Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C[Si]([C:15]#[CH:16])(C)C.[F-].[K+].C(Cl)Cl>CCN(CC)CC.O1CCOCC1.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>[C:15]([C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1)#[CH:16]
Reactant: C#C[Si](C)(C)C
Reactant: OCCc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [F-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C#Cc1ccc(CCO)cc1
Reaction time: 8 h

Procedure:
A flask is flushed with N2 and charged with 4-bromo-phenethyl alcohol (20 mmol) and dissolved in 1/1 Et3N/dioxane. Bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2) (0.2 mmol) is added, followed by 0.4 mmol of CuI. Trimethylsilylacetylene (24 mmol) is added drop-wise to the reaction mixture. The reaction mixture is stirred overnight under N2. The solvent is removed under vacuum and the resulting liquid is extracted by washing with ethyl ether. The ethyl ether extracts are combined and washed with H2O, then dried over anhydrous sodium sulfate. The solvent is removed under vacuum and the product is purified by column chromatography. The purified product is placed in a N2-flushed flask and dissolved in methanol. Potassium fluoride (65 mmol) is added and the reaction stirred under a N2 blanket for 16 h. The reaction mixture is poured into CH2Cl2 and extracted with H2O, then dried over Na2SO4, filtered and the solvent is removed under vacuum. The resulting product is purified by column chromatography to yield 2-(4-ethynyl-phenyl)-ethanol (2).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.[F:28]C1C=CC(NC(=O)OC(C)(C)C)=CC=1NC1C(C=O)=CN=C(SC)N=1>>[F:28][C:19]1[CH:18]=[CH:17][C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:15][C:14]=1[N:9]1[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=[CH:11][C:10]1=[O:13]
Reactant: CSc1ncc(C=O)c(Nc2cc(NC(=O)OC(C)(C)C)ccc2F)n1
Reactant: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Product: CSc1ncc2ccc(=O)n(-c3cc(NC(=O)OC(C)(C)C)ccc3F)c2n1
Yield: 59 %

Procedure:
This compound (270 mg, 59% yield) as a light yellow crystalline solid was prepared according to the procedures described for Intermediate 51, using tert-butyl (4-fluoro-3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (58) (430 mg, 1.14 mmol) as the starting material. m/z (ESI, +ve ion) 403.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.64 (1H, s), 7.70 (1H, d, J=9.6 Hz), 7.55 (1H, br. s.), 7.28-7.35 (1H, m), 7.17 (1H, t, J=9.0 Hz), 6.72 (1H, d, J=9.6 Hz), 6.56 (1H, br. s.), 2.22 (3H, s), 1.49 (9H, s). 19F NMR (376 MHz, DMSO-d6) δ ppm-126.87 (1F, s).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][N:37]([S:77]([C:80]1[S:81][CH:82]=[CH:83][CH:84]=1)(=[O:79])=[O:78])[C:38]1[CH:39]=[C:40]([O:72][C:73]([F:76])([F:75])[F:74])[CH:41]=[C:42]2[C:46]=1[NH:45][C:44]([C:47]([NH:49][CH2:50][CH2:51][S:52]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)=[CH:43]2.C(=O)([O-])O.[Na+]>ClCCl>[S:52]1[CH2:51][CH2:50][N:49]=[C:47]1[C:44]1[NH:45][C:46]2[C:42]([CH:43]=1)=[CH:41][C:40]([O:72][C:73]([F:76])([F:74])[F:75])=[CH:39][C:38]=2[N:37]([CH3:36])[S:77]([C:80]1[S:81][CH:82]=[CH:83][CH:84]=1)(=[O:79])=[O:78]
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCCS3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A mixture of triphenylphosphine oxide (0.37 g), trifluoromethanesulfonic anhydride (0.11 mL), and dichloromethane (5 mL) was stirred for 15 min under ice-cooling. Then, 7-[methyl(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (0.16 g) was added, and the mixture was stirred for 3 hr under ice-cooling. The reaction solution was poured into aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4-1:2), and the obtained crystals were washed with diethyl ether-hexane to give the title compound (84 mg, yield 82%) as colorless crystals. melting point 179-180° C.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:18](O)=[O:19])[C:11]3[O:15][CH:14]([CH3:16])[CH2:13][C:12]=3[CH:17]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.ClC(OCC)=O.[C:31]1([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH:39]2[CH2:43][NH2:44])[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1>C(O)(=O)C.O.C(N(CC)CC)C>[C:31]1([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH:39]2[CH2:43][NH:44][C:18]([C:10]2[C:11]3[O:15][CH:14]([CH3:16])[CH2:13][C:12]=3[CH:17]=[C:8]([S:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)(=[O:7])=[O:6])[CH:9]=2)=[O:19])[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1
Reactant: CC1Cc2cc(S(=O)(=O)CC3CC3)cc(C(=O)O)c2O1
Reactant: NCC1CCCN1CC1=CCCCC1
Agent: CCOC(=O)Cl
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1Cc2cc(S(=O)(=O)CC3CC3)cc(C(=O)NCC3CCCN3CC3=CCCCC3)c2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
97 g of 5-cyclopropylmethylsulphonyl-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid, 350 ml of chloroform and 34 g of triethylamine were introduced into a 1-liter round-bottomed flask. The solution was cooled to 0° C. and 36 g of ethyl chloroformate were then added dropwise, while maintaining the temperature between 0° C. and 5° C. The contents were then stirred for 1 hour between 0° C. and 5° C. and 67 g of 1-cyclohexenylmethyl-2-aminomethylpyrrolidine were then poured in dropwise, between 5° C. and 10° C. The mixture was stirred for 1 hour, between 5° and 10° C. and the temperature was then allowed to rise. The solution obtained was taken up with 2 liters of water. Acetic acid was added until a pH of 4 was obtained and the chloroform was distilled off. The solution remaining was filtered and then made alkaline with 30% sodium hydroxide until a color change of phenolphthalein was observed. The oil formed was decanted and extracted with ether and the solution containing ether was then dried over potassium carbonate. The ether was distilled off, the distillation towards the end being carried out under vacuum, until a constant weight was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:7][C:6]([C:14](OC(C)C)=[O:15])([C:8](OC(C)C)=[O:9])[CH2:5]1)#[N:2].O1CCCC1.[BH4-].[Li+].Cl.C([O-])(O)=O.[Na+]>CO>[OH:15][CH2:14][C:6]1([CH2:8][OH:9])[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:41])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:7]1
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)(CO)C4)c3)ncnc21
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
Diisopropyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutane-1,1-dicarboxylate (0.3 g, 0.5 mmol) was dissolved in tetrahydrofuran (15 mL, 180 mmol) and lithium tetrahydroborate (0.017 g, 0.77 mmol) was added at 0° C. The reaction was then heated to 50° C. for 30 min. To the reaction was added MeOH (10 mL). The reaction was held at 50° C. for 15 min, then stripped to near dryness. The residue was treated with 1N HCl, then neutralized with solid NaHCO3. The mixture was partitioned between water and EtOAc. The phases were separated and the aq. phase was washed with EtOAc. The combined organic phases were washed with water, then brine, dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-100% EtOAc/Hex) to give the desired product (0.145 g, 60%) as colorless oil. LCMS calculated for C23H33N6O3Si(M+H)+: 469.2; Found: 469.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[O:24][C:25]=1[CH3:26].FC(F)(F)C1C=C(C=CC=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2cccc(C(F)(F)F)c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: O=Cc1cccc(C(F)(F)F)c1
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cccc(C(F)(F)F)c3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 4-chloromethyl-5-methyl-2-(3-trifluoromethyl-phenyl)-oxazole (prepared from 3-trifluoromethyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@H:4]([C:7]([NH:9][C:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][C:11]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8])[CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C@@H:2]3[CH2:6][CH2:5][C@H:4]([C:7]([NH:9][C:10]4[CH2:17][CH2:16][C:13]5([CH2:15][CH2:14]5)[CH2:12][C:11]=4[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8])[CH2:3]3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)C1=C(NC(=O)[C@H]2CCC(=O)C2)CCC2(CC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C1=C(NC(=O)[C@H]2CC[C@@H](N3CCN(c4ccc(F)cc4)CC3)C2)CCC2(CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of (S)-ethyl 6-(3-oxocyclopentanecarboxamido)spiro[2.5]oct-5-ene-5-carboxylate (0.7 g, 2.23 mmol) in 1,2-dichloroethane (10 ml) were added 1-(4-fluorophenyl)piperazine (0.43 g, 2.40 mmol), glacial acetic acid (0.14 g, 2.40 mmol) and sodium triacetoxy borohydride (0.7 g, 3.44 mmol). The mixture was stirred at RT for 24 h before removal of the solvent. The residue was treated with saturated sodium bicarbonate, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain a diastereomeric mixture (7:3) of title compound (0.9 g, 84%).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19]=[C:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CN(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1nc2ccccc2s1

Procedure:
5-(4-[2-(N-Methyl-N-(2-benzothiazolyl)amino)ethoxy] benzylidene)-2,4-thiazolidinedione (2 g) in dry 1,4-dioxan (70 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (3 g) at ambient temperature and atmospheric pressure until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (m.p. 167°-8° C.) was obtained after crystallisation from methanol.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(=O)(O)[O-].[Na+].[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][C:14]=1[Cl:22]>C(OCC)C.O>[Cl:22][C:14]1[CH:15]=[C:16]([NH:19][C:20]([N:4]([O:3][CH3:2])[CH3:5])=[O:21])[CH:17]=[CH:18][C:13]=1[CH2:12][Br:11]
Reactant: CNOC
Reactant: O=C=Nc1ccc(CBr)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CON(C)C(=O)Nc1ccc(CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A stirred solution of 58.3 grams (0.597 mole) of O,N-dimethylhydroxylamine hydrochloride in 400 ml of diethyl ether was cooled to 0° C. and a slurry of 50.2 grams (0.597 mole) of sodium bicarbonate in 50 ml of water was added. Upon completion of addition the reaction mixture stirred at 0° C. for one hour, then a solution of 147.2 grams (0.597 mole) of 4-bromomethyl-3-chlorophenylisocyanate in 100 ml of diethyl ether was added. During the addition, additional diethyl ether was added to the reaction mixture to promote stirring. Upon completion of addition the reaction mixture was stirred for an additional one hour, then was filtered. The filtrate was dried with magnesium sulfate and refiltered. The filtrate was concentrated under reduced pressure to a solid residue. The solid was triturated with ethanol to remove a yellow color. The solid was collected by filtration to give 51.5 grams of 2-chloro-4-[(N-methoxy-N-methylamino)carbonylamino]phenylmethyl bromide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH2:13][C:14]#[CH:15])[C:8]=2[CH:16]=1)([O-])=O.O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH2:13][C:14]#[CH:15])[C:8]=2[CH:16]=1
Reactant: C#CCn1c(=O)oc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#CCn1c(=O)oc2ccc(N)cc21
Temperature: 80 °C
Yield: 54.5 %

Procedure:
Electrolytic iron (11.39 g) was suspended in 5% aqueous acetic acid solution (22 ml) and heated to 80° C. To the suspension, a solution of 5-nitro-3-(2-propynyl)-3H-benzoxazol-2-one (4.15 g) in acetic acid (20 ml) and ethyl acetate (20 ml) was dropwise added, and the resultant mixture was stirred at 70° C. for 3 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 5-amino-3-(2-propynyl)-3H-benzoxazol-2-one (1.95 g). m.p., 102.1° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[O:19]1[C:24]2[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[O:19]1[C:24]2[C:25]([NH:29][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc2c1OCCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2c1OCCN2
Yield: 26.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 166 mg of 3,4-dihydro-2H-1,4-benzoxazin-8-ylamine and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 100 mg of N-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH2:12][CH3:13])([O-:11])=[O:10].O>O1CCCC1.C(O)(C)(C)C.CC(C)([O-])C.[K+]>[N+:9]([CH:12]([CH3:13])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8])([O-:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: CC[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C(O)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of benzaldehyde (20.0 g) and nitroethane (28.4 g) in tetrahydrofuran (50 mL) and tert-butanol (50 mL) was added potassium tert-butoxide (1.27 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=10:1) to give the title compound as a blue oil (yield 32.0 g, 93%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([S:14](Cl)(=[O:16])=[O:15])[CH:10]=[CH:11][C:12]=1[Cl:13]>>[Cl:6][C:7]1[CH:8]=[C:9]([S:14]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][S:14]([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)(=[O:16])=[O:15])(=[O:16])=[O:15])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CNCCO
Product: CN(CCOS(=O)(=O)c1ccc(Cl)c(Cl)c1)S(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 2-methylamino ethanol and 3,4 dichlorophenyl sulfonylchloride using the method described in Description 1.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=12.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CC#N.CCOC(C)=O>[C:21]1([O:20][C:18](=[O:19])[NH:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccn2ccnc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1cccn2ccnc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.2 %

Procedure:
To a solution of imidazo[1,2-a]pyridin-8-ylamine (397 mg, 2.98 mmol) in dry CH3CN (5.0 mL) was added pyridine (282 mg, 3.57 mmol) and phenyl chloroformate (467 mg, 2.98 mmol) and the reaction mixture was stirred at rt. After 4 h, the mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified (FCC) to give imidazo[1,2-a]pyridin-8-yl-carbamic acid phenyl ester (409.1 mg, 54%). MS (ESI+): calcd for C14H11N3O2 m/z 253.09, found 254.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:9])([C:5](=[O:8])[CH2:6][CH3:7])[CH3:4].[N:10](OCCCC)=[O:11]>C(OCC)C.C1(C)C=CC=CC=1>[OH:11][N:10]=[C:6]([CH3:7])[C:5](=[O:8])[C:3]([CH3:9])([CH3:4])[CH3:2]
Reactant: CCC(=O)C(C)(C)C
Reactant: CCCCON=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=NO)C(=O)C(C)(C)C
Temperature: -10 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
A solution of 40 g of hydrogen chloride in 156 g of diethyl ether is added dropwise at room temperature to 96 g (0.84 mol) of 2,2-dimethyl-3-pentanone in 960 g of toluene. After cooling to −10° C., a solution of 95 g of n-butyl nitrite in 470 g of diethyl ether is added dropwise. The mixture is stirred at from −10° C. to 0° C. for 4 hours and then allowed to come to room temperature. After a total of 16 h, the reaction mixture is washed three times with 1 l of ice-water each time and then extracted twice with 1 l of 1M sodium hydroxide solution each time. The alkaline phase is separated off and neutralized with 20% strength sulfuric acid. The crude product is filtered off with suction and, after drying, recrystallized from n-hexane. 66 g (55%) of the title compound are obtained as a pale yellow powder of melting point 107-110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br-].[K+]>[Cu].O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc(Nc2cccc3ccc(C)nc23)n1
Reactant: Brc1ccccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: Cc1cccc(N(c2ccccn2)c2cccc3ccc(C)nc23)n1
Reaction time: 16 h

Procedure:
To a flask were added 2.5 g of 2-methyl-N-(6-methylpyridin-2-yl)quinolin-8-amine, 4.7 g of 2-bromopyridine, 1.6 g of sodium carbonate, 51 mg of copper bronze, 5 mg of potassium bromide, and 3 ml of mesytylene. After stirring under nitrogen at 160 C for 16 hours, the mixture was cooled to 22 C, and 35 ml of water was added and the product was extracted with 50 ml ethyl acetate. After washing twice with 20 ml of water, the solvent was removed, and the product was purified by silica gel chromatography using 50% ethyl acetate, 50% hexane, and 0.1% triethylamine resulting in 3.0 g of a light yellow oil.
Reaction SMILES: C(OC(C)C)(=O)C.[Si:8]([O:15][C:16]1[C:17]([CH3:26])=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C1(O)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:34][CH2:26][C:17]1[C:16]([O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10])=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Oc1ccccc1
Solvent: CC(=O)OC(C)C
Product: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1CBr
Temperature: 70 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The isopropyl acetate solution of methyl 3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (157 g, 560 mmol, from step 2, with an amount of residue free phenol≦0.2%) was added to a 3 liter jacketed bottom drop reactor. Additional isopropyl acetate was added and the mixture was distilled under vacuum at 40 to 55° C., if necessary, to bring total volume to about 9× (1410 mL, KF≦0.05%). 1-Bromopyrrolidine-2,5-dione (NBS, 103.6 g, 580 mmol, 0.66×) and 2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (AIBN, 1.9 g, 11 mmol, 0.012×) were added to the solution. The reaction mixture was heated to 70° C. over at least 2 hours and stirred at 70° C. for 2 hours. The color changed from orange to yellow. If conversion was less than 95%, additional 0.05 molar equiv. of NBS was added and the mixture was stirred at 70° C. for 1 hour. The process was repeated, in necessary, until conversion reached 95%. The mixture was cooled to 20° C. and held at 20° C. for at least 1 hour. The solid (succinimide) was filtered and washed with isopropyl acetate (75 mL, 0.5×). The filtrate was washed with solution of sodium sulfite (157 g, 1×) in water (1413 mL, 9×), followed by water (315 mL, 2×). The organic layer was distilled under vacuum at 30 to 40° C. to ˜2× volume. Additional isopropyl acetate (315 mL, 2×) was added and distilled back to 2× volume, if necessary, until KF was no more than 0.1%. Then the organic layer was distilled at 30 to 40° C. to give methyl 2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)benzoate as an oil (expected 180 g, 90% yield); 1H NMR (DMSO-d6, 300 MHz) δ 7.47 (dd, J=7.8, 1.2 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.15 (dd, J=8.1, 1.2 Hz, 1H), 4.96 (s, 2H), 3.86 (s, 3H), 1.03 (s, 9H), 0.30 (s, 6H) ppm.