Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11](Cl)[CH:10]=[CH:9]2)=[O:5])[CH3:2].[NH2:17][C@H:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:17][C@H:18]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]1)[CH:10]=[CH:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2nc(Cl)ccc2c1
Reactant: N[C@@H]1CCc2ccccc21
Product: CCOC(=O)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 120 °C
Yield: 95.4 %

Procedure:
A stirred mixture of 2-chloro-quinoline-6-carboxylic acid ethyl ester [CAS-No. 29969-56-0] (500 mg, 2.12 mmol) and commercially available (R)-1-aminoindane (848 mg, 6.36 mmol) was heated in a sealed tube for 16 h at 120° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane) yielded 2-((R)-indan-1-ylamino)-quinoline-6-carboxylic acid ethyl ester as a light brown solid (672 mg, 95%), MS (ISP) 333.2 [(M+H)+]; m.p. 137° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[OH:25])[C:15]3=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1COCC1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[OH:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[N:14]1[CH2:13][C:12]2[C:16](=[CH:17][C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)=[CH:3][CH:4]=3)=[CH:10][CH:11]=2)[C:15]1=[O:18]
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)ccc2CN1[C@@H]1CCCC[C@H]1O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(Cc3ccc4c(c3)C(=O)N([C@@H]3CCCC[C@H]3O)C4)cn2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of rac-6-((6-chloropyridin-3-yl)methyl)-2-(trans-2-hydroxycyclohexyl)isoindolin-1-one (0.09 g) in a mixed solvent of THF (9.00 mL)-water (3.00 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.11 g), cesium carbonate (0.33 g) and bis(tri-tert-butylphosphine)palladium(0) (0.03 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (0.03 g).
Reaction SMILES: O.[CH:2](=[O:6])/[CH:3]=[CH:4]/[CH3:5].[CH2:7]([OH:11])[CH:8]=[CH:9][CH3:10]>CCCCCC>[CH2:2]([O:6][CH:7]([O:11][CH2:2][CH:3]=[CH:4][CH3:5])/[CH:8]=[CH:9]/[CH3:10])[CH:3]=[CH:4][CH3:5]
Reactant: CC=CCO
Reactant: C/C=C/C=O
Solvent: O
Solvent: CCCCCC
Product: CC=CCOC(/C=C/C)OCC=CC
Temperature: 70 °C
Yield: 185.6 %

Procedure:
In a 300-ml three-necked flask equipped with a water separator, 70 g (1 mole) of crotonaldehyde, 144 g (2 mole) of crotyl alcohol, 3 mg of stannous chloride dihydrate and 40 g of hexane were charged. The resulting mixture was heated at 70° C. under atmospheric pressure and for 4 hours in a nitrogen atmosphere while removing the water formed from the reaction mixture by azeotropic distillation. When water was no longer distilled, the solvent (hexane) and unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 182.2 g of crotonaldehyde dicrotyl acetal [R1 =a 1-propenyl group, R2 =a hydrogen atom and R3 =a crotyl group) (boiling point: 120° C./25 mmHg) (yield: 91.9%).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:9][C:10]([C:12]1[N:13]=[C:14]([CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH:18]=[CH:17][CH:16]=2)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1.CO>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:20]=2[CH:21]=[C:12]([C:10]([NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([OH:39])=[O:2])=[O:11])[N:13]=[C:14]3[CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:24][CH:25]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)[C@@H](NC(=O)c1cc2c(Oc3ccc(C(C)(C)C)cc3)cccc2c(CC2CCCC2)n1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(Oc2cccc3c(CC4CCCC4)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)cc23)cc1
Yield: 89.3 %

Procedure:
A solution of (2S)-{[5-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3,3-dimethyl-butyric acid methyl ester (28 mg, 0.052 mmol) in THF-MeOH (2.0 mL) was treated with LiOH solution (2.0M, 0.400 mL) by the general procedure I to give 24 mg of (2S)-{[5-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3,3-dimethyl-butyric acid as a white solid.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:23][CH:24]=1)(=[O:4])=[O:5]
Reactant: Clc1ncccn1
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(OCc2csc(C3CCN(c4ncccn4)CC3)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of 4-[4-(4-methylsulfonyl-phenoxymethyl)-thiazole-2-yl]-piperidine hydrochloride (100 mg, 0.24 mmol), 2-chloropyrimidine (30 mg, 1.1 eq.) and diisopropylethylamine (122 mg, 4 eq.) in i-PrOH (5 mL) was heated at 90° C. for 1.5 hours. The solvent was removed in vacuo. The residue was purified on silica gel (60% EtOAc in hexanes) to afford the desired product. 1H NMR (CDCl3): δ 8.32 (2H, d, J=4.8 Hz), 7.88 (2H, d, J=8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J=8.8 Hz), 6.49 (1H, t, J=4.8 Hz), 5.24 (2H, s), 4.89 (2H, m), 3.32 (1H, m), 3.06 (2H, m), 3.04 (3H, s), 2.22 (2H, m), 1.81 (2H, m).
Reaction SMILES: [CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[CH:3]\[CH2:4][OH:5]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=1)=[CH:3]\[CH:4]=[O:5]
Reactant: CC(/C=C/c1ccc(C(F)(F)F)cc1)=C\CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(/C=C/c1ccc(C(F)(F)F)cc1)=C\C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
In 10 ml of methylene chloride were dissolved 460 mg (1.90 mmol) of (2E,4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadien-1-ol, and 5 g of active manganese dioxide were added to the mixture, followed by stirring of the resulting mixture at room temperature for 30 minutes. The solid was removed by filtration, and after the filtrate was concentrated, it was purified over silica gel chromatography (eluting solvent: 4% ethyl acetate-hexane) to obtain 460 mg of the title compound as an oil.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:12])=O>CN(C)C=O>[CH:1]1([CH2:6][C:7]([Cl:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CC1CCCC1

Procedure:
To a solution of 50 g. of cyclopentaneacetic acid containing 2.9 ml. of N,N-dimethylformamide is added dropwise with stirring, 51 g. of thionyl chloride over a period of 15 minutes. After stirring for an additional 60 minutes excess thionyl chloride is removed in vacuo and the residual oil is distilled to give 55.4 g. (97%) of product, b.p. 57°-58° C. (10 mm.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16](=[O:38])[CH2:17][CH:18]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:10][CH2:9][CH2:8]2.[CH:39](=O)[CH:40]([CH3:42])[CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Cl:37][C:32]1[CH:31]=[C:30]([S:27]([NH:26][CH:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][C:16]([NH:15][CH:11]2[C:12]3[C:7](=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:14][CH:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:38])(=[O:29])=[O:28])[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: CC(C)C=O
Reactant: NCCCc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CNCCCc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[6-(3-aminopropyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3,4-dichloro-benzenesulfonylamino)-3-(4-fluoro-phenyl)-propionamide(63 mg, 0.109 mmol) in dry CH2Cl2 (5 mL) was added isobutyraldehyde (10 μL, 0.109 mmol) and HOAc (1 drop). The resulting mixture was stirred at RT under N2 After 1 h, MS showed the formation of imine; NaBH(OAc)3 (46 mg, 0.218 mmol) was then added. The resulting mixture was stirred for 10 min. The reaction mixture was quenched with sat. NaHCO3. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH(2M NH3) mixture (95:5) gave final compound. MS m/z: 635.11 (M+H). Calc'd. for C32H38Cl2FN3O3S-634.63.
Reaction SMILES: [C:1]([P:3](=[O:10])([O:7]CC)[O:4][CH2:5][CH3:6])#[N:2].C[C:12]([N:14]([CH3:16])[CH3:15])=O>[Cl-].C[N+](C)(C)C>[CH2:5]([O:4][P:3]([C:1]#[N:2])(=[O:7])[O-:10])[CH3:6].[CH3:12][N+:14]([CH3:16])([CH3:1])[CH3:15]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CC(=O)N(C)C
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: CCOP(=O)([O-])C#N
Temperature: 80 °C
Yield: 70 %

Procedure:
Diethyl cyanophosphonate (0.50 g, 3.06 mmol) and tetramethylammonium chloride (0.338 g, 3.06 mmol) were added to dimethylacetamide (0.5 mL) which was heated to 80° C. for 3 hours. Then dimethylacetamide was removed under vacuum to give 0.45 g (70% yield) of a viscous residue which was analyzed by NMR and mass spectrometry without additional purification. 31P NMR (CD3CN) δ (ppm) major peak (87%) -22.4 (t, 3JPH =8.8 Hz), minor peaks: -13.0 to -14.0 (10%), -3.0 (3%); 1H NMR (D2O) δ (ppm) 1.30 (t), 3.20 (s), and 4.05 (qnt); 13C NMR (D2O) δ (ppm) 119.7 (d, 1JCP =175.5 Hz), 63.9 (d, 2JCP =6.3 Hz), 55.8 (t, J=4.0 Hz) 16.0 (d, 3J CP =6.87 Hz). Mass spectral analysis (FAB+, thioglycerol) detected a peak at m/z 282.3, corresponding to the complex species [[+N(CH3)4 ]2-O(OC2H5)POCN]+ !, the presence of a cation at m/z 74.1 [[N(CH3)4 ]+ ] and an anionic species (FAB- thioglycerol) at m/z 133.9 [NCP(O)(OC2H5)O- ], and to the cluster [[+N(CH3)4 ] O(OC2H5)POCN- [O(OC2H5)POCN]- at m/z 342.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH2:25]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:24][C:8]1[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:19]=2)=[O:25])=[N:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C

Procedure:
In an embodiment, the process comprises contacting 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole (rabeprazole sulfide) with a chiral reagent in an organic solvent and water followed by addition of titanium isopropoxide. A base is added to this reaction mass followed by an oxidizing agent to obtain dexrabeprazole. The so-obtained dexrabeprazole may then be reacted with the alcoholic solution of magnesium chloride to form dexrabeprazole magnesium hydrate. Alternatively, the dexrabeprazole obtained after reaction with the oxidizing agent is converted to a salt, suitably the potassium salt, and the salt of dexrabeprazole is reacted with the alcoholic solution of magnesium chloride to form dexrabeprazole magnesium hydrate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[CH:32]([OH:37])[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[CH:32]([O:37][CH2:2][C:3]5[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=5)[C:31]=4[C:38]=3[CH3:39])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Product: COC(=O)c1ccc(COC2c3c(C)c(N4CCN(c5ccc(OC)cc5)CC4)c(C)c(C)c3OC2(C)C)cc1
Yield: 76 %

Procedure:
Using methyl 4-(bromomethyl)benzoate and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 94. Oily material. Yield 76%. 1H-NMR (CDCl3) δ: 1.36 (3H, s), 1.59 (3H, s), 2.09 (3H, s), 2.26 (6H, s), 3.10–3.30 (8H, m), 3.79 (3H, s), 3.91 (3H, s), 4.57 (2H, s), 4.69 (1H, s), 6.86 (2H, d, J=9.2 Hz), 6.97 (2H, d, J=9.2 Hz), 7.39 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O1CCCC1.C(OCC)(=O)C>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(Cl)nc2)c1
Yield: 73.2 %

Procedure:
Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg) was dissolved in absolute tetrahydrofuran (15 mL), and sodium hydride (60% in oil, 180 mg) was added at room temperature while stirring. After stirring at the same temperature for 15 min, 15-crown-5 (0.90 mL) was added, and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridin-3-ylsulfonyl chloride (827 mg) was added, and the mixture was further stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as an oil (yield 762 mg, 73%).
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39](=[O:41])[NH2:40])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[CH:23]1)[C:12]([NH:14][C@@:15]([CH3:21])(O)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.C[OH:44]>CCOC(C)=O>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:25]=[CH:26][N:22]([C@@H:11]([C:12]([NH:14][C@H:15]([CH2:21][OH:44])[C:16]([CH3:18])([CH3:17])[CH3:19])=[O:13])[CH2:10][C:9]([OH:8])=[O:42])[CH:23]=3)=[CH:28][CH:29]=2)=[CH:38][CH:37]=1)(=[O:41])[NH2:40]
Reactant: CC(C)(C)[C@](C)(O)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1
Reactant: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1
Yield: 88 %

Procedure:
According to the procedures described in Example 1(a), 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(1(S)-hydroxy-methyl-2,2-dimethyl-propyl)succinamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to afford in 88% yield 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(1(S)-hydroxymethyl-2,2-dimethyl-propyl)succinamic acid as a white powder, mp 192-4° C. 1H NMR (CD3OD): δ 7.95 (d, 2H, J=8.4 Hz), 7.72 (d, 2H, J=8.1 Hz), 7.60 (s, 4H), 7.32 (d, 1H, J=1.6 Hz), 6.92 (t, 1H, J=2.5 Hz), 6.51 (s, 1H), 5.20 (t, 1H, J=7.5 Hz), 3.85-3.75 (m, 2H), 3.02 (dd, 1H, J=7.2, 17.0 Hz), 0.92 (s, 9H). IR (KBr): 3360, 2961, 1710, 1658, 1404, 1201, 770 cm1; HRFABMS: Calculated for C27H32N3O5 (M+H)+: 478.2342. Found: 478.2360. Anal. Calculated for C27H32N3O5 (M+H)+. 478.2342. Found: 478.2360. Anal Calculated for C27H31N3O5.0.25CH2Cl2: C, 65.62; H, 6.37; N, 8.42. Found: C, 65.86, H, 6.69; N, 8.30.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20](O)=[O:21])[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C(P(=O)(OCC)OCC)#N>>[CH:37]1([NH:40][C:20]([C:16]2[CH:15]=[C:14]([C:13]3[N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[N:11]=[C:10]4[C:9]=3[C:8](=[O:34])[N:7]([CH3:35])[C:6](=[O:36])[N:5]4[CH2:1][CH:2]([CH3:4])[CH3:3])[N:18]([CH3:19])[CH:17]=2)=[O:21])[CH2:39][CH2:38]1
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Reactant: NC1CC1
Agent: CCOP(=O)(C#N)OCC
Product: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)NC5CC5)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1

Procedure:
This compound was synthesized by the reaction of 5-{7-isobutyl-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and cyclopropylamine using diethyl cyanophosphonate as a coupling reagent Mass: 528.30 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH2:14]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CN
Product: CNc1nc(Cl)nc2ccccc12

Procedure:
Prepared as in Example 38 from 2,4-dichloroquinazoline and methylamine. 1H NMR (400 MHz, DMSO-d6) δ 2.98 (d, J=4.4 Hz, 3H), 7.53-7.49 (m, 1H), 7.61-7.58 (m, 1H), 7.79-7.75 (m, 1H), 88.19-8.17 (m, 1H), 78 (bs, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.CO>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[OH:8])=[CH:19][CH:20]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: NC1CCCCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(CCNC2CCCCC2O)cc1
Temperature: 100 °C

Procedure:
Mix (±)-2-aminocyclohexanol (1.5227 g, 13.2 mmol), K2CO3 (4.56 g, 33.0 mmol), and 1-(2-chloroethyl)-4-methoxybenzene (2.0 mL, 13.2 mmol) in DMF (30 mL). Heat at 100° C. for 24 hours. Cool down to room temperature and filtrate with MeOH wash. Concentrate and remove DMF azeotropically with xylenes. Take up the residue in CH2C2 and H2O (100 mL each). Separate the layers and extract the aqueous layer with CH2Cl2 (2×100 mL). Wash the organic layers with H2O and brine (100 mL each). Dry the combined organic layers over MgSO4, concentrate and purify by flash chromatography, eluting with 50:45:5 EtOAc/CH2Cl/2.0 M NH3 in MeOH to afford 2-(4-methoxyphenethylamino)cyclohexanol. (1.38 g, 42%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:40])=[N-]>CO>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:37][CH3:40])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Solvent: CO
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
The resulting 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester is taken up in methanol and treated, at 0° C., with an excess of an ethereal solution of diazomethane. After a reaction time of 5 minutes, the solution is concentrated completely and the oily residue is chromatographed on silica gel thick layer plates (toluene/ethyl acetate, 3:1). The silica gel in the zone at Rf=0.19 is extracted with ethyl acetate and gives 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester; melting point 120° C. (from ether), IR spectrum (in CHCl3); 3310, 1775, 1700, 1690 and 1600 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:12]([CH3:11])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CNCCc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccn1)C(=O)c1ccc(N)cc1
Reaction time: 3 h

Procedure:
p-Aminobenzoic acid (1 g, 0.0073 mol) was dissolved in DMF (15 ml), methyl-(2-pyridin-2-yl-ethyl)amine (5 ml, 5 eq) was added, followed by DIPEA (1.91 ml, 1.5 eq), and HATU (4.1 g, 1.5 eq). After stirring for 3 h, TLC showed complete consumption of starting material. Water was added and the mixture extracted with CH2Cl2, the organic extracts were washed with NaHCO3 (sat), NH4Cl (sat), dried (MgSO4), concentrated under reduced pressure, and purified by flash chromatography (SiO2, EtOAc-EtOAc/MeOH 95:5) to give 1.43 g of 4-amino-N-methyl-N-(2-pyridin-2-ylethyl)benzamide. Step B: Preparation 1B (100 mg, 0.371 mmol) and the product of step A (142 mg, 1.5 eq) were dissolved in DMF (2 ml), potassium tert-butoxide (91 mg, 2.2 eq) was added and the mixture allowed to stir overnight. Water was added and the mixture extracted with EtOAc, dried (MgSO4), concentrated under reduced pressure, and the residue purified by flash chromatography (SiO2, hexane-EtOAc) to give 56 mg of the title compound. LCMS: MH+=489.3.