Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:20])[C:5]2[CH:11]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][N:16]=3)[C:9](=[O:17])[N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd]>[CH2:18]([N:8]1[C:6]2[N:7]=[C:2]([NH:1][C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)[N:3]=[C:4]([CH3:20])[C:5]=2[CH:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:9]1=[O:17])[CH3:19]
Reactant: CCn1c(=O)c(-c2nccs2)cc2c(C)nc(N)nc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cc2)CC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: CCC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCn1c(=O)c(-c2nccs2)cc2c(C)nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc21
Temperature: 70 °C
Reaction time: 60 h
Yield: 36.9 %

Procedure:
Acetato(2′-di-t-butylphosphino-1,1′-biphenyl-2-yl)palladium(II) (45 mg, 0.098 mmol) was added to pressure tube charged with 2-amino-8-ethyl-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (141 mg, 0.490 mmol), tert-butyl-4-(4-iodophenyl)tetrahydro-1(2H)pyrazinecarboxylate (209 mg, 0.539 mmol), and sodium tert-pentoxide (135 mg, 1.23 mmol) in dry toluene (1.5 mL). The pressure was capped under nitrogen and heated to 70° C.). After 60 hours, the reaction was cooled to room temperature and filtered through a pad of Celite. The filtrate was purified on silica gel (1:1 hexanes:ethyl acetate) to provide the product, tert-butyl 4-(4-(8-ethyl-4-methyl-7-oxo-6-(thiazol-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)piperazine-1-carboxylate (99 mg, 34% yield).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=[C:14]2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:32])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1.C([Si]([O:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][CH:66]2[CH2:68][O:67]2)=[CH:60][CH:59]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:34]([NH:33][C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH2:22][C:14]2[N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][CH2:68][C@H:66]([OH:67])[CH2:65][O:64][C:61]4[CH:62]=[CH:63][C:58]([OH:57])=[CH:59][CH:60]=4)=[CH:8][CH:9]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:29][CH:28]=1)=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCNC(=O)Nc1ccc(CCc2nc3cccnc3n2-c2ccc(CCN)cc2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCNC(=O)Nc1ccc(CCc2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)cc1
Yield: 35.5 %

Procedure:
N-[4-(2-{3-[4-(2-Aminoethyl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}ethyl)phenyl]-N′-hexylurea formate (0.541 g, 1.03 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.250 g, 0.619 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.195 g, 0.220 mmol).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]2[CH:23]=[CH:22][C:11]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.[ClH:24]>>[ClH:24].[NH2:14][CH2:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:1])[NH:7][CH:6]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc(=O)[nH]c2)cc1
Agent: Cl
Product: NCCc1ccc(-c2ccc(=O)[nH]c2)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (10.25 g, 31.0 mmol) was added aqueous hydrochloric acid (6 M, 220 mL) and the reaction mixture stirred at reflux overnight. The reaction was cooled to room temperature and the precipitate was filtered, washed with water (5 mL) and dried under reduced pressure (50° C.). The acidic solution was concentrated under reduced pressure and the resultant solid combined with the filtered solid to give 5-(4-(2-aminoethyl)phenyl)pyridin-2(1H)-one hydrochloride (7.80 g, 31.0 mmol, 100% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH:15]=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1.[OH-].[K+].[I:18]I>CN(C=O)C>[I:18][C:15]1[C:9]2[C:10](=[CH:11][N:12]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)[NH:13][N:14]=1
Reactant: c1cncc(-c2cc3cn[nH]c3cn2)c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2cnc(-c3cccnc3)cc12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
5-(Pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine (196 g, 1 mol) was dissolved in 1000 mL DMF. KOH (112 g, 2 mol) was added. After stirring for 30 min, I2 (303 g, 1.2 mol) was added. The mixture was stirred for 1 h at room temperature. After reaction, the reaction was quenched with saturated aq. Na2S2O5 solution followed by the addition water (5 L). The solid was filtered and washed with water to give 3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine as a yellow solid (290 g, 90%)
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15](O)[CH:16]2[C:20](=[O:21])[C:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])=[C:18]([O:31]C)[CH2:17]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.Cl>CC(C)=O.O>[CH3:1][O:8][CH:9]1[CH2:14][CH2:13][CH:12](/[CH:15]=[C:16]2/[C:20](=[O:21])[CH:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[C:18](=[O:31])[CH2:17]/2)[CH2:11][CH2:10]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCC(OCc3ccccc3)CC2)C1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COC1CCC(/C=C2\CC(=O)C(c3c(C)cc(C)cc3C)C2=O)CC1
Temperature: 120 °C
Yield: 23.5 %

Procedure:
To a solution of 5-[(4-benzyloxy-cyclohexyl)-hydroxy-methyl]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (1.5 g, 4.0 mmol) in acetone (3 ml) is added 2N aqueous hydrochloric acid (3 ml) and the mixture heated for 1 hour at 120° C. by microwave irradiation. The reaction mixtures is then diluted with water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a brown gum. The gum is purified by flash chromatography eluting with hexane/ethyl acetate to give 4-[1-(4-Methoxy-cyclohexyl)-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione as a colourless solid (0.32 g).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[C:11]([O:14][C@@H:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([OH:18])=O)(=[O:13])[CH3:12].Cl.[C:26]1([C:32]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@@H:40]3[C@@H:36]([CH2:37][NH:38][CH2:39]3)[C@@:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])([OH:41])[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:50]1([C:32]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:40]3[C@@H:36]([CH2:37][N:38]([C:16](=[O:18])[C@@H:15]([O:14][C:11](=[O:13])[CH3:12])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:39]3)[C@@:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])([OH:41])[CH2:34][CH2:33]2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: CC(=O)O[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)[C@@H](OC(C)=O)c3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
0.024 g of 1-hydroxybenzotriazole and 0.33 g of (S)-2-acetyloxy-2-phenylacetic acid are added to a suspension of 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 60 cm3 of dry methylene chloride, this solution is then cooled to +5° C. and a suspension of 0.4 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in 20 cm3 of dry methylene chloride is rapidly added, followed by a solution of 0.63 cm3 of diisopropylethylamine in 20 cm3 of dry methylene chloride. The reaction mixture is stirred at +5° C. for 2 hours and at room temperature for 24 hours, diluted with 120 cm3 of methylene chloride, washed with 100 cm3 of water and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.5 cm, height 39 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting fractions of 60 cm3. Fractions 6 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.96 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[2-acetyloxy-2-phenyl-(S)-acetyl]-perhydroisoindol-4-ol are obtained in the form of a white foam.
Reaction SMILES: [Cl-].[CH3:2][NH2+:3][CH3:4].[N:5]1[C:14]2[CH:13]=[CH:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>>[CH3:2][N:3]([CH3:4])[CH:12]1[CH2:13][C:14]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:10][CH2:11]1
Reactant: C[NH2+]C
Reactant: C1=Cc2ncccc2CC1
Agent: [Cl-]
Product: CN(C)C1CCc2cccnc2C1

Procedure:
This compound was prepared from dimethylammonium chloride (1.63 g, 20 mmol) and 5,6-dihydroquinoline (1.31 g, 10 mmol) using the experimental and purification method describes in Example 48. The product (0.72 g) was an oil which was identical to the compound isolated in Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:28]C[CH2:26]3)=[O:24])=[CH:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].BrC1C=CC(C(N(C)C)=O)=C([F:41])C=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[N:25]([CH3:28])[CH3:26])=[C:19]([F:41])[CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Reactant: CN(C)C(=O)c1ccc(Br)cc1F
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-bromo-2-fluoro-N,N-dimethyl-benzamide (589 mg, 2.65 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (652 mg, 2.65 mmol) to give a white solid (861 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 7.33-7.43 (m, 1 H) 7.25 (s, 1 H) 7.22 (s, 1 H) 6.75-6.84 (m, 1 H) 6.66-6.73 (m, 1 H) 3.88 (s, 3 H) 3.13 (s, 3 H) 2.98 (s, 3 H) 2.90 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H22FNO5 m/z 388.00 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([OH:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([F:12])[C:7]=1[CH:8]=[CH:9][O:10]C.Cl>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:13]([OH:16])([CH3:14])[CH3:15])[CH:5]=[C:6]([F:12])[C:7]=1[CH2:8][CH:9]=[O:10]
Reactant: COC=Cc1c(F)cc(C(C)(C)O)cc1F
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)(O)c1cc(F)c(CC=O)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-{3,5-difluoro-4-[2-methoxyvinyl]phenyl}propan-2-ol (5.0 g, 22 mmol) in acetone (25 mL) was added dropwise to 4 M aqueous hydrochloric acid (25 mL, 100 mmol) with ice-water cooling, keeping the temperature below 10° C. Then the mixture was stirred at room temperature for six hours. The resulting mixture was extracted with ethyl acetate (2×) and the combined organic phases were washed with saturated aqueous sodium bicarbonate and brine. The organic layer was then dried and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH2:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(C2CCCCC2)cc1
Temperature: 0 °C

Procedure:
50 Parts of 4′-cyclohexylacetophenone was dissolved in 250 parts of chloroform, After cooled to 0° C., 40 parts of bromine was added dropwise thereto. After the reaction, the mixture was washed with 5% aqueous NaHSO3 solution, with 2% aqueous K2CO3 solution and with water, organic layer obtained was concentrated to obtain 60 parts of 2-bromo-4′-cyclohexylacetophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]2=1.Cl[S:17]([C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:19])=[O:18]>N1C=CC=CC=1>[O:15]=[C:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][S:17]([C:20]3[CH:24]=[CH:23][S:22][C:21]=3[C:25]([O:27][CH3:28])=[O:26])(=[O:18])=[O:19])[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: Nc1cccc2c3c([nH]c12)C(=O)CCC3
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1cccc2c3c([nH]c12)C(=O)CCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of 8-amino-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.30 g) and pyridine (8 mL) was added methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (0.43 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.47 g, yield 80%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 239-240° C. (decomposition).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH2:5])=O.[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]#[N:5])=[O:12]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)[C@H]1CCCN1
Product: N#C[C@H]1CCCN1C(=O)CCl
Yield: 66 %

Procedure:
In a similar procedure as employed in the Intermediate Example 1, D-proline amide (3.2 g) was reacted with chloroacetyl chloride (2.5 ml) and then subjected to dehydration reaction to give the title compound (3.2 g, Y.:66%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32]C1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCCCCCC#CCCCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CC(C)(C)[Si](OCCCCCCCC#CCCCCO)(c1ccccc1)c1ccccc1
Yield: 91.4 %

Procedure:
Following the procedure applied in the synthesis of analog 25, 1-tert-butyldiphenylsilyloxy-13-(tetrahydro-2H-pyran-2-yloxy)tridec-8-yne (10.0 g, 18.70 mmol) was deprotected with PPTS to give 13-(tert-butyldiphenylsilyloxy)tridec-5-yn-1-ol (7.70 g, 91%) as a colorless syrup. TLC: EtOAc/hexanes (3:7), Rf˜0.43; 1H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.62 (t, J=5.6 Hz, 4H), 2.06-2.22 (m, 4H), 1.50-1.64 (m, 14H), 1.04 (s, 9H); 13C NMR (100 MHz) δ 135.82, 134.37, 129.76, 127.85, 80.93, 80.04, 64.21, 62.63, 32.77, 32.09, 29.33, 29.13, 29.10, 27.14, 25.92, 25.63, 19.47, 19.0, 18.81. HRMS calcd for C29H43O2Si [M+1]+ 451.3032. found 451.3032.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10](Cl)[CH:9]=1.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[N:19]1([CH2:18][CH2:17][O:14][C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCCCC1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
15.4 g (111.00 mmol) of potassium carbonate was added to a solution of 4.0 g (27.86 mmol) of 4-amino-2-chlorophenol and 5.1 g (27.86 mmol) of 1-(2-chloro-ethyl)-piperidine in 50 mL acetonitrile and the mixture was stirred for 48 hours at RT. The solvent was evaporated off i. vac., the residue was combined with water and the aqueous phase was exhaustively extracted with EtOAc. The combined org. extracts were washed with water, dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane/MeOH/conc. aqueous ammonia 90:10:1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:21])[C@H:11]([NH2:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([NH:29][C@@H:30]([C:42](O)=[O:43])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(OC(C)(C)C)=O>>[C:35]([N:20]([C@@H:11]([CH:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[OH:21])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:42](=[O:43])[C@H:30]([NH2:29])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H](CCc1ccccc1)C(O)c1nc2ccccc2s1
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)N(C(=O)OC(C)(C)C)[C@H](CCc1ccccc1)C(O)c1nc2ccccc2s1

Procedure:
(1 R)-1-[(RS)-(2-Benzothiazolyl)hydroxymethyl]-3-phenylpropylamine (72 mg) was coupled to N,N′-bis-Boc-D-ornithine to afford the title compound (11 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3, 3:2 mixture of diastereomers) δ 1.41 (s, 9H), 1.44 (s, 9H), 1.60 (m, 2H), 1.19 (m, 4H), 2.20 (m, 2H), 2.72-2.91 (m, 2H), 4.11 (m, 1H), 4.31 (m, 0.4H), 4.41 (m, 0.6H), 5.06 (m, 0.6H), 5.19 (d, J=1.1 Hz, 0.4H), 7.20 (m, 3H), 7.26 (m, 2H), 7.40 (t, J=8.5 Hz, 1H), 7.49 (t, J=9.3 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), and 7.98 (d, J=9.4 Hz, 1H).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH:12]2[N:17]3[C:18](=[O:31])[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]2([Cl:33])[CH3:32])=[O:11])=CC=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[O:23]([CH2:22][C:21]([NH:20][CH:19]1[C:18](=[O:31])[N:17]2[CH:12]([C:10]([OH:11])=[O:9])[C:13]([Cl:33])([CH3:32])[CH2:14][S:15][C@H:16]12)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(Cl)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(Cl)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Yield: 51.5 %

Procedure:
In 30 ml of ethyl acetate was dissolved 470 mg of 7-phenoxyacetoamido-3-chloro-3-methyl-cepham-4-carboxylic acid p-nitrobenzylester. To the solution was added 470 mg of 5% palladium-charcoal and the solution was stirred for 19 hours in a stream of hydrogen. After the catalyst was filtered off from the reaction mixture, the filtrate was extracted with 50 ml of 2% aquous sodium hydrogencarbonate solution. After the aqueous layer was separated and adjusted to pH 2 by adding diluted hydrochloric acid, the aqueous layer was extracted again with ethyl acetate. The ethyl acetate layer was washed with water, dried and distilled under reduced pressure. There was obtained 179 mg of 7-phenoxyacetoamido-3-chloro-3-methyl-cepham-4-carboxylic acid as a colourless powder (yield, 15%). The following NMR spectra agreed with those expected from the anticipated structure:
Reaction SMILES: Br.[N:2]1[C:3](=[O:11])[CH2:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1([CH:22]=[C:4]2[N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]3=[N:2][C:3]2=[O:11])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: O=C1CN2C=CC=CC2=N1
Agent: Br
Solvent: CCO
Product: O=C1N=C2C=CC=CN2C1=Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1 g (4.7 mmol) of imidazo[1,2-a]pyridin-2-one hydrobromide salt and 726 mg (4.7 mmol) of 1-naphthaldehyde in 20 mL of ethanol is heated at reflux for 1 h and then cooled to room temperature. The precipitate is collected. The isolated solid is suspended in 40 mL of 2M potassium carbonate solution and the resulting mixture is stirred for 48 h at room temperature. The precipitated solid is collected and washed with water to give the desired compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:34][CH2:35]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: CC(=O)c1cccc(OCCCCCCCl)c1
Product: CC(=O)c1cccc(OCCCCCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{3-[(6-chlorohexyl)oxy]phenyl}ethanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 463.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.[OH-].[K+]>O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:6]=2)[CH:13]=1
Reactant: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Yield: 99.8 %

Procedure:
To 2.60 g (8.14 mmol) of 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid methyl ester, prepared as in Example 187B, was added 15 mL of methanol, and a solution of 0.79 g (12 mmol) of 85% KOH in 3 mL of water. The mixture was stirred at reflux for 3 hours, then concentrated in vacuo. The residue was taken up in 5 mL of water and treated with 12 mL of 1M aqueous HCl. The precipitated product was filtered and washed with a small amount of water. The combined washings and filtrate were adjusted to pH 4 with 1M HCl, and additional precipitate was collected, then washed with water. The combined precipitates were dried in vacuo to give 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid (2.48 g, 99%) as an off-white powder. 1H NMR (300 MHz, d6-DMSO) δ 5.31 (s, 2H), 7.31-7.56 (m, 9H), 7.76 (d, J=7.5 Hz, 1H), 8.19 (dd, J=1.0, 6.0 Hz, 1H), 8.39 (d, J=3.0 Hz, 1H), 12.8 (br s, 1H).