Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][CH2:8][C:9]1[N:10]([CH2:22][C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH3:6].C(N(CC)CC)C>ClCCl>[C:1]([N:26]1[CH2:27][CH2:28][C:23]([CH2:22][N:10]2[C:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=[C:9]2[CH2:8][O:7][CH2:5][CH3:6])([OH:29])[CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(C)=O)CC1
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Acetyl chloride (0.57 mL, 8.1 mmol) was added to a suspension of 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol (2.50 g, 7.34 mmol) and triethylamine (1.50 mL, 11.0 mmol) in dichloromethane (37 mL) at rt. The resulting solution was stirred for 1 h. The solution was diluted with dichloromethane (100 mL) and washed with water (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The combined aqueous layers were back-extracted with dichloromethane (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to a brown foam. Purification by flash chromatography (silica gel, eluted with 10% methanol/dichloromethane) provided 1-acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol as a white foam (1.8 g, 64%).
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=O)=[CH:6][CH:5]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCO>O>[F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14](/[CH:15]=[N:32]/[NH:31][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)(=[O:29])=[O:30])[CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=Cc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N/N=C/c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 3-{[4-(difluoromethoxy)phenyl]ethynyl}benzaldehyde (3.69 g, 13.57 mmol), 4-methylbenzenesulfonohydrazide (2.9 g, 15.6 mmol) and EtOH (11 mL) was refluxed for 30 minutes. cooled to room temperature, poured into water and extracted with ethyl ether. The organic extracts were combined dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel (Biotage) using hexanes/EtOAc (2/1) as the eluting solvents to give N′-[(1E)-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzenesulfonohydrazide as a tan solid (5.4 g, 90% yield), MS m/e (M+H)+ 441; 1H NMR (400 MHz, DMSO-d6) 2.32 (s, 3H), 7.2 (d, J=8.66 Hz, 2H), 7.3-7.6 (m, 8H), 7.72 (d, J=8.3 Hz, 2H), 7.88 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[P:21](Cl)([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][P:21]([NH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3)(=[O:22])[O:26][CH2:27][CH3:28])[CH3:25]
Reactant: CCOP(=O)(Cl)OCC
Reactant: NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Solvent: CN(C)C=O
Product: CCOP(=O)(NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2)OCC
Yield: 50 %

Procedure:
To a solution of compound 49 (0.5 mmol) in anhydrous DMF (20 mL) was added diethyl chlorophosphate (1.5 mmol). After 3 hours solution was concentrated in vacuo, and 50 mL of water was added. The aqueous layer was extracted with 30 mL of EtOAc twice. Organic layers were combined and washed with 30 mL of brine. Organic layer was dried with MgSO4. Solvent was removed to afford a white solid, which was recrystallized in 10% of EtOAc in hexanes to afford a white solid 54 in 50% yield. MS (ES−): 400; Mp: 222.3-224.5° C.; 1H-NMR (CDCl3, 400 MHz): 10.21 (s, 1H), 8.10 (d, J=2.5 Hz, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.5 and 2.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 4.12 (m, 6H), 1.32 (t, J=6.5 Hz, 6H); Anal. Calcd. for C19H20N3O5P.(0.3H2O): C, 56.10; H, 5.10; N, 10.33. Found: C, 56.00; H, 5.03; N, 10.13.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH:15]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([N:14]2[CH:15]=[C:11]([CH2:10][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[CH:12]=[N:13]2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: Cc1ncc[nH]1
Reactant: ClCc1cnn(-c2ccc(Cl)c(Cl)c2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1nccn1Cc1cnn(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
2-Methylimidazole was deprotonated with sodium hydride and then treated with 4-chloromethyl-1-(3,4-dichloro-phenyl)-1H-pyrazole. Extractive and chromatographic workup gave the title compound as a white crystalline solid. Mp. 176-177° C. (AcOEt), MS: m/e=307 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:4]=2[C:5]2[C:19]([CH3:20])=[N:18][O:17][C:6]=2[C@H:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:8]=1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:25][C:22]1[S:21][C:4]2[C:5]3[C:19]([CH3:20])=[N:18][O:17][C:6]=3[C@H:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:8]=[C:2]([O:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:3]=2[C:23]=1[CH3:24]
Reactant: Oc1ccccc1
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(Cl)=N[C@H]2CC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: Cc1noc2c1-c1sc(C)c(C)c1C(Oc1ccccc1)=N[C@H]2CC(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 7.9 %

Procedure:
A mixture of tert-butyl 2-((6S)-4-chloro-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate, a form of intermediate 18, prepared according to Example 14 (0.220 g, 0.58 mmol) and phenol (0.276 g, 2.90 mmol) in pyridine (1 mL) was heated at 130° C. for 1 h by MW. After the solvent was removed in vacuo, the residue was washed with 1 N NaOH, dried by anhydrous Na2SO4. The product was purified by Prep-TLC (PE:EA=4:1) to give tert-butyl 2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate (0.020 g, 7.9% yield) as a white solid. tert-butyl 2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate was converted to target compound 2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamide using Step L in Example 14. 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 2H), 7.22-7.07 (m, 3H), 6.07 (s, 1H), 5.18 (s, 1H), 4.46 (q, J=4.5 Hz, 1H), 2.99-2.84 (m, 2H), 2.48 (s, 3H), 2.45 (s, 3H), 2.42 (s, 3H); LC/MS m/z 382 [M+H]+.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22](C(OC4C=CC=CC=4)=O)[CH2:21][CH2:20]3)=[N:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C.O>[N:19]1([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=C(Oc1ccccc1)N1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 1-benzenesulfonyl-3-(1-phenoxycarbonyl-4-piperazinyl)-1H-indazole (31.3 g, 67.7 mmol) in ethanol (500 ml) was added 50% KOH (aq). (100 g of KOH in 100 g H2O) at room temperature. The reaction mixture was warmed to reflux for 6.5 hours and cooled to room temperature. After adjuting the pH to about two using HCl (con., 120 ml), the volatiles were removed under reduced pressure. The remaining residue was diluted with water and removed via filtration. The aqueous filtrate was washed with EtOAc and basified to pH=8 using 50% NaOH (aq.). The product was extracted into 10:1 dichloromethane/isopropylalcohol. The combined organics were dried (MgSO4), filtered, and concentrated to give 13.0 g of desired 3-piperazin-1-yl-1H-indazole as a brown solid which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)(O)[CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C>[F:1][C:2]([F:14])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[CH2:4]
Reactant: COc1ccc(C(C)(O)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: C=C(c1ccc(OC)cc1)C(F)(F)F

Procedure:
9.0 g of 1,1,1-trifluoro-2-(4-methoxyphenyl)-2-propanol were heated with 0.4 g of p-toluenesulfonic acid hydrate in 30 ml of glacial acetic acid until the elimination of water had ended. The reaction solution was concentrated, the residue was taken up in water, neutralised with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. Distillation of the residue under reduced pressure (5.1×10−1 torr) gave the title product as a colourless oil.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:13][CH2:14]Cl)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].[CH2:40]([O:42][C:43](=[O:56])[CH2:44][S:45]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=1)(=[O:47])=[O:46])[CH3:41]>CC(C)=O>[CH2:40]([O:42][C:43]([C:44]1([S:45]([C:48]2[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=2)(=[O:47])=[O:46])[CH2:14][CH2:13][N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:3]1)=[O:56])[CH3:41]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccccc2)CC1

Procedure:
To a stirred solution of bis-(2-chloro-ethyl)-benzyl amine hydrochloride (6.6 g, 24.7 mmol), 18-Crown-6 (500 mg), and anhydrous K2CO3 (30 gm, excess) in dry acetone (250 ml), (4-methoxy-phenylsulfonyl)-acetic acid ethyl ester (6.12 gm, 24 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 16 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H2O. The organic layer was further washed well with water, dried over MgSO4, filtered and concentrated. The dark brown reaction mixture was purified by silica gel column chromatography by eluting it with 30% ethylacetate:hexane and the product 4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid ethyl ester was isolated as Brown oil. Yield: 6.0 g, 60%; MS: 418 (M+H).
Reaction SMILES: ClC1C2SC=CC=2N[C:6](=[O:10])[C:7]=1[C:8]#[N:9].[CH3:14][O:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[NH2:23])=[O:17].COC(=O)CC#N>>[CH3:14][O:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[NH:23][C:6](=[O:10])[CH2:7][C:8]#[N:9])=[O:17]
Reactant: N#Cc1c(Cl)c2sccc2[nH]c1=O
Reactant: COC(=O)c1sccc1N
Agent: COC(=O)CC#N
Product: COC(=O)c1sccc1NC(=O)CC#N

Procedure:
To prepare compounds of structure (I) with R2 as carbonitrile, and R1 and R3 as defined above, 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile, depicted by formula (12), was used as a key intermediate. To prepare this intermediate, methyl-3-amino-thiophene-2-carboxylate was reacted with methylcyanoacetate to yield intermediate 3-(2-cyano-acetylamino)-thiophene-2-carboxylic acid methyl ester, depicted by formula (10). This intermediate was converted to 7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile, depicted by formula (11), by reacting with sodium ethoxide, and was then converted into 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile, depicted by formula (12), as shown in Scheme 5.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)C.Cl>O1CCCC1>[CH3:21][S:20][C:16]1[N:15]=[C:14]([C:13]2[C:5]([CH:4]=[O:3])=[N:6][N:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=23)[CH:19]=[CH:18][N:17]=1
Reactant: CCOC(OCC)c1nn2ccccc2c1-c1ccnc(SC)n1
Agent: Cl
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(C=O)nn3ccccc23)n1
Yield: 78.3 %

Procedure:
A solution of 2-(diethoxymethyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (1.3 g, 3.8 mmol) in tetrahydrofuran (20 mL) was treated with aqueous hydrochloric acid (10 mL 4 M), the resultant solution was stirred for 18 h. The solvents were removed in vacuo and the residue was taken up in dichloromethane and the pH adjusted to >7 with 1N aqueous sodium hydroxide. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed flash chromatography on silica gel (1:1 to 1:2 hexane-ethyl acetate) provided 3-[2-(Methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine-2-carbaldehyde (804 mg, 790%) as a yellow solid. 1H NMR (CDCl3) δ 10.42 (s, 1H), 8.61–8.58 (m, 3H), 7.92 (d, 1H), 7.44 (m, 1H), 7.12 (m, 1H), 2.65 (s, 3H); MS m/z 271 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49].[Cl-].[NH4+]>O1CCCC1>[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48]([N:15]1[C:11]([C:10]2[C:5]([C:3]#[N:4])=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:12][C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:14]1)(=[O:50])=[O:49]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2Cl)c1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) at room temperature, and the mixture was stirred for 15 min. After stirring, 15-crown-5 (143 mg) and 2-chlorobenzenesulfonyl chloride (214 mg) were added dropwise and the mixture was further stirred at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with 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=9:1→2:1) to give the title compound as a pale-yellow oil (yield 211 mg, 87%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:11])[CH:8]=2)[NH:3]1.[CH2:12]([CH2:16][C:17](=O)[CH3:18])[C:13]([CH3:15])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:18][C:17]1[N:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C@H:2]([CH3:1])[CH2:10]3)[C:13]([CH3:15])=[CH:12][CH:16]=1
Reactant: CC(=O)CCC(C)=O
Reactant: C[C@@H]1Cc2cc(N)ccc2N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2
Temperature: 68 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (2R)-2,3-dihydro-2-methyl-1H-indol-5-amine (Step 1, 0.896 g, 6.05 mmol) in THF (180 mL) is added acetonylacetone (0.732 mL, 6.05 mmol) and p-toluenesulfonic acid (0.008 g). The reaction mixture is stirred at 68° C. for 6 h and then concentrated under reduced pressure, and the residue is purified by chromatography on a Biotage Flash 40M 90 g silica gel cartridge (10% EtOAc/Hexanes eluent) to give the title compound, MS (ESI+) for C15H18N2 m/z 227 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:29]1[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Product: CC(C)(C)CN(CCOc1ccc(S(C)(=O)=O)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methanesulfonylphenol: MS (ESI) m/z 455 (M+1).
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[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2[CH:34]=[CH:35][CH:36]=CC=2N=N1.C(N(CC)C(C)C)(C)C.NCC1CC1>CN(C=O)C.O>[CH:34]1([CH2:33][NH:29][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:36][CH2:35]1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (150 mg, 0.48 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (170 mg, 0.55 mmol), N,N-diisopropyl ethyl amine (410 μL, 2.4 mmol) and aminomethylcyclopropane (41 mg, 0.58 mmol). The resulting reaction mixture was stirred for 30 min at room temperature and diluted with water. The mixture was then extracted with ethyl acetate and the combined organic layers washed with aqueous sodium carbonate (saturated) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=90:10 to 60:40) (117 mg, 67%) which was obtained as an off-white solid. MS: m/e=365.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][N@@:7]1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:17]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: COC(=O)C1C[N@]1S(=O)(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)C1C[N@@]1S(=O)(=O)c1ccccc1

Procedure:
In analogy to example 1, (S)-2-benzenesulfonylamino-3-hydroxy-propionic acid methyl ester was treated with triphenylphosphine and DEAD to give (S)-1-benzenesulfonyl-aziridine-2-carboxylic acid methyl ester.
Reaction SMILES: Cl.[F:2][C:3]([F:31])([F:30])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)([OH:18])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1.[CH2:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Cl)=[CH:38][CH:37]=1)[C:33]#[CH:34].[F-].[K+]>>[CH2:32]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][N:15]2[CH2:16][CH2:17][CH:12]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]([F:30])([F:2])[F:31])=[CH:10][CH:9]=3)([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=3)[OH:18])[CH2:13][CH2:14]2)=[CH:40][CH:41]=1)[C:33]#[CH:34]
Reactant: C#CCOc1ccc(CCl)cc1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Product: C#CCOc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 64.7 %

Procedure:
A stirred mixture of 0.8 gram (0.0016 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine hydrochloride, 0.3 gram (0.0016 mole) of 4-(2-propyn-1-yloxy)phenylmethyl chloride and 0.5 gram (0.0079 mole) of potassium fluoride on Celite® filter aid in 50 mL of acetonitrile was heated at reflux for about 1.3 hours. After this time 0.5 mL (excess) of triethylamine was added, and the reaction mixture became homogeneous. Upon completion of addition, the reaction mixture was heated at reflux for an additional 18 hours. After this time the reaction mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with mixtures of 10-70% diethyl ether in hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.6 gram of N-[4-(2-propyn-1-yloxy)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([CH2:12]C)[CH2:8][CH2:9]CC)(=[O:4])[CH:2]=[CH2:3].C(O[CH2:20][CH2:21][CH2:22][CH3:23])(=O)C(C)=C.C=CC=C.C=CC(=C)C>>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[CH2:9]=[CH:8][C:7](=[CH2:6])[CH3:12].[CH2:20]=[CH:21][CH:22]=[CH2:23]
Reactant: C=C(C)C(=O)OCCCC
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: C=CC=C
Solvent: C=CC(=C)C
Product: C=CC(=O)[O-]

Procedure:
The procedure of preparation example 3 was repeated with the exception that 70 parts by weight of 2-ethylhexyl acrylate was charged in place of 80 parts by weight of butyl methacrylate and, after sufficient replacement of the atmosphere with nitrogen, 20 parts by weight of butadiene and 10 parts by weight of isoprene were added in place of 20 parts by weight of isoprene, to prepare the objective graft copolymer.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O>CN(C=O)C>[CH3:27][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.34 g, 0.78 mmol) in DMF (10 mL) was added piperidine (0.27 g, 3.14 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, water was added and the product was extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with water, then brine, and dried over anhydrous Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 0.33 g (96%). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (br s, 1H), 7.87 (s, 2H), 6.72 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.86 (m, 6H), 3.82 (s, 2H), 2.63 (t, J=5.6 Hz, 2H), 2.42 (m, 4H), 2.28 (s, 6H), 1.50 (m, 4H), 1.37 (m, 2H). MS (ES) m/z 438.63 (M+1).