Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:47])([CH2:45][CH3:46])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=3)=[CH:34][CH:33]=2)[OH:31])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:47])([CH2:45][CH3:46])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=3)=[CH:34][CH:33]=2)[OH:31])[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(CC(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrogen chloride (4 M in dioxane) (1.5 mL, 0.67 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanol (200 mg, 0.33 mmol) in methanol (6 mL). After stirring at ambient temperature for 3 h, volatiles were removed. The residue was partitioned between 1 N hydrochloric acid and diethyl ether. The aqueous phase was washed with diethyl ether, basified with saturated aqueous sodium carbonate and extracted with diethyl ether and ethyl acetate. Combined extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. Purification by HPLC (Gilson; Chiralcel OJ column; 10 mL/min; 10% isopropanol/heptane). (M+H) found 368.
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]([CH: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].[H-].[Na+].[CH:30]([OH:33])([CH3:32])[CH3:31]>O1CCOCC1.CN(C=O)C>[CH:30]([O:33][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]([CH: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])([CH3:32])[CH3:31]
Reactant: CC(C)O
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(OC(C)C)c3)nc12

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with sodium hydride and isopropanol in dioxane and DMF. ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22].CCOCC>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:1]1[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:22]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CBr)N1CCCCc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a 0° C. solution of 2,3,4,5-Tetrahydro-1H-benzo[b]azepine (5.5 g, 37.4 mmol) and triethylamine (5.21 mL, 37.4 mmol) in anhydrous methylene chloride (180 mL) under N2 was added dropwise bromoacetyl bromide (3.25 mL, 37.4 mmol). The mixture was stirred at 0° C. for 2 h, then allowed to warm to ambient temperature and stirred for 1 h. The mixture was worked up by washing with 0.5 M aq. HCl (100 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated to give the crude product as a brown semi-solid. Trituration with ether gave the product (5.69 g) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][N:10]=1
Reactant: O=c1ncc(-c2ccc(F)cc2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2cnc(Cl)nn2)cc1

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3(2H)-one (1.0 g, 5.23 mmol) and phosphoryl chloride (8.0 mL) in chloroform (5.0 mL) was heated under reflux conditions overnight. After cooling, the volatiles were removed under reduced pressure. The residue was dissolved in dichloromethane (60 mL) and was poured into ice with stirring. The mixture was neutralized with aqueous 2N potassium carbonate and filtered through a pad of Celite. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the desired product. (600 mg, 54.6%) 1H-NMR (300 MHz, CDCl3): 8.88 (s, 1H), 8.06-8.12 (m, 2H), 7.06-7.14 (m, 2H). LCMS: (M+H)=210.1/212.1.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10]3([C:32]4[C:23](=[CH:24][C:25]5[O:30][CH2:29][CH2:28][O:27][C:26]=5[CH:31]=4)[O:22][CH2:21]3)[C:9]2=[O:33])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[C:16]2[C:11]=1[C:10]1([C:32]3[C:23](=[CH:24][C:25]4[O:30][CH2:29][CH2:28][O:27][C:26]=4[CH:31]=3)[O:22][CH2:21]1)[C:9](=[O:33])[NH:8]2
Reactant: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C21COc2cc3c(cc21)OCCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: COc1cc2c(c(OC)c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one was obtained (55%): 1H NMR (300 MHz, CDCl3) δ10.42 (s, 1H), 6.35 (s, 1H), 6.15 (d, J=2.0 Hz, 1H), 6.10 (d, J=2.0 Hz, 1H), 6.08 (s, 1H), 4.58 (ABq, 2H), 4.17-4.03 (m, 4H), 3.72 (s, 3H), 3.58 (s, 3H); MS (ES+) m/z 356.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:14]([CH2:32][CH2:33][CH2:34][Cl:35])[C:15]2[C:20]([C:21]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:35][CH2:34][CH2:33][CH2:32][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)[C:21]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:13]1[C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccn3C(=O)OC(C)(C)C)n(CCCCl)c2c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc[nH]3)n(CCCCl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of methyl 2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-1-(3-chloropropyl)-3-cyclohexyl-1H-indole-6-carboxylate (167 mg, 0.344 mmol) in chloroform (1.5 ml) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was evaporated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 1-(3-chloropropyl)-3-cyclohexyl-2-(1H-pyrrol-2-yl)-1H-indole-6-carboxylate (135 mg, yield 98%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[Cl:14][C:15]1[C:23]2[O:22][CH2:21][C:20](=O)[C:19]=2[CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:14][C:15]1[C:23]2[O:22][CH:21]=[C:20]([CH2:5][C:3]#[N:4])[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1COc2c(Cl)cccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1coc2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
To a stirred suspension of NaH 50% dispersion in mineral oil, washed with hexane; 1.82 g, 0.0378 mol) in THF (70 mL) was added a solution of diethyl cyanomethylphosphonate (6.7 g, 0.0378 mol) in THF (30 mL) dropwise over 20 minutes. After 20 minutes, the mixture was cooled to 0° C. and a solution of 7-chlorobenzofuran-3-one (5.8 g, 0.0344 mol) in THF (80 mL) was added dropwise over 30 minutes. The cooling bath was removed and stirring was continued at room temperature overnight. H2O (400 mL) and ether were added. The organic phase was washed with saturated aqueous NaCl, dried (MgSO4), and concentrated to give a red solid (6.4 g, 97%).
Reaction SMILES: Cl[C:2](=[N:24][OH:25])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Br:26][C:27]1[N:28]=[C:29]([C:48]#[CH:49])[C:30]([N:33]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:31][CH:32]=1.CCN(CC)CC>C(Cl)Cl.O>[C:44]([O:43][C:41](=[O:42])[N:33]([C:30]1[C:29]([C:48]2[O:25][N:24]=[C:2]([C:3]3[CH:23]=[CH:22][C:6]([CH2:7][N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:5][CH:4]=3)[CH:49]=2)=[N:28][C:27]([Br:26])=[CH:32][N:31]=1)[C:34]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:40])([CH3:45])([CH3:46])[CH3:47]
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(Cl)=NO)cc1)C1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCOCC3)cc2)no1
Temperature: 20 °C
Yield: 78.1 %

Procedure:
A solution of tert-butyl 4-(chloro(hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4-i) (1.60 kg, 4.34 mol) and tert-butyl N-(5-bromo-3-ethynylpyrazin-2-yl)-N-tert-butoxycarbonylcarbamate (Compound A-4-ii) (1.73 kg, 4.34 mol) in CH2Cl2 (12.8 L) is stirred at 20° C. Et3N (483 g, 665 mL; 4.77 mol) is added and the reaction temperature maintained below 30° C. The suspension stirred at 20° C. to complete the reaction then diluted with water (8.0 L) and agitated. The phases are separated and the organic phase is washed with water (8.0 L) and then concentrated. i-PrOAc (1.6 L) is added and the mixture and heated at 50° C. Heptane (4.0 L) was slowly added then the suspension is allowed to cool to ambient temperature and stirred overnight. Additional heptane (7.2 L) is added to the suspension and it is stirred for 1 h. The solid is collected by filtration. The filter-cake is washed with heptane (2×1.6 L) and dried to afford tert-butyl(5-bromo-3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate (A-5) (2.478 kg; 78%, 97.8 area % purity by HPLC) as a fine, tan powder. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.31 (m, 3H), 4.42 (br m, 3H), 4.03-3.82 (m, 2H), 3.38 (br s, 2H), 1.60 (m, 4H), 1.36 (s, 27H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].[SH:12][CH2:13][CH:14]([OH:16])[CH3:15]>>[OH:16][CH:14]([CH3:15])[CH2:13][S:12][CH2:3][CH2:2][CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11]
Reactant: CC(O)CS
Reactant: C=CCc1cccc(C)c1O
Product: Cc1cccc(CCCSCC(C)O)c1O

Procedure:
In the same manner as in Synthetic example 1, 2-allyl-6 -methylphenol and 1-mercapto-2-propanol were reacted to obtain 2-[3-(2-hydroxypropylthio)propyl]-6-methylphenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[NH4+:22].C(OCC)(=O)C.CCCCCC>CO>[NH2:22]/[C:11](/[CH2:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])=[CH:12]\[C:13]([O:15][CH3:16])=[O:14]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Cc1cc(F)c(F)cc1F
Agent: CC(=O)[O-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)/C=C(\N)Cc1cc(F)c(F)cc1F
Temperature: 61.5 °C

Procedure:
The methyl 4-(2,4,5-trifluorophenyl)acetoacetate (350.0 gm, 1.42 mol) (21) and ammonium acetate (6.0 eq, 657.0 gm) were charged in methanol (5.0 vol, 1.75 Ltr) and the solution was refluxed for 5-6 hours at 60-63° C. After 5-6 hours refluxing, the methanol was distilled out completely to give a pale yellow coloured residue. The pale yellow coloured residue was further stirred with ethyl acetate (20.0 vol, 7.0 Ltr) at 25-30° C. The precipitated ammonium acetate was filtered and the ethyl acetate was distilled out completely to give a pale yellow product. The product was further stirred with hexane (10.0 vol, 3.5 Ltr) at 25-30° C. for 1 hour, filtered and dried under reduced pressure at 45-50° C. for 4-5 hours.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([Cl:16])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([N:23]([CH3:31])C(=O)OC(C)(C)C)[CH2:18]1)[C:2]#[C:3][CH3:4].[OH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH2:37])=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl.NC1CCCN(C2N(CC#CC)C3C(=O)N(CC4C=CC=CC=4C#N)C(C#N)=NC=3N=2)C1>CN1CCCC1=O>[ClH:16].[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:32][C:33]3[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=3[C:35]([NH2:37])=[O:36])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:23][CH3:31])[CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: NC(=O)c1ccccc1O
Reactant: CC#CCn1c(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc2nc(Cl)n(C)c(=O)c21
Agent: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC#CCn1c(N2CCCC(NC)C2)nc2nc(Oc3ccccc3C(N)=O)n(C)c(=O)c21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture consisting of 20 mg of t-butyl N-[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]-N-methylcarbamate, 20 mg of 2-hydroxybenzamide, 20 mg of anhydrous potassium carbonate, and 0.3 ml of N-methyl-2-pyrrolidone was stirred in an oil bath at 80° C. for 4 hours. Subsequent synthesis steps were carried out according to the same procedure as used in Examples 242(f) and (g) to give the title compound.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:30])[NH:6][C:7]1[N:8]([C:16]2[N:17]=[CH:18][N:19]([CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:20]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.C(C1C=C(NC([NH:53][C@@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:57]([O:64][C:65]3[CH:66]=[CH:67][C:68]4[N:69]([C:71]([N:74]5[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]5)=[N:72][N:73]=4)[CH:70]=3)[CH2:56][CH2:55]2)=O)N(C2C=CC(CO)=CC=2)N=1)(C)(C)C>>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][C@@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:57]([O:64][C:65]3[CH:66]=[CH:67][C:68]4[N:69]([C:71]([N:74]5[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]5)=[N:72][N:73]=4)[CH:70]=3)[CH2:56][CH2:55]2)=[O:30])[N:8]([C:16]2[N:17]=[CH:18][N:19]([CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:20]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cn(CCOC3CCCCO3)cn2)n1
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCOC3CCCCO3)cn2)n1

Procedure:
The title compound was prepared starting from Intermediate 3c and Intermediate 119c using analogous procedures to those described in Intermediate 106a. LCMS (Method 4): Rt 5.52 min, m/z 723 [MH+].
Reaction SMILES: [CH3:1][S:2]([C:4]([S:12][CH3:13])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.S(Cl)([Cl:16])=O>C(Cl)Cl>[CH3:1][S:2][C:4]([S:12][CH3:13])=[C:5]([Cl:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CSC(=Cc1ccccc1)S(C)=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CSC(SC)=C(Cl)c1ccccc1

Procedure:
1-Methylsulfinyl-1-methylthio-2-phenylethylene (1.868 g) was dissolved in 10 ml of methylene chloride, and with stirring under ice cooling, a solution consisting of 0.71 ml of thionyl chloride and 6 ml of methylene chloride was added dropwise over the course of 30 minutes. Under ice cooling, the mixture was stirred for 1.5 hours, and concentrated under reduced pressure. The residue was chromatographed on a Florisil column using benzene/hexane as an eluant to afford 1.494 g of 1,1-bis(methylthio)-2-chloro-2-phenylethylene as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].Cl[C:14]([CH3:27])=[CH:15][C:16]1[S:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[N+:20]=1[CH2:21][CH3:22]>C(#N)C>[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].[CH2:1]([N+:3]1[C:6]2[C:19](=[CH:18][CH:26]=[CH:25][CH:7]=2)[CH:23]=[CH:5][C:4]=1[C:27]#[C:14][CH:15]=[C:16]1[N:20]([CH2:21][CH3:22])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC[n+]1c(C=C(C)Cl)sc2ccccc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CCN1C(=CC#Cc2ccc3ccccc3[n+]2CC)Sc2ccccc21
Reaction time: 0.08 h

Procedure:
Triethylamine (2.1 ml, 0.015 mol) is added to a stirred suspension of 2-(2-chloropropenyl)-3-ethylbenzothiazolium perchlorate and anhydro-1-ethyl-2-sulfoquinolinium hydroxide (1.19 g, 0.005 mol) in acetonitrile. The mixture is stirred for 5 minutes, filtered, and the filtrate is diluted to 200 ml. with ether. The ether is decanted and the residue treated with methanol (25 ml). After chilling, the solid is collected and recrystallized from methanol. The yield of purified dye is 0.32 g (14%) mp indistinct.
Reaction SMILES: C(NC1CCCCC1)(C)C.[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15].[CH3:27][C:28]([CH3:30])=[O:29].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[C@@H:20]([C:28]([OH:29])([CH3:30])[CH3:27])[C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC(C)=O
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Agent: CC(C)NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.55M Butyl lithium-hexane solution (2.82 ml) was added to a solution of N-isopropylcyclohexylamine (0.72 ml) in tetrahydrofuran (6 ml) at -70° C., and the mixture was stirred for 20 minutes at -70° C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (247 mg) in tetrahydrofuran (6 ml) at -70° C. and the mixture was stirred for 1 hour at -70° C., and for 30 minutes at -30° C. Acetone (0.12 ml) was added to the reaction mixture at -70° C., and the mixture was stirred for 1 hour at -70° C. and for 30 minutes at -30° C.-15° C. 3N Hydrochloric acid was added to the reaction mixture at -70° C. and the mixture was diluted with ethyl acetate (200 ml). The solution was washed with water, brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. Triethylamine (0.15 ml) was added to a solution of the residue in dichloromethane (3 ml) at 0° C. and the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.1N hydrochloric acid (15 ml) brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of benzene and acetone (10:1-2:1) to give methyl 3-methyl-2-[(3S, 4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg); IR (CH2Cl2): 1740, 1715 cm-1. NMR (CDCl3) δ: 1.31 (s, 3H), 1.38 (s, 3H), 1.96 (s, 3H), 2.18 (s, 3H), 2.2-2.5 (m, 3H), 2.90 (d, 1H, J=3 Hz), 3.76 (s, 3H), 3.81 (dt, 1H, J=3, 7 Hz), 4.9-5.2 (m, 2H), 5.5-6.0 (m, 1H) and methyl 3-methyl-2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH2:19])=[N:11][O:12]C1CCCCO1>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH2:19])=[N:11][OH:12]
Reactant: NC(=NOC1CCCCO1)Nc1c(Cl)cccc1Cl
Agent: Cl
Product: NC(=NO)Nc1c(Cl)cccc1Cl
Yield: 82 %

Procedure:
17.2 g 1-(2,6-dichlorophenyl)-2-tetrahydropyranyloxyguanidine are hydrolyzed with 150 ml ethanolic hydrochloric acid for 15 hours at room temperature. After evaporation of the ethanol, the residue is dissolved in water, neutralized with 2-N NaOH, and extracted with methylene chloride. 10.2 g 1-(2,6-dichlorophenyl)-2-hydroxyguanidine having a melting point of 113° C. (decomp.) is obtained.
Reaction SMILES: O(CC([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([OH:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1.C(N(CC)C1C=CC=CC=1)C.C(Cl)(=O)C.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.ClCl.C(O)C(C)C>C(Cl)Cl>[NH2:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([OH:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: ClCl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: CC(C)CO
Solvent: CCN(CC)c1ccccc1
Product: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -15 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
To a slurry of 3.40 gm (10 mmol) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid, 0.158 ml (1.34 mmol) of quinoline, and 2.38 ml (15 mmol) of N,N-diethylaniline in 30 ml. of methylene chloride at room temperature was added 2.46 ml (34.5 mmol) of acetyl chloride. The reaction mixture was allowed to stir for about 6 hours at a temperature of 18° to 22° C. The reaction mixture was then cooled to -15° C. Then 0.6 ml (3.75 mmol) of N,N-diethylaniline and a solution of the triphenyl phosphitechlorine reagent derived from 3.68 ml of triphenyl phosphite and chlorine in 15 ml of methylene chloride, were added. The reaction mixture was then removed from the cooling bath and allowed to warm to near room temperature over the next seven minutes. The reaction mixture was then cooled to -20° C. Then 10.7 ml (116 mmol) of isobutanol added. Again the reaction mixture was removed from the cooling bath. About 45 minutes after the addition of the alcohol, a copious amount of solid precipitate was observed. After an additional 1/2 hour at room temperature the reaction mixture was cooled to 0° C. and filtered to provide 1.95 gm (73%) of 7-ADCA. Some impurities were visible in an nmr spectrum of the product.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.CO[C:27]1C=C(B(O)O)C=C[C:32]=1OC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[N:10]=[CH:11][C:2]([CH:27]=[CH2:32])=[CH:3][C:4]=3[C:5]3=[N:24][CH:23]=[N:22][N:6]3[C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: C=Cc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Temperature: 120 °C
Yield: 9.5 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (75 mg, 0.19 mmol), 3,4-dimethoxyphenylboronic acid (75 mg, 0.41 mmol), potassium phosphate (104 mg, 0.49 mmol) and ethyleneglycol dimethyl ether (3 ml) were combined and nitrogen was bubbled through for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.01 mmol) was added and the mixture was heated for 2 hours at 120° C. in the microwave. The mixture was filtered and purified by HPLC to afford 6 mg (7%) of the title compound as a white solid.