Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.BrCC1CCCCO1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:37]3[C:33]4=[N:34][O:35][N:36]=[C:32]4[CH:31]=[CH:30][C:29]=3[O:28][CH2:27]2)[C:19]1=[O:38]>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3([C:37]4[C:33]5=[N:34][O:35][N:36]=[C:32]5[CH:31]=[CH:30][C:29]=4[O:28][CH2:27]3)[C:19]2=[O:38])[CH:5]=1
Reactant: BrCc1cccnc1
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2cccnc2)c2ccccc2C12COc1ccc3nonc3c12

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(pyridin-3-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (47%) as a colorless solid: mp 230-232° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.59 (d, J=2.7 Hz, 1H), 7.88-7.82 (m, 2H), 7.39-7.16 (m, 4H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 5.35-5.24 (m, 2H), 4.99 (d, J=9.3 Hz, 1H), 4.84 (d, J=15.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.1, 162.9, 149.4, 148.8, 148.3, 144.8, 141.7, 135.1, 130.8, 129.8, 129.7, 123.9, 121.8, 119.4, 109.6, 106.9, 81.9, 57.2, 42.0; MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([Br:15])[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nn(-c2ccc(Cl)nn2)c(C)c1Br
Reaction time: 3 h

Procedure:
A mixture of 2.09 g (0.01 moles) of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 21 ml of carbon tetrachloride and 1.96 g (0.011 moles) of N-bromosuccinimide is boiled under stirring for 3 hours. After cooling the precipitate is filtered, washed with carbon tetrachloride and recrystallized from ethanol. Yield: 1.44 g (50.5%); m.p.: 143°-145° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([O:20]CC)=[O:19])[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1.[OH-].[Na+].S(=O)(=O)(O)O>C(O)C.ClCCl>[C:14]([O:13][C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([Br:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:4]([C:18]([OH:20])=[O:19])=[C:5]2[CH2:10]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)c(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCn2c(Br)c(-c3cccc(F)c3)c(C(=O)O)c2C1
Temperature: 70 °C
Yield: 72.8 %

Procedure:
To a suspension of 2.41 g (5.16 mmol) of 2-tert-butyl 8-ethyl 6-bromo-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in 18 ml of ethanol are added 10.3 ml (10.3 mmol) of 1N sodium hydroxide solution and the mixture is heated at 70° C. for 2 days. The mixture is then taken up in dichloromethane and acidified by addition of 25 ml of aqueous 1N sulfuric acid. The organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure, to give a yellow solid, which is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 4% methanol in dichloromethane, to give 1.65 g of 2-(tert-butyloxycarbonyl)-6-bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid in the form of a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[C:11]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])([CH3:13])[CH3:12].CC#N>CN(C)C1C=CN=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
5-Bromoindoline (3.96 g, 20 mmol), di-t-butylcarbonate (4.37 g, 20 mmol), 4-dimethylaminopyridine (2.69 g, 22 mmol) and CH3CN (50 mL) were mixed and stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (300 mL) and the organic solution was washed successively with water (50 mL), a 1 N HCl solution (50 mL), a saturated NaHCO3 solution (2×50 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a solid. Trituration with hexane and drying in vacuo provided a white solid (2.26 g, 38% yield): 1H NMR (DMSO-d6, 300 MHz): 7.36 (s, 1H), 7.29 (d, 2H, J=7), 3.86 (t, 2H, J=7), 3.04 (t, 2H, J=7), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:26]([O:30][CH2:31]Cl)(=[O:29])[CH2:27][CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:31][O:30][C:26]([CH2:27][CH3:28])=[O:29])=[O:24])(=[O:21])=[O:20]
Reactant: CCC(=O)OCCl
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(C(=O)OCOC(=O)CC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
In a similar manner to Example 12, bumetanide can be reacted with chloromethyl propionate, triethylamine and sodium iodide in dimethylformamide (DMF) to yield ethylcarbonyloxymethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Cl.O>CS(C)=O>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1Cc1c(Cl)cccc1Cl
Reaction time: 1.7 h
Yield: 21 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 48.9 g (0.25 mole) of 2,6-dichlorobenzyl chloride. The reaction mixture was heated to 105° over 0.3 hours, held at 105° for 1.7 hours and poured into 1.5 l of water all with rapid stirring. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure leaving %) 48 g (79(of a light yellow viscous oil. The crude product was crystallized using 125 ml of ether, filtered, air dried and dried to a constant weight at 60° to give 13 g (21%) of a white solid m.p. 156°-158°.
Reaction SMILES: O1C=CC(NC[C@@H:8]2[O:12][C:11](=[O:13])N(C3C=CC(N4CC[C@H](NC(=O)C)C4)=C(F)C=3)C2)=N1.Cl.[NH2:31][C@@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][N:49]([C:58]4[CH:62]=[CH:61][O:60][N:59]=4)[C:50]([O:52][CH2:53][C:54]([Cl:57])([Cl:56])[Cl:55])=[O:51])[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1.ClC(OC)=O>>[CH3:8][O:12][C:11]([NH:31][C@@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][N:49]([C:58]4[CH:62]=[CH:61][O:60][N:59]=4)[C:50]([O:52][CH2:53][C:54]([Cl:57])([Cl:55])[Cl:56])=[O:51])[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1)=[O:13]
Reactant: N[C@@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Agent: COC(=O)Cl
Agent: Cl
Product: COC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4-(3(R)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (1.61 g, 2.81 mM) and methyl chloroformate gave the desired product (1.61 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)=[O:4].N([O-])=[O:13].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:11][C:7]1[N:6]=[C:5]([C:3](=[O:4])[CH2:2][OH:13])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(Br)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CO)c1cccc(Br)n1
Reaction time: 14 h

Procedure:
To a solution of 2-bromo-1-(6-bromopyridin-2-yl)ethanone (500 mg, 1.79 mmol) in dimethylformamide (11.5 mL) was added sodium nitrite (124 mg, 1.79 mmol). After 14 hours, the reaction was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (2×100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound. 1H NMR (600 MHz, DMSO): δ 7.94 (m, 2H), 7.91 (m, 1H), 5.07 (t, J=5.9 Hz, 1H), 4.85 (d, J=5.9 Hz, 2H).
Reaction SMILES: [N:1]#[N:2].C([O:7][C:8](=[O:43])[CH2:9][N:10]([C:17](=[O:42])[C@H:18]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])[NH:19][S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C>FC(F)(F)C(O)=O>[N:1]#[N:2].[CH3:34][O:33][C:27]1[CH:26]=[C:25]2[C:30]([CH:31]=[CH:32][C:23]([S:20]([NH:19][C@H:18]([C:17]([N:10]([CH2:11][CH:12]3[O:16][CH2:15][CH2:14][CH2:13]3)[CH2:9][C:8]([OH:43])=[O:7])=[O:42])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])(=[O:21])=[O:22])=[CH:24]2)=[CH:29][CH:28]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)OC(C)(C)C)CC3CCCO3)cc2c1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)O)CC3CCCO3)cc2c1
Yield: 64.1 %

Procedure:
A solution of 4.8 g of N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine tert-butyl ester in 10 ml of trifluoroacetic acid was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 300 ml of Daiaion® SA 10A ion exchange resin (100-200 mesh, OH- form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with 50% ethanol-water and eluted with ethanol-water-acetic acid solution (5:4:1). The main fraction eluted from the ethanol-water-acetic acid solution was evaporated to dryness to give a gummy material. This was recrystallized from ethanol-water to give 2.8 g of N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine in the form of a powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cccnc2n(C)c1=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCCC2)c2cccnc2n(C)c1=O

Procedure:
A stirred mixture of 2.7 g. (0.01 mole) of 4-chloro-1,2-dihydro-1-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 0.7 g. (0.01 mole) of pyrrolidine and 1.06 g. (0.01 mole) of sodium carbonate in 25 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was cooled in ice. The precipitate which formed was collected and was dissolved in 20 ml. of ethyl acetate. The solution was diluted with petroleum ether to the cloudy point. The precipitate which formed was collected to yield 0.5 g. of product, m.p. 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]([CH3:11])[CH3:10])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:11])[CH3:10])=[C:4]([C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: CC(C)C(O)c1ccc(Cl)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
8.00 g (42 mmol) 1-(4-chloro-2-trifluoromethyl-phenyl)-2-methyl-propan-1-ol and 2.5 g p-toluenesulphonic acid monohydrate in 200 mL toluene are refluxed overnight, while the water formed is captured using a water separator. The reaction mixture is left to cool, combined with water and the organic phase is separated off. It is extracted with toluene and the organic phases are combined and evaporated down. The residue is added to a short silica gel column and eluted with hexane. Colourless oil.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[Br:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:38][CH3:39])[CH:34]=2)[CH:29]=1>C(O)C>[C:5]12([C:32]3[CH:31]=[C:30]4[C:35]([CH:36]=[CH:37][C:28]([Br:27])=[CH:29]4)=[CH:34][C:33]=3[O:38][CH3:39])[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: CCO
Product: COc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 48 h
Yield: 20.9 %

Procedure:
In a 100 ml flask, under a nitrogen atmosphere, are placed 1 g of 1-acetoxyadamantane and 30 ml of n-heptane, and 0.25 g of concentrated sulfuric acid is introduced. At a temperature of about 20° C., 1.22 g of 2-bromo-6-methoxynaphthalene are poured in slowly and the mixture is left in vigorous agitation for 48 hours. Next, 20 ml of denatured ethanol are introduced and the mixture is evaporated to dryness under reduced pressure. The product is taken up in denatured ethanol and the precipitate is filtered with sintered glass. After drying of the raw product in a vacuum oven for 24 hours at 30° C., one purifies using silica column chromatography. There were obtained 0.4 g of the desired raw product (Melting point: 164°-168° C.).
Reaction SMILES: I[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[Br:10][C:11]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:12]=1[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH2:16][CH2:15]1>CN(C)C=O>[Br:10][C:11]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][CH3:3])=[CH:30][C:12]=1[CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH2:18][CH2:19]1
Reactant: O=C(Cc1ccccc1Cl)N1CCC(Cc2cc(O)ccc2Br)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)c(CC2CCN(C(=O)Cc3ccccc3Cl)CC2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Iodoethane (311.9 mg, 2.000 mmol) and potassium carbonate (500.0 mg, 3.619 mmol) were added to a solution (3 ml) of 4-(2-bromo-5-hydroxybenzyl)-1-[(2-chlorophenyl)-acetyl]piperidine (400.0 mg, 0.952 mmol) in N,N-dimethylformamide, and the resulting mixture was stirred at 60° C. for 3 hours. The reaction was terminated by adding water (20 ml), followed by extraction with diethyl ether. The extract layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent, whereby the title compound (426.7 mg, 0.952 mmol) was quantitatively obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH2:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][NH2:22])[CH3:11]>CO.C(O)(=O)C>[CH2:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][N:22]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2])[CH3:11]
Reactant: CCn1c(NN)nc2ccccc21
Reactant: CC(=O)c1ccccn1
Solvent: CC(=O)O
Solvent: CO
Product: CCn1c(NN=C(C)c2ccccn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-acetyl pyridine (0.62 g, 5.11 mmol) and 1-ethyl-2-hydrazinobenzimidazole (0.90 g, 5.11 mmol) in 20 ml of methanol is stirred at room temperature for 24 hours after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with 50% methanol and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.99 g (70% of theory).
Reaction SMILES: [I:1][C:2]1[C:3](O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.P(Br)(Br)([Br:17])=O>>[Br:17][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: Oc1nc(-c2ccccc2)ncc1I
Reactant: O=P(Br)(Br)Br
Product: Brc1nc(-c2ccccc2)ncc1I
Temperature: 100 °C
Yield: 62.3 %

Procedure:
A mixture of 5-iodo-2-phenylpyrimidin-4-ol (1.97 g, 6.67 mmol, 1.0 eq) and POBr3 (100 g) was heated to 100° C. for 8 hours. The solution was cooled down to 55° C. and poured into ice-water while stirring vigorously. The mixture was maintained below 25° C. during the quench. The reaction mixture was extracted with CH2Cl2. The organic layer was washed (cold water), dried (Na2SO4), evaporated and purified by silica gel chromatography (hexane as eluent) to afford 4-bromo-5-iodo-2-phenylpyrimidine (1.5 g, 62.5%). LC-MS (m/z): 360.8 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.47-7.50 (m, 3H), 8.37-8.40 (m, 2H), 8.91 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][C:6]=2[CH:13]=1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[Si:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][C:6]=2[CH:13]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)c1cc2cc(O)ccc2o1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2o1
Yield: 92.8 %

Procedure:
Using 1-(5-hydroxy-1-benzofuran-2-yl)ethanone (1.15 g, 6.53 mmol), DMF (10 mL), tert-butyldimethylchlorosilane (1.07 g, 7.18 mmol) and imidazole (666 mg, 9.80 mmol), an operation in the same manner as in Reference Example 16 was performed to give the title compound (1.76 g, yield 98%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([OH:10])[N:7]2[C:11]([SH:14])=[N:12][N:13]=[C:6]2[N:5]=1)([OH:3])=[O:2].C(O[CH2:19][C:20]1[CH2:27][S:26][C@H:25]2[N:22]([C:23](=[O:41])[C@H:24]2[NH:28][C:29](=[O:40])/[C:30](/[C:34]2[N:35]=[C:36]([NH2:39])[S:37][CH:38]=2)=[N:31]\[O:32][CH3:33])[C:21]=1[C:42]([OH:44])=[O:43])(=O)C.C(=O)(O)[O-].[Na+]>P([O-])([O-])([O-])=O>[NH2:39][C:36]1[S:37][CH:38]=[C:34](/[C:30](=[N:31]/[O:32][CH3:33])/[C:29]([NH:28][C@@H:24]2[C:23](=[O:41])[N:22]3[C@@H:25]2[S:26][CH2:27][C:20]([CH2:19][S:14][C:11]2[N:7]4[C:8]([OH:10])=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[N:5][C:6]4=[N:13][N:12]=2)=[C:21]3[C:42]([OH:44])=[O:43])=[O:40])[N:35]=1
Reactant: O=C(O)c1cc(O)n2c(S)nnc2n1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnc4nc(C(=O)O)cc(O)n34)CS[C@H]12)c1csc(N)n1
Yield: 15.6 %

Procedure:
Starting from the product obtained in Step 2 (6.7 g) and the product obtained in Step 2 of Example 7 (15 g) and using 240 ml of 0.1M phosphate buffer (pH 6.4) and 8.0 g of sodium bicarbonate, 3 g of the objective compound was obtained in a manner similar to Step 4 of Example 37.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22][C:23]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)=O)[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO.C(Cl)Cl>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([C@H:23]2[C:14]3[C:13](=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:16][CH:15]=3)[C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22]2)[CH:26]=[C:27]([O:35][CH3:36])[C:28]=1[O:33][CH3:34]
Reactant: COc1cc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)cc(OC)c1OC
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc(OC)c1OC
Yield: 85 %

Procedure:
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl-pyrrolidin-1-yl}-1-(3,4,5-trimethoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.47 g (85%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C29H40N2O5, 496.3; m/z found, 497.4 [M+H]+. 1H NMR (MeOH-d4): 7.10 (m, 3H), 6.86 (m, 2H), 6.68 (m, 1H), 3.85 (m, 3H), 3.72 (s, 6H), 3.71 (s, 3H), 3.35 (m, 2H), 3.22 (m, 1H), 2.36 (m, 6H), 2.07 (m, 1H), 1.86 (m, 3H), 1.72 (m, 1H), 1.65 (m, 1H), 1.50 (m, 4H), 1.37 (br s, 2H).
Reaction SMILES: OC(C)(C)[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:36]([O-:39])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[OH:9][C:4]([CH3:5])([CH3:3])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:14]3[CH:13]=[CH:11][NH:7][C:36](=[O:39])[CH:15]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 120 °C
Yield: 71 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (2.646 g, 5.52 mmol) in 1,4-dioxane (60 mL) were added 4-iodopyridin-2(1K)-one (1.200 g, 5.43 mmol), 2 M Cs2CO3 (14.5 mL), and PdCl2(dppf)nCH2Cl2 (0.230 g, 0.28 mmol). The mixture was degassed and heated, under a nitrogen atmosphere, at 120° C. for 15 h. The mixture was diluted with CH2Cl2, dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with MeOH/CH2Cl2 to afford 1.717 g (71%) of (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.23 min, m/z 389, 447 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=6.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.29-7.20 (m, 5H), 6.96 (d, J=8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q, J=7.0 Hz, 1H), 2.98-2.93 (m, 1H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1H), 2.07 (s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).