Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([OH:26])=[O:16]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3)cc2Cl)c1

Procedure:
3-(3-Chloro-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 2-chloro-4-phenylphenol (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 76 mg. Mass spectrum MH+=339.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].[O:9]=[C:10]1[NH:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[N:13][CH:12]=[C:11]1[C:24]#[N:25].Cl>O1CCCC1.O>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[NH:15][C:10](=[O:9])[C:11]([C:24]2[NH:25][N:3]=[N:2][N:1]=2)=[CH:12][N:13]=1
Reactant: COc1ccccc1-c1ncc(C#N)c(=O)[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Yield: 36.4 %

Procedure:
Sodium azide (283 mg., 4.35 mmole) was added to a solution of aluminum chloride (193 mg., 1.45 mmole) in tetrahydrofuran (8 ml.). The mixture was stirred under reflux for 0.5 hours. 1,6-Dihydro-6-oxo-2-(2-methoxyphenyl)pyrimidine-5-carbonitrile (300 mg., 1.32 mmole) was then added and the mixture stirred under reflux for 24 hours. The cooled mixture was diluted with water (15 ml.) and acidified with 6N hydrochloric acid. The mixture was filtered. The collected solid was recrystallized from glacial acetic acid to give the title compound (130 mg., 36.4% yield), m.p. 282°- 283° with decomposition. Anal. Calcd. for C12H10N6O2 : C, 53.33; H, 3.73; N, 31.10. Found: C, 53.20; H, 3.74; N, 31.50.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[C:33]([CH:42]=[CH:41][CH:40]=1)[CH2:32][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45 mmol) and potassium carbonate (0.124 g, 0.9 mmol) in N,N-dimethylformamide (4 mL), was added methyl 3-(bromomethyl)benzoate (0.114 g, 0.5 mmol). After stirring at 60° C. for 60 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated to a yellowish brown solid (0.2 g, 93%); 1H NMR (DMSO-d6): δ 1.45 (s, 9H), 1.64 (d, 2H, J=13.6 Hz), 2.41-2.49 (m, 2H), 3.48 (br, 2H), 3.85 (s, 3H), 3.86-3.90 (m, 2H), 4.59-4.64 (m, 4H), 6.68 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.4 Hz), 7.17 (t, 2H, J=8 Hz), 7.54-7.60 (m, 2H), 7.89-7.92 (m, 2H); MS for C27H33N3O5 m/z 480.08 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)OCC[O:9]1.Cl>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:9]
Reactant: Fc1ccc(C2(CCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)OCCO2)cc1
Agent: Cl
Solvent: CCO
Product: O=C(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2.0 g of 2-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl}-2-(4-fluoro-phenyl)-[1,3]dioxolane are dissolved in 20 ml of ethanol, and 1.95 g of 10% aqueous hydrochloric acid are added thereto. After stirring for 16 hours at 80° C., the reaction mixture is concentrated. After purification over silica gel, 4-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-1-(4-fluoro-phenyl)-butan-1-one is obtained.
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1CBr.[OH-].[K+]>O.[Na]>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:8][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccccc1-c1ccc2ccccc2c1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccccc1-c1ccc2ccccc2c1)C(=O)O
Temperature: 130 °C
Yield: 83774.2 %

Procedure:
70 g (0.37 mmol) of diethyl methylmalonate dissolved in 50 cm3 of H2O-free EtOH were added dropwise at room temperature to 8.5 g (0.37 mmol) of sodium in 100 cm3 of H2O-free EtOH. 110 g (0.37 mmol) of 26 in 200 cm3 of H2O-free EtOH were subsequently added dropwise, and the mixture was refluxed for 3 hours. 62 g (1.1 mol) of KOH dissolved in 100 cm3 of H2O were added at room temperature, and the mixture was refluxed for a further 4 hours. The solvent was removed in vacuo, H2O was added to the residue until the latter had dissolved completely, and the mixture was acidified to pH 1 by means of concentrated aqueous HCl. The precipitate which had formed was filtered off with suction, dried and heated at 130° C. for 1 hour, giving 90 g (84%) of 27 as a viscous oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9](O)=[O:10].CC[N:15](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([NH2:15])=[O:10]
Reactant: CC(C(=O)O)c1ccccc1I
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C(N)=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-iodophenyl)propanoic acid (9.73 g, 35.2 mmol) in THF (24 mL), DMF (4 mL) and DIPEA (30.7 mL, 0.176 mol) was stirred with HOBt (7.14 g, 52.9 mmol) and EDCl.HCl (10.1 g, 52.9 mmol) for 10 minutes at room temperature under N2. Ammonium carbonate (16.9 g, 0.176 mol) was then added and the reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure before sat. aq. NaHCO3 (100 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3×100 mL) and the combined organics were washed with brine, dried over MgSO4 and the volatiles were removed in vacuo to give the impure title compound I13 as a pale yellow solid (˜95% purity, 10.05 g, >95%). LCMS-D: rt 3.12 min; m/z 276 [M+H]+.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cn1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 6-methoxypyridine-3-amine as the starting materials.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH3:20][C:21](C)([O-])[CH3:22].[K+].BrCCC>O1CCCC1>[CH2:20]([N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:21][CH3:22]
Reactant: CC(C)(C)[O-]
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Agent: [K+]
Solvent: CCCBr
Solvent: C1CCOC1
Product: CCCN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.94 g) in dry tetrahydrofuran (150 ml) was added potassium tert-butoxide (2.62 g). The mixture was stirred for 15 mins, 1-bromopropane (7.07 ml) was added, and the reaction mixture was refluxed overnight. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was to adhered to silica, and flash chromatographed (30% ethyl acetate/hexane). The appropriate fractions were evaporated and the residue was triturated with diethyl ether to yield 4.39 g (76%) of 1,3,9,10,11,12-hexahydro-1-propyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[Cl:15][C:16]1[CH:17]=[C:18]([C@@H:22]2[C@@H:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:26]([C@@H:35]([CH:39]3[CH2:41][CH2:40]3)[C:36](=[O:38])[CH3:37])[C:25](=[O:42])[C@:24]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C@@H:22]2[C@@H:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:26]([C@@H:35]([CH:39]3[CH2:41][CH2:40]3)[C@@H:36]([OH:38])[CH3:37])[C:25](=[O:42])[C@:24]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](O)[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
L-Selectride® (Aldrich, St. Louis, Mo.), (1M in THF, 5.0 ml, 5.00 mmol) was added dropwise over the course of 5 minutes to a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 257, Step E, 1.035 g, 2.12 mmol) in THF (35 ml) at −78° C. After 90 min, the mixture was allowed to warm to 0° C. and was carefully quenched by the addition of saturated ammonium chloride. The aqueous phase was extracted three times with ethyl acetate. The combined organic layer was washed with 1 M HCl, water, sat. aq. NaCl solution and dried over sodium sulfate. After concentration in vacuo, the residue was purified by silica chromatography eluting with a gradient of isopropanol in hexanes. Fractions containing the major isomer were concentrated and then lyophilized from acetonitrile/water to provide the title compound as a white powder. Stereochemistry assigned by analogy to Example 152.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].C(Cl)(=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15](=[O:17])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:12]1)[CH2:10][C:9]2=[O:26]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2
Yield: 97.2 %

Procedure:
A suspension of Intermediate 4 (280 mg, 0.90 mmol) in DCM (7.5 ml) was treated with benzoyl chloride (0.16 ml, 1.4 mmol) and DIPEA (0.32 ml, 1.8 mmol) as described in Example 36, Step A, giving (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester as a white solid (330 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]=1.[BH4-].[Na+]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]=1
Reactant: CCCCCC(=O)c1cccc(C=Cc2cccs2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)c1cccc(C=Cc2cccs2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The ketone of Example 20 (1 g) is dissolved in ethanol, and sodium borohydride (0.2 g) is added. The mixture is stirred at room temperature overnight. Excess of the borohydride is destroyed by carefully adding a dilute HCl solution. The aqueous solution is extracted thoroughly with ether, and then the ether extract is washed with brine and dried. On removal of all volatiles, the pure alcohol is obtained as a clear, coloreess liquid in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][C@H:21]([C:19]#[N:20])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1

Procedure:
Following the procedure of Example 8, (R)-2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid and (S)-α-cyano-3-phenoxybenzyl alcohol are combined, in the presence of 4-dimethylaminopyridine and dicyclohexylcarbodiimide, to yield (S)-α-cyano-3-phenoxybenzyl (R)-2-(4-trifluoromethylphenylamino)-3-methylbutanoate, specific rotation=+62.1° (c=9 mg/ml in CHCl3).
Reaction SMILES: Br[C:2]1[C:3]([C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:16][C:17]2[CH:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[N:27]1([C:2]2[C:3]([C:8]([NH:10][C@H:11]3[CH2:15][CH2:14][CH2:13][C@@H:12]3[NH:16][C:17]3[CH:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:31]=[CH:30][CH:29]=[N:28]1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1Br
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1-n1cccn1

Procedure:
A solution of 3-bromo-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 28; 100 mg, 0.23 mmol), 1H-pyrazole (CAS number 288-13-1; 32 mg, 0.47 mmol), cesium carbonate (151 mg, 0.47 mmol), copper (I) iodide (2.2 mg, 0.012 mmol) and trans-1-N,2-N-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.012 mmol) in dry DMF (0.8 ml) was subjected to microwave irradiation at 120° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×3) and brine, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][CH2:19][CH:18]([CH3:22])[CH3:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CC(C)CCN
Solvent: CCN(CC)CC
Product: CC(C)CCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(3-methylbutyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-methylbutylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:11]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13](=[O:19])[CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O>[Si:1]([O:8][C@H:9]([C@H:11]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]([OH:19])[CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CC(C)(C)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CC(O)CC(C)(C)N1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of (S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-one (42 mg, 0.15 mmol) in MeOH (3 mL) was added NaBH4 (5.6 mg, 0.15 mmol) at 0° C. After the mixture was stirred for 1 h, the mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL). The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (EtOAc/Heptane) gave 32 mg (76%) of (6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-ol (a 5:1 mixture of diastereomers): 1H NMR (400 MHz, CHLOROFORM-d) δ 4.17-4.27 (m, 1H), 3.71-3.78 (m, 1H), 2.92-3.02 (m, 1H), 1.56-1.67 (m, 2H), 1.30-1.37 (m, 2H), 1.25 (s, 3H), 1.07 (d, J=6.1 Hz, 3H), 1.02 (s, 3H), 0.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27](Cl)=[O:28]>O>[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:28]
Reactant: O=C(Cl)CSCC(F)(F)F
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CSCC(F)(F)F)[C@H]3SC2)s1
Temperature: 25 °C

Procedure:
7-Amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (3.96 g, 14 mmol) was reacted with trifluoroethylmercaptoacetyl chloride in the same manner as described in Example 1. After stirring at room temperature the solution was diluted with water (50 ml), washed with ether (3 × 150 ml), acidified to pH 2 with 3N HCl and extracted with ethyl acetate (3 × 150 ml). The extracts were washed with water, dried, and concentrated. The product was collected and converted to its sodium salt by the procedure in Example 1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:30][N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[CH:13][C:12]([O:26][CH3:27])=[C:11]([O:28][CH3:29])[CH:10]=2)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:27][O:26][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:28][CH3:29])[N:8]=[C:7]([CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c(C(=O)O)c(Cn3cncn3)nc3cc(OC)c(OC)cc23)cc1OC
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (3.0 g), 2N sodium hydroxide (15.6 ml) and ethanol (50 ml) was stirred under refluxing conditions for 8 hours. The reaction mixture was cooled with ice and adjusted to pH 5 with 2N hydrochloric acid, after which it was concentrated under reduced pressure. The residue was dissolved in ethanol, and the insoluble substances were filtered off. After the filtrate was concentrated, the residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-methanol (4:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol- 1-ylmethyl)quinoline-3-carboxylic acid (1.3 g, 46%), which was then recrystallized from dichloromethane-ethanol to yield a colorless prismatic crystal having a melting point of 270° to 271° C. (decomposed).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C@@H:27]([OH:28])[CH2:29][NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)=[CH:23][CH:22]=1
Reactant: NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Product: O=S(=O)(Nc1ccc(CCNC[C@H](O)COc2ccc(F)cc2)cc1)c1ccccc1

Procedure:
In a manner analogous to that of Example 7, the title compound was prepared from the amine from Example 6 and the epoxide from Example 141: 1H NMR (300 MHz, CD3OD): 2.93 (m, 2H), 3.1-3.28 (m, 4H), 3.96 (m, 2H), 4.2 (m, 1H), 6.9-7.16 (m, 8H), 7.5 (m, 3H), 7.74 (d, J=7Hz, 1H); FAB-MS m/z 445 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:22]([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:10][C:11]([O:13][CH3:22])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 15 mL of DMF charged with (3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid (8 mmol, 2.0 g), methyl iodide (15 mmol, 1.9 mL) and K2CO3 (15 mmol, 2.1 g), was stirred at ambient temperature for 16 h. The reaction mixture was poured into 50 mL of saturated NaHCO3, and the resulting solution was extracted with ether (3×50 mL). The combined organic phase was washed with 50 mL of H2O, dried with MgSO4, and the solvent removed under reduced pressure to yield the title compound as a slightly yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.26-7.38 (m, 5 H), 5.49 (br s, 1H), 5.13 (br s, 1H), 3.65 (s, 3H), 2.80-2.96 (m, 2H), 1.45 (s, 9H). MS (ESI): m/z 302 (M+Na).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12]([O:13][C:14]2[C:15]([C:27]#[N:28])=[N:16][CH:17]=[C:18]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:19]=2)=[C:11]([CH3:29])[CH:10]=[CH:9][N:8]=1.[OH-:30].[Na+]>>[CH3:6][C:7]1[C:12]([O:13][C:14]2[C:15]([C:27]([NH2:28])=[O:30])=[N:16][CH:17]=[C:18]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:19]=2)=[C:11]([CH3:29])[CH:10]=[CH:9][N:8]=1
Reactant: [OH-]
Reactant: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Concentrated sulfuric acid (8 mL) was added to 3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (2.03 g, 6.07 mmol). The reaction was stirred overnight, then poured onto ice (100 g), cooled in an ice bath and made basic to pH 10 with 50% NaOH. The reaction was extracted with ethyl acetate, washed with brine, dried (MgSO4), and concentrated to afford 3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (2.02 g, 5.73 mmol, 94.4% yield) as a white solid.