Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10]C)=[O:9])=[C:4]([NH:14][C:15](OCC)=O)[CH:3]=1.BrC[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=1)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:15]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=3)=[O:23])[NH:14]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)OC
Reactant: Cc1ccc(C(=O)CBr)nc1
Product: Cc1ccc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)nc1

Procedure:
Two diastreomers of the title compound were prepared according the procedure described in step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and 2-bromoacetyl-5-methylpyridine.*
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:24]=1>CCCCCC>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[CH2:12][CH2:11]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(C(=CC2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=C(O)CCCc1cccnc1
Solvent: CCCCCC
Product: O=C(CCCc1cccnc1)N1CCC(C=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 64.8 %

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of example 10 starting with 9.0 g of 4-[2,2-bis(4-fluorophenyl)ethenyl]piperidine, 0.15 molar hexane solvate and the acid chloride prepared from 6.6 g of 3-pyridine butanoic acid. The toluene extracts were evaporated and the residue was crystallized from ether to give 8.7 g (65%) of pure 4-[2,2-bis[4-fluorophenyl)ethenyl]1-[1-oxo-4-(3-pyridinyl)butyl]piperidine, mp 100°-102° C. Analysis Calculated for C28H28F2N2O: C, 75.31; H, 6.32; N, 6.27; F, 8.51. Found: C, 75.36; H, 6.30; N, 6.24; F, 8.30.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Na].[CH2:13]([O:15][C:16](=[O:25])[C:17]([C:22](=O)[CH3:23])=[CH:18]N(C)C)[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[C:22]([CH3:23])=[N:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([F:2])=[CH:4][CH:5]=2)=[N:9][CH:18]=1)=[O:25])[CH3:14]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: N=C(N)c1ccc(F)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccc(F)cc2)nc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
4-Fluorobenzamidine hydrochloride (1.25 g, 7.16 mmol) is added to a solution of sodium metal (0.17 g, 7.39 mmol) in dry ethanol (25 mL) and stirred at room temperature for 20 min. Ethyl-2-acetyl-3-(dimethylamino)acrylate (1.35 g, 7.16 mmol) is added. The mixture is heated to reflux for 3 hours. The solvent is removed in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford ethyl-2-(4-fluorophenyl)-4-methyl-pyrimidine-5-carboxylate (1.65 g, 87%) as a solid. MS: 261 (M+H) 261.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
Part A: To a cooled (ice bath) solution of 2,4-dichlorobenzoyl chloride (5 mL, 35.66 mmol) in 50 mL CH2Cl2 was added phenol (3.13 mL, 35.66 mmol), followed by triethylamine (4.97 mL, 35.66 mmol). The resulting reaction mixture was stirred at room temperature for 5 h. The mixture was then partitioned between CH2Cl2 and water. The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo to yield 9.5 g of phenyl 2,4-dichlorobenzoate. MS (NH3-CI) 284 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][CH2:12][CH2:13][C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:21][CH:22]=[CH2:23])[CH2:15][C:16]([O:18]CC)=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:21]([C:14]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:13][CH2:12][N:11]([C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH3:10])[C:16](=[O:18])[CH2:15]1)[CH:22]=[CH2:23]
Reactant: C=CCC(CCN[C@@H](CC)c1ccc(Br)cc1)(CC(=O)OCC)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCC1(c2ccccc2)CCN([C@@H](CC)c2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of ethyl 3-(2-((S)-1-(4-bromophenyl)propylamino)ethyl)-3-phenylhex-5-enoate (0.5028 g, 1.10 mmol) and DBU (1.30 g, 8.54 mmol) in toluene (10 mL) was heated to reflux under nitrogen for 2 d. The reaction mixture was cooled to rt, quenched with 2 N aq HCl, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.3045 g (67%) of 4-allyl-1-((S)-1-(4-bromophenyl)propyl)-4-phenylpiperidin-2-one. LC-MS Method 3 tR=2.18, 2.22 min, m/z 412, 414 (MH+).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10](C)(C)[O:11]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].CO.[CH3:17][Si:18]([O:28][CH3:29])([O:26][CH3:27])[O:19][Si:20]([CH3:25])(OC)[O:21][CH3:22]>C(O)(=O)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][SiH2:10][O:11][Si:20]([CH3:25])([O:21][CH3:22])[O:19][Si:18]([CH3:17])([O:28][CH3:29])[O:26][CH3:27])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CO[Si](C)(OC)O[Si](C)(OC)OC
Reactant: C=C(C)C(=O)OCCC[Si](C)(C)OC
Solvent: CC(=O)O
Solvent: CO
Product: C=C(C)C(=O)OCCC[SiH2]O[Si](C)(OC)O[Si](C)(OC)OC
Reaction time: 1 h
Yield: 82 %

Procedure:
A flask was charged with 216 g of γ-methacryloxypropyldimethylmethoxysilane and 500 g of methanol. Under a nitrogen stream, the flask was cooled to 5° C., to which 18.0 g of 0.2N acetic acid was added dropwise over 15 minutes while the liquid temperature was maintained below 10° C. After the completion of dropwise addition, stirring continued for one hour at room temperature. Then, 2260 g of 1,3-dimethyl-1,1,3,3-tetramethoxydisiloxane was added. Stirring continued for 2 hours at room temperature and for a further 8 hours at 60° C. The methanol and volatile matter were removed from the reaction solution by heating in vacuum, obtaining 1-(γ-methacryloxypropyl)-3,5-dimethyl-3,5,5-trimethoxytrisiloxane (M-2) in a yield of 82%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[F:15][C:16]([F:18])([F:17])[CH:7]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[OH:8]
Reactant: Cn1cncc1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)C(F)(F)F
Yield: 73.1 %

Procedure:
According to Reference Example 8-2, by use of 1-methyl-1H-imidazole-5-carbaldehyde (300 mg, 2.72 mmol) dissolved in N,N-dimethylformamide (4.5 mL), potassium carbonate (75 mg, 0.54 mmol) and (trifluoromethyl)trimethylsilane (0.442 mL, 2.99 mmol), the mixture was stirred and reacted at room temperature for 3 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=10/1) was performed to give 2,2,2-trifluoro-1-(1-methyl-1H-imidazol-5-yl)ethanol (Compound DK) (358 mg, yield: 73%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:3].[Na].[OH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>O1CCCC1>[O:13]=[C:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:4]([C:2]([O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:3])=[CH:5][C:6]1=2
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: O=C(O)CCO
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(O)CCOC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1.0 gm of 2-chlorocarbonyl-6,11-dihydro-11-oxodibenz[b,e]oxepin in 20 cc of tetrahydrofuran and add 1.0 gm of the sodium salt of β-hydroxypropionic acid. Stir the mixture at room temperature for 18 hours. Filter and evaporate the filtrate to dryness. Recrystallize the solid residue from ethanol to obtain the title product.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10](C3C=NC=C(C(F)(F)F)C=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([Cl:54])[CH:49]=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([Cl:54])[CH:49]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(Cl)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-chloropyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=467, obsd.=467).
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:10]1([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]4([CH3:29])[CH2:28][O:27]4)[C:20]=3[CH:30]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:28][C:26]2([CH3:29])[O:27][C:22](=[O:24])[N:21]([C:20]3[CH:30]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:17]=[CH:18][C:19]=3[OH:23])[CH2:25]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(Cn2c(=O)oc3ccc(-c4ccccc4)cc32)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CN(c2cc(-c3ccccc3)ccc2O)C(=O)O1
Yield: 48.3 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (1.3 g, 8.78 mmol), 5-phenyl-3-(2-methyloxiran-2-yl-methyl)-3H-benzoxazol-2-one (2.47 g, 8.78 mmol), sodium acetate (792 mg, 9.66 mmol) and ethanol (30 ml) was stirred under reflux for 10 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) to afford 5-(2-chloro-4-nitroimidazol-1-ylmethyl)-3-(4-hydroxybiphenyl-3-yl)-5-methyloxazolidin-2-one (1.82 g, yield 61%) as a white powder.
Reaction SMILES: CC([O:5][C:6]([C:8]1[NH:9][C:10](=[O:14])[NH:11][C:12]=1[CH3:13])=[O:7])(C)C.FC(F)(F)C(O)=O>>[CH3:13][C:12]1[NH:11][C:10](=[O:14])[NH:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(=O)[nH]c1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,3-Dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylic acid 1,1-dimethylethyl ester (110.1 g, 0.556 mol) is added in portions to stirred trifluoroacetic acid (500g). After stirring the resulting mixture at room temperature for 20 minutes the suspension is evaporated in vacuo. The solid residue is mixed with water (700 mL), the mixture filtered, and the solid residue washed with an additional portion of water (700 mL). The filter cake is then dried for 1.5 hr at ca. 105° C., then overnight at room temperature to produce the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[C:4](OCOC)[C:3]=1[C:16](=[O:18])C>C(O)C>[CH3:6][O:8][CH2:9][O:10][C:5]1[CH:4]=[C:3]([CH:2]=[CH:7][C:6]=1[O:8][CH2:9][O:10][CH3:11])[CH:16]=[O:18]
Reactant: COCOc1cc(O)c(C(C)=O)c(OCOC)c1
Solvent: CCO
Product: COCOc1ccc(C=O)cc1OCOC
Yield: 218.6 %

Procedure:
In 260 ml of ethanol were dissolved 33.37 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone obtained in Production Example 11 and 32.20 g of the 3,4-bis(methoxymethoxy)benzaldehyde obtained in Production Example 24, and 300 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution and the mixture was stirred for 24 hours to effect a reaction. After the reaction, the pH value of the reaction liquid was adjusted to about 6 by 6 N hydrochloric acid, and the formed precipitate was recovered by filtration, washed with water and dried to obtain 53.17 g (yield=87.9%) of 2'-hydroxy-3,4,4',6'-tetrakis(methoxymethoxy)chalcone.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])#[CH:19].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CC#N>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:19]#[C:18][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: C#Cc1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl(2-bromo-4-chlorophenoxy)acetate (350 mg; 1.09 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 165 mg; 1.20 mmol) in degassed, anhydrous CH3CN (2.80 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (38 mg; 0.05 mmol), copper(I) iodide (10 mg; 0.05 mmol) and triethylamine (0.45 mL; 3.26 mmol). The reaction mixture was heated at 50° C. under stirring for 16 hours. The solvent was evaporated and the residue dissolved in DCM (1 mL) and an HCl solution (4 N in dioxane, 2.7 mL) was added. After stirring for 16 hours, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as an off-white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8]O.[CH2:10]([NH2:17])[CH2:11][S:12]S(O)(=O)=O>C(O)(=O)C>[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][S:12][CH2:11][CH2:10][NH2:17]
Reactant: Cc1nc[nH]c1CO
Reactant: NCCSS(=O)(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc[nH]c1CSCCN
Yield: 86.1 %

Procedure:
9.0 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 10.2 g of 2-aminoethanethiolsulfuric acid are heated at reflux for 80 minutes in 50 ml of acetic acid, and the reaction mixture is concentrated, passed through 250 ml of a strongly basic anion exchange resin (trade name: Amberlite IRA-410[OH- ]) and eluted with water. The eluate is concentrated under reduced pressure and dried to yield 8.93 g of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole as an oily product (yield: 86.2%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].[Br:21]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:8][Br:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
A 500 mL round-bottomed flask equipped with a magnetic stirrer was charged with 3.6 g of 3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl alcohol and 25 mL of anhydrous CH2Cl2. The solution was cooled in an ice water bath and was treated with 5.68 g of dibromotriphenylphosphorane (Aldrich). The reaction mixture was warmed to RT, stirred for 2.5 h and then diluted with 100 mL of CH2Cl2. The resulting solution was washed with 5% aqueous NaHCO3 (4×60 mL), dried over anhydrous MgSO4 and concentrated to give a white solid. The crude product was purified by flash chromatography on silica gel (95:5 hexane:EtOAc) to afford 3.86 g (88%) of 3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl bromide as a white crystalline solid, m.p. 54-55° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[CH2:4][C:3]1=[O:15].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26].Cl>CN(C)C=O>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[CH:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:3]1=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1C(=O)Cc2cc3c(cc21)OCCO3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(c2ccccc2[N+](=O)[O-])c2cc3c(cc21)OCCO3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
To a stirred solution of 6-methyl-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (1.03 g, 5.01 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% w/w dispersion in mineral oil, 0.26 g, 6.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, 1-fluoro-2-nitrobenzene (0.70 mL, 6.6 mmol) was added and the mixture was stirred at ambient temperature for 18 h, 10% w/v hydrochloric acid (10 mL) was added at 0° C. and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/hexanes (1/2) to afford 6-methyl-8-(2-nitrophenyl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (0.41 g, 24%): 1H NMR (300 MHz, CDCl3) δ 8.05-8.01 (m, 1H), 7.58-7.51 (m, 1H), 7.49-7.42 (m, 1H), 7.23-7.19 (m, 1H), 6.69 (s, 1H), 6.45 (s, 1H), 5.28 (s, 1H), 4.28-4.18 (m, 4H), 3.21 (s, 3H).
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]3=[N:9][C:10]3[N:11]2CO[CH:16]=3)[C:3](=O)[CH:2]=1.N.[ClH:19].[C:20](=[O:37])([O:22]CC1NC2C=CC=C3C=2C(N=1)=CC=C3)[NH2:21]>C(COC)OC>[ClH:19].[NH:11]1[C:12]2=[C:13]3[C:4](=[CH:3][CH:2]=[CH:1]2)[CH:5]=[CH:6][CH:7]=[C:8]3[N:9]=[C:10]1[CH2:16][NH:21][C:20](=[O:22])[OH:37]
Reactant: O=c1ccc2n3c(nc4cccc1c4=2)=COC3
Reactant: NC(=O)OCC1=Nc2cccc3cccc(c23)N1
Agent: Cl
Agent: N
Solvent: COCCOC
Product: O=C(O)NCC1=Nc2cccc3cccc(c23)N1

Procedure:
A sample of 1H, 3H-oxazolo[3,4-a]perimidine-3-one is dissolved in dimethoxyethane and is treated with excess conc. ammonia. The separated solid, (2-perimidyl)methyl carbamate, is filtered, dissolved in ethanol and treated with hydrochloric acid to give the acid addition salt, (2-perimidyl)methyl carbamate hydrochloride, m.p. 240° (dec.).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27]>CN(C)C=O>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: COC(CCBr)OC
Reactant: Cc1nc(C)c(-c2c[nH]c(=O)[nH]c2=O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2sc(C)nc2C)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a suspension of 5-(2,4-dimethyl-1,3-thiazol-5-yl)-2,4(1H,3H)-pyrimidinedione (Prep34, 250 mg, 1.120 mmol) in N,N-Dimethylformamide (DMF) (4 mL), Potassium carbonate (124 mg, 0.896 mmol) was added and the mixture was stirred at rt for 1 hour. Afterwards 3-bromo-1,1-bis(methyloxy)propane (0.170 mL, 1.120 mmol) was added dropwise and the reaction mixture was stirred at rt overnight. The day after the reaction was quenched with water and extracted with AcOEt. Organic phase was dried over Na2SO4 and concentrated under vacuum providing a crude as a clear oil. The latter was purified by flash chromatography (eluent:DCM/MeOH/NH3 97:3:0.1) affording the title compound (155 mg, 0.429 mmol) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[S:20][CH:19]=[N:18][CH:17]=1>>[S:20]1[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=2)=[CH:17][N:18]=[CH:19]1
Reactant: Brc1cncs1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: O=C(O)CCc1ccc(C#Cc2cncs2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 5-bromothiazole (50 μL, 0.56 mmol) according to the general procedure IF. After concentration the residue was hydrolyzed according to the general procedure II to give 28 mg (21%) of a white solid after purification by flash chromatography (SiO2, EtOAc [with 1.25% AcOH]:PE, 1:2): Rf=0.12 ([EtOAc with 1.25% AcOH]:PE, 1:2); 1H NMR (DMSO-d6) δ 12.14 (s, 1H), 9.16 (d, J=0.6 Hz, 1H), 8.20 (d, J=0.6 Hz, 1H), 7.49 (d, J=8.2 Hz, 3H), 7.31 (d, J=8.3 Hz, 3H), 2.86 (t, J=7.5 Hz, 3H), 2.56 (t, J=7.6 Hz, 3H); 13C NMR (DMSO-d6) δ 173.5, 155.7, 147.2, 142.6, 131.2, 128.7, 118.8, 118.0, 96.0, 78.4, 34.6, 30.1; ESI-MS calcd for C14H11NO2S (M+Na+) 280.0403. found 280.0400.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][CH2:37][CH:38]1[O:42][NH:41][C:40](=[O:43])[CH2:39]1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:36][CH2:37][CH:38]2[O:42][NH:41][C:40](=[O:43])[CH2:39]2)=[O:21])=[CH:17][N:16]=1
Reactant: NCC1CC(=O)NO1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CC(=O)NO2)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) in DMF (2 mL) was added 1,1′-carbonyl-diimidazole (115 mg, 0.71 mmol) and the reaction mixture was stirred for 0.5 h at 80° C. After cooling to ambient temperature 5-aminomethyl-isoxazolidin-3-one (82 mg, 0.71 mmol) was added and stirring was continued for 1 h at this temperature and for 2 h at 80° C. It was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=40:60:0 to 0:90:10) afforded the title compound (13 mg, 5%) as a white solid. MS: m/e=409.3 [M+H]+.