Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCC.C(Cl)(=O)CCCCCCC.C(Cl)(=O)CCCCCCCCCCCCCCC>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: CCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1

Procedure:
This compound was prepared using the procedure for palmitoyl-2'-deoxyguanosine, substituting the appropriate amount of octanoyl chloride for palmitoyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 85.3 %

Procedure:
A solution of 3,17β-dihydroxyestra-1,3,5(10)-triene (4.73 g, 17.4 mmol) in DMF (10 mL) was added slowly to a stirred and cooled mixture of 60% NaH (1.1 g, 27.5 mmol) in DMF (10 mL). After addition was complete, the cooling bath was removed and the mixture stirred at room temperature for 1 hour until all of the NaH had reacted. Benzyl bromide (2.9 mL, 27.8 mmol) was added in a stream and the solution stirred at room temperature for 20 hours. After concentrating under reduced pressure, the residue was partitioned between EtOAc and 10% citric acid. The aqueous layer was extracted with EtOAc again and the organic extracts combined, washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The residue was triturated with Et2O-hexane to give 5.38 g (85%) of the above-titled product, mp=97°-100°.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH:41]4[CH2:43][CH2:42]4)[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl[C:47]([O:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:48]>CC#N>[CH2:50]([O:49][C:47](=[O:48])[NH:45][C@@H:21]1[CH2:22][C@H:23]([C:25](=[O:44])[N:26]([CH:41]2[CH2:42][CH2:43]2)[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[CH2:24][NH:19][CH2:20]1)[CH:51]([CH3:53])[CH3:52]
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1C
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)OCC(C)C)C2)C2CC2)ccc1C

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{cyclopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 98A.) and isobutyl chloroformate. MS: 476.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.40 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC/C=C/c1ccccn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCc1ccccn1
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of ethyl (4E)-5-(2-pyridyl)-4-pentenoate (1.84 g) in ethanol (15 ml) was added 10% palladium on carbon (145 mg), and the mixture was stirred for 3 hours under an atmosphere of hydrogen (4 atm), and then filtered through a celite pad. Removal of the solvent in vacuo gave ethyl 5-(2-pyridyl)pentanoate (1.84 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S([O-])(=O)(=O)C.[CH2:22]([O:24][C:25](=[O:48])[CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34](=[O:46])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:36]=2)[CH:31]=[CH:30][C:29]=1O)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:48])[CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34](=[O:46])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:23]
Reactant: CC(=O)c1ccc(CCCCCCO)cc1
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Agent: CS(=O)(=O)[O-]
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCc1ccc(C(C)=O)cc1
Yield: 80.3 %

Procedure:
In a manner analogous to Example 92B, 2.85 g of 6-(4-acetylphenyl)hexanol were converted into its mesylate and reacted with 1.78 g of 5-[3-(ethoxycarbonyl)benzoyl]-2-hydroxybenzenepropanoic acid ethyl ester to provide 2.21 g of the desired title product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[O:11][N:10]=1.Br[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:33]=[CH:32]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[N:35]=[C:34]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:33]=[CH:32]4)=[CH:18][CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[O:11][N:10]=1
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(B(O)O)cc1
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: COCCOC
Product: CCOC(=O)c1ccc2cc(-c3ccc(SCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 70 °C
Yield: 23.1 %

Procedure:
A mixture of crude [4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]boronic acid (76 mg, 0.18 mmol), ethyl 6-bromo-2-quinolinecarboxylate (42 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.0006 mmol) in 1,2-dimethoxyethane (0.8 mL), and 2 M sodium carbonate (0.65 mL) was heated in a 70° C. oil bath for 1.5 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with magnesium sulfate filtered and concentrated. The residue was purified by silica gel chromatography (hexane to 2:5 ethyl acetate:hexanes gradient elution) to give 20 mg (22% as 0.4 ethyl acetate) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]-2-quinolinecarboxylate. 1H NMR (400 MHz, CDCl3): δ 8.38-8.32 (m, 2H), 8.21 (d, J=9 Hz, 1H), 7.98 (s, 1H), 7.96 (d, J=2 Hz, 1H), 7.59 (d, J=8 Hz, 2H), 7.43-7.32 (m, 5H), 4.57 (q, J=7 Hz, 2H), 3.82 (s, 2H), 3.07 (septet, J=7 Hz, 1H), 1.50 (t, J=7 Hz, 3H), 1.27 (d, J=7 Hz, 6H).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]([N+:16]([O-])=O)=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.[C].[Pd]>[CH:1]1([CH2:7][O:8][C:9]2[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cnc([N+](=O)[O-])c(OCC2CCCCC2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cnc(N)c(OCC2CCCCC2)c1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 1.8 g of 3-(cyclohexylmethoxy)-5-methyl-2-nitropyridine in 16 ml of THF was added 325 mg of 10% palladium-carbon (wet), followed by stirring for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure to obtain 1.38 g of 3-(cyclohexylmethoxy)-5-methylpyridin-2-amine.
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(C2C=CC=CC=2)=CC1.[CH3:30][C:31]1([CH3:59])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49]CC)=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[CH:33][CH2:32]1>>[CH3:30][C:31]1([CH3:59])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[CH:33][CH2:32]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3c2nccs2)cc1
Agent: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CC=C(c2nccs2)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-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 177 mg (0.43 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl]benzoate (Compound 88) was converted to the title compound (white solid) using 91 mg (4.3 ml, 2.14 mmol) of LiOH (0.5M aqueous solution).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[NH:21][C:20]3[C:15]2=[N:16][C:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[N:18][C:19]=3[C:24]([O:26]CC)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:36]C1C(C(OCC)=O)=NC(C2C=CC=C(O)C=2)=NC=1NC1CCN(C(OC(C)(C)C)=O)CC1>ClCCl>[OH:35][C:31]1[CH:30]=[C:29]([C:17]2[N:16]=[C:15]3[C:20]([NH:21][C:22](=[O:23])[N:14]3[CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:19]([C:24]([NH2:36])=[O:26])[N:18]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1N
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCNCC1
Yield: 19 %

Procedure:
Ethyl 9-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-6-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(3-hydroxyphenyl)pyrimidine-4-carboxylate (0.120 g, 0.260 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.425 g, 2.62 mmol) in dichloromethane (10 mL) were reacted according to General Procedure F and purified via biotage chromatography (0-70% EtOAc in hexanes) to afford the title compound (0.050 g, 19%). MS (ESI) m/z 484.3 [M+1]+.
Reaction SMILES: [F:1][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]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.[NH2:22][C:23]1[CH:24]=[C:25]2[N:31]=[C:30]([CH3:32])[S:29][C:26]2=[N:27][CH:28]=1>>[CH3:32][C:30]1[S:29][C:26]2[C:25]([N:31]=1)=[CH:24][C:23]([NH:22][C:19]([C:6]1[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:8]3[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:20])=[CH:28][N:27]=2
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Cc1nc2cc(N)cnc2s1
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc2s1
Yield: 45 %

Procedure:
The process is performed according to a method similar to that of Example 1.2, starting with 0.5 g (1.74 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1 and 0.345 g (2.09 mmol) of 6-amino-2-methylthiazolo[5,4-b]pyridine (Yakugaku Zasshi 1950, 70, 187). At the end of the reaction, the product is concentrated under reduced pressure and then taken up in 100 mL of water. A precipitate is collected by filtration, and is purified by chromatography on a column of alumina, eluting with a mixture of dichloromethane and methanol. The resulting product is recrystallized from methanol, and a solid is collected by filtration, and dried under reduced pressure. 340 mg of the expected product are thus isolated.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH3:13][CH:14](O)[CH3:15]>>[CH:14]([O:7][C:6]([C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)=[O:8])([CH3:15])[CH3:13]
Reactant: O=C(O)c1c[nH]cn1
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1c[nH]cn1

Procedure:
To imidazole-4-carboxylic acid (CAS#1072-84-0, 3.0 g, 26.7 mmol) in propan-2-ol (60 mL) is added thionyl chloride (15.9 g, 13.4 mmol) and the solution is refluxed overnight. The volatiles are removed in vacuo and the residue is partitioned between ethyl acetate and 4M aqueous sodium hydroxide. The organic layer is dried-over Na2SO4, filtered and concentrated to afford imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 155.0 (M+H)+.
Reaction SMILES: Br[CH:2](Br)[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10][CH3:11])=[O:9].[O:13]1CCCC1.[Cl-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>[N+]([O-])([O-])=O.[Ag+].O>[CH:2]([C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10][CH3:11])=[O:9])=[O:13]
Reactant: C1CCOC1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(Br)Br
Agent: [Ag+]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: COC(=O)[C@@H]1CCC[C@H]1C=O

Procedure:
A solution of 25 g. (83.3 mmoles) of trans-2-dibromomethyl-1-cyclopentanecarboxylic acid, methyl ester [prepared as described in Chem. Ber. 110, 1823 (1977), from cyclopentene and dibromoketene] in 140 ml. of tetrahydrofuran is heated to reflux in a nitrogen atmosphere. While stirring, a solution of 33.0 g. (194 mmole) of silver nitrate in 55 ml. of water is added over a period of ten minutes. After an additional thirty minutes of heating and stirring the mixture is cooled and saturated aqueous sodium chloride solution is added. The mixture is then neutralized with saturated aqueous sodium carbonate solution and the insoluble salts are removed by filtration through a Celite (diatomaceous earth) pad. The pad is washed with ether and some solid sodium chloride is added to the filtrate. The layers are separated and the aqueous portion is reextracted twice with ether. The combined organic layers are dried over magnesium sulfate, filtered and taken to dryness in vacuo leaving 7.5 g. of amber oil. This is distilled at reduced pressure collecting 4.1 g. (32%) of product, trans-2-formylcyclopentanecarboxylic acid, methyl ester, boiling at 60°-85°/0.4 mm.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH:15]=[O:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])([CH3:4])([CH3:3])[CH3:2].P([O-])(O)(O)=[O:27].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:14])([C:15]([OH:27])=[O:16])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:6]=1[O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C=O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1(C(=O)O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a solution of 0.5 g of 4,6-di-t-butyl-2-formyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran in 5 ml of t-butyl alcohol were added 5 ml of a saturated aqueous sodium dihydrogenphosphate solution and 0.73 ml of 2-methyl-2-butene, and the mixture was cooled to -5° C. To this solution was added dropwise a solution of 0.14 g of sodium chlorite in 5 ml of distilled water, and the mixture was stirred for 20 minutes, then further stirred at room temperature for 15 minutes. The reaction solution was extracted with diethyl ether, and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was recrystallized from hexane to give 0.38 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid as a colorless powder (yield 73%).
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11](O)=[O:12])[C:6]1=[O:14])(=O)C.O[N:16]1C(=O)CCC1=O>C(Cl)(Cl)Cl>[OH:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH2:16])=[O:12])[C:6]1=[O:14]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(=O)OC1CCN(CC(=O)O)C1=O
Solvent: ClC(Cl)Cl
Product: NC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.64 g of dicyclohexylcarbondiimide dissolved in 20 ml of chloroform are added at room temperature to 1.5 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid, 40 ml of chloroform and 0.86 g of N-hydroxysuccinimide. After 4 hours, the solid is filtered, whereupon the filtrate is concentrated and again filtered. The filtrate is evaporated. The residue is treated at room temperature with 40 ml of a saturated solution of ammonia in methanol. The mixture is stirred at room temperature for 5 minutes, 10 ml of ion-free water are then added thereto and the mixture is stirred at room temperature for an additional minutes. The precipitated solid is filtererd. The filtrate is evaporated, the residue is stirred in 30 ml of acetonitrile and the crystallized-out product is recrystallized two more times from acetonitrile. There is obtained (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide of melting point 162°-164°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J35) (347 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (320 mg, 57%).
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].C(O)(=O)C.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.N1CCOCC1.C(O)(=O)C>C(#N)C>[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[CH:3]=[CH:4][C:5]#[N:6]
Reactant: N#CC=CO
Reactant: C1COCCN1
Agent: [Na]
Solvent: CC#N
Solvent: CC(=O)O
Product: N#CC=CC1COCCN1
Temperature: 65 °C
Yield: 75.3 %

Procedure:
30.3 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 75%) is added to a solution of morpholine acetate (prepared from 26.1 g (0.3 mol) of morpholine and 18 g (0.3 mol) of acetic acid) in 200 ml of acetonitrile and is heated for 8 h at 65° C. After working up as in Example 55, 26.0 g (75.4%) of 3-morpholine acrylonitrile was obtained.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[S:4][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1>O1CCCC1>[Cl:2][C:3]1[S:4][C:5]([S:9]([NH2:1])(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: Cc1nc(Cl)sc1S(N)(=O)=O

Procedure:
117.7 g (1.8 mol) of 26% strength aqueous ammonia solution are added dropwise to a solution of 208 g (95% pure, 0.9 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulfonyl chloride in 1000 ml of tetrahydrofuran at −10° C. The reaction mixture is left to stirr without further cooling for 2 h and is then concentrated in a rotary evaporator. The crude product is employed without further purification in the next stage.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1)[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].C(=O)(O)[O-].[Na+:36]>O>[CH3:1][O:2][N:3]=[C:4]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1)[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O-:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+:36]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1cccc(O)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.98 g.) was suspended in water (15 ml.) and dissolved by adding sodium bicarbonate (0.35 g.) with stirring at ambient temperature. The solution was lyophilized and dried to give sodium 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (syn isomer) (1.9 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(OC2CCN(c3ccncn3)CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(OC2CCN(c3ccncn3)CC2)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
To a solution of methyl 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoate (335 mg, 0.926 mmol) in methanol (10 mL) was added 8 M sodium hydroxide (0.926 mL, 7.41 mmol). The resulting solution was stirred at room temperature for 3 days, at which time the methanol was removed in vacuo and the residue diluted with water (2 mL). The mixture was acidified with 6 M HCl (1.157 mL, 6.94 mmol) and the resulting suspension was stirred at room temperature for 20 min. The white solid was collected via vacuum filtration and air dried under vacuum to give 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoic acid (172 mg, 0.494 mmol, 53.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (br. s., 1H), 8.50 (s, 1H), 8.18 (d, J=6.32 Hz, 1H), 7.35 (d, J=2.02 Hz, 1H), 7.29 (d, J=2.02 Hz, 1H), 6.88 (dd, J=1.26, 6.32 Hz, 1H), 4.82 (tt, J=3.60, 7.26 Hz, 1H), 3.91 (d, J=4.55 Hz, 2H), 3.51-3.72 (m, 2H), 2.30 (s, 3H), 1.89-2.04 (m, 2H), 1.54-1.74 (m, 2H). MS(ES) [M+H]+ 348.1.