Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[P:17]([O-:21])([O-:20])([O-:19])=[O:18].[K+:22].[K+].[K+]>O>[CH2:2]1[C@H:1]([N:9]2[C:10](=[O:11])[NH:12][C:13](=[O:14])[CH:15]=[CH:16]2)[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]1[OH:4].[OH:19][P:17]([O-:21])([OH:20])=[O:18].[K+:22]
Reactant: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: [K+]
Solvent: O
Product: O=P([O-])(O)O

Procedure:
5.4 grams (equal to 32 mMoles) of 2-chloroadenine were weighed and suspended while being stirred in 50 ml of DMSO. Solubilisation occurred with the addition of 70 ml of 25% (w:v) KOH, obtaining a perfectly clear solution with a 266 mMolar concentration of 2-chloroAdenine. 14.6 grams (equal to 64 mMoles) of 2′-deoxyuridine and 4 grams (equal to 30 mMoles) of anhydrous monobasic potassium phosphate were dissolved in about 600 ml of deionised water, obtaining a 106 mM for the 2-deoxyUridine and 50 mM for KH2PO4. The pH was corrected to a value of 7.5 with 25% (w:v) KOH as required.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccc(C(F)(F)F)cn2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncc(Sc2ccc(C(F)(F)F)cn2)s1
Yield: 75.6 %

Procedure:
A mixture of 2-acetylamino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (3.2 g) in a mixture of ethanol (60 ml), tetrahydrofuran (30 ml) and aqueous 6N-hydrochloric acid (10 ml) was refluxed for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and extracted with mixture of tetrahydrofuran and ethyl acetate (1:1) and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (2.1 g yield: 75.8%).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)([O:3]C)=[O:2].[Li+].[OH-].C1COCC1>CO>[C:16]1([C:9]2[C:8]3[C:13](=[CH:14][C:5]([C:1]([OH:3])=[O:2])=[CH:6][CH:7]=3)[O:12][C:11](=[O:15])[CH:10]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2c(-c3ccccc3)cc(=O)oc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(-c3ccccc3)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
A mixture of 7-carbomethoxy-4-phenylcoumarin (510 mg), 1N LiOH (10 mL), THF (7 mL) and MeOH (10 mL) was heated at reflux for 1 hr. The solution was concentrated then H2O (10 mL), 1N HCl (15 mL), THF (10 mL) and Et2O (10 mL) were added and stirring continued for 1 hr. After this time, the organic layer was separated and concentrated to yield the title compound which was used as such in the next step.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])=[C:6]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=1.CO.O.[OH-].[Li+]>O>[CH3:20][C:17]1[N:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][C:6]=2[O:21][C:22]([F:25])([F:23])[F:24])=[N:15][CH:16]=1
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cnc(NC(=O)Nc2ccc(C(=O)O)cc2OC(F)(F)F)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a stirred suspension of 4-[3-(5-methyl-pyrazin-2-yl)-ureido]-3-trifluoromethoxy-benzoic acid methyl ester (136 mg, 0.37 mmol) in 4 mL 3:1 MeOH:H2O under nitrogen was added lithium hydroxide monohydrate (154 mg, 3.7 mmol), and the reaction heated to 65° C. The reaction turned yellow/green and eventually became a solution. After stirring overnight, the reaction was cooled to RT and partially concentrated by rotovap to remove most of the MeOH. The residual suspension was neutratized with 2N HCl until pH=6. The reaction formed a floculent precipitate which was filtered off with H2O and dried overnight under high vacuum to give the acid as a white solid (102 mg, 78%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].BrC(C)C.[C:14]12([C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[OH:31])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.C12(C3C=C(C=CC=3O)C=O)CC3CC(CC(C3)C1)C2>>[C:14]12([C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:15][CH:16]3[CH2:22][CH:20]([CH2:19][CH:18]([CH2:17]3)[CH2:23]1)[CH2:21]2
Reactant: Oc1ccc(I)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CCCCCCCCBr
Agent: O=Cc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Solvent: CC(C)Br
Product: CCCCCCCCOc1ccc(I)cc1C12CC3CC(CC(C3)C1)C2
Yield: 72 %

Procedure:
When 1-bromooctane was substituted for 2-bromopropane and 2-(1-admantyl)-4-iodo-phenol was substituted for 3-(1-admantyl)-4-hydroxybenzaldehyde in Example 60, Step A, the identical process afforded the title compound in 72% yield. 1H-NMR (CDCl3) 0.87 (tr, 3H, J=5.22 Hz); 1.26-1.29 (m, 9H); 1.51-1.53 (m, 2H); 1.75 (s, 6H); 1.81-1.86 (m, 2H); 2.07 (5, 9H); 3.91 (tr, 2H, J=6.28 Hz); 6.58-6.6 (d, 1H, J=8.21 Hz); 7.39-7.42r(m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C#CCCCCCC.I[C:24]1[CH:25]=[C:26]([C:30]#[C:31][C:32]2([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34][CH2:33]2)[CH:27]=[CH:28][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:43]([O:42][C:41](=[O:47])[NH:40][C:32]1([C:31]#[C:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:14]#[C:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:25]=2)[CH2:33][O:34][C:35]([CH3:39])([CH3:38])[O:36][CH2:37]1)([CH3:44])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2cccc(I)c2)COC(C)(C)OC1
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1cc(C#Cc2cccc(C#CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)c2)cc(OC)c1OC
Yield: 64 %

Procedure:
When 3,4,5-trimethoxyphenyl-acetylene was substituted for 1-octyne and the product of Step A was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 64% yield, as pale paste. 1H-NMR (CDCl3) 1.43 (s, 3H); 1.47 (s, 9H); 1.49 (5, 3H); 3.84 (s, 3H); 3.87 (s, 6H); 4.00 (d, 2H, J=11.4 Hz); 4.10 (d, 2H, J=11.33 Hz); 5.19 (broad s, 1H), 6.74 (s, 2H); 6.74-6.76 (m, 1H); 7.26-7.38 (m, 1H); 7.43 (d, 1H, J=7.67 Hz); 7.60 (broad s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:16]([CH2:20][OH:21])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13](N)=[O:14])[CH:12]=1)[CH3:2].[OH-:27].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:16]([CH2:20][OH:21])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([OH:27])=[O:14])[CH:12]=1)[CH3:2]
Reactant: CCc1cccc(C)c1CNc1cc(C(N)=O)cn2c(CO)c(C)nc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(CO)c(C)nc12
Yield: 59.8 %

Procedure:
8-(2-ethyl-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine-6-carboxamide (0.02 g, 0.057 m mol) and sodium hydroxide (0.02 g, 0.29 mmol) were solved in ethanol (95%) (1 ml) and was refluxed for 20 h. The solvent was evaporated under reduced pressure and to the residue was added water (1 ml). The pH was adjusted to 5 by addition of acetic acid and the solid that precipitated was isolated by filtration, washed with water and dried to give 0.012 g (60%) of the title compound.
Reaction SMILES: [C:1]1([N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:11]([O:19][CH3:20])(=[O:18])[C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15]>>[N:6]1([C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]=2[C:11]([O:19][CH3:20])=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C1=C(N2CCCC2)CCC1
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)C1=CCCCC(N2CCCC2)=C1C(=O)OC

Procedure:
1-(1-Cyclopenten-1-yl)pyrrolidine and 2-butynedioic acid, dimethyl ester are reacted according to the procedure set forth in J.O. C., Vol. 28, p. 1464 (1963) to yield 3-(1-pyrrolidinyl)-2,7-cycloheptadiene-1,2-dicarboxylic acid, dimethyl ester.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[CH:7]=[CH:6][N:5]=1.C(O)C.[H][H]>[Pd].CCCCCC>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1
Reactant: FC(F)Oc1cc(OCc2ccccc2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Product: Oc1ccnc(OC(F)F)c1
Yield: 87.3 %

Procedure:
2-Difluoromethoxy-4-benzyloxypyridine (219.75 g, 0.875 mol), ethanol (500 mL) and palladium on carbon (7.8 g, 5 mol %, 50% by weight water) were shaken on a Parr hydrogenator at 5393 kPa of hydrogen at RT for 2.5 h. The mixture was then filtered through celite and the solvent was evaporated in-vacuo. 2-Difluoromethoxy-4-hydroxypyridine (123 g, 87% yield) was obtained as a white solid after trituration with hexane, mp=88.6° C. -89.8° C. Anal. Calcd. for C6H5NO2F2 : C,44.73; H,3.13; N,8.69 Found: C,44.82; H,3.13; N,8.76.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C2C(C(C3CCN(C)CC3)=CN2)=CC=1.FC1C=CC(S(Cl)(=O)=O)=CC=1>>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:12][N:11]2[S:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:15][CH:16]=1
Reactant: CN1CCC(c2cn(S(=O)(=O)c3ccc(F)cc3)c3cc(Cl)ccc23)CC1
Agent: CN1CCC(c2c[nH]c3cc(Cl)ccc23)CC1
Agent: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccccc3)c3cc(Cl)ccc23)CC1

Procedure:
1-(4-Fluorophenylsulfonyl)-6-chloro-3-(1-methyl-4-piperidinyl)indole: (26.8 mg, 65%), from 6-chloro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5b, 25 mg, 0.10 mmol) and 4-fluorophenylsulfonyl chloride (29.2 mg, 0.15 mmol), HRMS-FAB+ for C20H20N2O2SClF, calculated MH+ : 407.09964; found: 407.09929.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=1>O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OCCN2CCCC2)nc1
Reaction time: 1 h

Procedure:
To a stirred DMF solution (25 mL) containing N-(2-hydroxyethyl)pyrrolidine (2.18 g, 18.9 mmol) under N2 was added 60% NaH in mineral oil (0.76 g, 18.9 mmol). The mixture was stirred for 1 hr while gas evolution ceased. Subsequently 2-chloro-5-nitropyridine (2.0 g, 12.6 mmol) was added. After stirring overnight, the dark solution was poured into H2O (100 mL) and extracted 3× with EtOAc. The combined organic layers were washed 2× with H2O prior to drying over Na2SO4, Concentration under vacuum yielded an orange oil which was chromatographed on silica gel employing ˜10% MeOH/CH2Cl2 to elute 1.62 g of 5-nitro-2-(pyrrolidin-1-yl)-ethoxy)pyridine (54%). The above product reduced, to the corresponding substituted aminopyridine by hydrogenation in an EtOH solution (20 mL) containing 10% Pd/C (0.1 g) under 60 psi of H2 for 4 hr. Upon completion the reaction was filtered prior to concentration under vacuum. The resulting dark oil was chromatographed on silica. Gradient elution (CH2CL2 to 20% MeOH/CH2Cl2) eluted 1.03 g of the title compound as a broad peak.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]2=[O:16])=[CH:5][CH:4]=1.C1C(=O)N([Br:24])C(=O)C1.S(C)C.O>C(Cl)Cl.CCOC(C)=O>[Br:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn(-c2ccc(CO)cc2)c1=O
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: Cc1nccn(-c2ccc(CBr)cc2)c1=O
Reaction time: 8 h

Procedure:
The pyrazinone intermediate from Step 3 (430 mg , 1.99 mmol) was dissolved in CH2Cl2 and added to a yellow suspension of NBS (531 mg , 2.98 mmol) and Me2S (0.248 mL, 3.38 mmol) at -20°. The sulfoxium salt was formed at 0° then cooled to -20° before the addition of alcohol. After addition of the alcohol, the reaction mixture was stirred at 0° for several hours and then the cooling bath was allowed to expire overnight. The light brown solution was poured into H2O and extracted with CHCl3 (3×). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a dark brown oil. Dissolved in EtOAc and filtered off resulting brown solid. The filtrate solidified to give the title compound as a yellow solid which will be used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Br:26]Br>C(Cl)(Cl)Cl>[Br:26][CH:10]([C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[S:17]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18]
Reactant: CC(C)(C)C(=O)CC(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Reaction time: 4 h
Yield: 93.1 %

Procedure:
To a solution of 39.9 g of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one in 500 ml of chloroform, 16.8 g of bromine was added dropwise at 60° C. and the mixture was then kept at 60° C. for 4 hours. The reaction mixture was treated in the same way as that of Example 3 to give 44.5 g of crystals of the captioned compound. m.p. 135°-136° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[C:17]([F:19])[C:16]3[N:15]([CH3:20])[C:14]4[CH2:21][CH:22]5[NH:26][CH:25]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34]>C(OCC)C>[ClH:34].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([F:19])[CH:18]=2)[N:15]([CH3:20])[C:14]2[CH2:21][CH:22]4[NH:26][CH:25]([C:13]3=2)[CH2:24][CH2:23]4)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)cc(F)c31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)cc(F)c31)C1CCC(C2)N1

Procedure:
The product of step D was subjected to Boc-deprotection with 2 N HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (90:9:1 dichloromethane/methanol/ammonium hydroxide) to give 2-phenylsulfonyl-4-fluoro-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (40 mg, 84%, HPLC, AUC 97.8%.) as a white solid: mp 251-256° C. dec; 1H NMR (DMSO-d6, 300 MHz): δ 8.24 (d, J=1.5 Hz, 1H), 7.94-8.00 (m, 2H), 7.56-7.70 (m, 3H), 7.48 (dd, J=12.0, 1.5 Hz, 1H), 5.36 (d, J=3.9 Hz, 1H), 4.44-4.52 (m, 1H), 3.82 (s, 3H), 3.34-3.39 (m, 1H), 3.00 (d, J=17.1 Hz, 1H), 2.18-2.30 (m, 2H), 2.03-2.12 (m, 1H), 1.70-1.87 (m, 1H); APCI MS m/z 371 [M+H]+
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:18](=[O:19])[N:11]4[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]4=[N:9][C:8]=3[S:20][C:5]=2[C:4](=[O:21])[CH2:3][CH2:2]1.[BH4-].[Na+]>C1COCC1.CCO>[OH:21][CH:4]1[C:5]2[S:20][C:8]3[N:9]=[C:10]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]4[C:18](=[O:19])[C:7]=3[C:6]=2[CH2:1][CH2:2][CH2:3]1
Reactant: O=C1CCCc2c1sc1nc3n(c(=O)c21)CCCCCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1c2c3c(sc2nc2n1CCCCCC2)C(O)CCC3
Reaction time: 0.25 h

Procedure:
To compound 3d (200 mg, 0.66 mmol) in 5 ml of THF and 15 ml of EtOH, NaBH4 (33 mg, 0.86 mmol) was added and the reaction mixture was stirred for 15 minutes. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with brine and dried with NaaSO2. After filtration the solvent was evaporated. The product was purified by flash chromatography using CH2Cl2/EtOAc 1:1 as an eluent.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]2[C:23](=[O:53])[CH:24]([CH2:27][C:28]3[N:29]=[CH:30][N:31]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]=3[CH3:33])[CH2:25][CH2:26][C:15]=12.C(Br)C=C>O1CCCC1.CCCCCC>[CH2:3]([C:24]1([CH2:27][C:28]2[N:29]=[CH:30][N:31]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:32]=2[CH3:33])[C:23](=[O:53])[N:16]2[C:17]3[C:22]([C:14]([CH3:13])=[C:15]2[CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:1]=[CH2:2]
Reactant: CC(C)NC(C)C
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CCc2c(C)c3ccccc3n2C1=O
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
To a solution of diisopropylamine (395 mg) in tetrahydrofuran (5 ml) at -70° C. under a nitrogen atmosphere was added 1.64M butyllithium in hexane (2.62 ml). After being stirred at the same temperature for 20 minutes, the mixture was treated with a solution of 8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.61 g) in tetrahydrofuran (5 ml) over 15 minutes. The mixture was stirred at -65° C. for 30 minutes and at -30°~-40° C. for 30 minutes and a solution of allyl bromide (363 mg) in tetrahydrofuran (5 ml) was added dropwise at -65° C. over 10 minutes. After the mixture was stirred at -65° C. for 1 hour, at -20° C. for 1 hour and at ambient temperature for 1 hour. The resultant mixture was washed with water (10 ml×2) and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. Purification of the residue with silica gel column chromatography (5% ethyl acetate-chloroform) gave 7-allyl-8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.15 g).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:18]([OH:25])[C:19]#[C:20][Si](C)(C)C)[C:3]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4].[F-].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C@@H:2]([C@@H:18]([OH:25])[C:19]#[CH:20])[C:3]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4]
Reactant: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@@H](O)C#C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#C[C@H](O)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 1.67 h
Yield: 61.6 %

Procedure:
A solution of (4S)-N-[(2S,3R)-2-methyl-3-hydroxy-5-trimethylsilyl-4-pentynoyl]-4-benzyl-2-oxazolidinone (0.13 g) in 3 mL of dimethylformamide was treated with 48% aqueous HF (2.6 uL) and KF.2H2O at ambient temperature for 100 min. Upon completion of the reaction, saturated aqueous sodium bicarbonate was added to neutralize the HF, and the mixture was extracted three times with equal portions of ether. The organic extracts were combined, filtered, and dried over MgSO4. Filtration and evaporation gave the crude product, which was purified by silica gel chromatography (3:2 hexanes/ethyl acetate) to yield 64 mg of product.
Reaction SMILES: [I-].[CH:2]([O:15][C:16]([C:18]1[N:23]2[C:24](=[O:33])[C:25](=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:22]2[S:21][CH:20]([NH2:34])[C:19]=1[CH2:35][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[C:57](=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[CH:26](=[C:25]1[C:24](=[O:33])[N:23]2[C:18]([C:16]([O:15][CH:2]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:17])=[C:19]([CH:35]=[CH2:57])[CH:20]([NH2:34])[S:21][C@H:22]12)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC1S[C@@H]2C(=Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(=Cc3ccccc3)[C@H]2SC1N
Temperature: 25 °C

Procedure:
To a solution of [4-benzhydryloxycarbonyl-7-benzylidene-amino-3-cephem-3-yl]methyltriphenyl-phosphonium iodide (16.9 g) in methylene chloride, (200 ml) and water (100 ml) was added 36% aqueous formaldehyde (48 ml), followed by adjusting to pH 9.0 with sodium carbonate. After the mixture was stirred at ambient temperature for an hour, the separated organic solution was washed with an aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave benzhydryl 7-benzylidene-amino-3-vinyl-3-cephem-4-carboxylate (8.6 g), mp 124°-132° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:18]([NH:20][C:21]2([C:24]#[N:25])[CH2:23][CH2:22]2)=[O:19])[CH2:15][CH2:16][CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:24]([C:21]1([NH:20][C:18](=[O:19])[C@H:14]([CH2:15][CH2:16][CH3:17])[NH:13][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[CH2:23][CH2:22]1)#[N:25]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: 82.5 °C

Procedure:
A mixture of N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide (6.46 g, 15.44 mmol), 4-methanesulfonylphenyl-boronic acid (3.40 g, 16.98 mmol), and 2M K2CO3 (19.3 mL) was dissolved in DMF (75 mL) in a thick-walled flask. The reaction mixture was degassed, and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.678 g, 0.926 mmol) was added. The flask was sealed, heated at 80-85° C. for 3 hours, cooled, and diluted with ethyl acetate (300 mL). The solution was washed with 1:1 water/brine (200 mL), brine (200 mL), filtered through a three-layered plug of silica (bottom) DARCO, and MgSO4 (top), concentrated in vacuo, and purified on a plug of silica gel (50-70% ethyl acetate/hexane elution). The product was then further purified by recrystallization from ethyl acetate/hexanes to yield the title compound.