Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cc(F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.2 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 2,5-difluorophenol (6.50 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.60 mg, 29.3% yield) as a thick oil: 1H NMR δ 7.46 (s, 1H), 7.40-7.32 (m, 4H), 7.31-7.20 (m, 2H), 7.17 (s, 1H), 7.01-6.92 (m, 2H), 6.65-6.42 (m, 2H), 5.27 (m, 1H), 3.13 (m, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.28-1.80 (m, 8H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 493.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH:39]([C:41]5[N:42]([CH2:46][CH2:47][CH3:48])[CH:43]=[CH:44][N:45]=5)[CH3:40])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH:39]([C:41]5[N:42]([CH2:46][CH2:47][CH3:48])[CH:43]=[CH:44][N:45]=5)[CH3:40])=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SC(C)c4nccn4CCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)C(C)c4nccn4CCC)cc2)CCN3CC(C)C)cc1
Yield: 81.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-[1-propylimidazol-2-yl]ethyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (170 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (92 mg) in dichloromethane (10 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and an aqueous solution of sodium thiosulfate was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-[1-propylimidazol-2-yl]ethyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (142 mg) (Compound 396) as yellow amorphous.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3C(OC(C)(C)C)=O)=[N:11][CH:10]=2)=[CH:5][N:4]=1>CO>[ClH:2].[ClH:1].[ClH:2].[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[N:11][CH:10]=2)=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)[nH]1
Agent: Cl
Solvent: CO
Product: Clc1ncc(-c2cnc([C@@H]3CCCN3)[nH]2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cold (0° C.) 4 N HCl in dioxanes (5 mL) was added via syringe to (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152d-1, 0.50 g, 1.43 mmol) in a 100 mL pear-shaped flask followed by MeOH (1.0 mL). The suspension was stirred at room temperature for 4 h before it was concentrated down to dryness and placed under high vacuum for 1 h. There was isolated intermediate (S)-2-chloro-5-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyrimidine trihydrochloride as a pale yellow solid (with an orange tint) which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[CH:8][CH:7]=1.[S:31]1[CH:35]=[C:34]([CH:36]=O)[N:33]=[CH:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[C:23]2[CH2:28][CH2:27][N:26]([CH2:36][C:34]3[N:33]=[CH:32][S:31][CH:35]=3)[CH2:25][CH2:24]2)=[CH:10][CH:11]=1
Reactant: CN(CCO)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(Cc3cscn3)CC2)c2cccc3cccnc23)cc1
Reaction time: 20 h
Yield: 48.6 %

Procedure:
Compound 1C (3.3 g, 8.3 mmol) and 4-thiazolecarboxaldehyde (1.4 g, 12.4 mmol) in dichloroethane (16 mL) were stirred for 30 min. under nitrogen. Sodium triacetoxyborohydride (5.3 g, 24.9 mmol) was added and the reaction was stirred for 20 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated. Column chromatography (120 g silica gel, eluting with 4% 7N NH3/MeOH in CH2Cl2) gave 2.01 g 1D as a white solid (49%). 1H NMR (500.333 MHz, CDCl3) δ 8.90 (dd, J=4.1, 1.7 Hz, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.11 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (dd, J=7.3, 2.3 Hz, 1H), 7.51-7.46 (m, 2H), 7.37-7.33 (m, 3H), 7.31-7.29 (m, 2H), 7.18 (s, 1H), 3.85 (s, br, 2H), 3.76 (s, 2H), 3.67 (br s, 2H), 3.26 (br s, 1H), 3.02 (s, 3H), 2.78-2.71 (m, 1H), 2.67-2.52 (m, 4H), 2.46-2.37 (m, 1H), 2.14-2.04 (m, 2H). TOF MS E+499.21.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([OH:20])[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].CC1N=[C:24]([O:39][CH2:40]COC)[C:25]2N=C(C3C=CC(F)=CC=3)C=CC=2N=1>COCCO>[CH2:1]([C:3]1[N:4]=[C:5]([O:20][CH2:25][CH2:24][O:39][CH3:40])[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: COCCOc1nc(C)nc2ccc(-c3ccc(F)cc3)nc12
Reactant: CCc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1
Solvent: COCCO
Product: CCc1nc(OCCOC)c2nc(-c3ccc(F)cc3)ccc2n1
Yield: 46 %

Procedure:
was synthesized from 2-ethyl-6-(4-fluorophenyl)-4-hydroxyl pyrido[3,2-d]pyrimidine and 2-methoxyethanol in 46% yield, using the procedure described for the synthesis of 2-methyl-4-(2-methoxyethoxy)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine. The mass spectrum was as follows: MS (m/z): 328 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[N:23]=[C:24]([N:29]([CH3:31])[CH3:30])[S:25][C:26]=1[CH:27]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[S:25][C:24]([N:29]([CH3:31])[CH3:30])=[N:23][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1nc(Cl)c(C=O)s1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN(C)c1nc(Cl)c(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)s1
Yield: 24.5 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 4-Chloro-2-dimethylamino-thiazole-5-carbaldehyde (53.5 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 29.03 mg (24%) of the title compound. (300 MHz, DMSO-d6) 7.93 (s, 1H), 7.76 (s, 1H), 7.23 (m, 2H), 6.38-6.31 (m, 2H), 4.99 (t, J=17 Hz, 8.5 Hz, 1H), 3.11 (s, 6H), 2.87 (s, 4H), 2.75 (s, 1H), 2.58 (d, J=8 Hz, 1H), 2.19 (d, J=8 Hz, 1H), 1.36 (d, J=8 Hz, 1H). MS=464 (M+H), HPLC: 2.37 min. (G Method)
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3].[ClH:14].[H][H]>C(O)C.[Pt]=O>[ClH:14].[CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NCCc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)NCCC1CCNCC1
Reaction time: 8 h

Procedure:
4-(2-methanesulphonamidoethyl)pyridine (8.4 g.) in ethanol (85 ml.) was acidified to pH 2 with 2 N HCl and hydrogenated at room temperature and a pressure of 50 p.s.i. over a platinum oxide catalyst until hydrogen uptake ceased. The catalyst was then removed by filtration and the filtrate was taken to dryness in vacuo to give a white solid which was dissolved in the minimum volume of hot ethanol, filtered quickly, and left at room temperature overnight. The resultant white crystals were collected by filtration and dried to yield 4-(2-methanesulphonamidoethyl)piperidine hydrochloride (8.3 g.), m.p. 165°-167° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])C=CC=CC=1.[H][H]>CCOC(C)=O.C(O)(=O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:9]1=[O:28]
Reactant: [H][H]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 65.8 %

Procedure:
To a solution of 1′-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (2.10 g, 4.70 mmol) in EtOAc (100 mL) and acetic acid (0.10 mL) was added palladium on carbon (1.00 g). The reaction mixture was hydrogenated under 60 psi of hydrogen at ambient temperature for 5 days and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to yield the title compound (0.87 g, 66%) as a white powder: mp 252° C. (dec.); 1H NMR (300 MHz, CDCl3) δ 10.55 (s, 1H), 7.25-6.84 (m, 4H), 6.64 (s, 1H), 6.22 (s, 1H), 5.88 (s, 2H), 4.76-4.57 (dd, 2H); MS (ES+) m/z 282.2 (M+1).
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[Mo:10](=O)(=O)=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O>[Mo:10].[N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3]
Reactant: O=[Mo](=O)=O
Agent: Nc1nc(N)nc(N)n1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: [Mo]
Temperature: 105 °C

Procedure:
Melaminium octamolybdate having a 2/1 molybdenum/melamine molar ratio was prepared in the following manner. 10 grams of melamine, 22.83 grams of molybdenum trioxide, 15.72 grams of ammonium sulfate and 300 milliliters of water were added to a 500 milliliter round-bottom flask equipped with a water-cooled condenser. The mixture was refluxed at about 105° C. for 2 hours while being stirred continuously and then was cooled to room temperature and filtered. A white crystalline solid was recovered from the liquid phase. The white product was washed with water and vacuum dried for 11/4 hours at 120° C. The white product was identified to be melaminium octamolybdate by infrared and x-ray diffraction analyses. 33.15 grams of the white solid product was recovered, representing a yield of 98.84 percent of the theoretical yield.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=2[O:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])=[CH:7][CH:6]=1.[ClH:28]>O1CCOCC1>[ClH:28].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=2[O:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(CCc2ccccc2OCCC2CCCN2C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCC1CCOc1ccccc1CCc1ccc(O)cc1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
0.400 g of 2-(2-{2-[2-(4-methoxymethoxyphenyl)ethyl]phenoxy}ethyl)-1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 5 ml of dioxane, and 5 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then allowed to stand at room temperature for 30 minutes, after which it was concentrated by distillation under reduced pressure. The resulting colorless solid was dissolved in a small amount of methanol, and about 50 ml of ethyl acetate were added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 0.219 g (yield 56%) of the title compound as colorless crystals, melting at 132°-133.5° C.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:12]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=2)[C:13]([C:19]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)=[O:20])=[C:14]([CH3:18])[NH:15][C:16]=1[CH3:17])=[O:10])([O-:3])=[O:2].C(Cl)(Cl)[Cl:43]>>[ClH:43].[N+:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:12]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=2)[C:13]([C:19]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)=[O:20])=[C:14]([CH3:18])[NH:15][C:16]=1[CH3:17])=[O:10])([O-:3])=[O:2]
Reactant: ClC(Cl)Cl
Agent: CC1=C(C(=O)OCCCO[N+](=O)[O-])C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCNC(=O)c2cccnc2)=C(C)N1
Product: Cl

Procedure:
Into a solution of Compound 2 in chloroform was introduced hydrogene chloride gas, and evaporation of the solvent under reduced pressure gave the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:38]/[O:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])/[C:15]([NH:17][C@@H:18]2[C:36](=[O:37])[N:20]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][O:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:38]/[O:39][CH2:40][C:41]([OH:43])=[O:42])/[C:15]([NH:17][C@@H:18]2[C:36](=[O:37])[N:20]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][O:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)OC(C)(C)C)c3nsc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)O)c3nsc(N)n3)[C@H]2SC1
Yield: 95.2 %

Procedure:
To 50 ml of trifluoroacetic acid is added 23 g of 7β-[2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid with stirring under ice-cooling. After removing the cooling-bath, the mixture is stirred for 1.5 hours. To the residue is added 50 ml of ethyl acetate and the solvent is evaporated off under reduced pressure. Fifty milliliter of ethyl acetate is added to the residue. Trituration and filtration of the resulting precipitate give 17 g of the above-identified compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].Br[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][OH:7]
Reactant: BrCCOc1ccccc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCCN(CCO)CCOc1ccccc1
Yield: 78 %

Procedure:
The reaction mixture of 2-(2-hydroxy-ethylamino)ethanol (32 g, 310 mmol), 1-(2-bromoethoxy)benzene (51 g, 256 mmol), and potassium carbonate (70 g, 512 mmol) in ethanol (200 mL) was refluxed overnight, concentrated, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to afford the title compound (45 g, 78%).
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH:7]=[CH:8][CH2:9][CH:2]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>C1COCC1>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][CH:4]1[C:5](=[O:6])[O:1][CH:2]2[CH2:9][CH:8]=[CH:7][CH:3]12
Reactant: O=C1CC2C=CCC2O1
Reactant: BrCc1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC2CC=CC2C1Cc1ccc2ccccc2c1

Procedure:
Analogously to the procedure of Example 1, the title compound was prepared from 7.4 g (59.6 mmol) of 3,3a,6,6a-tetrahydro-cyclopenta[b]furan-2-one, 60 ml of a 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 13.2 g (59.7 mmol) of 2-(bromomethyl)-naphthalene in 180 ml of THF. Chromatographic purification is carried out using a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100:4. Yield: 10.6 g (67.3%), pale yellow oil, diastereomeric mixture: 2.5:1 (Example 7). MS (ESI)[m/e]: 287 [M+Na+]
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.[C:41]1([CH2:47][C@@H:48]([C:50]2[O:54][N:53]=[C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[N:51]=2)[NH2:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[F:61][C:62]1[CH:63]=[C:64]2[C:68](=[CH:69][CH:70]=1)[NH:67][CH:66]=[C:65]2[CH2:71][C:72](O)=[O:73]>>[F:61][C:62]1[CH:63]=[C:64]2[C:68](=[CH:69][CH:70]=1)[NH:67][CH:66]=[C:65]2[CH2:71][C:72]([NH:49][C@H:48]([C:50]1[O:54][N:53]=[C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:51]=1)[CH2:47][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:73]
Reactant: N[C@@H](Cc1ccccc1)c1nc(-c2ccccc2)no1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: O=C(Cc1c[nH]c2ccc(F)cc12)N[C@@H](Cc1ccccc1)c1nc(-c2ccccc2)no1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 18A and 2-(5-fluoro-1H-indol-3-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.90 (d, J=8.0 Hz, 1H), 7.94 (m, 2H), 7.68-7.39 (m, 3H), 7.37-7.06 (m, 8H), 6.85 (td, J=9.2, 2.5 Hz, 1H), 5.34 (dd, J=13.8, 9.2 Hz, 1H), 3.46-3.20 (m, 4H); MS (m/z) 441.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16]C(Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[C:12]([C:3]1[C:2]([OH:1])=[C:7]([C:6]([O:8][CH3:9])=[C:5]([O:10][CH3:11])[CH:4]=1)[CH:15]=[O:16])(=[O:14])[CH3:13]
Reactant: COC(Cl)Cl
Reactant: COc1cc(O)c(C(C)=O)cc1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(C)=O)c(O)c(C=O)c1OC
Temperature: 0 °C
Yield: 10.5 %

Procedure:
A solution of 2′-hydroxy-4′,5′-dimethoxyacetophenone (1.0 g, 5.1 mmol) in methylene chloride (20 mL) was added with dichloromethyl methyl ether (1.6 g, 14 mmol) under an argon atmosphere. Then, the mixture was slowly added with titanium(IV) chloride (2.2 mL, 20 mmol) at 0° C., and then the mixture was refluxed for 18 hours by heating. The reaction mixture was added with ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (3:1→1:1)) to obtain 3-acetyl-2-hydroxy-5,6-dimethoxybenzaldehyde (0.12 g, 10%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]I)[N:33]=2)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:33]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2nc(CI)c(C)o2)cc1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: COc1ccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(4-methoxyphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 71 of molecular weight 465.55 (C27H31NO6), MS(ESI): 466.37 (M+H+).
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[Br:22][C:18]1[N:17]=[C:16]([NH:15][C:14]([C@@H:13]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[NH:8]2)=[O:23])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cccc(Br)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(Br)n1)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S,5R)-3-(6-bromo-pyridin-2-ylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (561 mg, 1.47 mmol) in CH2Cl2 (11 mL) was added TFA (1.13 mL, 14.7 mmol) and the solution was stirred at RT overnight. CH2Cl2 was concentrated and the crude residue was dried under high vacuum to give the desired material which was used without further purification in the next step. MS: 282.1/284.1 [M+H]+, 304.0/306.1 [M+Na]+, 563.1/565.2 [2M+H]+; tR (HPLC conditions f): 0.96 min.