Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C@:17]12[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]1[CH2:21][S:20][C:19]([N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]2.O.Br[C:44]1[CH:45]=[N:46][CH:47]=[C:48]([O:50][CH:51]2[CH2:53][CH2:52]2)[CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C([O-])(O)=O.[Na+].C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[CH:51]1([O:50][C:48]2[CH:49]=[C:44]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:17]45[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]4[CH2:21][S:20][C:19]([NH2:27])=[N:18]5)[CH:4]=3)[CH:45]=[N:46][CH:47]=2)[CH2:53][CH2:52]1
Reactant: Brc1cncc(OC2CC2)c1
Reactant: C[C@H]1OC[C@]2(c3cc(B4OC(C)(C)C(C)(C)O4)ccc3F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)SC[C@H]12
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: C[C@H]1OC[C@]2(c3cc(-c4cncc(OC5CC5)c4)ccc3F)N=C(N)SC[C@H]12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
di-tert-Butyl {(4aS,5R,7aS)-7a-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl}imidodicarbonate (0.13 g, 0.22 mmol) was dissolved in 1,2-dimethoxyethane (1.5 mL), water (0.7 mL) and ethanol (0.5 mL) The resulting solution was heated to 100° C. and to it was added 3-bromo-5-(cyclopropyloxy)pyridine (0.28 g, 1.32 mmol), cesium carbonate (0.43 g, 1.32 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.046 g, 0.066 mmol) and the reaction was stirred at 100° C. After 1 hour, the reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using column chromatography gradient 0-60% EtOAc in hexane). The purified product was dissolved in DCM (2 mL) and trifluoroacetic acid (1 mL). After 1 hour, the solvents were removed in vacuo. The residue was basified with saturated aqueous NaHCO3 and extracted with DCM (×3). The combined organic layers were dried (MgSO4), filtered and concentrated to leave the title compound. (58 mg)
Reaction SMILES: C([Li])CCC.[CH:6]1([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[I:16]I.O>O1CCCC1>[CH:6]1([N:11]2[C:15]([I:16])=[N:14][N:13]=[N:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: II
Reactant: c1nnnn1C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Ic1nnnn1C1CCCC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
In an atmosphere of inert gas, 10.42 mmol of butyllithium (1.6M in hexane) was added dropwise to a solution, cooled to −75° C., of 8.68 mmol (1.20 g) of 1-cyclopentyltetrazole in 27 ml of anhydrous tetrahydrofuran such that the temperature of the reaction mixture did not exceed −70° C. The mixture was stirred at this temperature for 30 minutes, and 8.68 mmol (2.2 g) of iodine in 4 ml of anhydrous tetrahydrofuran was then added dropwise. After 30 minutes of stirring at this temperature, the reaction mixture was warmed to 23° C., and water was added carefully. The solvent was extracted with ethyl acetate and the combined organic phase was washed with sodium thiosulphate solution and saturated sodium chloride solution and dried over sodium sulphate. The solid obtained after distillative removal of solvent under reduced pressure was stirred with diisopropyl ether and yielded 1.55 g (68%) of 1-cyclopentyl-5-iodotetrazole with a melting point of 119° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[CH3:36][C:37]1[O:41][N:40]=[C:39]([CH2:42]O)[CH:38]=1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:42][C:39]3[CH:38]=[C:37]([CH3:36])[O:41][N:40]=3)[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1cc(CO)no1
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1cc(CN2C(=O)N(c3ccccc3C)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)no1

Procedure:
The title compound, MS: m/e=595.0 (M+), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 5-methylisoxazole-3-methanol.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14]>>[Cl-:10].[CH3:11][N:12]([CH2:8][P+:3]([CH2:1][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])([CH2:4][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[CH2:6][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: OC[P+](CO)(CO)CO
Reactant: CNC(=O)NC
Agent: [Cl-]
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 25 %

Procedure:
A solution of 80% THPC (59.55 g, 0.25 mol) and 1,3-dimethylurea (88.12 g, 1 mol) was heated to reflux in an oil bath, held at reflux for 4 hrs., allowed to cool, and stripped to dryness in a rotary evaporator. The residue (130.67 g) was shaken with acetonitrile (100 ml) and filtered, giving 29.40 g (25.0%) of tetrakis(1,3-dimethylureidomethyl)phosphonium chloride (I, R=R'=CH3, R"=H, X=Cl) as a white, crystalline solid, mp 189°-190° C. dec. The remainder, a heavy oil, yielded no more product nor water even when subjected to azeotropic distillation with toluene and more 1,3-dimethylurea.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:28])[C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])=[CH:14][CH:13]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-]>>[F:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([F:27])[C:20]=1[C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:8]([CH3:11])=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:17][CH:16]=1)=[O:28]
Reactant: COC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(C(=O)O)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1

Procedure:
Compound 1 was hydrolyzed by heating it in a solution of LiOH to yield 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid. A mixture of 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (800 mg, 2.2 mmol), 2,2-diethoxy-ethylamine (0.32 mL, 2.2. mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (5 mmol) in dry DMF (5 mL) was stirred at room temperature for 24 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (EtOAc) (2×20 mL). The organic extract was washed with water and dried. The oil obtained on concentration of the organic layer was purified by flash chromatograghed on silica gel to give 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (2,2-diethoxy-ethyl)-amide as colorless oil (0.68 g).
Reaction SMILES: NCC([O:5][C:6]1[CH:21]=[C:20]([O:22]C(=O)CN)[C:9]2[C:10](C)=[C:11]3[N:16]([C:17](=[O:18])[C:8]=2[CH:7]=1)[CH2:15][CH2:14][CH2:13][CH2:12]3)=O.OC1C=C(O)C2C(C)=C3N(C(=O)C=2C=1)CCCC3.C(OC1C2C(=O)N3C(CCCC3)=C(C)C=2C=CC=1OC(=O)C)(=O)C.COC1C=C(OC)C2C(C)=C3N(C(=O)C=2C=1)CCCC3>>[OH:5][C:6]1[CH:21]=[C:20]([OH:22])[C:9]2[CH:10]=[C:11]3[N:16]([C:17](=[O:18])[C:8]=2[CH:7]=1)[CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: Cc1c2n(c(=O)c3cc(OC(=O)CN)cc(OC(=O)CN)c13)CCCC2
Agent: CC(=O)Oc1ccc2c(C)c3n(c(=O)c2c1OC(C)=O)CCCC3
Agent: COc1cc(OC)c2c(C)c3n(c(=O)c2c1)CCCC3
Agent: Cc1c2n(c(=O)c3cc(O)cc(O)c13)CCCC2
Product: O=c1c2cc(O)cc(O)c2cc2n1CCCC2

Procedure:
Preferred specifies are compounds selected from the following compounds A through E, wherein the structure and name is providing for each: ##STR7## 8,10-bis(acetyloxy)-1,2,3,4-tetrahydro-11-methyl-6H-benzo[b]quinolizin-6-one; ##STR8## 8,10-bis[(aminoacetyl)oxy]-11-methyl-1,2,3,4-tetrahydro-6H-benzo[b]quinolizin-6-one; ##STR9## 1,2,3,4-tetrahydro-8,10-dihydroxy-11-methyl-6H-benzo[b]quinolizin-6-one; ##STR10## 7,8-bis(acetyloxy)-1,2,3,4-tetrahydro-11-methyl-6H-benzo[b]quinolizin-6-one; ##STR11## 8,10-bis(methoxy)-1,2,3,4-tetrahydro-11-methyl-6H-benzo[b]quinolizin-6-one;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[N:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].N12CCCCC1C=NCCC2.Cl>O1CCOCC1.O>[N:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:11]([NH:10][C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[N:6]=2)=[O:13])(=[O:30])=[O:31])=[CH:25][CH:24]=1)=[N+:21]=[N-:22]
Reactant: COc1cc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: [N-]=[N+]=Nc1ccc(S(N)(=O)=O)cc1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccc(N=[N+]=[N-])cc2)n1
Reaction time: 3 h
Yield: 67 %

Procedure:
A solution of 2.9 g of N-(4-methoxy-6-methylpyrimidin-2-yl)phenylcarbamate in 10 ml of dioxan is added dropwise at 20°-25° C. to a solution of 2 g of 4-azidophenylsulfonamide and 1.6 ml of 1,5-diazabicyclo(5,4,0)-undec-5-ene in 20 ml of dioxan and the mixture is stirred for 3 hours at the same temperature. The reaction mixture is then taken up in 200 ml of water and the aqueous mixture is then acidified with hydrochloric acid to pH 2. The precipitated product is isolated, washed with ethyl acetate and dried, affording N-(4-azidophenylsulfonyl)-N'-(4-methoxy-6-methylpyrimidin-2-yl)urea in 67% yield in the form of greenish crystals with a melting point of 192° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[N-:14]=[N+:15]=[N-:16].[Na+].[Cl-].[NH4+]>CO>[N:14]([CH2:3][CH:2]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[OH:1])=[N+:15]=[N-:16]
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC(O)C1CCC2(CC1)OCCO2
Temperature: 80 °C

Procedure:
To a solution of 8-(oxiran-2-yl)-1,4-dioxaspiro[4.5]decane (205 mg, 1.11 mmol), prepared in the previous step, in methanol (5 mL) water (0.5 mL) was added sodium azide (361 mg, 5.56 mmol) and ammonium chloride (119 mg, 2.22 mmol). The mixture was stirred, heating to 80° C. under argon overnight and then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ether) to afford the product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][NH:17]2)=[CH:13][CH:12]=1)([O-])=O>C(O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccncc1Nc1ccc2cn[nH]c2c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccncc1Nc1ccc2cn[nH]c2c1
Reaction time: 20 h

Procedure:
To PtO2 (0.3 g) in 10 ml of ethanol was added N-(4-nitro-3-pyridinyl)-1H-indazol-6-amine, N6 -oxide (2.0 g) in 240 ml of ethanol and this was hydrogenated on a Parr apparatus at 60 psi for 20 hours. The mixture was filtered and concentrated to an oil (2.1 g). This material was eluted with 20% methanol/DCM on a silica gel column via HPLC. The desired fractions were concentrated to a solid (0.7 g), which was recrystallized from acetonitrile to yield a solid 0.5 g, m.p. 214°-216° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([N:14]([CH2:23][C:24]2[C:25](=[O:35])[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])([CH3:13])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:34][N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[C:24]([CH2:23][N:14]([C:10]2([CH3:13])[CH2:11][CH2:12][NH:8][CH2:9]2)[C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[C:25]1=[O:35]
Reactant: Cn1c(=O)c(CN(C(=O)C2CCCCC2)C2(C)CCN(Cc3ccccc3)C2)cc2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cn1c(=O)c(CN(C(=O)C2CCCCC2)C2(C)CCNC2)cc2ccccc21
Temperature: 60 °C

Procedure:
N-(1-benzyl-3-methylpyrrolidin-3-yl)-N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]cyclohexanecarboxamide (1750 mg, 3.71 mmol) and ammonium formate (936 mg, 14.84 mmol) were combined in MeOH (37 mL). 10% Pd/C (350 mg, 3.288 mmol) was added as a slurry in MeOH and the reaction heated to 60° C. for 15 hours. The reaction mixture was filtered through a 0.45 um syringe-tip filter and concentrated in vacuo. The resulting material was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. This material was carried on without further purification. 1.5 g, 106%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:26][C:10]3=[CH:11][C:12]4[C:13]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:27][C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[CH2:24]([C:13]1([CH2:22][CH3:23])[C:12]2[CH:11]=[C:10]3[NH:26][C:7]([C:3]4[C:2]([NH:1][C:31]([C:28]5([CH3:27])[CH2:30][CH2:29]5)=[O:32])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[N:15]([CH:18]([CH3:20])[CH3:19])[C:14]1=[O:21])[CH3:25]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Reactant: CC1(C(=O)O)CC1
Product: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4NC(=O)C4(C)CC4)[nH]c3cc21

Procedure:
Methyl-cyclopropanecarboxylic acid[3-(7,7-diethyl-5-isopropyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-Amino-1H-pyrazol-3-yl)-7,7-diethyl-5-isopropyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.43 mmol) and 1-methyl-cyclopropane-carboxylic acid (51 mg, 0.43 mmol). 17 mg (9%) %) of the title compound were obtained.
Reaction SMILES: C(N(CC)C(C)C)C.[F:9][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[C:20]([CH3:22])[C:19]([C:23]([OH:25])=O)=[CH:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1.[N:26]1([NH2:35])[C:30]2=[CH:31][N:32]=[CH:33][CH:34]=[C:29]2[CH:28]=[CH:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[N:26]1([NH:35][C:23]([C:19]2[C:20]([CH3:22])=[N:21][C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=3)=[N:17][CH:18]=2)=[O:25])[C:30]2=[CH:31][N:32]=[CH:33][CH:34]=[C:29]2[CH:28]=[CH:27]1
Reactant: Nn1ccc2ccncc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2ccncc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
Diethyl-iso-propylamine (1.13 mmol) is added a solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (0.75 mmol), pyrrolo[2,3-c]pyridine-1-ylamine (0.75 mmol) and TBTU (0.9 mmol) in anhydrous DMF (7 mL) at rt, and the reaction mixture is stirred at 80° C. overnight. Water is added and the mixture is extracted with EtOAc. The organic layer is separated, washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 40-100% MeOH in DCM to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid pyrrolo[2,3-c]pyridin-1-ylamide (117 mg, 45%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.84 (s, 3H), 6.72 (d, H), 7.29 (m, H), 7.55 (m, H), 7.71 (m, H), 8.14-8.29 (m, 2H), 8.36 (d, 3), 8.75 (s, H), 9.17 (s, H). IC50=28.5 nM.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[C-:14]#[N:15].[K+].CCO>O>[CH3:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:2][C:14]#[N:15]
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2ccccc2c1CC#N
Temperature: 80 °C
Reaction time: 18 h

Procedure:
1-Chloromethyl-2-methylnaphthalene (5.00 g, 26.3 mmol) and KCN (5.12 g, 78.8 mmol) were combined in H2O (20 mL) and EtOH (40 mL) in a round bottom flask fitted with a reflux condenser. The mix was stirred at 80° C. for 18 hours. TLC analysis (silica, 10% acetone-hexanes) indicated consumption of the starting chloromethylnaphthalene. The reaction was allowed to cool to room temperature and then was diluted with H2O. The dilution was extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, decanted, and concentrated to give (2-methyl-naphthalen-1-yl)-acetonitrile in quantitative yield. MS (APCI) m/z 180.1 (M−H). 1H NMR (400 MHz) CDCl3 δ 7.96 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.61 (m ,1H), 7.50 (m, 1H), 7.34 (d, J=8.4, 1H), 4.07 (s, 2H), 2.58 (s, 3H).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1.Cl[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>C1COCC1>[N+:15]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[O:7][CH:5]1[CH2:6][O:3][CH2:4]1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnccc1OC1COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
NaH (164.0 mg, 4.100 mmol) was added portionwise to a stirred solution of oxetan-3-ol (280.4 mg, 3.785 mmol) in THF (10.00 mL) to form a white suspension. The reaction mixture was stirred at ambient temperature for 10 mins then was added dropwise to a suspension of 4-chloro-3-nitro-pyridine (500 mg, 3.154 mmol) in THF (3 mL). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction was quenched with water (20 mL) and partitioned with ethyl acetate (3×20 mL). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to dryness to afford the desired product as a beige solid (499 mg, 81%). LC-MS (M+H)+ 198.1; 1H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.66 (d, J=5.9 Hz, 1H), 7.09 (d, J=5.9 Hz, 1H), 5.60 (tt, J=6.0, 4.7 Hz, 1H), 4.99 (ddd, J=7.9, 6.0, 1.1 Hz, 2H), 4.61 (ddd, J=7.7, 4.7, 1.1 Hz, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[O:32][CH3:33])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CO[C@@H]1Cc2c(F)cc(F)cc2[C@H]1n1nc(-c2cccc(C#N)c2)c2c1CCN(C(C)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
According to Scheme 10: To a solution of 3-[5-acetyl-1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11t) (0.10 g, 0.276 mmol) in dry DMF (1 ml) at −10° C. NaHMDS (50 mg) was added. After 5 min iodomethane (39 mg, 0.276 mmol) was added and the mixture was allowed to warm to 25° C. After 90 min the mixture was cooled to −10° C. and the same amount of both NaHMDS and iodomethane was added again. After stirring overnight the mixture was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 27 mg of 3-[5-acetyl-1-((1R,2R)-4,6-difluoro-2-methoxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (16a). Rt=1.29 min (LC method 4). Detected mass: 449.32 [M+H+]
Reaction SMILES: C(C(C(=[P:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)CC1CS[C@@H]2[C@H](NC(=O)CC3SC=CC=3)C(=O)N2C=1C(OC(C)(C)C)=O)=O)C.O>O1CCCC1>[C:45]1([P:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCC(=O)C(CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 71.9 %

Procedure:
A solution of t-butyl 3-(2-ethylcarbonyl-2-triphenylphosphoranylideneethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (500 mg.) in tetrahydrofuran (10 ml.) was treated with aluminum amalgam (500 mg., prepared as described in L.G. Fiester and M. Fieser, Reagents for Organic Synthesis, P. 20) and water (0.2 ml.), and the mixture stirred at 23°After 2 and 3 hours further amounts (0.2 ml., and 0.1 ml. respectively) of water were added. After a total of 4 hours the mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in benzene and filtered through a short column of Merck Kieselgel (0.05 - 0.2mm, 10 g.) to give, on evaporation, triphenylphosphine (130 mg., 73%). Further elution with benzene ethyl acetate (1:1) gave the title compound (230 mg., 72%) as a foam, λmax. (EtOH) 270 nm (ε, 5,020), νmax. (CHBr3) 3450 and 3360 (NH), 1786 (β-lactam), 1730 (CO2R) and 1686 and 1518 cm-1 (CONH), τ(CDCl3) 3.51 (NH, doublet, J 9 Hz), 4.26 (C(7) -H, double doublet, J 9 and 4.5 Hz), 5.09 (C(6) -H, doublet, J 4.5 Hz), 5.88 and 8.74 (OCH2CH3, quartet and triplet), 6.17 (CH2CONH), 6.50 and 6.8 (C(2) -CH2, AB-quartet, J 18 Hz), 7.3-7.7 (--CH2CH2 --0--, 4 proton multiplet) and 8.47 (C[CH3]3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Cl.O1CCOCC1>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:23])([F:24])[F:25])[NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C(F)(F)F)n2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2)c1
Yield: 93 %

Procedure:
A solution of 4-Methyl-2-[4′-trifluoromethyl-5-(6-trifluoromethyl-pyridin-2-yl)-biphenyl-3-yl]-pentanoic acid ethyl ester, compound 7a (865 mg, 1.7mmol) in MeOH (50 mL), platinum oxide (39.0 mg, 0. 17 mmol) and 4N HCl/dioxane (500 μl) was hydrogenated at 20 psi for 4 hours. The reaction mixture was filtered through celite, washed with MeOH and concentrated in vacuo. The residue was partitioned between dichloromethane and Na2CO3 to give the free base. Purification by silica gel chromatography gave the desired product (813 mg, 93%) (M+H) 515.53, Found 516.3.