Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][C:18]3=[O:21])=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Product: O=C1CCCc2ccc(Nc3nc(Cl)ncc3F)cc21

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-1-tetralone were reacted to provide 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.08 (s, 1H), 8.31 (d, 1H, J=3.3 Hz), 8.15 (d, 1H, J=2.4 Hz), 7.82 (dd, 1H, J=2.4 and 8.1 Hz), 7.36 (d, 1H, J=8.1 Hz), 2.91 (t, 2H, J=6.0 Hz), 2.59 (t, 2H, J=6.0 Hz), 2.07-1.98 (m, 2H); LCMS: purity: 93%; MS (m/e): 294 (MH+).
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].CO[C:9](OC)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>C1C=CC=CC=1>[C:10]1([C:9]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:1][CH2:2][CH:3]([CH2:4][OH:5])[O:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(OC)(c1ccccc1)c1ccccc1
Reactant: OCC(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: OCC1CSC(c2ccccc2)(c2ccccc2)O1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
3-Mercapto-1,2-propanediol(3.26 g, 30.00 mmol) was dissolved in benzene (60 mL). Benzophenone dimethyl ketal (13.48 g, 60.0 mmol, 2 equiv.) and CSA (0.70 mg, 3.00 mmol, 0.1 equiv.) were added. The solution was heated with an oil bath to reflux. Benzene/methanol was collected and removed while more benzene was added to the refluxing reaction. After about 200 mL benzene/methanol was distilled out, the reaction was cooled to room temperature, applied directly onto a silica gel column. The column was then eluted was 20%-40% etherlpetroleum ether to afford a thick oil as the desired product (3.78 g, 46). Rf =0.25, 20% ether/petroleum ether. 1H NMR (400 MIHz, C6D6) δ=2.56 (dd, J 6.3, 10.2 Hz, 1 H), 2.83 (dd, J=7.7, 10.2 Hz, 1 H), 3.35 (br dd, J=5.3, 11.6 Hz, 1 H), 3.44 (br dd, J=3.5, 11.6 Hz, 1 H), 3.88-3.95 (m, 1 H), 6.94-7.20 (m, 6H), 7.54 (d, J=7.5 Hz, 2 H), 7.70 (d, J=7.5 Hz, 2 H). 13C NMR (100 MHz, C6D6) δ=35.90, 63.97, 83.29, 100.20, 126-129 (m).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][Si](C(C)(C)C)(C)C>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(CCCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.26 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 92 mg (0.31 mmol) of (6-bromohexyloxy)-tert-butyldimethylsilane. The product was purified by means of flash chromatography on silica gel. The protecting group was cleaved off as already described using an HCl solution in dioxane. The product is in the form of the hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OS(C(F)(F)F)(=O)=O)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][C:26]=3[Cl:28])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2ccc(Br)cc2o1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(Cl)cc2Cl)c2ccc(Br)cc2o1
Temperature: 70 °C
Yield: 67.9 %

Procedure:
To a solution of the triflate from Step 1 (712 mg, 1.91 mmol) in 15 ml THF was added 2,4-dichlorophenyl boronic acid (400 mg, 2.10 mmol), (Ph3P)4Pd (110 mg, 0.095 mmol) and aqueous Na2CO3 (1.91 mL, 3.82 mmol). The mixture was heated at 70° C. for 2 h, cooled and partitioned between aqueous NH4Cl and EtOAc (50 mL each). The layers were separated and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was evaporated and the residue chromatographed on silica gel (hexane: EtOAc 9:1) to give 480 mg (68%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:25](I)=[C:24]([CH:27]2[CH2:30][CH:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28]2)[O:23][N:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1(B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:25]([CH:36]2[CH2:38][CH2:37]2)=[C:24]([CH:27]2[CH2:30][CH:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28]2)[O:23][N:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2I)C1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
tert-Butyl 6-benzyloxy-3-{5-[3-(2,2-dimethylpropyl)cyclobutyl]-4-iodoisoxazole-3-yl}hexanoate (4.20 g), 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.34 g), tripotassium phosphate (5.92 g), DMF (90 mL) and water (10 mL) were mixed. The mixture was degassed by bubbling argon gas. To the mixture was added PdCl2(PPh3)2 (734 mg). The mixture was stirred at 80° C. for 1 hr. To the reaction mixture was added ethyl acetate, and then the mixture was filtered. The aqueous layer was removed, and the organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/25) to give the title compound (980 mg). A mixture of the title compound and impurities thereof (1.24 g) was also obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[C:4]([CH2:19][CH:20]([NH:33][C:34](=O)[O:35]C(C)(C)C)[C:21]2[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:23]=[CH:24][N:25]=2)[CH:3]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH:66]([N:69]2[CH2:78][C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[NH:71][C:70]2=[O:79])[CH2:65][CH2:64]1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:19][CH:20]([NH:33][C:34]([N:63]2[CH2:64][CH2:65][CH:66]([N:69]3[CH2:78][C:77]4[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=4)[NH:71][C:70]3=[O:79])[CH2:67][CH2:68]2)=[O:35])[C:21]2[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:23]=[CH:24][N:25]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccccn2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nccn2Cc2ccccn2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(1-(pyridin-2-ylmethyl)-1H-imidazol-2-yl)ethylcarbamate (35.2 mg, 0.063 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen overnight. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (11.0 mg, 0.066 mmol, 1.05 equiv) and diisopropylethylamine (44.0 μL, 4.0 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (17.6 mg, 0.066 mmol, 1.05 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 4.6 mg (12%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.48-1.65 (m, 4H), 2.03 (s, 1H), 2.45 (s, 3H), 2.69-2.82 (m, 2H), 3.99-4.16 (m, 2H), 4.19 (s, 2H), 5.24 (d, J=16.5, 1H), 6.67 (d, J=7.6, 1H), 6.80 (d, J=7.9, 1H), 6.89 (s, 1H), 6.97 (dd, J=8.2, 7.6, 1H), 7.10-7.23 (m, 5H), 7.30 (s, 1H), 7.37-7.42 (m, 1H), 7.94 (s, 1H). Mass spec.: 590.3 (MH)+.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[O:3].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:26][O:27][C:28](OC)([CH3:33])[C:29]([O:31][CH3:32])=[O:30].C1(C=CC(O)=CC=1)O>CO>[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[O:3].[CH3:26][O:27][C:28](=[CH2:33])[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)C(C)(OC)OC
Agent: COC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: COC(OC)OC
Solvent: CO
Product: C=C(OC)C(=O)OC

Procedure:
The dimethyl acetal of methyl pyruvate was prepared using methyl pyruvate, trimethyl orthoformate, MeOH and p-toluenesulfonic acid according to the method of Wermuth (Bull. Soc. Chim. France, 732 (1964)). Methyl pyruvate dimethylacetal (50 g) p-toluenesulfonic acid (1.34 g) and hydroquinone (1.90 g) were heated in an oil bath (approx. 150° C.) and MeOH was allowed to distill off slowly (approx. 10 mL). The residue was then distilled to afford the title ester, bp approx. 50° C./20 mmHg.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][S:12][C:13](=[O:22])[C:14]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[O:15]>O>[CH3:11][S:12][C:13](=[O:22])[C:14]([C:16]1[N:17]=[C:18]([NH:21][CH:1]=[O:3])[S:19][CH:20]=1)=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: CSC(=O)C(=O)c1csc(N)n1
Solvent: O=CO
Solvent: O
Product: CSC(=O)C(=O)c1csc(NC=O)n1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of 40.8 g of acetic anhydride and 18.4 g of formic acid was stirred at 40° to 45° C. for 1 hour. To the resulting mixture was added 20.2 g of 2-(2-aminothiazol-4-yl)thioglyoxylic S-acid metyl ester, with water-cooling, after which the resulting mixture was stirred at 25° C. for 1 hour. Subsequently, 160 ml of water was added dropwise to the thus obtained reaction mixture with ice-cooling, after which the resulting mixture was stirred with water-cooling for 30 minutes, and the deposited crystals were collected by filtration. The crystals were washed successively with water and acetone and then dried to obtain 21.9 g (94.4% yield) of 2-(2-formylaminothiazol-4-yl)thioglyoxylic S-acid methyl ester having a melting point of above 230° C.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][N:16]3[C:20](=[O:21])[CH2:19][CH2:18][C:17]3=[O:22])[N:14]=2)[CH2:7]1)(=O)=O.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][N:16]3[C:17](=[O:22])[CH2:18][CH2:19][C:20]3=[O:21])[N:14]=2)[CH2:9]1)(=[O:26])[CH3:24]
Reactant: CS(=O)(=O)OC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (515 mg, 1.49 mmol) (obtained as described in Reference Example 69(3)) in dimethylformamide (15 ml) was added potassium thioacetate (1.02 g, 8.95 mmol) at room temperature, and then stirred in an oil bath (90° C.) for 8 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-acetylthio-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (238 mg, yield 49%) as a pale brown solid.
Reaction SMILES: [NH+:1]1([O-])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: [O-][NH+]1C=Cc2cccnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2[nH]ccc12

Procedure:
1H-Pyrrolo[2,3-b]pyridine-N-oxide (Reference Example 65) (10.0 g) in phosphorous oxychloride (75 mL) was heated at reflux for 8 hours. The excess phosphorous oxychloride was evaporated and the residue was taken up in water and the solution was brought to a pH=8-9, the resultant precipitate was filtered and air-dried to give the title compound as an off-white solid (10.2 g). MS: 152 (MH+). 1H NMR (CDCl3): δ 8.2 (d, 1H), 7.5 (d,,1H), 7.2 (d, 2H), 6.6 (d, 2H).
Reaction SMILES: [C:1]([C:3]([C:23](=O)[CH3:24])=[CH:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:6]=1)#[N:2].[NH2:26][C:27]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[CH:28][C:29]#[N:30]>C(O)(=O)C>[C:29]([C:28]1[CH:4]([C:5]2[O:13][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:7]=3[CH:6]=2)[C:3]([C:1]#[N:2])=[C:23]([CH3:24])[NH:26][C:27]=1[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)#[N:30]
Reactant: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Reactant: N#CC=C(N)c1ccc(F)cc1
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(c2ccc(F)cc2)N1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 200 mg (0.604 mmol) N-{2-(2-cyano-3-oxobut-1-en-1-yl)furo[3,2-c]pyridin-4-yl}benzamide (Example 4A) and 117 mg (0.724 mmol) 3-amino-3-(4-fluorophenyl)prop-2-enenitrile (Example 5A) in acetic acid (2 ml) was stirred for 30 min at 110° C. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient, final mixture 90:10 v/v) to yield 235 mg (82% of th.) of the racemic title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18](I)[CH:19]=[CH:20][C:13]=3[O:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33]>C1COCC1.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>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18]([C:33]#[C:32][CH2:31][OH:34])[CH:19]=[CH:20][C:13]=3[O:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(I)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(C#CCO)cc2c1=O
Temperature: 25 °C

Procedure:
Under an argon atmosphere, a mixture of N-(4-chlorobenzyl)-6-iodo-4-oxo-4H-1,2-benzoxazine-3-carboxamide (Preparation 18, 0.117 g), dichlorobis (triphenyl-phosphine)palladium (12.8 mg), copper(I) iodide (3.7 mg), and triethylamine (1 mL) in THF (6 mL) is cooled in an ice-brine bath. A solution of propargyl alcohol (32 mg) in THF (3 mL) is added slowly via a syringe to the reaction mixture. The reaction mixture is stirred at ice-brine temperature for 2 h and then allowed to warm to room temperature overnight. The mixture is concentrated in vacuo and the residue is flash chromatographed on silica gel (230-400 mesh, 8 g), eluting with 1% methanol in dichloromethane, pooling desirable fractions and concentrating in vacuo provides the title compound as a pale yellow solid. Physical characteristics: m.p. 117-120° C.: 1H NMR (400 MHz, DMSO-d6) δ4.35, 4.50, 5.55, 7.42, 7.77, 7.97, 9.4; 13C NMR (DMSO-d6) δ49.2, 49.3, 67.8, 79.4, 81.8, 91.8, 117.5, 119.8, 120.2, 126.6, 128.3, 129.0, 131.6, 137.2, 138.8, 155.2, 159.2, 160.3, 165.2; MS (FAB) m/z 369 (MH+, 99); HRMS (FAB) m/z 369.0645 (C19H13ClN2O4+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:30]Br.O.O.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Br:30])[CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: c1ccc(COCCc2ccccc2OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Benzyl 2-(2-benzyloxyethyl)phenyl ether (159 mg) and 123 mg of sodium acetate was suspended in 2 ml of acetic acid, 29 μl of bromine was added to the suspension with stirring at room temperature, and the mixture was subjected to 1 hour of reaction. Then, a solution of 100 mg of sodium sulfite heptahydrate in 20 ml of water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous saturated sodium bicarbonate solution and water in that order and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/methylene chloride=2/1) to give 173 mg of benzyl 2-(2-benzyloxyethyl)-4-bromophenyl ether in an oily form.
Reaction SMILES: [C:1]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].Cl[CH2:19][C:20]([O-:22])=[O:21].[Na+]>>[C:1]([C:6]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([CH2:19][C:20]([OH:22])=[O:21])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C([O-])CCl
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Agent: [Na+]
Product: CCOC(=O)C1(c2ccccc2)CCN(CC(=O)O)CC1
Reaction time: 7 h
Yield: 58 %

Procedure:
4-Carbethoxy-4-phenylpiperidine (4.01 g.) was dissolved in 13 ml. absolute alcohol and refluxed together with 2.01 g. sodium chloroacetate. After 7 hours no starting material was present as evidenced by TLC. The precipitated sodium chloride was removed by filtration and washed with 3 ml. ethanol. On cooling of the filtrate white cyrstals appeared. Filtration and drying gave 2.9 g. (58%) of the title compound. m.p. 148°-150°C. Evaporation of the mother liquor gave a glass which did not crystallize from acetone/hexane.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5]C.C1(C#C)C=CC=CC=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]#N>C(#N)C1C=CC=CC=1>[C:20]([C:16]1[O:15][CH:19]=[CH:18][CH:17]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C#CCCCC
Reactant: N#Cc1ccco1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCC#Cc1ccco1
Reaction time: 4 h
Yield: 69 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-hexyne (0.450 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-furonitrile (0.175 ml; 0.186 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 4 h at 65° C. showed the presence of 1.38 mmol (69% yield) of 2-(1-hexynyl)furan and no remaining 2-furonitrile in the reaction mixture.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:32]([BH3-])#N.[Na+]>CO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]([C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2c(cc1N(C)C1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
A solution of 3-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.16 g, 0.40 mmol) and paraformaldehyde (neat, 0.024 g, 0.80 mmol) in MeOH (10 mL) and HOAc (1 mL) was heated at 70° C. for 14 h. The mixture was cooled to ambient temperature and sodium cyanoborohydride (0.050 g, 0.80 mmol) was added. The resulting dark solution was stirred at 70° C. for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 33-60% EtOAc in petroleum ether) to give 3-[(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-methyl-amino]-azetidine-1-carboxylic acid tert-butyl ester as yellow solid (0.081 g, 49%). LC/MS (Table 1, Method 2) Rt=1.168 min.; MS m/z: 416 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11](Cl)[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[F:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:12]=[C:11]([O:23][C:18]2[CH:19]=[CH:20][C:21]([F:22])=[C:16]([F:15])[CH:17]=2)[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(Oc2ccc(F)c(F)c2)nc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of ethyl 2,6-dichloro-5-fluoronicotinate (20 g, 84 mmol) and 3,4-difluorophenol (10.93 g, 84 mmol) in acetonitrile (200 mL) was added potassium carbonate (20.90 g, 151 mmol). The reaction mixture was stirred at 80° C. for 2 hr. and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with Hex/EtOAc (10:1) to give ethyl 2-chloro-6-(3,4-difluorophenoxy)-5-fluoronicotinate (23.5 g, 80%).
Reaction SMILES: CN(C=O)C1C=CC=CC=1.C([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=C.ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([CH:51]([CH3:53])[CH3:52])C=2)=[CH:38][CH:37]=1>C(#N)C>[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([CH:51]([CH3:53])[CH3:52])[C:17]=2[CH:16]=[CH:15][CH:14]=[O:13])=[CH:38][CH:37]=1
Reactant: C=COCCCC
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Agent: CN(C=O)c1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)n1c(C=CC=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 5 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of N-methylformanilide (30 g), butyl vinyl ether (22.2 g) in 15 ml of acetonitrile under stirring at 5° C., a solution of bis-trichloromethylcarbonate (26.1 g) in 70 ml of acetonitrile is added dropwise in 80 min. The reaction mixture is kept under stirring at 5° C. overnight, then phosphorus oxychloride (31.4 g) is added dropwise in 30 minutes, then the reaction mixture is stirred at 5° C. for 15 minutes. 3-[3-(4-Fluorophenyl)-1-(1-Methylethyl)-1H-Indole (35.8 g) and acetonitrile (25 ml) are added. The mixture is warmed to 80° C. and kept under stirring for about 24 hours. The reaction mixture is worked up as described in Example 3b to give the product (69% yield).