Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[F:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:18][C:17]1[CH:16]=[CH:15][C:14]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[NH2:11]
Reactant: Nc1cc(O)ccc1F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (6.34 g, 40 mmol), 3-amino-4-fluorophenol (5.08 g, 40 mmol) and potassium carbonate (5.52 g, 40 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (7.90 g, 79%) as a yellow powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:50])=[C:8]([N:10]2[CH2:49][CH2:48][C:13]3[N:14]=[C:15]([C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[C:30]([CH3:47])=[CH:31][N:32]5S(C4C=CC(C)=CC=4)(=O)=O)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][C@H:19]4[CH3:27])[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[NH4+].[OH-].[OH-].[K+]>CCO.CCOC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:50])=[C:8]([N:10]2[CH2:49][CH2:48][C:13]3[N:14]=[C:15]([C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[C:30]([CH3:47])=[CH:31][NH:32]5)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][C@H:19]4[CH3:27])[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2cc(C(C)C)ccc2C)CC3)[C@H](C)C1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)N1CCN(c2nc(-c3cccc4[nH]cc(C)c34)nc3c2CN(c2cc(C(C)C)ccc2C)CC3)[C@H](C)C1
Temperature: 100 °C

Procedure:
(R)-1-(4-(6-(5-Isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)ethanone was dissolved in EtOH (2 mL), then NH4OH (0.54 mL, 13.7 mmol) was added followed by KOH (46 mg, 0.821 mmol). The mixture was heated in a microwave reactor at 100° C. for 1 h. The reaction was then diluted with EtOAc and washed with brine. After concentration, the resulting residue was purified by HPLC (C18, 15-85% acetonitrile in H2O with 0.1% NH4OH) to provide (R)-1-(4-(6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)ethanone. 1H NMR (400 MHz, CD3CN) δ ppm 9.15 (br. s., 1 H) 7.46 (d, J=8.08 Hz, 1 H) 7.26 (d, J=7.33 Hz, 1 H) 7.16 (dd, J=16.29, 7.96 Hz, 2 H) 7.06 (d, J=13.64 Hz, 2 H) 6.91 (dd, J=7.58, 1.52 Hz, 1 H) 3.98-4.16 (m, 4 H) 3.46-3.67 (m, 2 H) 3.26-3.46 (m, 4 H) 2.84-3.13 (m, 4 H) 2.26 (s, 3 H) 2.00-2.06 (m, 6 H) 1.23 (d, J=6.82 Hz, 6H) 1.11-1.21 (m, 3 H); MS (ESI+) m/z 537.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[CH:16]=O>>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[CH:16]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CC(C)(C)c1cc(C=O)cc(Br)c1O
Product: CC(C)(C)c1cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc(Br)c1O
Yield: 80.9 %

Procedure:
5-Chloro-2-oxindole (167 mg, 1 mmol) was condensed with 3-bromo-5-tert-butyl-4-hydroxybenzaldehyde (308.5 mg, 1.2 mmol) using method B to give 329 mg (81%) of 3-(3-bromo-5-tert-butyl-4-hydroxybenzylidene)-5-chloro-1,3-dihydroindol-2-one as a mixture of isomers.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.C[N:17](C)[CH2:18][CH2:19][CH2:20]N=C=NCC.O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C(N)C#C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH:10]([C:12](=[O:14])[NH:17][CH2:18][C:19]#[CH:20])[CH2:11]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: C#CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.5 g (2.48 mmol) boc-azetidine-3-carboxylic acid in 5 mL DCM were added 0.52 g (2.73 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.4 g (2.98 mmol) 1-hydroxybenzotriazole hydrate and 0.9 mL (5.47 mmol) DIPEA, and the reaction was stirred at room temperature for 30 minutes. 0.19 mL (2.73 mmol) propargylamine was added and the reaction was stirred for 16 hours at room temperature. 5 mL DCM was added and the mixture was washed with 10 mL aqueous HCl (1 M), then 10 mL aqueous NaHCO3 (1 M) and 10 mL brine. The organic layer was dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 7:3).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]2[CH:6]([C:7]2([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])[CH3:10])[CH2:5]1)[CH:2]=[CH2:3].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH2:1]([N:4]1[CH2:5][CH:6]2[CH:8]([C:7]2([C:11]2[CH:12]=[C:13]([NH:14][S:19]([CH3:18])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH2:9]1)[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: c1ccncc1
Product: C=CCN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Reaction time: 16 h
Yield: 67.6 %

Procedure:
To 3-(3-allyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)aniline (Preparation 52, 8.5 g, 37.2 mmol) dissolved in pyridine (70 ml) at 0° C. was added methanesulphonyl chloride (4.32 ml, 55.8 mmol) dropwise over 20 min. The reaction mixture was allowed to stir for 16 h and was then quenched with ice (5 g). The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution, followed by water. The organic extracts were concentrated in vacuo and then purified by flash chromatography on silica gel, eluting with ethyl acetate:dichloromethane:2N ammonia in methanol (30:69:1). The product was obtained as a viscous brown oil (7.7 g, 68%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28]Br)=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][O:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=2)[C:15]([F:16])([F:17])[F:18])=[CH:22][CH:21]=1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Reactant: Clc1ccc(Oc2cccc(CBr)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(COCc2cccc(Oc3ccc(Cl)cc3)c2)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 171 mg of sodium hydride (60% oil dispersion) was added to 20 ml of dry THF. A solution of 1.0 g of 2-(4-ethoxyphenyl)-3,3,3-trifluoropropanol and 1.25 g of 3-(4-chlorophenoxy)-benzyl bromide in 30 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 12 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (50:1) mixture] to obtain 1.22 of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.[C:35](O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl>[CH3:35][N:16]([C@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[NH:23][C:24]([NH:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:25]
Reactant: CC(=O)O
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CN([C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1)[C@@H]1CCCC[C@H]1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a round bottom flask was added 1-((1R,2R)-2-((S)-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea (prepared as described in Example 1) (30 mg, 0.069 mmol), formaldehyde (0.079 mL, 1.028 mmol) (37% in water), acetic acid (0.2 mL), CH2Cl2 (1 mL) and NaSO4 (3 gms). The reaction was stirred at rt for 2 hrs. Then sodium cyanoborohydride (21.54 mg, 0.343 mmol) was added to the reaction and the reaction was stirred for an additional 1 hr. After this time, the reaction was quenched with water (2 ml). The reaction was partitioned between CH2Cl2 (15 ml) and saturated aqueous NaHCO3 (10 ml). The organic layer was washed with water (10 ml) and saturated aqueous NaCl (10 ml). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC (Method A). The desired fractions were concentrated to give the product, 1-((1R,2R)-2-(methyl((S)-1-(4-nitrophenyl)piperidin-3-yl)amino)cyclohexyl)-3-phenylurea (18 mg, 0.038 mmol, 55.2% yield) as a yellow solid. Anal. Calcd. for C25H33N5O3 m/z 451.5, found: 452.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 10.60 (br. s., 1H), 7.89 (d, J=8.80 Hz, 2H), 7.52 (br. s., 1H), 7.33 (d, J=8.25 Hz, 2H), 7.30-7.19 (m, 2H), 7.03 (t, J=7.15 Hz, 1H), 6.75 (d, J=8.80 Hz, 2H), 3.87-3.56 (m, 4H), 3.51-3.34 (m, 4H), 3.23-3.13 (m, 1H), 2.82 (br. s., 3H), 2.25-1.32 (m, 10H); 13C NMR (126 MHz, CDCl3) δ ppm 158.25, 154.02, 139.91, 138.67, 128.85, 125.71, 123.04, 118.88, 114.37, 68.41, 60.22, 50.63, 48.67, 48.25, 32.33, 31.60, 25.29, 25.13, 24.18, 23.74, 22.28.
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.CN(C=O)C.C(=O)([O-])O.[K+].Cl[CH2:56][O:57][C:58](=[O:67])[C:59]([CH3:66])([CH3:65])[CH2:60][O:61][CH2:62][O:63][CH3:64]>C(OCC)(=O)C>[NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[N:15]=[C:14]([O:16][CH2:56][O:57][C:58](=[O:67])[C:59]([CH3:65])([CH3:66])[CH2:60][O:61][CH2:62][O:63][CH3:64])[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=2)=[CH:5][CH:4]=1
Reactant: COCOCC(C)(C)C(=O)OCCl
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 60 °C
Reaction time: 14 h
Yield: 25.8 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (120 mg) and DMF (3 mL), potassium hydrogen carbonate (30 mg) and 3-methoxymethoxy-2,2-dimethylpropionic acid chloromethyl ester (54.8 mg) were sequentially added, and the resulting mixture was stirred at 60° C. for 14 hours. To the mixture, ethyl acetate (100 mL) was added. The resulting mixture was sequentially washed three times with water (50 mL) and with saturated aqueous sodium chloride solution (50 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by NAM silica gel column chromatography (mixed solvent of heptane-ethyl acetate and methanol-ethyl acetate) to obtain the captioned compound (40 mg).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC(=O)COC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(O)COC(C)(C)C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Ethyl 4-t-butoxyacetoacetate (20.0 g) synthesized according to the method described in Heterocycles 26, 2841 (1987) was dissolved in methanol (150 mL) and sodium borohydride (1.68 g) was added at a temperature of from 5° C. to 15° C. The mixture was stirred for 1 hr and water (100 mL) was added. The solvent was mostly evaporated, and the organic layer extracted twice with MTBE (150 mL) was washed well with water. MTBE was evaporated to give ethyl (±)-4-t-butoxy-3-hydroxybutanoate (16.9 g). To a solution of lithium diisopropylamide 1.5 M cyclohexane solution (73 mL) in THF (100 mL) was added a solution of ethyl (±)-4-t-butoxy-3-hydroxybutanoate (10.66 g) in THF (30 mL) at a temperature of from −58° C. to −48° C. and the temperature was raised to −20° C. Separately, 2-iodoethanol (21.5 g) and ethyl vinyl ether (11.4 g) were mixed in the presence of p-toluenesulfonic acid monohydrate (10 mg) to give 2-(1-ethoxyethoxy)ethyl iodide (19.1 g) and 15.3 g thereof was added dropwise at a temperature near −20° C. to 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was poured into a 1N aqueous hydrochloric acid (100 mL), MTBE (100 mL) was added and the mixture was extracted and washed with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated and ethanol (150 mL) and p-toluenesulfonic acid monohydrate (1.3 g) were added to the residue. The mixture was stirred at room temperature for 6 hr. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture and the solvent was mostly evaporated. The residue was extracted with MTBE (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to flash chromatography using heptane/ethyl acetate (3:1) as an eluent to give the title compound (2.0 g) as pale yellow crystals.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@H:44]1[C@H:48]([O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:47]([O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:46]([C:67]2[N:68]=[N:69][N:70]([CH2:72][CH3:73])[CH:71]=2)[O:45]1)(=O)C1C=CC=CC=1>>[C:59]([O:58][C@H:47]1[C@@H:48]([O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:44]([N:15]2[CH:14]=[N:13][C:12]3[C:16]2=[N:17][C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:24])=[N:19][C:11]=3[NH:10][CH2:9][CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:45][C@@H:46]1[C:67]1[N:68]=[N:69][N:70]([CH2:72][CH3:73])[CH:71]=1)(=[O:66])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CCn1cc([C@H]2O[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)nn1
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: Cl
Product: CCn1cc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)nn1

Procedure:
Prepared by the same method as Preparation 26 from N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulphonamide hydrochloride (Preparation 8) and (2S,3R,4R, 5R)-3,4-bis(benzoyloxy)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)tetrahydro-2-furanyl benzoate (Preparation 25).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:29][O:30][CH3:31])[C:12]([NH:14][CH:15]2[C:27](=[O:28])[N:17]3[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.O.O.O.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.O1CCCC1.O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:29][O:30][CH3:31])[C:12]([NH:14][CH:15]2[C:27](=[O:28])[N:17]3[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(N)n1
Yield: 89.6 %

Procedure:
A solution of 7-[2-{2-(2,2,2-trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.55 g.) and sodium acetate trihydrate (1,76 g.) in ethyl acetate (3 ml.), tetrahydrofuran (3 ml.) and water (5.5 ml.) was stirred at room temperature overnight. The aqueous layer was separated from the resultant mixture, washed with dichloromethane, and then evaporated under reduced pressure to remove the organic solvent. The aqueous solution was adjusted to pH 4.2 under ice-cooling, and subjected to column chromatography on Diaion HP-20 resin (Trade mark: manufactured by Mitsubishi Chemical Industries Ltd., 15 ml.). After washing the column with water, the object compound was eluted with 20% aqueous isopropyl alcohol. The eluate was concentrated under reduced pressure and the residue was lyophilized to give 7-{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-3-methoxy-3-cephem-4-carboxylic acid (syn isomer 0.4 g.), m.p. 185° to 190° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].Cl.[NH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[C:22]([F:31])[CH:21]=1)[CH3:19].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([C:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:18]([NH:17][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH3:19])=[CH:21][C:22]=1[F:31])([CH3:29])[CH3:30])#[N:28]
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(F)c1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C(C)(C)C#N)c(F)c1

Procedure:
The amide is synthesized according to modified example 1 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (781 mg, 3.68 mmol) prepared according to scheme 2, 2-[4-(1-Aminoethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (1.07 mg, 4.41 mmol) prepared according to scheme 7, Et3N (1.23 mL, 8.82 mmol) and HATU (1.68 g, 4.41 mmol) in DMF (15.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5u) 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA), (565 mg as TFA salt, 1.10 mmol, 30%); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38 (d, J=6.84 Hz, 3H), 1.71 (s, 6H), 4.87-5.00 (m, J=7.23, 7.23 Hz, 1H), 5.09 (s, 2H), 7.16-7.29 (m, 3H), 7.36-7.51 (m, 2H), 8.19 (s, 1H), 8.86 (d, J=7.62 Hz, 1H). MS [M+H], calcd: 401.4. found: 401.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([O:33][CH3:34])[CH:30]=[N:31][CH:32]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:32]=[N:31][CH:30]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COc1cncc(Br)c1
Product: COc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-3-methoxypyridine (169 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (210 mg, 45%). MS (ISP) 463.2 [(M+H)+]; mp 232-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:5][N:6]([C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1)[C@H:7]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:16]([CH3:18])=[CH:17][C:8]1=2.[Br:36]N1C(=O)CCC1=O>C(O)(=O)C>[Br:36][C:14]1[C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C@H:7]([N:6]([CH2:5][C:4]3[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=[C:2]([Cl:1])[CH:3]=3)[C:23]3[N:24]=[N:25][N:26]([CH3:28])[N:27]=3)[C:8]=2[CH:17]=[C:16]([CH3:18])[C:15]=1[C:19]([F:20])([F:21])[F:22]
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Cc1cc2c(c(Br)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Yield: 80.4 %

Procedure:
Stir (S)-(3-chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine (0.53 g, 1.02 mmol) with N-bromosuccinimide (0.22 g, 1.22 mmol) in acetic acid (2 mL) at room temperature for 2 h. Evaporate the solvent under reduced pressure. Dilute the residue with water and neutralize with saturated NaHCO3 and extract with EtOAc (3×25 mL). Combine the organic layers and wash with water and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography, eluting with hexane/ethyl acetate (5-40% EtOAc in hexane), to provide the title compound (0.49 g, 83%). MS (ES+): 599 (M+H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:16]O>>[CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: CCCC[C@@H](C)CC(=O)O
Agent: O=S(=O)(O)O
Product: CCCC[C@@H](C)CC(=O)OC
Yield: 76.8 %

Procedure:
In a 500 ml flask were charged 300 ml of methanol, 35.5 g of (R)-3-methylheptanoic acid obtained in Step 3, and 0.5 g of concentrated sulfuric acid, and the mixture was heated at a methanol refluxing temperature for 18 hours. Methanol was distilled off under reduced pressure, and the residue was extracted with diethyl ether. The extract was washed with water, neutralized with a sodium carbonate aqueous solution, and then washed with a sodium chloride aqueous solution. Diethyl ether was removed by distillation, and the residue was distilled under reduced pressure to obtain 29 g (76.8%) of the titled compound (b.p.: 80° C./20 mmHg).