Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:13]C)[C:8](OC)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].Br.C(O)(=[O:18])C>>[CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:13])[C:6]=1[OH:18])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1ccc(OC)c(OC)c1
Agent: Br
Product: CCCCc1cccc(O)c1O
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 5.64 g (29 mM) of 4-n-butylveratrole, 18.54 g (309 mM) of acetic acid and 55.62 g (323 mM) of 47% hydrobromic acid was heated under reflux for 4 hours with stirring. The reaction mixture was cooled to the room temperature and added with 50 ml of eater. The separated oil was extracted with ether. The ether solution was successively washed with 50 ml of water, 75 g of 5% aqueous sodium thiosulfate solution, and further twice with each 50 ml of water. The resulting solution was dried with anhydrous sodium sulfate, distilled off ether, and vacuum distilled to obtain 3.89 g (23 mM) of n-butylcatechol as light yellow liquid having a boiling point of 125° C./3 mmHg.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]>ClCCl>[Br:1][C:11]1[CH:12]=[CH:13][C:4]([OH:3])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrBr
Reactant: COC(=O)c1cccc(O)c1
Solvent: ClCCl
Product: COC(=O)c1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
Bromine (6.74 mL) was added to a solution of methyl 3-hydroxybenzoate (20.0 g) in dichloromethane (200 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated, diisopropyl ether (40 mL) was added and the solid separated out therefrom was filtered to give the aimed compound (28.3 g, 93%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:16][CH2:15][CH2:14][O:13][C:12]1[CH:17]=[CH:18][C:9]([NH:8][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:10][CH:11]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(Nc2ncc(Br)cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(Nc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-(5-Bromopyrimidin-2-ylamino)phenoxy)ethanol 10 (26.6 mmol) is dissolved in DCM (50 mL) followed by addition of MsCl (32 mmol). The reaction vessel is chilled in an ice-water bath and triethylamine (53.3 mmol) is added slowly. The mixture is stirred at rt for 16 h. The solvent is removed and the residue is triturated with water (300 mL). The solid is filtered and dried under vacuum for 12 h to give 2-(4-(5-Bromopyrimidin-2-ylamino)phenoxy)ethyl methanesulfonate 11 as off-white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.71 (s, 1H), 8.54 (s, 2H), 7.59 (d, J=9.2 Hz, 2H), 6.93 (d, J=9.2 Hz, 2H), 4.52 (m, 2H), 4.22 (m, 2H), 3.24 (s, 3H). MS (m/z) (M+1)+: 388.0, 340.0.
Reaction SMILES: N(OCCC(C)C)=O.[C:9]1([C:15]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][C:22]3[N:21]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[N:20]=[C:19](N)[C:18]=3[CH:17]=[CH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:41]CI>>[I:41][C:19]1[C:18]2[CH:17]=[CH:16][C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][C:22]=2[N:21]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(N)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Reactant: ICI
Agent: CC(C)CCON=O
Product: Cc1ccc(S(=O)(=O)n2nc(I)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Temperature: 80 °C

Procedure:
1.21 cm3 of isoamyl nitrite are added to a solution of 1 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazol-3-ylamine in 10 cm3 of diiodomethane, and the solution obtained is heated in the region of 80° C. for one hour. The mixture is purified directly by flash chromatography on a column of silica [eluent: cyclohexane/ethyl acetate (95/5 by volume)], and 0.6 g of 3-iodo-6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazole is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[C:2]1[CH2:26][C:10]2([CH:15]=[CH:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1COCC[Si](C)(C)C.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[NH:13]1[CH2:12][CH2:11][C:10]2([C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2](=[O:1])[CH2:26]2)[CH2:15][CH2:14]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CC2(C=CN(C(=O)OCc3ccccc3)CC2)c2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: O=C1CC2(CCNCC2)c2cccnc2N1
Reaction time: 3 h
Yield: 74.8 %

Procedure:
To a mixture of benzyl 2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,2′,3,3′-tetrahydro-1H,1′H-spiro[1,8-naphthyridine-4,4′-pyridine]-1′-carboxylate (384 mg, 0.800 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). After 3 h, the reaction was concentrated, diluted with dichloromethane (10 mL) and ethylenediamine (720 mg, 12.0 mmol) was added. After 18 h, the reaction was concentrated, the residue partitioned between saturated aqueous NaHCO3 and dichloromethane, and the layers separated. The aqueous phase was extracted with further portions of dichloromethane (2×), the organic layers combined, dried, and concentrated. 10% Palladium on carbon (300 mg) was added to a solution of this material in EtOH (10 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 24 h, the mixture was filtered though celite and concentrated to give the title compound (130 mg). MS: m/z=218.1 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.14 (dd, J=1.6, 5.0 Hz, 1H), 7.80 (dd, J=1.6, 7.7 Hz, 1H), 7.10 (dd, J=5.0, 7.7 Hz, 1H), 2.98-2.95 (m, 4H), 2.78 (s, 2H), 1.96-1.90 (m, 2H), 1.69 (brd, J=11.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17](OCC)=[O:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([CH2:17][OH:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)c(F)c2)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(C(F)(F)F)c(F)c2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of ethyl 5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (2.0 g, 6.60 mmol) in tetrahydrofuran (25 mL) was added lithium aluminium hydride (375 mg, 9.89 mmol) and the reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched by the addition of water (0.18 mL) followed by an aqueous solution of 1N NaOH (0.18 mL) and finally water (0.54 mL) over a 30 minute period. The resultant viscous grey slurry was diluted with diethyl ether (50 mL) and stirred for 30 minutes before filtering through a celite pad. The cake was washed with diethyl ether (3×70 mL) and the filtrate evaporated to dryness in vacuo to obtain (5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazol-3-yl)methanol (1.43 g, 5.48 mmol).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1.O.[NH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[NH2:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1nc2ccc(Br)nc2s1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cccc(N)c3)nc2s1
Temperature: 94.5 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
N-(5-bromothiazolo[5,4-b]pyridin-2-yl)acetamide (1.504 g, 5.527 mmol), 3-aminophenylboronic acid monohydrate (1.316 g, 8.493 mmol), Pd(dppf)C12-DCM complex (604.4 mg, 0.7401 mmol), and potassium carbonate (2.292 g, 16.58 mmol) were suspended in 1,4-dioxane (45 ml) and water (15 ml) was added. Argon was bubbled through the solution for about 30 seconds, and then the flask was fit with a reflux condensor and placed in a preheated oil bath (90-99° C.) and stirred under argon for 4 hours. The reaction was cooled to room temperature, filtered, and the solid was washed with DCM and MeOH. The filtrate was concentrated, treated with DCM and MeOH, and filtered. The solid was collected and set aside, and the filtrate was concentrated, treated with Et2O, and filtered. Solid washed with Et2O. This solid was combined with the first batch and dried under high vacuum first at room temperature, and then at ˜50° C. This solid was treated with deionized water and filtered, and the solid was washed with water, collected, and dried under high vacuum in water bath (˜50° C.) to afford N-(5-(3-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)acetamide (1.22 g, 78% yield). MS (ESI pos. ion) m/z: 285. Calculated exact mass for C14H12N4OS 284.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[C:15](=O)[O:16]CC.[H-].[Na+].Cl>C(O)C>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:14]1[C:3]2[C:4]([C:10]([F:12])([F:11])[F:13])=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=2[NH:1][C:15]1=[O:16]
Reactant: CCOC(=O)N(Cc1ccccc1Cl)c1c(N)cc(C#N)cc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2Cc1ccccc1Cl
Yield: 95.8 %

Procedure:
Ethyl 2-amino-4-cyano-6-(trifluoromethyl)phenyl(2-chlorobenzyl)carbamate (338.7 mg) was dissolved in ethanol (20 ml), and to the solution was added sodium hydride (37.5 mg). The reaction mixture was heated at reflux for 1 hour. After allowing to cool, to the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted 4 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (287.0 mg, 96%).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:2]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[CH2:3][O:4]C(C)(C)C>C(O)(C(F)(F)F)=O.O>[NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[C@H:2]([C:9]([O:11][CH2:12][C:13]([Cl:14])([Cl:15])[Cl:16])=[O:10])[CH2:3][OH:4]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](CO)C(=O)OCC(Cl)(Cl)Cl)OCC1c2ccccc2-c2ccccc21
Reaction time: 5 h

Procedure:
Fmoc-Ser(tBu)-OTce was dissolved in TFA-H2O (19:1, 10 mL) and allowed to stir for 5 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (EtOAc-Hexane, 3:7) to give Fmoc-Ser-OTce (0.83 g, 1.8 mmol, 69% overall yield for the two steps).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:19]([OH:21])[CH3:20])[C@H:12]([CH3:18])[CH2:13][C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CCOCC.C(=O)(O)[O-].[Na+].O.CCOC(C)=O.CCCCCC>[C:19]([C@@H:11]([NH:10][S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])[C@H:12]([CH3:18])[CH2:13][C:14]([F:17])([F:16])[F:15])(=[O:21])[CH3:20]
Reactant: CC(O)[C@@H](NS(=O)(=O)c1ccc(Cl)s1)[C@H](C)CC(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)s1)[C@H](C)CC(F)(F)F
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A solution of 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(1-hydroxyethyl)-2-methylbutyl]thiophene-2-sulfonamide (0.390 g, 1.06 mmol) in CH2Cl2 saturated with water (30 mL) was stirred under nitrogen at 0° C. Dess-Martin periodinane reagent (0.95 g, 2.23 mmol) was added in one portion. The resulting suspension was stirred at 25° C., monitoring the progress of reaction by TLC analysis (1:2 EtOAc/hexane). As the rate of conversion of the starting material slowed, additional 1 mL portions of CH2Cl2 saturated with water were added (three portions over 15 min). After 19 h at 250C, the reaction was complete by TLC. The solution was diluted with Et2O (50 mL) and a solution of sodium thiosulfate, Na2S2O3 (11.83 mmol, 4.8 g, 11 eq) in 80% saturated aqueous sodium bicarbonate solution (40 mL) was added. The mixture was stirred rapidly for 10 min until both phases were clear. The layers were separated and the aqueous phase was extracted with ether (20 mL). The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to obtain a crude oil (0.38 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford N-[(1S,2R)-1-acetyl-4,4,4-trifluoro-2-methylbutyl]-5-chlorothiophene-2-sulfonamide as a white solid (0.265g, 73.10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](O)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=[O:21])[N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCNCC1
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Product: C[C@H]1C(=O)N(CCC(=O)N2CCCCC2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 73 %

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and piperidine gave the titled compound in 73% yield as white solid. MS: 441.1 (MH+, 2Cl).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([O:26]COCC[Si](C)(C)C)[C:23]4[C:18](=[C:19]([N:37]5[CH2:43][CH2:42][CH2:41][N:40]([CH3:44])[CH2:39][CH2:38]5)[CH:20]=[C:21]([O:35][CH3:36])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[NH:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:35][CH3:36])=[CH:20][C:19]=4[N:37]3[CH2:43][CH2:42][CH2:41][N:40]([CH3:44])[CH2:39][CH2:38]3)=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(N2CCCN(C)CC2)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(OCOCC[Si](C)(C)C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N2CCCN(C)CC2)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
A solution of 6-methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid (4-morpholin4-yl-phenyl)-amide (Reference Example 27d) (0.989 g, 1.59 mmol) in 20 mL methanol was poured into 300 mL 0.05 N hydrochloric acid. The clear dark yellow solution became cloudy within 5 minutes. The mixture was stirred at room temperature for 45 minutes and then adjusted to pH 7 with 10% sodium hydroxide. The resulting yellow precipitate was isolated by filtration, washed with water, and dried under high vacuum to afford the desired product as a yellow solid (0.629 g, 80%). 1H NMR (300 MHz, DMSO, d6) δ 9.97 (bs, 1 H, C(O)NH), 7.67 (d, 2 H, Jo=8.8 Hz, ArH2′ & H6′), 7.47 (bs, 1 H, ArH5), 7.00 (s, 1 H, C═CH), 6.99 (d, 2 H, Jo=8.8 Hz, ArH3′ & H5′), 6.71 (bs, 1 H, ArH7), 3.85 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.6 Hz, OCH2CH2N), 3.70 (bs, 2 H, ArNCH2CH2CH2NCH3), 3.55 (bs, 2 H, ArNCH2CH2NCH3), 3.09 (t, 4 H, J=4.6 Hz, OCH2CH2N), 2.95 (bs, 2 H, ArNCH2CH2NCH3), 2.73 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.36 (s, 3 H, NCH3), 2.07 (bs, 2 H ArNCH2CH2CH2NCH3); Mass Spec.: calc. for [C27H33N5O4+H]+ Theor. m/z=492; Obs.=492. Analysis for C27H33N5O4. 1.0 eq HCl. 0.3 eq H2O: Calculated C 60.79 H 6.54 N 13.13. Found C 60.82 H 6.53 N 13.17.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH:6]=[CH:5]1)=[N+:2]=[N-:3].[H-].[Na+].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O>O1CCCC1>[N:1]([C@@H:4]1[CH2:8][C@H:7]([O:9][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1C=C[C@@H](O)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CO[C@@H]1C=C[C@H](N=[N+]=[N-])C1
Temperature: 25 °C

Procedure:
(1S-cis)-4-Azido-2-cyclopenten-1-ol (3.4 g) (prepared as described by D. R. Deardorff et al., J. Org. Chem, 1989, 54, 2759) in tetrahydrofuran (60 ml) was added dropwise to a suspension of sodium hydride (1.1 g. of a 60% suspension in oil) in tetrahydrofuran (60 ml) at 0° C. On completion of the addition the mixture was allowed to warm to ambient temperature the added dropwise to a solution of tert-butyl bromoacetate (10.1 ml) in tetrahydrofuran (60 ml) at 0° C. Water (200 ml) was added and the product extracted into ethyl acetate (200 ml) then dried and concentrated. Purification (SiO2, ethyl acetate:isohexane,10:90, as eluent) afforded the subtitle compound (3.6 g).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].Br[CH2:8][C:9](=O)[C:10]([OH:12])=[O:11]>C1COCC1>[C:1]([CH2:3][C:4]1[S:5][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[N:6]=1)#[N:2]
Reactant: O=C(O)C(=O)CBr
Reactant: N#CCC(N)=S
Solvent: C1CCOC1
Product: N#CCc1nc(C(=O)O)cs1
Temperature: 0 °C
Yield: 48.1 %

Procedure:
(Cyano)thioacetamide (2 g, 19.97 mmol) was stirred in excess THF (40 mL) under nitrogen atmosphere. The solution was cooled to 0° C. and the solution of 3-bromopyruvic acid (3.33 g, 19.97 mmol) dissolved in 5 mL THF was added dropwise. The mixture was refluxed for 3 h. Solvent was evaporated and the crude product was purified by flash chromatography (silica, eluent: 0-40% DCM-10% MeOH/DCM mixture) to yield 1.615 g of the title compound. 1H NMR (400 MHz; CDCl3): δ 4.20 (s, 2H), 8.33 (s, 1H).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[O:11][CH3:12].[OH-].[Na+].[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O>CN(C)C=O.CCOCC>[CH2:7]([NH:8][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[C:4]([O:11][CH3:12])[CH:5]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc(CN)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCC#CCCCCCCCC(=O)NCc1ccc(O)c(OC)c1

Procedure:
2.4 g of 4-hydroxy-3-methoxybenzylamine-HCl was suspended in 35 ml of N,N-dimethylformamide (DMF), and stirred. Added were 5 ml of a 5N solution of NaOH, and the mixture was stirred for an additional 10 to 15 minutes. The DMF mixture was chilled in an ice bath, and the stearoyl chloride, prepared above and dissolved in ether, was added dropwise. The mixture was then stirred for 3 hours, allowing it to come to room temperature. The mixture was then poured into 300 ml water, layers separated, and the aqueous layer extracted with ethyl ether. The extracts were washed with HCl, sodium bicarbonate, water, and brine, and then dried and filtered. 5.3 g of crude N-vanillyl-9-octadecynamide was obtained. Purification by recrystallization from toluene and hexane, and then benzene and hexane, gave 2.8 g of analytically pure product. Its structure was confirmed via nuclear magnetic resonance and infrared spectroscopy.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[N:35]1([C:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[N:3]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)=[O:14])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1
Reactant: C1CCNCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1)N1CCCCC1
Temperature: 0 °C
Yield: 26.2 %

Procedure:
3-Oxo-2-(5-chloro-2-pyridyl)isoindoline-1-acetic acid (1 g) and triethylamine (0.8 g) were dissolved in 20 ml of dry tetrahydrofuran and, under ice-cooling with stirring, 0.39 g of ethoxycarbonyl chloride was added portionwise. The mixture was stirred for 3 minutes, 0.56 g of piperidine was added, and the whole mixture was stirred for an additional 30 minutes. The reaction mixture was poured into 500 ml of ice water, followed by extraction with ethyl acetate. The extract was washed with water and dried. The ethyl acetate was then distilled off and the residue was treated with ether. The resulting crystals thus obtained were collected by filtration and recrystallized from ethyl acetate to give 0.32 g of colorless crystals, melted at 165°-166° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1.[F:32][C:33]([F:40])([F:39])[CH:34]=[CH:35][C:36](O)=[O:37].O>C1COCC1.CN(C=O)C>[Br:31][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:36](=[O:37])[CH:35]=[CH:34][C:33]([F:40])([F:39])[F:32])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: O=C(O)C=CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(C=CC(F)(F)F)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Yield: 34.8 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol) was added to a solution of 6-amino-4[(3-bromophenyl)amino]quinazoline (158 mg, 0.5 mmol) and 4,4,4,-trifluorobut-2-enoic acid (153 mg, 1.1 mmol) in THF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 1 hour water (10 mL) was added and after 15 minutes the precipitate was collected by Buchner filtration. The residue was rinsed with water (2×5 mL) and ether (10 mL) and air dried. The solid was suspended in EtOAc, (10 mL) refluxed briefly, and sonicated for 10 minutes, and the solid was collected by Buchner filtration, rinsed with EtOAc (5 mL) and dried in a vacuum oven at 75° C. for 1.5 hours to give N-[4-[(3-bromophenyl)amino]-quinazolin-6-yl]4,4,4-trifluorobut-2-enamide 0.4 hydrochloride (76 mg, 33%) as a light yellow solid, mp 273-278° C. Calculated for C18H13BrF3N4O.0.4 HCl: C, 47.85; H, 2.77; N, 12.40%. Found: C, 47.89, H, 2.66; N, 12.27%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:14](=[O:17])[CH:15]=[CH2:16]
Reactant: CNCc1sc2ccccc2c1C
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1sc2ccccc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine (1.95 g, 11.4 mmol) in CH2Cl2 (40 mL) was treated with acryloyl chloride (1.2 mL, 14 mmol) and triethylamine (3.2 mL, 22 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 (100 mL). The solution was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (silica gel, EtOAc/hexanes, 40/60) gave the title compound (2.10 g, 75%) as a pale yellow solid: MS (ESI) m/e 246 (M+H)+.