Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[CH:39]=3)[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[CH:39]=3)[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccnc(OCc3cn4c(-c5ccccc5)cccc4n3)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccnc(OCc3cn4c(-c5ccccc5)cccc4n3)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[2-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (1030 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (4 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[2-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (922 mg, yield: 95%). This was recrystallized from ethanol-hexane. Melting point: 177–178° C.
Reaction SMILES: Br[CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].[CH2:32]([N:34](CC)[CH2:35]C)C.CNC>C1(C)C=CC=CC=1>[CH3:32][N:34]([CH3:35])[CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16]
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CC(Br)CN1CCN(c2ccc(F)cc2)CC1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: Cc1ccccc1
Product: CN(C)C(CN1CCN(c2ccc(F)cc2)CC1)CN1c2cccc3cccc(c23)S1(=O)=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2-(2-Bromo-3-[4-(4-fluorophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (4.2 g), triethylamine (1.1 cc) and dimethylamine (0.5 cc) in toluene (50 cc) are introduced into a 250 cc bomb ap paratus cooled to a temperature of about 0° C. The mixture is stirred and heated for 8 hours to a temperature close to 120° C., then cooled to a temperature of about 20° C. Stirring is continued for 15 hours at this temperature, then the reaction mixture is concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant. After recrystallization from boiling acetonitrile (15 cc), 2(2-dimethylamino-3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.9 g) is obtained, m.p. 118° C. 2-(2-Bromo-3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}naphtho[ 1,8-cd]isothiazole 1,1-dioxide may be prepared in the following manner: phosphorus tribromide (1 cc) is poured into 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl}naphtho[1,8-cd]isothiazole 1,1dioxide (11.5 g) in toluene (150 cc). The mixture is heated at boiling point for 4 hours, then is cooled to a temperature of about 20° C. The reaction mixture is redissolved in distilled water (300 cc) and alkalinized to pH 11 with N caustic soda (20 cc). The organic phase is extracted with dichloromethane (4×300 cc), dried centrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified by flash-chromatogra-phy on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as diluent. 2-(2-Bromo-3-[4-(4-fluorophenyl)-1-piperazinyl]pripyl}naptho[1,8j-cd]isothiazole 1,1-dioxide (5.7 g) is obtained, m.p. 102° C, which is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][C:2]1(C)[C:6](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:20]1[C:21]([N:42]2[CH2:47][CH2:46][CH2:45][C@@H:44]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:43]2)=[C:22]2[C:28]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]2=[N:24][CH:25]=1>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:32]1([C:30]([NH:29][C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:2]([CH3:6])=[CH2:1])[C:21]=3[N:42]3[CH2:47][CH2:46][CH2:45][C@@H:44]([NH:48][C:49](=[O:50])[O:51][C:52]([CH3:53])([CH3:55])[CH3:54])[CH2:43]3)[NH:26][CH:27]=2)=[O:31])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3c2c(NC(=O)C2CC2)cn3C(=O)OC(C)(C)C)C1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(C)c1cnc2[nH]cc(NC(=O)C3CC3)c2c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 62.1 %

Procedure:
4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (436 mg, 2.59 mmol), PS-tetrakis (triphenylphosphine) palladium (786 mg, 0.0864 mmol, 0.10 mmol/1 g) and 2N sodium carbonate (1296 μL, 2.59 mmol) were added to (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (500 mg, 0.864 mmol; Example 107, Step A) in degassed dioxane (1 mL). The reaction was heated to 120° C. for an hour under microwave irradiation. The reaction was then heated to 150° C. for 30 minutes. The reaction was filtered and extracted with DCM. The organic layer was concentrated, and the resulting residue was purified by reverse phase chromatography (Gilson, C-18, 5-95% CH3CN/water) to yield (R)-tert-butyl 1-(3-(cyclopropanecarboxamido)-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (236 mg, 62% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1Br>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: Fc1cccc(F)c1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3c(F)cccc3F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2,6-difluorobromobenzene. MS (ESI): mass calcd. for C16H10F3N3, 301.08; m/z found, 302.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.02 (s, 1H), 7.97 (m, 1H), 7.56-7.47 (m, 1H), 7.43 (d, J=12.5, 1H), 7.37 (d, J=7.9, 1H), 7.25 (m, 2H), 6.76 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14][C@H:13]2[CH2:37][NH:38][S:39](=[O:42])(=[O:41])[NH2:40])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1>O1CCCC1.O.ClCCl.CO.S.[N+]([O-])([O-])=O.[Ag+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:37][NH:38][S:39](=[O:41])(=[O:42])[NH2:40])=[O:11])=[CH:43][CH:44]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: S
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: NS(=O)(=O)NC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-sulfamoylaminomethyl-4-tritylthiopyrrolidine (668 mg: 0.95 mmole) in tetrahydrofuran (6 ml), a solution of pyridine (0.254 ml: 2.7 eq.) and silver nitrate (403 mg: 2.5 eq.) in water (2 ml) is added under ice cooling. The mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with dichloromethane (3 ml) and methanol(3 ml), and hydrogen sulfide is bubbled through it under ice cooling for 10 minutes. The resulting precipitate is removed by filtering. The filtrate is diluted with dichloromethane, washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-sulfamoylaminomethyl-4-mercaptopyrrolidine (233 mg). Yield: 63%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([O:19][CH3:20])=[C:13]([O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:12]=2)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[NH4+]>ClCCl>[Cl:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:7]
Reactant: COc1cc2c(Cl)c(NC(=O)OC(C)(C)C)cnc2cc1OCCCN1CCCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Cl)c(N)cnc2cc1OCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
[4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-yl]-carbamic acid tert-butylester (1.8 g) was dissolved in dichloromethane and added trifluoroacetic acid (2 ml) and stirred at room temperature for 2 h. This was carefully basified with ammonium hydroxide solution and extracted the desired amino product with ethyl acetate. The solvent was evaporated to give 4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-ylamine (0.500 g). MS(ES) 350 (M+H).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16](N)[C:15]=3[N:14]=[CH:13]2)[C@H:9]([OH:22])[C@@H:8]1[OH:23])([OH:4])([OH:3])=[O:2].C1N=C([Cl:30])C2N=CN([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)C=2N=1.O=P(Cl)(Cl)Cl>O>[CH:19]1[N:18]=[C:16]([Cl:30])[C:15]2[N:14]=[CH:13][N:12]([C@@H:10]3[O:11][C@H:7]([CH2:6][O:5][P:1]([OH:4])([OH:3])=[O:2])[C@@H:8]([OH:23])[C@H:9]3[OH:22])[C:21]=2[N:20]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O

Procedure:
N6-(ω-amino-linker) adenosine 5′-monophosphate can be prepared by contacting 6-chloropurine riboside first with POCl3 then water to produce 6-chloropurine riboside 5′-monophosphate. This intermediate can be reacted with a diamine to produce an N6-(ω-amino-linker) adenosine 5′-monophosphate. Diamines include ethylenediamine (EDA), 1,4-butanediamine (BDA), 1,6-hexanediamine (HDA), 2,2′-oxydiethylamine (ODEA), 2,2′-(ethylenedioxy)diethylamine (EDODEA), and 4,7,10-trioxa-1,13-tridecanediamine (TOTDDA). These diamines provide linkers of (CH2)2, (CH2)4, (CH2)6, C2H4OC2H4 and C3H6OC2H4OC2H4OC3H6, respectively. Additional diamines (and polyamines) such as spermidine (NH2(CH2)3NH(CH2)4NH2), spermine, (NH2(CH2)3NH(CH2)4NH(CH2)3NH2), polyethylene glycol diamines (H2N-PEG-NH2), 1,4-bis(3-aminopropoxy)butane (H2N(CH2)3O (CH2)4O(CH2)3NH2), bis(3-aminopropyl)amine(H2N(CH2)3NH(CH2)3NH2), tris(2-aminoethyl)amine(N(CH2CH2NH2)3), 1,8-diaminooctane (H2N(CH2)8NH2), 1,10-diaminodecane (H2N(CH2)10NH2), and 1,12-diaminododecane (H2N(CH2)12NH2), can also be used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH2:33][C:34]([CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)[OH:38])([CH3:36])[CH3:35]>O1CCCC1>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)[C:34]([NH:33][C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:36])[CH3:35]
Reactant: COc1cccc(C(O)C(C)(C)N)c1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)C(C)(C)NC(=O)Cc2ccc(OC)c(OC)c2)c1
Temperature: 65 °C
Yield: 72 %

Procedure:
A solution of 50 g. (0.26 mole) of 3,4-dimethoxyphenylacetic acid, 68 g. (0.28 mole) of EEDQ and 50 g. (0.26 mole) of α-(1-amino-1-methylethyl)-3-methoxybenzenemethanol in 450 ml. tetrahydrofuran are stirred for three days at 25° C., and then heated for 5 hours at 65° C. Tetrahydrofuran is evaporated in vacuo, and the residue is taken up with ice and 10% aqueous H2SO4 solution to pH 2. The amide is extracted twice with 500 ml. ethyl acetate. The combined organic extracts are washed with 500 ml. dilute aqueous NH4OH solution, dried (Na2SO4) and evaporated to dryness in vacuo. The residual oil is dissolved in hot diethyl ether from which it crystallizes to give 72.0 g. of impure product. Recrystallization from diethyl ether gives 70 g. (72% yield) of N-(β-hydroxy-3-methoxy-α,α-dimethylphenethyl)-3,4-dimethoxybenzeneacetamide as white crystals of analytical purity, m.p. 137°-138° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:13])/[CH:11]=[CH:10]\[C:9]([OH:14])=[O:15]
Reactant: O=C1C=CC(=O)O1
Reactant: OCc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)/C=C\C(=O)OCc1ccccc1

Procedure:
Poly(styrene [50 mol %], benzyl hydrogen maleate [50 mol %]) was prepared by stirring at reflux for 25 hours a mixture of poly(styrene [50 mol %], maleic anhydride [50 mol %]), 200 mL of benzyl alcohol and 400 mL of THF. The THF was removed on a rotary evaporator, and the product was precipitated in hexane followed by precipitation from THF with diethyl ether to give 46 g of poly(styrene, benzyl hydrogen maleate). A mixture of 25 g of poly(styrene, benzyl hydrogen maleate), 150 mL of 3,4-dihydro-2H-pyran, and 0.5 g of pyridine hydrochloride was stirred at reflux 18 hours. THF was added to reduce the viscosity, and the mixture was stirred 1 hour with crosslinked poly(dimethylaminomethylstyrene). After filtration, the product was precipitated from the filtrate in methanol to give 29 g of poly(styrene, benzyl maleate, tetrahydropyranyl maleate). 1H HMR (360 MHz) shows the molar ratio of tetrahydropyranyl groups (δ 5.8 ppm) to benzyloxy groups (δ 5.0 ppm) to be about 4.4:1. Titration with 0.1N sodium hydroxide shows 0.09 meq/g of COOH groups. DSC: decomposition endotherm 140.75° C. TGA: 24.7% weight loss at 147.9° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)=[O:31].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:30](=[O:31])[CH2:29][N:7]2[C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:2]2=[O:1])=[CH:33][CH:34]=1
Reactant: CCCOc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (0.55 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.38 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.073 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.7 g, 90%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][O:19][C:20]([C:22]2[N:27]3[C:28](=[O:31])[C@@H:29]([NH2:30])[C@H:26]3[S:25][CH2:24][C:23]=2[CH2:32][Cl:33])=[O:21])=[CH:16][CH:15]=1.[C:36]([O:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47]([C:49](=[N:53][O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])[C:50](O)=[O:51])[N:48]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37].CN1CCOCC1.P(OCl)(OCl)(OC1C=CC=CC=1)=O>ClCCl.C(N(CC)CC)C>[C:36]([O:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47]([C:49](=[N:53][O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:56])[CH3:57])[C:50]([NH:30][C@@H:29]2[C:28](=[O:31])[N:27]3[C:22]([C:20]([O:19][CH2:18][C:17]4[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:35][CH:34]=4)=[O:21])=[C:23]([CH2:32][Cl:33])[CH2:24][S:25][C@H:26]23)=[O:51])[N:48]=1)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=NOC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P(OCl)(OCl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1

Procedure:
7β-Amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxy-benzyl ester p-toluenesulfonate in dichloromethane is treated with triethylamine, 2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetic acid, N-methylmorpholine, and phenyl dichloro phosphate to give p-methoxybenzyl 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=1.[F:25][C:26]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[F:24][C:4]1[C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=[C:2]([C:27]2[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:26]=2[F:25])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)cc(F)c3o2)CC1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)cc(F)c3o2)CC1
Yield: 20.3 %

Procedure:
Following the General Procedure-1, the titled compound (50 mg) was prepared from Intermediate 12 (200 mg, 0.50 mmol) and Intermediate 3 (151 mg, 0.50 mmol) as an off-white solid. M.P.: 155.3-158.4° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.82 (dd, J 1.8, 8.1, 1H), 7.78 (dd, J 1.7, 9.4, 1H), 7.69-7.63 (m, 2H), 7.29 (td, 1.3, 10.6, 1H), 4.16 (d, J 11.2, 2 H), 3.22-3.16 (m, 1H), 3.11 (s, 3H), 3.00 (t, J 13.3, 2H), 2.21-2.14 (m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH3:29])[N:20]=[CH:19][N:18]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:30][S-:31].[Na+].O>CN(C)C=O>[CH3:30][S:31][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:16][C:17]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH3:29])[N:20]=[CH:19][N:18]=2)=[CH:12][CH:13]=1
Reactant: C[S-]
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCOS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCSC)cc1
Yield: 75.8 %

Procedure:
A solution of ethyl 4-(2-(4-(2-methylsulfonyloxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.70 g, 1.66 mmol) in N,N-dimethylformamide (10 ml) was stirred under ice-cooling. Sodium thiomethoxide (0.13 g, 1.85 mmol) was added to the solution. The mixture was stirred under ice-cooling for 2 hours, and then water (40 ml) was added. The mixture was extracted with ethyl ether and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-(2-methylthioethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.47 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and phenylacetyl chloride the title compound was obtained as a light yellow solid (37%), MS: m/e=384 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[N:24]O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 0 °C

Procedure:
Under ice cooling and stirring, 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindoline (31 g) was added in portions to a suspension of lithium aluminum hydride (8.0 g) in tetrahydrofuran (500 ml) and then the resultant mixture was heated under reflux for 3 hr. Under cooling with ice water, water (8 ml), a 5 N aqueous solution (24 ml) of sodium hydroxide and further water (8 ml) were carefully added dropwise to the reaction solution followed by vigorous stirring. The resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure to give the crude title compound (about 30 g). A portion of this crude product was purified by NH-silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-isopropyl ether mixtures to give the title compound as a pale yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])=[C:11]([Cl:13])[CH:12]=1)C.[OH-].[Na+]>C1COCC1.O>[Cl:13][C:11]1[CH:12]=[C:7]([CH2:6][CH2:5][C:4]([OH:19])=[O:3])[CH:8]=[N:9][C:10]=1[C:14]([C:17]#[N:18])([CH3:16])[CH3:15]
Reactant: CCOC(=O)CCc1cnc(C(C)(C)C#N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)c1ncc(CCC(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-propionic acid ethyl ester (0.68 g, 2.43 mmol) from step 4 above, in 1:1 THF/H2O (4 mL) was added 2 N NaOH (2.43 mL). The resulting solution was stirred at 60° C. for 1 hour. Solvents were removed and residue was partitioned between ethyl acetate and 10% citric acid and extracted. The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue solidified to a white solid and was used without further purification. (0.39 g, 64%) as a white solid. ESIMS (MH−): 251.