Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[CH:6]=[C:7]([S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[O:8]2.C(OC([N:35](C(OC(C)(C)C)=O)[CH2:36][C:37](O)=[O:38])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:62]>ClCCl.C(OCC)(=O)C>[ClH:62].[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[CH:6]=[C:7]([S:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:37](=[O:38])[CH2:36][NH2:35])=[CH:24][CH:25]=1)[O:8]2
Reactant: COc1c(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c2c1OC
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1c(OC(C)C)cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c2c1OC
Reaction time: 1 h

Procedure:
300 ml in dichloromethane of 9.11 g of 5,6-dimethoxy-2-(4-hydroxyphenylthio)-7-isopropoxychromone obtained in Example 22, 4.52 g of N-t-butoxycarbonyl(Boc)glycine, and 5.32 g of dicyclohexylcarbodiimide (DCC) was stirred over 3.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that 10.95 g of N-t-butoxycarbonyl(Boc)glycine ester was obtained. 5.27 g of N-t-butoxycarbonyl(Boc)glycine ester thus prepared was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 1 hour. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and then dried, whereby 3.53 g of 5,6-dimethoxy-2-(4-glycyloxyphenylthio)-7-isopropoxychromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36]N)=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@@H:46]([CH2:52][CH:53]([CH3:55])[CH3:54])[C@@H:47]([OH:51])[CH2:48][CH2:49][OH:50])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:46]([CH2:52][CH:53]([CH3:55])[CH3:54])[C@@H:47]([OH:51])[CH2:48][CH2:49][OH:50])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CCO
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CCO

Procedure:
The procedure described in Example 12(c) was repeated, but using 125 mg. (0.25 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidine hydrazide and 65 mg. (0.25 mmole) of the alcohol prepared as described in (a) above. There were obtained 42 mg. of the desired compound as a white powdery solid, melting at 196°-198° C.; [α]24 -57.8° (C=0.5, methanol).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[C:7]([C:10]1[CH:34]=[CH:33][C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([OH:32])[C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)C(O)=O)=[CH:18][CH:17]=2)=[C:12]([Cl:35])[C:11]=1[OH:36])(=[O:9])[CH3:8].[N+](=C)=[N-]>O1CCCC1.CN(C)C=O>[C:7]([C:10]1[CH:34]=[CH:33][C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]([OH:32])[C:23]3[CH:31]=[C:30]([C:2](=[O:3])[CH2:1][Cl:6])[CH:29]=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[C:12]([Cl:35])[C:11]=1[OH:36])(=[O:9])[CH3:8]
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(Cl)c1O
Reactant: O=C(Cl)C(=O)Cl
Agent: C=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C(=O)CCl)c3)cc2)c(Cl)c1O
Reaction time: 2 h
Yield: 100 %

Procedure:
Add oxalyl chloride (256 mg, 2.02 mmol) to a solution of 3-{[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid (0.786 mg, 1.84 mmol) in tetrahydrofuran (0.20M). Add dimethylformamide (5 drops). Add ethereal solution of diazomethane (1.90 mmol) and stir for 2 hours. Add hydrochloric acid (4N in dioxane) to quench unreacted diazomethane and evaporate solvents to afford the title compound (0.786 mg, 1.84 mmol, 94%): MS (m/z): 457 (M−H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[CH:14][CH:13]=1>CN(C=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:17]([N:16]1[C:12]([NH:11][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:13][CH:14]=[N:15]1)([CH3:19])[CH3:18]
Reactant: O=C(O)c1ccccc1I
Reactant: CC(C)n1nccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nccc1Nc1ccccc1C(=O)O
Yield: 97.3 %

Procedure:
To 2-iodobenzoic acid (54 g, 0.218 mol) in DMF (570 ml) was added K2 CO3 (33.4 g, 0.242 mol), then 5-amino-1-isopropylpyrazole (27.3 g, 0.218 mol) and finally copper (II) acetate monohydrate (0.9 g, 4.5 mmol). The reaction mixture was refluxed overnight and then the DMF was evaporated. The residue was poured into ice/water and then the mixture was acidified with acetic acid and concentrated HCl to a pH of about 4. A precipitate formed which was collected by filtration, washed with water and dried in a vacuum oven at 40° C. to afford 52 g (97.2%) of N-(1-isopropylpyrazol-5-yl)anthranilic acid.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:41])=[C:12]([CH2:14][O:15][C:16]2[CH:40]=[CH:39][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:18][CH:17]=2)[N:13]=1.O.Cl>O1CCCC1.C(O)C>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:41])=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:39][CH:40]=2)[N:13]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
Lithium hydroxide monohydrate (163 mg) was added to a solution of ethyl E-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate (670 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.9 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoic acid (625 mg, yield 98%) as colorless crystals. m.p. 112-113° C.
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:22]([NH:24][NH2:25])=[O:23])=[N:14][C:15]3[N:16]([N:19]=[CH:20][CH:21]=3)[C:17]=2[F:18])=[C:7]([F:26])[CH:6]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[O:23][C:22]([C:13]2[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([Br:4])=[CH:6][C:7]=3[F:26])=[C:17]([F:18])[N:16]3[N:19]=[CH:20][CH:21]=[C:15]3[N:14]=2)=[N:24][N:25]=1
Reactant: NNC(=O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2nc3ccnn3c(F)c2Nc2ccc(Br)cc2F)o1
Reaction time: 17 h

Procedure:
Cyanogen bromide (2.02 equivalents) is added to a suspension of 6-(4-bromo-2-fluorophenylamino)-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid hydrazide (1.00 equivalent) in dioxane followed by an aqueous NaHCO3 solution (1.01 equivalents). After 17 hours, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated under reduced pressure. The product is purified by flash chromatography as necessary.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=3)=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1.[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([N:27]4[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]4)[CH:14]=[CH:15][CH:16]=3)=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(Br)cc23)n1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)CC1
Yield: 80 %

Procedure:
Following the procedures of Example 144, 5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl piperazine-1-carboxylate were reacted, triturated with ethyl ether, and collected by filtration to afford 910 mg (80%) of tert-Butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate. ESI MS m/z 543.2 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH2:8][N:9]=[N+]=[N-])(=O)=O.[P:26]([O:33]CC)([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29].P(=N)(OCC)(OCC)OCC>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=C(C)C=1>[Br:18][C:14]1[CH:13]=[C:12]([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=3)[CH2:8][N:9]([P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])[CH2:6]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OCC(CN=[N+]=[N-])(c1cccc(Br)c1)c1cccc(Br)c1
Reactant: CCOP(OCC)OCC
Agent: CCOP(=N)(OCC)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)c1
Product: CCOP(=O)(OCC)N1CC(c2cccc(Br)c2)(c2cccc(Br)c2)C1
Temperature: 150 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
To a solution of 3-azido-2,2-bis(3-bromophenyl)propyl methanesulfonate (1.3 g, 2.66 mmol) in anhydrous toluene (10 mL) and anhydrous THF (5 mL) under N2 was added triethyl phosphite (0.49 mL, 2.79 mmol) at 25° C. The mixture was stirred for 18 h. The reaction was concentrated by rotary evaporation in a dried apparatus. The residue was dried in vacuo, and used in the next reaction without further purification. The crude triethyl phosphorimidate was dissolved in anhydrous m-xylene (5 mL) under N2 and heated in an oil bath at 150° C. for 12 h. After cooled to room temperature, the solvent was removed by rotary evaporation (vacuum pump assisted) to give a thick light orange oil which was purified by prep-TLC (eluent with EtOAc: dichloromethane=1:5) to afford 960 mg of diethyl 3,3-bis(3-bromophenyl)azetidin-1-ylphosphonate (1.9 mmol, 71% after two steps). LC/MS: [M+1]=504. 1HNMR (CDCl3), 400 MHz: δ 1.25-1.36 (m, 6H), 4.05-4.39 (m, 4H), 4.40 (d, 2H, J=5.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=3[O:2][CH3:1])=[O:21])[N:19]=2)[CH:16]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: COc1ccccc1N
Product: COc1ccccc1NC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 2-methoxyaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]=[CH2:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].B1C2CCCC1CCC2.[OH2:32].[OH-].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:32])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C#N)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(CCO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To the solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-ethenylbenzonitrile (2.0 g, 6.18 mmol) in dry THF (14 mL), was added 9-BBN (18 mL, 9.00 mmol) at 0° C. The mixture was stirred at room temperature overnight. Water (1.113 mL, 61.8 mmol), aq. NaOH (12.36 mL, 37.1 mmol), and 30% H2O2 (3.16 mL, 30.9 mmol) were added then. The reaction mixture was heated at 55° C. for 4 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.0 g, 2.93 mmol, 47.4% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20](O)=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1.O1CCCC1.C(Cl)(=O)C([Cl:44])=O>CN(C)C=O>[CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20]([Cl:44])=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nn(C)c(C(=O)O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nn(C)c(C(=O)Cl)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reaction time: 2 h

Procedure:
At room temperature, to the mixture of 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid (described in Reference Preparation example 116) and tetrahydrofuran 50 ml was added oxalyl dichloride 0.5 g and N,N-dimethylformamide 0.1 ml. The mixture was stirred for two hours and concentrated under reduced pressure to give 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dim ethyl-2H-pyrazole-3-carbonylchloride 1.3 g.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[C:8]1([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(N(CCCC)CCCC)CCC>[CH3:7][C:4]1[CH:3]=[C:2]2[N:1]=[C:15]([OH:16])[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:20]([OH:21])[N:6]2[N:5]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cc2nc(O)c(-c3ccccc3)c(O)n2n1
Temperature: 25 °C

Procedure:
A solution of 4.5 g 5-amino-3-methylpyrazole and 12.2 mL diethyl phenylmalonate in N,N-dibutylbutan-1-amine was stirred at 185° C. over night. After cooling to room temperature the reaction mixture forms two layers. The top layer was removed and the lower layer was diluted with dichloromethane and methanol. The resulting solution was concentrated and extracted with a mixture of diethyl ether and 10% w/w NaOH solution. The organic layer was discarded and aqueous layer acidified with concentrated HCl. The precipitated product was collected by filtration.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)Cl.C(N(CC)CC)C.[C:37](Br)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[N:19]([C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)c1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Agent: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)n1c(=O)c(F)cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a solution of 0.50 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 20 ml of dioxane were added 0.75 ml of trimethylchlorosilane and 2.00 ml of triethylamine, and the mixture was stirred at room temperature for 2 hours. Then, the resulting mixture was left to stand at 60° C. for 30 minutes. To the reaction mixture were added 0.42 g of benzoyl bromide and 1.00 ml of triethylamine, and the mixture was left to stand at 60° C. for 1 hour. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate. Then, the solution was washed with saturated aqueous solution of sodium chloride. The ethyl acetate layer was separated and concentrated. The residue was dissolved in 30 ml of methanol and 0.5 ml of acetic acid was added thereto. The mixture was left to stand overnight. The solvent was distilled off and the residue was applied to a silica gel column to conduct gradient elution using chloroform and mixtures of methanol (up to 2%) and chloroform, giving 0.35 g of the title compound as a powder in a yield of 54%.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
esterifying L-phenylalanine with methanol in the presence of sulfuric acid to produce a solution of L-phenylalanine methyl ester;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15].O>CO.C1C=CC=CC=1.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([S:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)C(Br)c1ccc(Sc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)C(Oc1ccc(F)cc1)c1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
To a solution of 2.8 g of p-fluorophenol, 1.19 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol was added 7.43 g of methyl α-bromo-α-[p-(p-chlorophenylthio)phenyl]acetate in 10 ml of benzene. The mixture was refluxed overnight and then cooled to room temperature. The mixture was poured into 100 ml of water and extracted with 2 × 75 ml of ether. The combined extracts were washed with 50 ml of 5% NaOH, 50 ml water, saturated brine, and dried (MgSO4). Evaporation of the solvent at reduced pressure afforded an amber oil, which was chromatographed on 100 g of silica gel (benzene). Concentration of the eluate yielded an amber oil which crystallized on trituration with 100 ml of petroleum ether, mp 84.5°-86.5° C (weight 6.05 g). Recrystallization from 50 ml of hexane yielded 5.3 g of a white solid, mp 84.5°-87° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH3:13][C:12]1[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=2)[CH2:2][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOP(OCC)OCC
Reactant: Cc1cccnc1Oc1cccc(CCl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(Oc2ncccc2C)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
2-(3-(Chloromethyl)phenoxy)-3-methylpyridine (3.6 g, 15 mmol) from Step 2 was treated neat with triethylphosphite (3.3 mL, 19.3 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-60%, EtOAc:CH2Cl2) to afford the title compound (4.3 g, 83% yield) as a thick oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([S:18]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(Sc2c[nH]c3ccccc23)cc1
Solvent: ClCCl
Product: O=S(c1ccccc1)c1c[nH]c2ccccc12

Procedure:
Solid m-chloroperbenzoic acid (1.93 g, 9.77 mmol) was added in small portions to a well stirred solution of 3-phenylthioindole (2.0 g, 8.88 mmol) in dry dichloromethane (100 ml) at 0°. Five min after the addition was terminated, the reaction was completed. The solution was washed with saturated sodium bicarbonate solution, the organic phase diluted with ether, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ether-hexane to give the title compound, M.P.-126°-127° C.
Reaction SMILES: C(OC([NH:8][CH:9]([C:39]([O:41]CC1C=CC(OC)=CC=1)=[O:40])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:35](=[O:38])[CH:36]=[O:37])[CH:20]2[CH2:23][N:22]([CH:24]([C:31]([OH:33])=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]2=[O:34])=[CH:15][CH:14]=1)=O)(C)(C)C.C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)C>[NH2:8][CH:9]([C:39]([OH:41])=[O:40])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:35](=[O:38])[CH:36]=[O:37])[CH:20]2[CH2:23][N:22]([CH:24]([C:31]([OH:33])=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]2=[O:34])=[CH:17][CH:18]=1
Reactant: COc1ccc(COC(=O)C(CCOc2ccc(N(C(=O)C=O)C3CN(C(C(=O)O)c4ccccc4)C3=O)cc2)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOCC
Product: NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3ccccc3)C2=O)cc1)C(=O)O
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a mixture of 3-[4-{3-tert-butoxycarbonylamino-3-(4-methoxybenzyloxycarbonyl)propoxy}phenylglyoxyloylamino]-1-(α-carboxybenzyl)-2-azetidinone (870 mg), benzene (4 ml) and anisol (1 ml), there was added 2,2,2-trifluoroacetic acid (2 ml) under ice-cooling. The mixture was stirred at the same temperature for 1.5 hours and then diethyl ether (50 ml) was added thereto. The mixture was stirred for half an hour and insoluble materials were collected by filtration and suspended in ethyl acetate (30 ml). After the suspension was stirred at ambient temperature for half an hour, insoluble materials were collected by filtration and then treated with diethyl ether to give 3-[4-(3-amino-3-carboxypropoxy)phenylglyoxyloylamino]-1-(α-carboxybenzyl)-2-azetidinone (0.52 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCN(C(C)=O)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 1-acetylpiperazine. ES-MS m/e (%): 519 (M+Na+, 32), 497 (M+H+, 100).