Azzindani/Open_Reaction_Data huggingface dataset:
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:15][C:14]([CH3:16])=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[NH2:22][S:23]([CH2:26][C:27](O)=[O:28])(=[O:25])=[O:24].ON1C(=O)CCC1=O>>[NH2:22][S:23]([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:15][C:14]([CH3:16])=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:28])(=[O:25])=[O:24]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: NS(=O)(=O)CC(=O)O
Agent: O=C1CCC(=O)N1O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(N)(=O)=O)[C@H]3SC2)s1

Procedure:
Using the procedure of Example 3, 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid is reacted with N-hydroxysuccinimidyl aminosulfonylacetate (prepared in a similar manner as set forth in Example 1 from aminosulfonylacetic acid and N-hydroxysuccinimide) to give the desired product.
Reaction SMILES: O.C([O-])=O.[NH4+].C([N:13]1[C:17]([CH2:18][CH2:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][N:15]=[CH:14]1)C1C=CC=CC=1>C(O)C.[Pd]>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:17]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(C(CCCc2cncn2Cc2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(C(CCCc2c[nH]cn2)c2ccccc2)cc1

Procedure:
A concentrated water solution of ammoniumformate (0,98 g, 15,6 mmol) is added dropwise to the boiling mixture of 1-benzyl-5-[4-(4-fluorophenyl)-4-phenylbutyl]-1H-imidazole (1,5 g, 3,9 mmol) and 10% Pd/C (0,156 g) in 16 ml of 50% ethanol. The mixture is refluxed for 2 hours. The catalyst is filtrated off and the solvent is evaporated. 2M NaOH is added and the product is extracted into ethyl acetate. The ethyl acetate phase is dried and evaporated to dryness to give the product. Yield 1,02 g. Melting point of the hydrochloride salt (from ethyl acetate) is 175°-182° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5](Br)=[CH:4][CH:3]=1.[Si:14]([O:21][CH2:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][C:28]=1B(O)O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5]([C:28]2[CH:27]=[CH:26][O:25][C:24]=2[CH2:23][CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1occc1B(O)O
Reactant: COC(=O)c1c(N)ccc(Br)c1O
Product: COC(=O)c1c(N)ccc(-c2ccoc2CCO[Si](C)(C)C(C)(C)C)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 26, starting from methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according to Wang et al, Bioorg Med Chem Lett 2007 17 2817) and 2-[2-(tert-butyldimethylsilanyloxy)-ethyl]-furan-3-yl-boronic acid (Intermediate 33). The material was used without further characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[C:14](#[N:16])C.[C-]#N>C1(C)C=CC=CC=1.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([C:14]#[N:16])=[O:7]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC#N
Agent: [Cu]
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)C#N)cc1OC
Reaction time: 0.5 h

Procedure:
A well stirred mixture [paddle stirrer] of 3,4-dimethoxybenzoyl chloride [AcrosOrganics] (14.05 g; 0.070 mol), dry toluene (32 cm3), dry acetonitrile (8.0 cm3), copper I cyanide (8.5; 0.095 mol) and Celite (5 g) was heated under reflux until no acid chloride remained (−1.5 hrs). The dark reaction mixture was cooled to ˜70° and diluted with toluene (150 cm3). After stirring for an additional ˜30 minutes, the resulting slurry was filtered through a bed of chromatographic silica gel (˜2.5 cm) and the pale yellow filtrate evaporated in vacuo to constant weight to give the title compound as a lemon yellow solid. Yield=11.41 g (85.3%), Mpt=143-145° C. The product was used directly in next stage.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][C:6]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:18][CH2:17]1)=[N:7]2.[C:27]([O-:30])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[CH:5][C:6]([N:16]3[CH2:21][CH2:20][CH:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:18][CH2:17]3)=[N:7]2)=[C:2]([C:10]2[C:27](=[O:30])[NH:4][CH:3]=[CH:2][CH:11]=2)[CH:11]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(Br)c2ncc(N3CCC(NS(C)(=O)=O)CC3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2ccc[nH]c2=O)c2ncc(N3CCC(NS(C)(=O)=O)CC3)nc2c1

Procedure:
step 2—To a solution of 42 (0.040 g, 0.10 mmol) in MeOH and DCM (3 mL/1 mL), was added Na2CO3 (0.029 g, 0.27 mmol), 30 (0.012 g, 0.11 mmol) and Pd(PPh3)4 (0.010 g, 0.010 mmol). The reaction was irradiated in a microwave synthesizer at 115° C. for 30 min. The reaction was cooled, concentrated and partitioned between EtOAc/H2O (25 mL/25 mL). The aqueous layer was separated and washed EtOAc (2×25 mL). The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The crude product was adsorbed onto SiO2 and purified by SiO2 chromatography eluting with 10% MeOH/DCM to afford 0.030 g (73%) of I-3.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[CH:4]=[C:3]([CH2:10][OH:11])[N:2]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[CH:4]=[C:3]([CH:10]=[O:11])[N:2]=1
Reactant: OCc1cc2c(cn1)CCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2c(cn1)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of 6,7-dihydro-5H-cyclopenta[c]pyridin-3-ylmethanol (189 mg, 1.267 mmol) in DCM (10 ml) at rt under argon was treated with manganese dioxide (1.101 g, 12.67 mmol) and then stirred at rt for 2 h, filtered through a thin pad of Kieselguhr, eluting with DCM (40 ml), the organic extracts were evaporated to give the crude product as a brown oil (110 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCOCC>[Cl:1][C:2]1[C:3]([O:13][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1nc(C(Cl)(Cl)Cl)nc(C)c1Cl
Yield: 80.8 %

Procedure:
To a solution of 5.8 g (0.02 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 2.0 g (0.02 mole) triethylamine, and 100 ml ether was added 2.2 g (0.02 mole) ethyl chloroformate. An immediate reaction ensued and a precipitate formed. After refluxing 2 hours longer the mixture was filtered, and the filtrate was washed with aqueous potassium carbonate and then with water. Rotary evaporation yielded 5.4 g residue which was recrystallized from ligroin to give 4.6 g (69% yield) of pure product (mp 43.5°-44.5° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN1CCCC1=O.ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(-c2c[nH]cn2)c1
Reactant: Brc1ccccn1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: N#Cc1cccc(-c2cn(-c3ccccn3)cn2)c1
Temperature: 160 °C
Yield: 9.2 %

Procedure:
A solution of 4-(3-cyanophenyl)imidazole (0.02 g, 0.11 mmol) in N-methylpyrrolidinone (0.5 mL) was treated with 2-bromopyridine (1.05 mL, 11.1 mmol) and the reaction mixture heated overnight at 160° C. After cooling the reaction mixture was diluted with dichloromethane (40 mL) and the organic phase was successively washed with water (10×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using 30% ethyl acetate in hexanes afforded 2.5 mg (9%) of 4-(3-cyanophenyl)-1-(2-pyridyl)-1H-imidazole, as an off-white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:19]1[CH:24]=[CH:23][C:22](=[O:25])[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O.[Cu]>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([N:19]2[CH:24]=[CH:23][C:22](=[O:25])[CH:21]=[CH:20]2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: O=c1cc[nH]cc1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc2nc(-c3nc(-n4ccc(=O)cc4)cnc3N)[nH]c2c1
Yield: 29.5 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (80 mg, 0.263 mmol), pyridin-4(1H)-one (287 mg, 2.63 mmol), cesium carbonate (257 mg, 0.8 mmol) and copper (5 mg, 0.08 mmol) were heated in NMP (2 mL) at 150° C. for 1 hour. The reaction mixture was diluted with EtOAc, washed with 1N NaOH, and the organic layer filtered through a pad of celite and concentrated in vacuo. The resulting solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (24.7 mg, 30% Yield).
Reaction SMILES: [N:1]1([NH:14][CH:15]([CH3:17])[CH3:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:30].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH:15]([NH:14][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:30])[C:4]=2[N:3]=[CH:2]1)([CH3:17])[CH3:16]
Reactant: CC(C)Nn1cnc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)Nn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (1.36 g, 5.66 mmol) in 50 mL of chloroform was cooled in a cold water bath. The solution was treated with MCPBA (2.03 g, 7.07 mmol) over 5 min and then allowed to warm to ambient temperature. After 1 h, TLC showed complete conversion to the intermediate 5-N-oxide. The reaction mixture was again cooled with a cold water bath. The solution was treated with concentrated ammonium hydroxide solution (25 mL, 30%) and stirred rapidly to homogenize. The reaction mixture was treated with p-toluenesulfonyl chloride (1.13 g, 5.94 g) over 5 min and allowed to warm to ambient temperature. After 30 min, the reaction mixture was diluted with 50 mL of CHCl3 and 25 mL of water. An undissolved solid between the phases was filtered off, saved, and the phases were separated. The organic portion was washed with saturated NaHCO3 solution (30 mL), water (30 mL) and brine (30 mL). The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan/orange solid. A high-performance liquid chromatography (HPLC) analysis of the filtered solid matched that of the solid from the concentrated organic extracts. The combined solid was recrystallized twice from MeOH to give 1.18 g of N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OC(C)C(=O)OCC)ccc(C(C)=O)c1O
Yield: 73 %

Procedure:
A mixture of 10.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 8.4 ml of ethyl 2-bromopropionate and 10.7 g of anhydrous potassium carbonate in 125 ml of anhydrous acetone was stirred at reflux for 42 hours. The reaction mixture was filtered and the filtrate was concentrated to an oil which was purified by high pressure liquid chromatography using 2% ethyl acetate-toluene to yield 11.4 g (73%) of racemic-(4-acetyl-3-hydroxy-2-propylphenoxy)-alpha-methylacetic acid ethyl ester as an oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=1>CO>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][S:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)=[CH:16][CH:15]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CO
Product: COC(=O)c1ccc(CSc2nc3ccccc3[nH]2)cc1
Yield: 60.3 %

Procedure:
1H-Benzoimidazol-2-thiol (1.5 g, 0.01 mol) and 4-bromomethyl benzoic acid methyl ester (2.29 g; 0.01 mol) were heated at reflux in methanol (100 mL) for a period of 24 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, then with water. The organic phase was evaporated. The residue was dissolved in methanol. The resulting solution was saturated with hydrogen chloride. The solution was then concentrated to the precipitation point. The solid was collected and dried to give (1.8 g, 54% yield) of the title compound as a mono-hydrochloride, white solid, m.p. 229°-231° C. Anal. Calcd. for C16H14N2 O2S.HCl: C, 57.40; H, 4.52; N, 8.37. Found: C, 57.54; H, 4.47; N, 8.36. Mass spectrum (EI; M+) m/z 298. 1H-NMR (DMSO-d6 ; 400 MHz) δ 7.89 (d, 2H0, 7.62-7.65 (m, 4H); 7.39 (m, 2H), 4.89 (s, 2H), and 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5].C(O[C:35]([N:37]([CH2:39][C:40](O)=[O:41])C)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:40](=[O:41])[CH2:39][NH:37][CH3:35])[CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNCC(=O)N(Cc1ccsc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(Cl)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general procedure E: to a stirred solution of 2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (62 mg, 0.137 mmol), (tert-butoxycarbonyl-methyl-amino)-acetic acid (28 mg, 0.159 mmol), HOBt (24 mg, 0.177 mmol) and DIPEA (59 μL, 0.34 mmol) in DMF (3 ml) was added EDCI (34 mg, 0.177 mmol). The reaction was stirred at rt overnight under N2 pressure. The resultant crude product (88 mg) was used in the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: COc1ccc(C=O)cc1C(C)C
Product: COc1ccc(C=C2C(=O)Nc3ccc(Br)cc32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:19](=[O:28])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:19](=[O:28])[N:20]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1(C(=O)NCc2ccccc2)CC(=O)N(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)N(Cc2ccccc2)Cc2ccccc2)CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl 1-benzyl-3-(benzylcarbamoyl)-5-oxopyrrolidine-3-carboxylate obtained in Preparative Example 1 (2) (20 g) in dimethylformamide (20 mI) was added to a mixture of 60% sodium hydride (2.5 g) and dimethylformamide (60 ml) under ice-cooling After the mixture was stirred at room temperature for 1.5 hours, benzyl bromide (9.7 g) was added under ice-cooling and the mixture was starred for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried, concentrated and purified by silica gel column chromatography to give 16.3 g of the object compound as white crystals, melting point 112°-115° C.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14]3[CH2:25][NH:24][C:23]([CH3:27])([CH3:26])[C:15]=3[N:16](C(OCC)=O)[N:17]=2)[C:9]([F:28])=[CH:8][N:7]=1)[CH3:4].C(N(C(C)C)CC)(C)C.[F:38][C:39]1([C:46](Cl)=[O:47])[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>C1COCC1>[CH2:3]([O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14]3[CH2:25][N:24]([C:46]([C:39]4([F:38])[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[O:47])[C:23]([CH3:26])([CH3:27])[C:15]=3[NH:16][N:17]=2)[C:9]([F:28])=[CH:8][N:7]=1)[CH3:4]
Reactant: CN1CCC(F)(C(=O)Cl)CC1
Reactant: CCOC(=O)n1nc(Nc2nc(OCC)ncc2F)c2c1C(C)(C)NC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)C2(F)CCN(C)CC2)C3(C)C)n1
Temperature: 65 °C

Procedure:
To a solution of ethyl 3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate dihydrochloride (120 mg, 0.27 mmol) in 15 mL THF containing diisopropylethyl amine (0.23 mL, 4 eq) was added a 5 mL THF suspension of 4-fluoro-1-methylpiperidine-4-carbonyl chloride (128 mg, 2.6 eq). After heating for 5 hours at 65° C., the reaction was concentrated to dryness and carried on without further purification. To a solution of ethyl 3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-5-[(4-fluoro-1-methylpiperidin-4-yl)carbonyl]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate in methanol was added 2 mL of a 10% sodium hydroxide solution in methanol. After removing the solvent in vacuo, the residue was purified as in Example K1 above. See Table 1 below for NMR data.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]1>>[N+:8]([C:7]1[C:2]([O:16][C@@H:13]2[CH2:14][CH2:15][O:11][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O[C@@H]1CCOC1
Reactant: O=[N+]([O-])c1cccnc1F
Product: O=[N+]([O-])c1cccnc1O[C@@H]1CCOC1

Procedure:
Prepared analogously to I.1 from 2-fluor-3-nitropyridine and (R)-tetrahydro-furan-3-ol.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:14]([N:9]1[CH2:10][CH2:11][CH2:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: c1ccc(C2=NNCCC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCCC(c2ccccc2)=N1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
3-Phenyl-1,4,5,6-tetrahydropyridazine (2.4 g) synthesized in Reference Example 1 was dissolved in chloroform (50 ml). Thereto were added nicotinic acid chloride hydrochloride (2.6 g) and triethylamine (3.2 g) with ice-cooling. Stirring was conducted for 30 minutes. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain 1.8 g of a title compound.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1([OH:20])[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].Cl>C1COCC1>[CH2:13]([N:10]1[CH2:11][CH2:12][C:7]2([O:20][C:21](=[O:22])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6]2)[CH2:8][CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)NCC1(O)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)N1CC2(CCN(Cc3ccccc3)CC2)OC1=O
Yield: 76.7 %

Procedure:
A mixture of (tert-butyl)(1-benzyl-4-hydroxypiperidin-4-ylmethyl)amine (11.9 g, 43 mmol), 1,1'-carbonyldiimidazole (8.4 g, 52 mmol) and THF (150 mL) was heated 3.5 hours at reflux. The mixture was cooled, poured into dilute hydrochloric acid and then washed with methylene chloride (2× 200 mL). The combined washes were extracted with dilute hydrochloric acid and the combined. aqueous layers were treated with sodium hydroxide and extracted with methylene chloride. The extract was dried (Na2 SO4) and concentrated and the residue was recrystallized from heptane to give 8-benzyl-3-tert-butyl-3,8-diaza-1-oxaspiro[4.5]decane-2-one (9.98 g, 33 mmol), m.p. 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[O:8]1[CH2:11][CH2:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: Nc1ccccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)NCCO2
Temperature: 100 °C
Yield: 32.3 %

Procedure:
A mixture of 2-aminophenol (5 g, 45.87 mmol), 1,2-dibromoethane (4.3 g, 22.93 mmol), and K2CO3 (15.8 g, 114.67 mmol) in THF (30 mL) was heated at 100° C. for 16 h. After completion of reaction, water was added and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (using 100-200 mesh size silica, the desired product was eluted at 15% EtOAc in hexane) to obtained 1 g of desired product.