Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])=[CH:5][CH:4]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:19])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[CH3:18])([CH3:21])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Cc1ccc(NCc2ccc(N(C)C)cc2)c(C)c1
Product: Cc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)c(C)c1
Yield: 43.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using [(4-dimethylaminophenyl)methyl](2,4-dimethylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (1.2 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(2,4-dimethylphenyl)urea (0.78 g) was obtained. melting point: 100° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]1[CH2:10][C:11]([OH:14])([CH3:13])[CH3:12]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:15])[C@H:3]([CH2:10][C:11]([OH:14])([CH3:12])[CH3:13])[C@@H:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C1C(CC(C)(C)O)C1(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1[C@@H](CC(C)(C)O)C1(C)C
Reaction time: 0.5 h

Procedure:
A mixture of a solution of the compound of Example 1 in ethyl acetate and 90 mg of 5% palladized carbon were placed in a hydrogenation apparatus and the mixture was stirred under a slight hydrogen pressure for 30 minutes. The mixture was filtered and the filtrate was evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 3-7 ether-hexane mixture to obtain 275 mg of ethyl cis 2,2-dimethyl-3-(2-hydroxy-2-methyl-propyl)-cyclopropane-1-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[C:36]([O:40][C:41](=[O:44])[CH2:42][NH2:43])([CH3:39])([CH3:38])[CH3:37]>>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:27])=[O:28])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][NH:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCC(=O)OC(C)(C)C)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 48.9 %

Procedure:
The product is prepared by following the procedure described in example 52c, starting with 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine and 0.193 g of glycine tert-butyl ester instead of the N-Boc-ethylenediamine used in example 52c. 0.174 g of tert-butyl {[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}-acetate is obtained with the following characteristics:
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[O:5]=[C:6]([CH2:13][CH2:14][CH3:15])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>O.C(O)(=O)C>[OH:3][N:1]=[C:7]([C:6](=[O:5])[CH2:13][CH2:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCC(=O)C(=NO)C(=O)OCC
Temperature: 20 °C
Reaction time: 15.5 h

Procedure:
A solution of sodium nitrite (2.94) in water (7 ml) was added over 1.5 h at 25°-30° C. to a stirred solution of ethyl 3-oxohexanoate (5.0 g) in glacial acetic acid (6 ml). The orange mixture was stirred at 25° C. for 0.5 h before dilution with water (2 ml) and stirring at 20° C. for 15.5 h. The mixture was extracted with ether (2×20 ml) and the combined extracts washed with water (20 ml), 8% sodium bicarbonate (2×20 ml) and saturated sodium chloride solution (20 ml). The yellow solution was then dried and evaporated in vacuo, to afford a mobile yellow oil (4.95 g).
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[C:23]4=[N:24][C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:22]4[N:21]=[C:20]3[CH2:30][CH3:31])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[C:23]4=[N:24][C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:22]4[N:21]=[C:20]3[CH2:30][CH3:31])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2[nH]ccc2c1
Temperature: 60 °C
Yield: 101.1 %

Procedure:
To a suspension of the product of Example 1 (500 mg, 1.225 mmol) in 10 ml of methanol was added 10 ml of 2N NaOH and the mixture heated to 60° C. After 18 hours the methanol was removed in vacuo. The reaction mixture was diluted with 150 mL of H2O and extracted with 3×200 mL of CH2Cl2. The combined extracts were dried over Na2SO4, filtered and concentrated to yield by the titled compound (377 mg, 100%) as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH2:14]Br)[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-:23].[Na+].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH:14]=[O:23])[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc(CBr)cc12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34686.7 %

Procedure:
To a well stirred solution of Methyl-7-cyclopentyloxy-2-bromomethylbenzo[b]furan-4-carboxylate (50.0 g, 0.140 moles) in dimethyl sulfoxide (250.0 mL) was added powdered sodium carbonate (22.0 g, 0.21 mmoles) at 105-110° C. and stirred for 2-3 hours. Reaction mixture was cooled to room temperature and diluted with water (2.0 L) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water (2×500 mL) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product (51 g) as brown viscous oil. Purification by silica gel column using chloroform: ethyl acetate (95:5) as an eluent afforded 21 g of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2[CH2:32][OH:33]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2[CH:32]=[O:33]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(CO)ncnc32)cc1OCc1c(OC)ccc(F)c1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(C=O)ncnc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-hydroxymethyl-7,9-dihydro-8H-purin-8-one (0.1%) in methylene chloride (3 mL) was added manganese(IV) oxide (272 mg), and the mixture was stirred at room temperature for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−1/3) to give the title compound (80 mg).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](OCC)=[O:20]>>[CH3:13][O:12][C:10](=[O:11])[CH:9]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[C:19]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: CCOC(=O)c1ccco1
Reactant: COC(=O)CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C(=O)c1ccco1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.3 %

Procedure:
To an ice cold suspension of 0.92 g (23 mmol) of sodium hydride (NaH 60% dispersion in mineral oil) (previously washed with hexane and dried under vacuum) in 25 mL of 1,2-dimethoxyethane (DME) was added 0.9 g (5.76 mmol) of methyl cyclohexylacetate, and the resulting mixture was stirred at 0° C. for 20 min. Then 1.2 g (8.56 mmol) of ethyl 2-furoate was added, and the reaction mixture was heated at reflux overnight. The mixture was then cooled to 0° C., quenched by the addition of 1 M HCl solution to pH=3, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to give a brown oil which was chromatographed on silica gel (Biotage; 10% hexane in dichloromethane) to afford 1.1 g (76% yield) of desired 2-cyclohexyl-3-furan-2-yl-3-oxo-propionic acid methyl ester as indicated by 1H NMR.
Reaction SMILES: CO[CH:3](OC)[CH2:4][Br:5].Br.O.[Br:10][C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15](Br)[N:16]=1>CN(C=O)C>[Br:5][C:4]1[N:16]=[C:11]([Br:10])[C:12]2[N:18]([CH:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: COC(CBr)OC
Reactant: Nc1ncc(Br)nc1Br
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cn2ccnc2c(Br)n1
Reaction time: 12 h
Yield: 81.3 %

Procedure:
A mixture of 5.0 g (30 mmol) of bromoacetaldehyde dimethyl acetal 1.0 ml of concentrated aqueous HBr solution and 4.0 ml of distilled water was brought to reflux for 1 h. After reaction, the mixture was alkalinized and extracted with ether. This organic phase was added to a solution of 1.0 g (4.0 mmol) of 3,5-dibromopyrazin-2-amine in 2 ml of DMF. The ether was removed and the mixture was stirred under a stream of nitrogen for 12 h. After reaction, the DMF was removed and the residue was dissolved in 5 ml of anhydrous ethanol and then it was brought to reflux for 1 h. The alcohol was then removed and the residue was dissolved in water, alkalinized with Na2CO3 and extracted with dichloromethane. After chromatography with alumina column (eluted with ether), 900 mg (yield: 82%) of 6,8-dibromoimidazo[1,2-a]pyrazine was obtained. ESI-MS (M+H+): 278.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=[C:8]([C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)[CH:9]=[CH:10][C:11]=1[C:12]2=[C:17]1[CH2:23][CH:22]2[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:19]([CH2:20][CH2:21]2)[CH2:18]1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=[C:8]([C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)[CH:9]=[CH:10][C:11]=1[C:12]2=[C:17]1[CH2:23][CH:22]2[N:24]([C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH:19]([CH2:20][CH2:21]2)[CH2:18]1
Reactant: COc1cccc2c1Oc1cc(-c3noc(=O)[nH]3)ccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N1C2CCC1CC(=C1c3ccc(-c4noc(=O)[nH]4)cc3Oc3c(O)cccc31)C2)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Compound 21h (0.355 g, 1.19 mmol) in CH2Cl2 (30 mL) was added dropwise BBr3 (1.0M in CH2Cl2, 5.97 mL, 5.97 mmol) at 0° C. The mixture was stirred at rt for 24 h, and quenched with a saturated NaHCO3 solution (20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was used in the next reaction without further purification. MS m/z (MH+) 485.8.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[CH:7][CH:8]=2)[N:3]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH-].[Na+].[N+:26]([O-])([OH:28])=[O:27]>>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[C:7]([N+:26]([O-:28])=[O:27])[CH:8]=2)[N:3]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(-n3ccnc3)cc21
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc21
Temperature: 25 °C
Yield: 26 %

Procedure:
At the temperature of 0C or less, 3.63 g of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate was dissolved in 15 ml of fuming nitric acid under stirring. The resulting solution was heated to room temperature, stirred for one hour, and poured into ice water, followed by adjustment to about pH 2.0 with an aqueous solution of sodium hydroxide. The resulting insoluble matter was removed by filtration. To the filtrate, an aqueous solution of sodium hydroxide was added to adjust the pH of the resulting liquid to about pH 6.5. The resulting insoluble matter was collected by filtration, washed with water and dried under reduced pressure to give 1.07 g (26%, purity: about 95% (HPLC)) of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[CH3:32][O:33][C:34](=[O:44])[CH:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)O>>[CH3:32][O:33][C:34](=[O:44])[CH:35]([O:8][C:7]1[C:6]([Br:9])=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:14][CH:15]=2)=[CH:3][C:2]=1[Br:1])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2cc(Br)c(O)c(Br)c2)cc1
Reactant: COC(=O)C(O)Cc1ccccc1
Product: COC(=O)C(Cc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3nc(-c4ccc(C(F)(F)F)cc4)oc3C)cc2)cc1Br

Procedure:
The title compound was prepared from 3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol, and 3-phenyllactic acid methyl ester in substantially the same manner, as described in Example 7, and was obtained as a white solid, mp 70-72° C.; MS m/e 713 (M+);
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:21][OH:22])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (9.37 mg, 0.234 mmol), (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (44.9 mg, 0.156 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidaz-o[1,2-c]pyrimidin-5(1H)-one (29 mg, 0.156 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][OH:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31].O>C(Cl)Cl>[C:30]([O:16][CH2:15][C:13]1[N:14]=[C:7]2[C:6]([NH:5][CH2:4][C:3]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:2]=3[CH3:1])=[CH:11][CH:10]=[CH:9][N:8]2[C:12]=1[CH3:17])(=[O:32])[CH3:31]
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1nc2c(NCc3c(C)cccc3C)cccn2c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.4 %

Procedure:
To a solution of 8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (0.3 g, 1.0 mmol) and triethylamine (0.014 ml, 1.0 mmol) in methylene chloride (10 ml) was added dropwise acetyl chloride (0.071 ml, 1.0 mmol). The reaction mixture was stirred for 1.5 h. at room temperature. Water was added and the organic layer was separated, washed with sodium bicarbonate solution, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using diethyl ether as eluent. Recrystallization from diethyl ether gave 0.16 g (47%) of the desired product.
Reaction SMILES: C([O:4][C@@H:5]([C@@H:12]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH3:15])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7])(=O)C.[OH-].[Na+]>CO.O>[CH:9]1([NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[C@@H:12]([N:16]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11]1
Reactant: CCC[C@@H]([C@H](OC(C)=O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC[C@@H]([C@H](O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 2.5 °C
Reaction time: 17 h
Yield: 74.1 %

Procedure:
(2S,3S)-1-(cyclopropylamino)-3-(dibenzylamino)-1-oxohexan-2-yl acetate (17 g) was dissolved in methanol (120 mL) at room temperature and the resulting solution cooled to 0-5° C. To this solution was added a previously prepared 1.1-M solution of sodium hydroxide by dissolving solid NaOH (2.49 g) in water (55 mL), which was then added to the reaction mixture at 0-5° C. The reaction was warmed to room temperature (25-30° C.) and stirred at this temperature for 16-18 hours. The reaction mixture was monitored by TLC for the disappearance of starting material. Once TLC indicated that the reaction was complete, the solvent was removed by distillation under reduced pressure, keeping the temperature below 45° C. Ethyl acetate (2.5 L) was added and the resulting solution was stirred for 20-30 minutes. The organic layer was washed with water (500 mL), followed by an aqueous solution of sodium chloride (brine; 300 mL). The organic layer was dried (sodium sulfate), filtered and the filtrate was concentrated under reduced pressure, keeping the temperature below 40° C. n-Hexane (100 mL) was added, and the slurry was stirred for one hour at 25-30° C. The resulting solid was filtered off, then dried under reduced pressure to provide (2S,3S)—N-cyclopropyl-3-(dibenzylamino)-2-hydroxyhexanamide (11.3 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[F:11])=[O:3].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:11][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-n2cncn2)cc1F

Procedure:
A solution of 2,4-difluoroacetophenone (2.43 mL), 1,2,4-triazole (1.59 g) and potassium carbonate (5.32 g) in toluene (10 mL) was stirred at 100° C. overnight. The reaction solution was returned to room temperature, and then water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 187 mg of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C1COCC1>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:12]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:9]=1)(=[O:14])=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccc(Br)cc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc2ccc(Br)cc2c1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A mixture of 207 (1.50 g, 4.92 mmol), dibenzylamine (1.45 g, 7.38 mmol), and Et3N (0.75 g, 7.38 mmol) in THF (15 mL) was stirred at room temperature for 48 h. The solvents were evaporated under reduced pressure and the residue was extracted with EtOAc. The EtOAc extracts were washed with water and brine, then dried and evaporated. The residue was purified by chromatography on silica gel eluting with petroleum ether/EtOAc (95:5 then 1:1) to give N,N-dibenzyl-7-bromo-2-naphthalenesulfonamide (208) (2.11 g, 92%). A sample was recrystallised from petroleum ether/EtOAc as colorless crystals: mp 127-129° C.; 1H NMR (CDCl3) δ 8.25 (d, J=1.4 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.79 (dd, J1=8.6, 1.8 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.71 (dd, J=8.8, 1.9 Hz, 1H), 7.22-7.15 (m, 6H), 7.09-7.04 (m, 4H), 4.39 (s, 4H); 13C NMR δ 138.9, 135.4, 133.3, 133.0, 132.1, 131.2, 129.4, 129.3, 128.6, 128.5, 127.8, 127.3, 123.0, 121.6, 50.6. Anal. (C24H20BrNO2S. 1/10Bn2NH) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[I:9](O)(=O)(=O)=O.II.S(=O)(=O)(O)O.S(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:9])=[C:4]([CH3:8])[N:3]=1
Reactant: Cc1cccc(N)n1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N)ccc1I
Temperature: 25 °C
Yield: 161.1 %

Procedure:
A mixture of 2-amino-6-picoline (5.40 g), periodic acid (2.28 g), and iodine (5.00 g) is heated in a solution of acetic acid (30 mL), water (6 mL), and sulfuric acid (0.9 mL) at 80° C. for 3 h. The reaction is cooled to room temperature and poured into 100 mL 10% aqueous sodium bisulfite. The aqueous solution is extracted with diethyl ether (3×100 mL). The combined organics are washed with 10% NaOH, then dried over Na2SO4, filtered, and concentrated. Purification by chromatography (eluent EtOAc) affords a yellow liquid. The liquid is further dried on the vacuum pump where it crystallizes to afford 2-amino-5-iodo-6-picoline (4.48 g, 38%). Physical characteristics are as follows: 1H NMR (300 MHz, DMSO-d6) δ 7.60, 6.09, 6.05, 2.38.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].[C:11]([C:15]1[CH:19]=[C:18]([NH2:20])[NH:17][N:16]=1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[NH2:20][C:18]1[N:17]([C:2]2[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:10])[CH:9]=2)[N:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:19]=1
Reactant: OCc1cc(F)cc(Br)c1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1cc(N)n(-c2cc(F)cc(CO)c2)n1
Temperature: 150 °C
Yield: 23.9 %

Procedure:
Degassed toluene (sparged with argon for 25 mins, 10.0 mL) was added to a mixture of 3-bromo-5-fluorobenzylalcohol (1.00 g, 4.88 mmol), 3-tert-butyl-1H-pyrazole-5-amine (678 mg, 4.88 mmol), copper (I) iodide (46.0 mg, 0.24 mmol) and potassium carbonate (1.41 g, 10.2 mmol). Trans-N,N′-dimethylcyclohexanediamine (154 μL, 0.98 mmol) was added and the reaction heated to 150° C. for 18 h using microwave irradiation. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound (307 mg, 24%). LCMS (Method 4): Rt 2.34 min, m/z 264 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.[Br:14][CH2:15][C:16](Cl)=[O:17]>C(N(CC)CC)C>[Br:14][CH2:15][C:16]([N:9]1[CH2:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)=[O:17]
Reactant: O=C(Cl)CBr
Reactant: COc1ccc2c(c1)CNCCS2
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C(=O)CBr)CCS2
Yield: 51.5 %

Procedure:
7-Methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.0 g), triethylamine (3.1 g) and bromoacetyl chloride (3.2 g) were reacted in the same manner as in Experimental Example 1 to give 4-bromoacetyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.5 g).