHz, DMSO-d6) 10.25 (s, 1H), 8.80 (s, 1H), 8.77 (d, J=5.2 Hz, 1H), 8.40 (d, J=8.1 Hz, 1H), 8.16 (d, J=9.9 Hz, 1H), 8.07 (t, J=2.0 Hz, 1H), 7.90 (dd, J=5.6, 7.9 Hz, 1H), 7.61 (dd, J=2.0, 8.2 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.20 (d, J=9.9 Hz, 1H), 7.08-7.06 (m, 1H), 5.11 (s, 2H), 4.89 (s, 2H); MH+367.3.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[C:35](Cl)=[N:34][CH:33]=[CH:32][N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[C:35]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:34][CH:33]=[CH:32][N:31]=1
Reactant: Clc1nccnc1Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nccnc2Cl)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0496 g, 0.130 mmol) and 2,3-Dichloropyrazine (0.0204 mL, 0.196 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.30 (d, J=2.5, 1H), 8.21 (d, J=8.8, 2H), 8.01 (d, J=2.5, 1 H), 7.49 (d, J=8.8, 2H), 6.15 (t, J=5.6, 1H), 4.55 (d, J=15.7, 2H), 3.82-3.63 (m, 6H), 3.56-3.45 (m, 4H), 3.17-3.07 (m, 2H), 2.86 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)=[O:7].C1COCC1.O>CCOC(C)=O.ClCCl>[Br:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][C:2](=[O:1])[CH3:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CC[O-]
Reactant: CC(=O)c1cccc(Br)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1cccc(Br)c1
Temperature: -5 °C
Reaction time: 4 h

Procedure:
To a suspension of sodium ethoxide (3.82 g, 55 mmol) in EtOAc (10 mL) that was cooled to −5° C. was added a solution of 3-bromoacetophenone (10.0 g, 50 mmol) in EtOac (10 mL) and THF (10 mL). The mixture was stirred at 0° C. for 4 hours before warming to ambient temperature and stirring for 48 hours. Water (20 mL) and dichloromethane (40 mL) were added. The aqueous layer was separated, and acidified to pH 1 by addition of 2N HCl. EtOAc (100 mL) was added and separated, and the water was washed with EtOAc (2×100 mL). The organic portions were combined, dried (Na2SO4) and concentrated in vacuo to yield title compound as a beige, waxy solid (9.57 g, 79%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:37](=[O:38])[N:12]2[CH:13]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:15][S:16][C@H:11]12)=[O:8].C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=O)C=1>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:37](=[O:38])[N:12]2[C:13]([C:21]([O:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:22])=[C:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CCC(=O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 5 °C

Procedure:
To a cooled (5° C.), stirred solution of 0.363 g. of benzhydryl 7-(2-thienylacetamido)-3-propionyl-2-cephem-4-carboxylate in 30 ml. of chloroform was added dropwise a solution of 0.149 g. of 85 percent m-chloroperbenzoic acid in 3 ml. of chloroform. The reaction was allowed to stir with cooling for one hour, after which time it was washed twice with aqueous sodium bicarbonate solution and twice with brine and then dried over anhydrous sodium sulfate. The solution was then evaporated in vacuo to provide a gel which was dissolved in 15 ml. of dimethylformamide. This solution was cooled for five minutes in an ice bath, removed from the ice bath, and subsequently treated with 0.145 ml. of phosphorous trichloride. This mixture was allowed to stir at room temperature for 45 minutes, after which time it was transferred to a separatory funnel with the aid of ethyl acetate and washed successively with aqueous sodium bicarbonate (2X), water (4X), and brine (2X) and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a product which when chromatographed on silica gel using a toluene-ethyl acetate gradient provided 0.267 g. (74 percent) of the title product as a white solid which crystallized as white needles from methylene chloride/hexane (m.p. 220°-221° decomp.): nmr (DMSO d-6) δ0.80 (t, 3, J = 7.0 Hz, --CH2CH3), 2.5 (m), 3.84 (s, 2, side chain CH2), 5.22 (d, 1, J = 4.0 Hz, C6 --H), 5.92 (q, 1, J = 4.0 and 8.0 Hz, C7 --H).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH3:12][N:13]([CH3:19])[C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>>[CH3:12][N:13]([CH3:19])[C@H:14]1[CH2:18][CH2:17][N:16]([C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:15]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Yield: 51.5 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (548 mg, 3.58 mmol) reacted with (3S)-(−)-3-dimethylamino-pyrrolidine (490 mg, 4.29 mmol) to give 460 mg (52%) of 3-[(3S)-3-dimethylamino-pyrrolidin-1-ylcarbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [Li+].[F:2][C:3]([F:22])([F:21])[C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([O-:20])=O)[CH2:11][CH2:10]2)=[N:6][N:5]=1.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:64]([F:67])([F:66])[F:65])([O-:50])=[O:49].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:59][CH2:60][N:61]([C:18](=[O:20])[CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:7]4[S:8][C:4]([C:3]([F:2])([F:22])[F:21])=[N:5][N:6]=4)[CH2:14][CH2:13]3)[CH2:62][CH2:63]2)=[CH:53][C:52]=1[C:64]([F:67])([F:65])[F:66])([O-:50])=[O:49]
Reactant: O=C([O-])CCCN1CCN(c2nnc(C(F)(F)F)s2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCN1CCN(c2nnc(C(F)(F)F)s2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of 4-[4-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazin-1-yl]-butyric acid lithium salt (17 mg; 0.05 mmol, prepared in accordance with Example 152) in tetrahydrofuran (0.5 mL) is added tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.25 mL) A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are then added and the reaction is stirred. After 3 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (16 mg; 0.0271 mmol). The structure was confirmed using Protocol I-D. Calculated mass=596; observed mass=596; HPLC retention time=1.42 min
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([CH:33]1[CH2:35][CH2:34]1)[C:30]([OH:32])=O.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[NH:37][NH2:38]>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([CH:33]1[CH2:35][CH2:34]1)[C:30]([NH:38][NH:37][C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:32]
Reactant: O=C(O)C(CCCCl)C1CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)C1CC1

Procedure:
IPEA (1.6 ml) and BOPCl (1.2 g) were added to a solution of the crude 5-chloro-2-cyclopropyl-valeric acid (550 mg) and tert-butyl carbazate (CAS No. 870-46-2, 555 mg) in methylene chloride (5 ml), and the reaction solution was stirred at room temperature for three hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 210 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([N+:17]([O-:19])=[O:18])[CH:5]=1.O.[OH-].[Li+]>C1COCC1.O>[C:11]([O:10][C:8](=[O:9])[C:7]1[CH:15]=[CH:16][C:4]([C:3]([OH:20])=[O:2])=[CH:5][C:6]=1[N+:17]([O-:19])=[O:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-Nitro-terephthalic acid 1-tert-butyl ester 4-methyl ester (21.49 mmol) was dissolved in THF (143 mL) and treated with lithium hydroxide monohydrate (1.35 g, 32.24 mmol) in water (97 mL). The reaction was stirred at room temperature for 2 hours then partially evaporated, cooled with an ice/water bath and treated with 1N HCl dropwise (35 mL). Precipitation of a solid occurred. The mixture was then extracted with DCM (150 mL and 2×50 mL) The aqueous phase was further treated with 1N HCl (10 mL) and extracted with DCM (2×50 mL). The combined organic layers were then washed with water and finally with brine. After drying over sodium sulphate and evaporation, 5.34 g of title compound were obtained as a reddish solid in 93% overall yield.