Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@@H:12]2[F:19])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:23]>O>[F:19][C@H:12]1[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][C@H:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:23])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3F)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]1
Reaction time: 24 h

Procedure:
2,6-Diamino-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purine (0.1 g, 0.35 mmoles) prepared as in Example 1, was dissolved in 10 ml of water. Calf intestine adenosine deaminase (10 I.U., Boehringer Mannheim) was added and the solution incubated at 37° C. for one day. The solvent was removed under vacuum. The residue was dissolved in acetonitrile/water (85/15) and chromatographed on silica gel with acetonitrile/water (85/15) as the solvent. Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilization yielded 0.14 g of the title compound that analysed as a 1.1 hydrate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[N:9][CH2:10][CH2:11][N:12]([CH2:24][CH2:25][N:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])[CH2:13][CH2:14][N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].[BH4-].[Na+]>CO.C(Cl)Cl>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:11][CH2:10][NH:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34]
Reactant: Oc1ccccc1C=NCCN(CCN=Cc1ccccc1O)CCN=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Oc1ccccc1CNCCN(CCNCc1ccccc1O)CCNCc1ccccc1O
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of N,N,N-tris[[[(2hydroxyphenyl)methylene]amino]ethyl]amine (40.0 g, 87 mmol) in 250 mL of methanol and 250 mL of methylene chloride was cooled in an ice bath. Sodium borohydride (10.0 g, 263 mmol) was added in several portions. Stirring was continued at room temperature for two hours. The solvents were evaporated and the residue was taken up in ether. This solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to afford N,N,N-tris[[[(2-hydroxyphenyl)methyl]amino]ethyl]amine(30.0 g, 74%) as a colorless glass.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.[C:19](OC(=O)C)(=[O:21])[CH3:20].Cl>O1CCCC1.C(OCC)C>[C:19]([C:8]1[S:7][C:6]2[C:10]([Cl:11])=[C:2]([Cl:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=2[CH:9]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ccsc2c(Cl)c1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 5.0 g of 6,7-dichloro-5-methoxybenzo[b]thiophene in 30 ml of dry tetrahydrofuran and 10 ml dry ethyl ether under nitrogen at -20° is added 11.7 ml of 2.2M n-butyllithium, while the temperature is maintained at -20°. After stirring for 2 hours at this temperature, the reaction mixture is added dropwise through a transfer needle to a stirred solution of 22 ml of freshly distilled acetic anhydride in 40 ml of dry tetrahydrofuran at -20°. Five minutes after the addition, the reaction mixture is poured onto 100 ml 10% hydrochloric acid. The mixture is extracted twice with dichloromethane, the organic layers are collected and dried and the solvent is removed to give a solid. The solid is washed with ethyl ether to give 1.5 g of 2-acetyl-6,7-dichloro-5-methoxybenzo[b]thiophene as a fluffy solid. Recrystallization of the residue obtained by evaporation of the filtrate from ethyl ether-hexane gives an additional 0.6 g of 2-acetyl-6,7-dichloro-5-methoxybenzo[b]thiophene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:22]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:22])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(Br)ccc2N1
Temperature: 110 °C

Procedure:
6-bromo-3,4-dihydroquinolin-2-(1H)-one (1.00 g, 4.42 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane2,4-disulfide (0.895 g, 2.21 mmol) were suspended in toluene (110 mL) and then heated to 110° C. overnight. The reaction was then cooled to room temperature and concentrated under reduced pressure. Dichloromethane was added, giving a mixture that was filtered to provide the title compound: LCMS m/z 243.95 [M+2+H]+; 1H NMR (500 MHz, DMSO) δ 7.44 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 2.92-2.89 (m, 2H), 2.81-2.78 (m, 2H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1>C(O)(=O)C>[Cl:4][CH2:21][C:20](=[O:22])[C:14](=[N:13][O:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:24][CH:23]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C(=O)CCl
Reaction time: 8 h

Procedure:
Sulfuryl chloride (39.26 g.) was added to a solution of ethyl 2-(4-chlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 75.03 g.), in acetic acid (75 ml.), and then stirred at 37° to 40° C. for 8 hours. After air was bubbled into the reaction mixture, the mixture was added to ice water. The mixture was extracted with methylene chloride, and the extract was washed with sodium bicarbonate saturated aqueous solution and sodium chloride saturated aqueous solution in turn. The solution was dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-chloro-2-(4-chlorobenzyloxyimino)-3-oxobutyrate (syn isomer), 77.23 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=O.C(N)CCC.[N+:23]([CH2:26][CH3:27])([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:26]([N+:23]([O-:25])=[O:24])[CH3:27])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1ccccc1
Reactant: CC[N+](=O)[O-]
Solvent: CCCCN
Solvent: Cc1ccccc1
Product: COc1cc(C=C(C)[N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 25 °C
Yield: 69 %

Procedure:
1.15 g of 3-methoxy-4-phenoxybenzaldehyde, 96 μl of n-butylamine, 10 ml of nitroethane and 5 ml of toluene were mixed and refluxed under heating for 2 hours. The reaction solution was left to cool to room temperature and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 953 mg (yield: 69%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:20])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=O)[CH3:29])=[C:24]([OH:31])[CH:23]=1>>[NH2:20][C:9]1[N:10]=[CH:11][N:12]=[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH:28]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][C:24]=3[OH:31])[CH3:29])[CH2:16][CH2:15]2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ncnc(N2CCNCC2)c1-c1ccc(F)cc1
Reactant: CC(=O)c1ccc(Cl)cc1O
Product: CC(c1ccc(Cl)cc1O)N1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in an analogous manner as Example (60) by 5-(4-fluorophenyl)-6-(piperazin-1-yl)pyrimidin-4-amine reacted with 1-(4-chloro-2-hydroxyphenyl)ethanone. LC-MS: (M+1=428, obsd.=428/430).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12]COC)=[C:7]([CH3:16])[CH:6]=1)[OH:4].[ClH:17]>O1CCOCC1>[ClH:17].[NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([CH3:16])[C:8]([OH:12])=[C:9]([CH3:11])[CH:10]=1)[OH:4]
Reactant: COCOc1c(C)cc(C(O)CN)cc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C(O)CN)cc(C)c1O

Procedure:
A solution of 10.55 g of 2-amino-1-(3,5-dimethyl-4-methoxymethoxyphenyl)ethanol [prepared as described in step (b), above] in 200 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 18 hours. The solvent was then removed by distillation under reduced pressure, to give 10.45 g of the title compound, melting at between 170° C. and 172° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C:16](=O)[CH2:15][CH2:14][CH:10]([C:11](O)=[O:12])[CH:9]1[C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1.[Cl-].[Na+].[OH-].[Na+]>O1CCCC1>[CH3:7][N:8]1[CH2:16][CH2:15][CH2:14][CH:10]([CH2:11][OH:12])[CH:9]1[C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1
Reactant: CN1C(=O)CCC(C(=O)O)C1c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCCC(CO)C1c1ccc2c(c1)OCO2

Procedure:
To a flask equipped with stirrer, dropping funnel and under a nitrogen atmosphere there is added 4.8 g. (0.126 mole) of lithium aluminum hydride to 250 ml. of anhydrous tetrahydrofuran. The resulting suspension is stirred and treated dropwise with a solution of 10.0 g. (0.036 mole) of 1-methyl-2-(3,4-methylenedioxyphenyl)-6-oxonipecotic acid in anhydrous tetrahydrofuran at such a rate that reflux occurs. The mixture is then stirred and refluxed for about 24 hours, cooled in an icebath and treated successively with 5 ml. of saturated sodium chloride solution, 5 ml. of 15% sodium hydroxide and 15 ml. of water and after separation stirred for an additional 2 hours. The resulting solid is filtered off and washed with tetrahydrofuran. The combined filtrates are then concentrated to yield 1-methyl-2-(3,4-methylenedioxyphenyl)-3-piperidinemethanol as an oil. The product is then dissolved in anhydrous methanol and saturated with dry hydrogen chloride gas. The solution is then concentrated to about 12 ml. and approximately 60 ml. of diethyl ether is then added. After stirring for 2 hours at room temperature the resultant solid is filtered off to give the hydrochloride salt of the title compound; m.p. 198° to 200° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=C[C:11]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)O)([O:12]N=C(C)C)[C:6]2=[CH:5][NH:4]1)[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCN1NC=C2C1=NC=CC2(ON=C(C)C)C(O)c1ccccn1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCn1ncc2c(O)c(-c3ccccn3)cnc21
Reaction time: 1 h
Yield: 95.2 %

Procedure:
(1-Ethyl-4-isopropylideneaminooxy-1H-pyrazolo[3,4-b]pyridine-4-yl) (2-pyridyl)carbinol (8.3 g) was dissolved in 150 ml of dichloromethane and to this was added 6.5 g of pyridinium chlorochromate. The reaction mixture was stirred 1 hour and then 300 ml of ether was added, after which the mixture was filtered through a pad of magnesium silicate. The pad was washed with a total of 2 liters of ether and then with 1 liter of 5% methanol/dichloromethane. Concentration of the combined filtrate under a reduced pressure gave 5.8 g of the 1-ethyl-4-hydroxy-5-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine, whose identity was confirmed by its mass spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([Cl:22])=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:22].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-4,5-bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12b) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 773.3 [(M+H)+]
Reaction SMILES: [CH3:1][N:2](/[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:5]1\[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[S:9]\1)[CH3:3].[OH:21]O>C(O)(=O)C>[CH3:3][N:2](/[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:5]1\[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[S:9]\1=[O:21])[CH3:1]
Reactant: OO
Reactant: CN(C)/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Solvent: CC(=O)O
Product: CN(C)/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1

Procedure:
Prepared analogous to Example 1 from (E)-2-[(dimethylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one and perhydrol in glacial acetic acid.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=2[N:17]=1)[CH3:4]>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:3][CH3:4])=[C:7]([C:12]2[NH:13][C:14](=[O:25])[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)[CH:8]=1
Reactant: BrBr
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Solvent: CC(=O)O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Temperature: 100 °C
Reaction time: 6.5 h

Procedure:
Bromine (0.93 g, 0.0058 mol) was added dropwise to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Preparation 7, 1.1 g, 0.00352 mol) in glacial acetic acid (20 ml). The mixture was stirred at 100° C. for 6.5 hours and the solvent was then removed by evaporation under vacuum. The residue was dissolved in a 9:1 mixture of methanol in dichloromethane (50 ml), and the solution washed with saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml) and saturated brine (50 ml), then dried (MgSO4) and evaporated under vacuum. The residue was chromatographed on silica gel (15 g) eluting with a mixture of methanol and dichloromethane (1:99) to give, after crystallisation from acetonitrile, the title compound (0.62 g, 45%), m.p. 157°-159° C. Found: C,52.41; H,5.25; N,14.01. C17H19BrN4O2 requires C, 52.18; H,4.89; N,14.32%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[Br:12]Br.CCOC(C)=O.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1>[Br:12][C:10]1[C:5]2[C:4]([Cl:11])=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[NH:8][CH:9]=1
Reactant: BrBr
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 935 mg 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3a) (5.0 mmol) in 100 mL of 1,4-dioxane was slowly added 256 μL of Br2 (5.0 mmol) at 0° C. over a period of 10 minutes. After stirring for 30 minutes at 0° C., the reaction mixture was poured into a mixture of 150 mL of EtOAc and 150 mL of saturated aqueous Na2SO3 then filtered through celite. The aqueous phase was extracted with EtOAc (3×100 mL) and combined organic layers were washed with brine, concentrated and purified by flash column chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][N:7]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: Cc1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c(=O)[nH]n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C2CCNCC2)c(=O)[nH]n1
Reaction time: 24 h
Yield: 100.5 %

Procedure:
Palladium (10% on carbon; 0.70 g) was added to a solution of benzyl 4-(6-methyl-3-oxo-2,3-dihydropyridazin-4-yl)piperidine-1-carboxylate (1.45 g, 4.43 mmol) in ethanol (100 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 24 h, the mixture was filtered through celite and concentrated to give the title compound (0.86 g). MS 194.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N1C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(OCC)(=O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:1][S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cnc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(Nc1cnc2ccccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 3-aminoquinoline (7.2 g, 50 mmol) in acetonitrile (150 mL) was added pyridine (25 mL) and the resulting mixture was cooled to 0° C. A solution of benzenesulfonyl chloride (7 mL, 55 mmol) in acetonitrile (20 mL) was added dropwise over 30 minutes. The mixture was allowed to warm to rt and stirred for 18 hours. The mixture was diluted with ethyl acetate (100 mL) and washed successively with 1N HCl, brine and saturated CuSO4, dried (MgSO4), and concentrated in vacuo to afford an oil. Purification by flash silica gel column chromatography eluting with 30% ethyl acetate in hexanes afforded compound C (13. g g, 95%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[CH2:13][CH:14]1[CH2:16][O:15]1.O>CN(C=O)C>[Cl:2][C:3]1[C:8]([O:9][CH2:13][CH:14]2[CH2:16][O:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Oc1cccnc1Cl
Reactant: ClCC1CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncccc1OCC1CO1
Reaction time: 0.5 h
Yield: 194.4 %

Procedure:
Reaction was carried out under nitrogen flow. A mixture of 2-chloro-3-pyridinol hydrochloride (1:1) (1.760 mol) in DMF (1000 ml) was added dropwise in 30 minutes to a mixture of NaH 60% (1.934 mol) in DMF (1200 ml) (temperature below 27° C.). The reaction mixture was stirred for 30 minutes. (Chloromethyl)-oxirane (3.530 mol) in DMF (1200 ml) was added dropwise over 30 minutes. The reaction mixture was stirred for 9 hours at 60° C. The mixture was cooled. Water was added dropwise on an ice bath. The mixture was extracted with DCM. The organic layer was dried, filtered and the solvent was evaporated. Petroleum ether was added to the residue, then decanted (3 times). This fraction was combined with analogously obtained fractions, then purified by HPLC over silica gel (eluent: hexane/ethyl acetate (50/50)). The desired fractions were collected and the solvent was evaporated, yielding 635 g of 2-chloro-3-(oxiranylmethoxy)-pyridine (intermediate 19).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([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.CON(C)[C:39]([C:41]1[C:42]([CH3:47])=[N:43][O:44][C:45]=1[CH3:46])=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[C:42]([CH3:47])=[N:43][O:44][C:45]=2[CH3:46])=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1c(C)noc1C
Product: Cc1noc(C)c1C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N,3,5-trimethyl-1,2-oxazole-4-carboxamide
Reaction SMILES: C(=O)(O)[O-].[Na+].[N+](C1C=CC(C[O:14][C:15]([C@@H:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:20]3[S:19][C@:18]2([CH2:37][O:38][C:39](=[O:44])[NH:40][C:41](=[O:43])[CH3:42])[CH3:36])=[O:16])=CC=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[C:41]([NH:40][C:39]([O:38][CH2:37][C@@:18]1([CH3:36])[C@H:17]([C:15]([OH:16])=[O:14])[N:21]2[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:20]2[S:19]1)=[O:44])(=[O:43])[CH3:42]
Reactant: [H][H]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Yield: 87 %

Procedure:
A suspension of 10% palladium on charcoal (400 mg) in ethyl acetate (40 ml) and aqueous 0.5% sodium bicarbonate was prehydrogenated and charged with (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (400 mg 0.68 mmol). The whole was shaken at 50 psi hydrogen pressure for 30 minutes and polish filtered. The aqueous was washed with ethyl acetate (20 ml), combined with a back extract of H2O (20 ml), overlayed with ethyl acetate (25 ml) and adjusted to pH 2.9 with 35% sulfuric acid. The layers were separated and the rich organic phase was washed with water (20 ml), combined with a back extract (EtOAc, 20 ml), dried (4A sieves), polish filtered and concentrated in vacuo to a colorless foam (270 mg) in 87% yield: nmr 100 MHz (CDCl3 --D2O) ppm 7.32 (2, m, m-phenyl H's) 6.96 (3, m, o,p-phenyl H's), 5.59 (2, br s, mag. equiv. C5,C6 --H's), 4.79 (1, s, C3 --H), 4.59 ##STR66## 4.08 (m, AB of C2 --CH2O), 2.25 ##STR67## and 1.58 (3, s, C3 --Me) with small ethyl acetate impurity.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O>[S:21]([O:8][CH2:7][C:3]1([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CCC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Temperature: 0 °C

Procedure:
3-ethyl-3-hydroxymethyloxetane (trade name of product, OXT-101®, manufactured by To a Gosei Co.; 116 g) was added to pyridine (500 mL) and cooled to 0° C. while stirring. p-Toluene sulfonyl chloride (190 g) was added divisionally for several times. After stirring for 5 hours while keeping at 0° C., the reaction mixture was poured to iced water (1 L). It was extracted with diethyl ether (500 mL), the pH was rendered acidic with 3% hydrochloric acid, and extracts were washed with water. Then, the extracts were washed with a saturated solution of sodium carbonate and water successively and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3-[(tosyloxy)methyl]3-ethyloxetane (243 g).