Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]2[C:16]([OH:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O[N:21]1C2C=CC=CC=2N=N1.O.N>ClCCl>[C:1]1([N:7]2[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]2[C:16]([NH2:21])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: On1nnc2ccccc21
Reactant: C[Si](C)(C)C1=CN(c2ccccc2)N(C(=O)O)N1
Agent: N
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)C1=CN(c2ccccc2)N(C(N)=O)N1
Temperature: -78 °C
Reaction time: 48 h
Yield: 87.6 %

Procedure:
In a nitrogen atmosphere, 630 mg of 3-phenyl-5-trimethylsilanyl-1H-[1,2,3]triazole-2-carboxylic acid which is the compound prepared in the above 2) was dissolved in 5 ml of dichloromethane, 671 mg of 1-hydroxybenzotriazole monohydrate and 907 mg of a water-soluble dichlorohexyl carbodiimide were added thereto, the reaction solution was cooled down to −78° C. and ammonia gas was introduced thereinto followed by stirring for 2 days. Water was added to the reaction solution, the mixture was extracted with ethyl acetate and the ethyl acetate layer washed with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was separated and purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to give 550 mg of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[Si]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2)(C(C)(C)C)(C)C.CS(O[CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=O)=O.O>CN(C=O)C>[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[N:15]=[CH:14]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(O)ccc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To a solution of NaH (60% in mineral oil) (43.5 mg, 1.81 mmol) in DMF at 0° C. was added 5-((tert-butyldimethylsilyl)oxy)-1H-indazole (300 mg, 1.21 mmol), and the mixture was stirred at 0° C. for 15 min. Tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (243 mg, 1.21 mmol) was then added to the mixture at 0° C. After addition, the mixture was stirred at 85° C. for 12 h. The mixture was poured into water, and the product extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by TLC (Pet.Ether:EtOAc=2:1) to give tert-butyl 4-(5-hydroxy-1H-indazol-1-yl)piperidine-1-carboxylate (250 mg, yield 65%) as a colorless oil. LCMS (m/z): 318.2 [M+H]+
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][O:20][CH:21]([C:25]([NH:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[O:26])[C:22](O)=[O:23]>>[CH3:19][O:20][CH:21]([C:25]([NH:27][CH2:28][C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])=[O:26])[C:22]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:23]
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: COC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: COC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
(S)-7-Amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in example 73 to yield 2-methoxy-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid. [α] 589=−71.8° (1% in CHCl3), MS m/e (%): 486.4 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:16](OC)(=[O:19])[C:17]#[CH:18]>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:18]=[CH:17][C:16]([OH:19])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C#CC(=O)OC
Reactant: NNc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Oc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of 57.5 g of 4-chlorophenylhydrazine hydrosulfate in 1,000 ml of tert-butanol was first treated in portions with 100.8 g of potassium tert-butoxide and then (after stirring for 10 min) in the course of 45 min at 45° C.-50° C. with a solution of 27.7 g of methyl propiolate in 90 ml of tertbutanol. After 1 h at boiling point, the mixture was allowed to cool and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in 1,200 ml of water. The aqueous phase was first washed with methylene chloride and then acidified, the product being deposited as a solid. 47.6 g of the title compound were obtained, m.p.: 185°-187° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:13]=[CH:12][C:11]=1[Cl:27]>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]1[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:13]=[CH:12][C:11]=1[Cl:27]
Reactant: CN(C)CCN1CCN(c2ccc(Cl)c(C(=O)Nc3ccccc3N)c2)CC1
Solvent: CC(=O)O
Product: CN(C)CCN1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Yield: 74.8 %

Procedure:
A solution of N-(2-amino-phenyl)-2-chloro-5-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-benzamide (0.35 g, 0.87 mmol) in acetic acid (15 mL) was heated for 7 h at 85° C., then solvent was removed under reduced pressure and the residue triturated with Et2O to obtain 0.25 g (75%) of the title compound as a solid without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][C@H:7]([CH3:9])[NH2:8].CO[C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1OC)[CH2:20][C@@H:21](C)N.O>C1C=CC=CC=1>[C:19]1([CH:20]([NH:8][CH:7]([CH2:6][C:5]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:9])[CH3:21])[CH:24]=[CH:25][CH:26]=[CH:17][CH:18]=1
Reactant: COc1ccc(C[C@@H](C)N)cc1OC
Reactant: COc1ccc(C[C@H](C)N)cc1OC
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(CC(C)NC(C)c2ccccc2)cc1OC

Procedure:
Said synthesis was developed by D. E. Nichols et al. ("J. Med. Chem.", 1973, 16, 480-48 and U.S. Pat. No. 4,000,197, of 12.28.1976) and was applied to the chiral synthesis of several methoxylated amphetamines, including (S)-3,4-dimethoxy-amphetamine, which is an enantiomer of (3). In U.S. Pat. No. 4,000,197, the synthesis of the iminic intermediate is carried out in benzene under refluxing conditions during 24 hours with formed water being simultaneously azeotroped off; the hydrogenation is carried out with Raney-Nickel as the catalyst, in absolute ethanol under medium-pressure hydrogen (3 atm of H2). The N-α-phenyl-ethyl-3,4-dimethoxy-amphetamine (15) intermediate is isolated as hydrochloride salt, by crystallization in aqueous acetone or acetone/isopropanol blend, in moderate yield (relatively to dimethoxy-phenyl-acetone), of 48%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[O:2])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:21])[F:23])[O:18][N:17]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 57 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (90 mg, 0.22 mmol), was converted, using 2,2,2-trifluoroethylamine instead of cyclopropanemethylamine, to the title compound (60 mg, 57%) which was obtained as a white solid. MS: m/e=482.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH:15]=[C:16]([C:23]2[S:24][CH:25]=[CH:26][C:27]=2[CH3:28])[C:17]2[S:18][CH:19]=[CH:20][C:21]=2[CH3:22])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:22][C:21]1[CH:20]=[CH:19][S:18][C:17]=1[C:16]([C:23]1[S:24][CH:25]=[CH:26][C:27]=1[CH3:28])=[CH:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2sccc2C)c2sccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccsc1C(=COCCN1CCC[C@@H](C(=O)O)C1)c1sccc1C
Yield: 86.8 %

Procedure:
(R)-1-[2-[[2,2-bis(3-Methyl-2-thienyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic ethyl ester (420 mg, 1 mmol) (example 11) was dissolved in ethanol (20 ml) and 10 N sodium hydroxide solution (1.00 ml) was introduced. After 3 h at room temperature the pH of the solution was adjusted to 9 with 2 N hydrochloric acid. The ethanol was removed by evaporation and the pH of the solution was adjusted to 2.5. Extraction with dichloromethane (4 × 15 ml), drying of the combined extracts (MgSO4) (charcoal decolourisation) and evaporation of the filtrate provided a residue, which was recrystallized from water. This provided the title compound (0.34 g, 84%) as a cream solid, m.p. 55°-70° C. TLC: rf 0.37 (SiO2, CH2Cl2 /MeOH 1/1).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].Cl>CN(C=O)C.O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=[O:27])=[O:4]
Reactant: CC(C)(N)CC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CC(=O)O)NC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 32.4 %

Procedure:
To a mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) and 3-amino-3-methyl-butyric acid (Oakwood) (199 mg, 1.7 mmol) in DMF (3 mL) was added sodium methoxide solid (73 mg, 1.36 mmoL). The mixture was gently refluxed for 2 h. After cooled, it was diluted with water (100 mL) and acidified by 1 N HCl aqueous solution to pH=3-4. Precipitate was collected and dried in vacuo. The crude product was purified by silica gel chromatography, eluting with 20%-100% EtOAc-hexanes, to provide the title compound (42 mg, 0.11 mmol) in 33% yield. LC-MS ESI−: 379.04 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([CH2:12]O)=[N:11][C:7]=2[CH:6]=1)=[O:4].S(Cl)([Cl:23])=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([CH2:12][Cl:23])=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)nc(CO)n2CCC(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)nc(CCl)n2CCC(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of 2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.00 g, 3.62 mmol) in DCM (10 mL) was added thionyl chloride (396 μL, 5.43 mmol). The solution was stirred at 0° C. for 15 min. and concentrated in vacuo to give 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester; HCl salt (1.20 g, 100%) as a white solid, which was used without further purification:
Reaction SMILES: C(C1C2C(=CC=CC=2)C(C([O:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29](=[O:31])[CH3:30])=[CH:21][CH:20]=2)=O)=O)=CC=1)(=O)C.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)(=O)C>[C:33]1([N:32]=[C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29](=[O:31])[CH3:30])=[CH:21][CH:20]=2)[OH:16])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)c1ccc(C(=O)OC(=O)c2ccc(C(C)=O)c3ccccc23)c2ccccc12
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)c1ccc(C(O)=Nc2ccccc2)c2ccccc12

Procedure:
The method consists of a first synthesis stage, in which a mixture of 4-acetylnaphthalic anhydride, aniline, and glacial acetic acid is heated under reflux, the reaction mixture is cooled, the precipitated gray crystals are separated by filtration, treated with hydrochloric acid solution, then with hot sodium carbonate solution, and recrystallized from acetic acid. Acetyl derivative, the 4-acetylnaphthalic acid phenylimide is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[C:16]([CH:17]=O)[C:15]([OH:20])=[CH:14][CH:13]=1.C(O)C>CO>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH:19]=1)[CH:17]=[N:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CCO
Solvent: CO
Product: O=C(O)c1ccc(N=Cc2cc(Cl)ccc2O)cc1
Yield: 94 %

Procedure:
Using the procedure of Sheeman et al [J.A.C.S., Vol. 84 (1982), p. 2457], 1.37 g of p-amino-benzoic acid, 2.35 g of 5-chlorosalicylaldehyde, 240 ml of ethanol and 17 ml of anhydrous methanol were reacted to obtain 2.59 g of 4-[(5-chloro-2-hydroxy-benzylidene)amino]-benzoic acid.
Reaction SMILES: [CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].[H-].[Na+].Cl[CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[N:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][CH2:20]3)[CH:14]=[N:15][CH:16]=1.O>CN(C=O)C>[CH3:27][N:23]1[C:22](=[O:28])[CH2:21][CH2:20][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH2:10][NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:16]=[N:15][CH:14]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CN1C(=O)CCc2nc(-c3cncc(CCl)c3)ccc21
Reactant: CCS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1cncc(-c2ccc3c(n2)CCC(=O)N3C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
To a stirred solution of ethanesulfonic acid amide (118 mg, 1.08 mmol) in DMF (5.0 mL) was added 60% NaH (35 mg, 0.81 mmol) at RT and the resulting reaction mixture was stirred for 0.5 hour before 6-(5-chloromethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one (156 mg, 0.54 mmol) was added. After continued stirring at RT for additional 2 hours, water (1.0 mL) was added. After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give title compound (15 mg, 7.7%) as a light yellow solid. MS: 361.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15][C:14]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])[CH2:5]2.Cl[CH2:39][CH2:40][O:41][CH2:42][CH2:43]Cl.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1>[CH2:31]([O:30][C:14]1[CH:15]=[C:16]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:17]([CH:19]([CH3:21])[CH3:20])=[CH:18][C:13]=1[C:11]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([N:1]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:3]=2)[CH2:7]1)=[O:12])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: ClCCOCCCl
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(N)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(N4CCOCC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of (5-amino-1,3-dihydro-isoindol-2-yl)-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-methanone (100 mg; 0.2 mmol), bis(2-chloroethyl)ether (30 μl; 1.1 equiv.), Hunigs base (125 μl; 3.5 equiv.) and tetrabutylammonium iodide (10 mg) in NMP (1 ml) was heated in a CEM microwave synthesiser at 150° C. for 30 minutes. A further 30 μl of Hunigs base and 125 μl of bis(2-chloroethyl)ether were added and heating repeated for the same time. The reaction mixture was partitioned between EtOAc and saturated NH4Cl solution, the EtOAc layer was separated, washed with more saturated NH4Cl solution, then brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (1:2 then 1:1 then 2:1 EtOAc/P.E. as eluant) gave 60 mg of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-morpholin-4-yl-1,3-dihydro-isoindol-2-yl)-methanone. MS: [M+H]+ 563.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27]C1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1ccc(F)cc1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1

Procedure:
2-[2-(4-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 160 mg of 2-(4-fluorophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (dd, 1H, J 2.9, 0.4 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.51 (m, 2H), 7.24 (m, 1H), 7.20 (dd, 1H, J 9.1, 0.4 Hz), 7.01 (d, 1H, J 2.8 Hz), 6.96 (dd, 1H, J 8.7, 2.8 Hz) 6.91 (d, 1H, 8.7 Hz), 5.15 (dd, 1H, J 10.3, 2.2 Hz), 2.94 (m, 1H), 2.76 (m, 1H) 2.17 (m, 1H), 2.01 (m, 1H).
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Br[C:26]1[CH:31]=[N:30][C:29]([I:32])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[N:30][C:29]([I:32])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: Brc1cnc(I)cn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2cnc(I)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-bromo-5-iodo-pyrazine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.51 min; Mass spectrum (ESI+): m/z=516 [M+H]+.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](O)=[O:19])[CH:13]=1)=[O:6].CO>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1)=[O:6]
Reactant: COC(=O)c1ncoc1-c1cccc(C(=O)O)c1
Agent: N#N
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ncoc1-c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 5-(3-carboxy-phenyl)-oxazole-4-carboxylic acid methyl ester (500 mg, 2.02 mmol) in THF (14.0 mL) at 0° C. was treated dropwise with a BH3 (10.1 mL of a 1M solution in THF, 10.11 mmol). The resulting mixture was stirred at 0° C. for 4 h. MeOH (14 mL) was then added dropwise. After 30 min, the solvent was removed under reduced pressure. EA (20 mL) was added and the organic phase was washed with 1N NaOH (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (93:7 CH2Cl2-MeOH) gave the title compound as a white solid. TLC: rf (93:7 CH2Cl2-MeOH)=0.32. LC-MS-conditions 02: tR=0.76 min, [M+H]+=234.39.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14](=[O:28])[N:15]([CH:25]([CH3:27])[CH3:26])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].N1C=CC=CC=1.Cl>ClCCl>[Cl:12][C:13]1[C:14](=[O:28])[N:15]([CH:25]([CH3:26])[CH3:27])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH:21]([OH:24])[CH2:22][O:23][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)n1ncc(NCC(O)CO)c(Cl)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)CNc2cnn(C(C)C)c(=O)c2Cl)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1.60 g of p-toluenesulfonyl chloride was added to a mixture comprising 2.09 g of 4-chloro-5-(2,3-dihydroxypropylamino)-2-i-propyl-3(2H)pyridazinone prepared in Reference Example 6, 12 ml of pyridine and 20 ml of dichloromethane, under cooling with ice. The mixture was stirred for 6 hours, and then left to stand for 2 days in an ice chamber. The reaction mixture was acidified to a pH of about 2 by adding cooled dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a colorless oily substance. The oily substance was purified by silica gel column chromatography, and 2.45 g of the above identified compound was obtained as a colorless viscous oily substance from the eluate with choroform-methanol (25:1, v/v).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][CH:11]([F:23])[O:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH:11]([F:10])[F:23])[CH:14]=2)(=[O:21])=[O:20])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
A round bottomed flask was charged with 3-amino-5-bromo-2-chloropyridine (1.5 g, 7 mmol, Asymchem Laboratories, Inc. Morrisville, N.C.) and pyridine (20 mL). To this solution, 3-(difluoromethoxy)benzenesulfonyl chloride (2 mL, 8 mmol, Sigma-Aldrich Corporation, St. Louis, Mo.) was added dropwise and the solution was stirred at 25° C. for 18 h. The mixture was concentrated in vacuum and the residue was suspended in H2O. The white solid was collected by filtration and then suspended in methanol (50 mL). To this suspension, potassium carbonate (1.9 g, 14 mmol) was added, and the mixture was stirred at 25° C. for 20 h. The suspension was filtered and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (10-50% EtOAC/Hexane) afforded the title compound (1.4 g, 47% yield) as a white solid. MS (ESI positive ion) m/z: 415 (M+1).