Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][C@H:15]([CH3:19])[C:16](O)=[O:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[C@H:15]([O:14][CH3:13])[CH3:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CO[C@H](C)C(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.5 g, 2.17 mmol; Example 1, Step H), (R)-2-methoxypropanoic acid (0.475 g, 4.56 mmol), BOP-Cl (1.16 g, 4.56 mmol), and triethylamine (1.51 mL, 10.9 mmol) were placed in DCM (5 mL) and stirred at room temperature for 1 hour. 3M aqueous LiOH (3 mL) was then added. The reaction was stirred for 10 minutes, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (500:15 DCM:MeOH) to give (R)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:30]=[CH:29][C:14]([O:15]C2C=C(N3CC4CC3CN4)C=NC=2)=[CH:13][CH:12]=1.COC1C=CC([O-])=CC=1.[Na+]>CN(C)C=O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:15][C:14]2[CH:29]=[CH:30][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COc1ccc(Oc2cncc(N3CC4CC3CN4)c2)cc1
Reactant: Brc1cncc(Br)c1
Agent: COc1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cncc(Br)c2)cc1

Procedure:
In an alternative approach to the synthesis of pyridine-substituted pyridyl diazabicyclic compounds, 3,5-dibromopyridine can be converted into the corresponding 3-bromo-5-alkoxy- and 3-bromo-5-arylopyridines by the action of sodium alkoxides or sodium aryloxides. Procedures such as those described by Comins et al., J. Org. Chem. 55: 69 (1990) and Hertog et al., Recueil Trav. Chim. Pays-Bas 74: 1171 (1955) are used. This is exemplified by the preparation 2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane. Reaction of 3,5-dibromopyridine with sodium 4-methoxyphenoxide in N,N-dimethylformamide gives 3-bromo-5-(4-methoxyphenoxy) pyridine. Coupling of 3-bromo-5-(4-methoxyphenoxy) pyridine with (1S,4S)-N-(tert-butoxycarbonyl)-2,5-diazbicyclo[2.2.1]heptane in the presence of sodium tert-butoxide and a catalytic amount of tris (dibenzylideneacetone)dipalladium(0) and 2,2′-bis (diphenylphosphino)-1,1′-binaphthyl in toluene provides (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane. Removal of the N-tert-butoxycarbonyl group, using trifluoroacetic acid, produces (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>ClCCl>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]([N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1)=[O:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To a stirred solution of 1-(6-nitro-pyridin-3-yl)-piperazine (3.00 g, 14.4 mmol) in dichloromethane (30 mL) was added triethylamine (2.91 g, 28.8 mmol) followed by the dropwise addition of pivaloyl chloride (1.90 g, 15.9 mmol) at r.t. and the resulting solution was stirred for 15 min. The reaction was quenched with sat. sodium bicarbonate solution and extracted with dichloromethane (×3). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was washed with petroleum ether to afford 2,2-dimethyl-1-[4-(6-nitro-pyridin-3-yl)-piperazin-1-yl]-propan-1-one (2.50 g, 59%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](SC)[N:9]=2)=[CH:4][CH:3]=1.O[O:17][S:18]([O-:20])=O.[K+].[CH3:22]C(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:18]([CH3:22])(=[O:20])=[O:17])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CC(C)=O
Reactant: CSc1nccc(-c2ccc(Cl)cc2)n1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nccc(-c2ccc(Cl)cc2)n1
Reaction time: 18 h

Procedure:
To a solution of 4-(4-chlorophenyl)-2-methylthiopyrimidine (1.1 g, 4.65 mmol) in acetone (30 ml) and water (10 ml) was added oxone (7.14 g, 11.62 mmol). The reaction mixture was stirred for 18 hours then diluted with water and extracted into dichloromethane. The extracts were dried over magnesium sulfate, filtered and concentrated to provide a white solid: EI-MS (m/z) 269 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[S:44]1[CH:48]=[CH:47][N:46]=[C:45]1[C@H:49]([NH2:51])[CH3:50]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36]([NH:51][C@@H:49]([C:45]2[S:44][CH:48]=[CH:47][N:46]=2)[CH3:50])=[O:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: C[C@@H](N)c1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)N[C@H](C)c4nccs4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (30 mg, yield 68%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[S:10])[CH:3]=1.[NH2:11][C:12]1[S:16][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[S:10])[NH:11][C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:14][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nnc(S(N)(=O)=O)s1
Reactant: S=C=Nc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NS(=O)(=O)c1nnc(NC(=S)Nc2cccc(I)c2)s1
Temperature: 75 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a solution of 1-iodo-3-isothiocyanatobenzene (0.13 g, 0.50 mmol) in acetonitrile (10 mL) was added 5-amino-1,3,4-thiadiazole-2-sulfonamide (0.108 g, 0.50 mmol) and anhydrous K2CO3 (0.40 g). The mixture was stirred at 75° C. for 4 hrs. Solvent was evaporated and diluted with water. The precipitated solid was filtered and dried over vacuum to give desired compound (99 mg, 45%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.99 (brs, 1H), 8.24 (brs, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.69 (t, J=1.8 Hz, 1H), 7.35 (m, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.02 (s, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl.NO.C([N:17](CC)CC)C.CCCP(=O)=O>CN(C)C=O.O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]#[N:17])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccnc(C2CC2)n1
Reactant: CCN(CC)CC
Agent: CCCP(=O)=O
Agent: Cl
Agent: NO
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccnc(C2CC2)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 2-cyclopropylpyrimidine-4-carbaldehyde (1.0 g, 6.68 mmol) in N,N-dimethylformamide (10 mL) were added hydroxylamine hydrochloride (500 mg, 7.02 mmol) and triethylamine (1.2 mL). The reaction mixture was heated to 50° C. and propylphosphonic anhydride (T3P) was added dropwise. After 16 h at 110° C., the mixture was cooled to room temperature, diluted with water and quenched with solid sodium bicarbonate. The mixture was extracted with ethyl acetate, then the organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified via silica gel chromatography to afford 2-cyclopropylpyrimidine-4-carbonitrile (600 mg, 62%) as a pale yellow liquid. MS (ES+APCI) (M+H) 145.9; LMCS retention time 2.224 min (Method G).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(OO)(=[O:25])C>CC(O)=O.O>[CH3:1][N:2]1[C@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:15]=[CH:16][C@:17]2([OH:25])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: CC(=O)OO
Solvent: O
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 200 mL flask, dried oripavine (10.00 g, 95% wt/wt %) was dissolved in HOAc/H2O (1:4, 100 mL) and cooled to 5° C. to 10° C. Peroxyacetic acid, CH3CO3H, (9.1 mL, 32% wt/wt %) was added over 3 minutes and the reaction mixture was stirred at 5° C. to 10° C. for 30 minutes. HPLC data showed that the reaction was completed. The reaction mixture was allowed to warm to 25° C. for 30 minutes. H2C2O4 (3.0 g) was added to the reaction mixture, and was stirred at room temperature for 30 minutes and then heated to 50° C. for 30 minutes. The solution was assayed by HPLC and >99% conversion was observed.
Reaction SMILES: BrC1C=[C:4]([CH2:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)(O)[C:10](F)(F)F)[CH:5]=[CH:6]C=1.[OH:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[N:33][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:42][C:43](N(C)C)=[O:44]>>[CH3:35][C:32]1[CH:31]=[CH:30][C:29]([O:28][C:4]2[CH:8]=[C:9]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:25])([F:26])[F:27])[CH:18]=3)[CH2:42][CH:43]([OH:44])[C:24]([F:27])([F:26])[F:25])[CH:10]=[CH:6][CH:5]=2)=[CH:34][N:33]=1
Reactant: OC(Cc1cccc(Br)c1)(NCc1cccc(OC(F)(F)F)c1)C(F)(F)F
Reactant: Cc1ccc(O)cn1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccc(Oc2cccc(N(Cc3cccc(OC(F)(F)F)c3)CC(O)C(F)(F)F)c2)cn1
Temperature: 105 °C
Yield: 61 %

Procedure:
The 3-[(3-bromophenyl)([[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (500 mg, 1.1 mmol) product from EX-633B and 5-hydroxy-2-methylpyridine (262 mg, 2.4 mmol) were dissolved in dimethylacetamide (6 mL). Cs2CO3 (1.0 g, 3.1 mmol) and (CuCF3SO3)2C6H6 (150 mg) were added, and the mixture was heated to 105° C. for 96 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that most of the starting materials had been consumed. After adding a water, the reaction mixture was extracted with ether, and the ether extracts were washed with brine and dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:12) to give 326 mg (61%) of the desired 3-[[3-(2-methyl-5-pyridyloxy)phenyl][[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 99% pure by HPLC analysis. 1H NMR (CDCl3) δ8.00 (s, 1H), 7.29 (t 1H), 6.99 (s, 1H), 7.02-7.15 (m, 5H), 6.46 (dd, 1H), 6.29 (t, 1H), 6.25 (dd, 1H), 4.88 (br s, 1H), 4.67 (ABq, 2H), 4.36 (m, 1H), 3.88 (dd, 1H), 3.56(dd, 1H), 2.49 (s, 3H). 19F NMR (CDCl3) δ−58.2, (s, 3F), −79.1 (d, 3F). HRMS calcd. for C23H20N2O3F6: 487.1456 [M+H]+, found: 487.1425.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]=1[O:18][CH3:19].[C-:20]#[N:21].[K+].O>CN(C=O)C.[Cl-].[Na+].O>[F:9][C:7]1[CH:6]=[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]([O:18][CH3:19])=[C:3]([CH2:2][C:20]#[N:21])[CH:8]=1
Reactant: [C-]#N
Reactant: COc1c(CCl)cc(F)cc1OCc1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(CC#N)cc(F)cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To a solution of 1-(chloromethyl)-5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]benzene (6.82 g, 24.3 mmol) in DMF (60 mL) was added potassium cyanide (3.2 g, 48.6 mmol), and the resulting mixture was stirred at 50° C. for 2 h 20 min before cooling to rt. Water and brine were added, and the resulting aqueous mixture was extracted with ethyl acetate. The organic phase was washed twice with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (80% hexanes, 20% ethyl acetate) to afford {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}acetonitrile (5.3 g, 19.5 mmol, 80% yield) as a colorless oil which eventually solidified. 1H NMR (400 MHz, CDCl3): δ 7.42-7.32 (m, 5H), 6.69-6.67 (m, 2H), 5.08 (s, 2H), 3.89 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1.O>CS(C)=O>[C:1]([CH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1)#[N:2]
Reactant: COc1cc(OC)nc(CCl)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)nc(CC#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
16.7 g of dried sodium cyanide was dissolved in 850 ml of dimethyl sulfoxide at 90° C. under N2 protective gas. At this temperature, 52.8 g of 2-chloromethyl-4,6-dimethoxypyrimidine, dissolved in 280 ml of dimethyl sulfoxide, are added dropwise over the course of 2 hours. Stirring is continued for 1 hour at 90° C., and the mixture is cooled to room temperature and poured into 300 ml of water. The aqueous phase is extracted seven times using ether, and the combined organic phases are washed using saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in a rotary evaporator. This gives 29.1 g of crude product, from which 2-cyanomethyl-4,6-dimethoxypyrimidines of melting point 65°-67° C. are obtained after column chromatography (SiO2 ; CH2Cl2 /CH3OH; 98.5/1.5).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][O:7][CH:8]([O:11][CH3:12])[CH2:9]Br.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[C:1]([O:4][CH2:9][CH:8]([O:11][CH3:12])[O:7][CH3:6])(=[O:3])[CH3:2]
Reactant: COC(CBr)OC
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(COC(C)=O)OC
Temperature: 134 °C
Reaction time: 16 h

Procedure:
A mixture of sodium acetate (1.0 g, 12.19 mmol), bromoacetaldehyde dimethyl acetal (1.43 mL, 12.19 mmol), and tetrabutylammoniumbromide (1.96 g, 6.09 mmol) in 8 mL of anhydrous CH3CN was stirred at 134° C. for 16 h in a sealed tube. It was cooled to room temperature, water was added and the mixture extracted with Et2O (3×100 mL). The combined organic phases were washed with saturated NaCl (1×75 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 40-60% ethyl acetate/hexanes to give the product 43b (product is volatile, some of the product is lost during the evaporation of solvents). 1H NMR (400 MHz, CDCl3) δ 2.03 (s, 3H), 3.36 (s, 6H), 4.08 (d, J=5.3 Hz, 2H), 4.54 (t, J=5.3 Hz, 1H).
Reaction SMILES: [H+].[H+].Cl[Pt-2:4](Cl)(Cl)(Cl)(Cl)Cl.[C:10](=O)(O)[O-].[Na+].[CH:15]([Si:17]([CH3:25])([CH3:24])[O:18][Si:19]([CH3:23])([CH3:22])[CH:20]=[CH2:21])=C.[Pt]>C(O)(C)C>[Pt:4].[CH:22]([Si:19]([CH:20]=[CH2:21])([CH3:23])[O:18][Si:17]([CH3:25])([CH3:24])[CH3:15])=[CH2:10]
Reactant: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Reactant: O=C([O-])O
Agent: [Pt]
Agent: [H+]
Agent: [Na+]
Solvent: CC(C)O
Product: C=C[Si](C)(C=C)O[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
3.0 kg chloroplatinic acid crystals (40% platinum content) and 15.0 kg isopropanol were placed in a 50-L reactor, and 6.0 kg sodium bicarbonate and 6.0 kg 1,3-divinyltetramethyldisiloxane were then added while stirring. The resulting suspension was heated while stirring. After reacting for 30 minutes at 65 to 75° C., the reaction mass was cooled and the solids were filtered off to give 22.0 kg of an isopropanol solution of platinum-divinyltetramethyldisiloxane complex catalyst. The platinum content was 4.1% as measured by x-ray fluorescence analysis, and the 1,3-divinyltetramethyldisiloxane content as measured by gas chromatography was 9.4%.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[N:15]([CH3:20])[C:16](=[O:19])[CH:17]=[CH:18][C:13]=2[CH:12]=[N:11]1>C(O)(=O)C.O>[Br:1][C:17]1[C:16](=[O:19])[N:15]([CH3:20])[C:14]2[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:11]=[CH:12][C:13]=2[CH:18]=1
Reactant: Cn1c(=O)ccc2cnn(-c3ccccc3Cl)c21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)c(Br)cc2cnn(-c3ccccc3Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
At RT, bromine (206 mg, 1.29 mmol) was added to a solution of 1(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (319 mg, 1.23 mmol) in 1.5 mL of glacial acetic acid. After stirring at RT for 30 min, it was diluted with water and stirred for 5 min. The precipitated white solid was filtered off and rinsed with water, collected and dried to afford 5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (323 mg). The filtrate was extracted three times with EtOAc. The combined EtOAc layers were washed with 2 N NaOH followed by brine, dried and concentrated to afford additional 5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (82 mg). The crude material was used without further purification. MS (ESI, pos.ion) m/z: 338.0/340.0 (M+1).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[CH2:6]([O:8][C:9](=[O:12])[CH2:10][NH2:11])[CH3:7].C(N(CC)CC)C.[CH3:20][OH:21]>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9](=[O:12])[CH2:10][NH:11][C:20]([O:2][CH3:1])=[O:21])[CH3:7]
Reactant: CCOC(=O)CN
Reactant: CO
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CNC(=O)OC
Reaction time: 2 h

Procedure:
To a solution of phosgene (70.4 g, 0.71 mole) in dry toluene (300 ml), a mixture of glycine ethyl ester hydrochloride (99.1 g, 0.71 mole) and triethylamine (158 g, 1.56 mole) was slowly added at 0° C. The reaction was exothermic. After 2 hrs. of stirring, anhydrous methanol was added to the reaction mixture and stirring was continued for another 0.5 hrs. The reaction mixture was partitioned between water and chloroform, then the pH of the solution was adjusted to 4 with concentrated HCl. The chloroform layer was dried and the solvent was evaporated to obtain the N-carbomethoxy glycine ethyl ester with the structure being confirmed by spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.Cl.[CH3:30][NH:31][CH2:32][CH2:33]N>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[N:31]([CH3:30])[CH2:32][CH2:33][N:28]=3)=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CNCCN
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc(C3=NCCN3C)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a lotion of the compound of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}(4-cyanophenyl)carboxamide (830 mg, 2.1 mmol) in anhydrous methanol (5 ml) and ethyl acetate (10 ml) was saturated with hydrogen chloride gas at 0° C. The mixture was stirred at r.t. overnight. After the evaporated the solvent, the residue was dissolved in anhydrous methanol (5 ml) and N-methylethylenediamine (0.926 ml, 10.5 mmol) was added. The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white powder. MS found for C24H22ClN5O2 M+=448, (M+2)+=450.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[C:3]=1[C:16]#[N:17].[OH:18]S(O)(=O)=O>>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[C:3]=1[C:16]([NH2:17])=[O:18]
Reactant: N#Cc1c(-c2cccc([N+](=O)[O-])c2)nsc1N
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(-c2cccc([N+](=O)[O-])c2)nsc1N
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of 5-amino-3-(3-nitrophenyl)isothiazole-4-carbonitrile (500 mg, 2.03 mmol) in 5 mL conc. H2SO4 was heated at 65° C. After 4 hours the mixture was slowly added to 75 mL ice water (including an additional reaction run on 0.50 mmol scale in 1.5 mL conc. H2SO4). The mixture was stirred for 10 min, and then the precipitate filtered and rinsed with water and 10% EtOAc/hexane to give the title compound as a light beige solid (572 mg, 86% combined yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C=C(CCCCc1ccccc1)c1ccc(OC)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CCCCc1ccccc1)c1ccc(OC)c(OC)c1
Yield: 73.6 %

Procedure:
A solution of ethyl 3-(3,4-dimethoxyphenyl)-7-phenyl-2-heptenoate (0.4 g, 1.1 mmol) in ethanol (20 mL) containing 10% Pd/C (few mg) is stirred under a balloon of hydrogen for 4 hours at room temperature. The catalyst is filtered and the solvent is removed in vacuo to produce ethyl 3-(3,4-dimethoxyphenyl)-7-phenylheptanoate (0.3 g, 73%) as an oil. 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.11-1.20 (t, 3H), 1.20-1.65 (m, 6H), 2.45-2.59 (m, 4H), 2.92-3.10 (m, 1H), 3.82 (s, 6H), 4.00-4.08 (q, 2H), 6.62-6.82 (m, 3H), 7.02-7.28 (m, 5H); MS (EI) m/e 370 (M+).
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1.[CH3:14]I>C(Cl)Cl>[CH3:14][O:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1
Reactant: COC(=O)c1coc(CO)n1
Reactant: CI
Agent: N#N
Solvent: ClCCl
Product: COCc1nc(C(=O)OC)co1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methyl 2-(hydroxymethyl)oxazole-4-carboxylate (231 mg, 1.47 mmol) in CH2Cl2 (0.9 mL) was treated with MeI (0.11 mL, 1.76 mmol) followed by Ag2O (511 mg, 2.21 mmol) and the resulting mixture (protected from light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a colorless oil: TLC: rf (1:1 hept-EA)=0.33. LC-MS-conditions 07: tR=0.49 min, [M+H]+=172.20.