Azzindani/Open_Reaction_Data huggingface dataset:
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:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[O:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:28]([CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)=[O:29])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: O=C(Cl)C1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C2CCOCC2)nn1
Yield: 91 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using tetrahydro-2H-pyran-4-carbonyl chloride instead of methoxyacetyl chloride, to the title compound (360 mg, 91%) which was obtained as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([O-:5])=O.CCN(CC)CC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([C@@H:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:33]=1>C1COCC1.ClC(OCC)=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([C@@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:3](=[O:5])[C:2]([F:1])([F:17])[C:6]2([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]2)[CH:33]=1
Reactant: COc1ccc(OCc2cc([C@@H]3CCCN3)no2)cc1OC
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)[O-])C1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)C(F)(F)C3(O)CC(C)(C)CC(C)(C)C3)no2)cc1OC
Reaction time: 0.5 h
Yield: 217 %

Procedure:
To a solution of 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetate (87.83 g) and Et3N (122 mL) in THF (2000 mL), ethyl chloroformate (30.8 mL) was added at room temperature and the mixture was stirred for 30 minutes. To the reaction mixture, a THF (500 mL) solution of the compound (89.00 g) obtained in Example 1-(1) was added dropwise at room temperature over an hour and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and AcOEt (2 L) and a saturated aqueous solution of NH4Cl (2 L) were added; after filtering the insoluble matter, the organic layer was separated and washed with saturated aqueous sodium bicarbonate (2 L), dried (MgSO4), filtered and concentrated to give a crude product (165.0 g). A similar method was applied using 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetate (34.64 g) and (S)-5-((3,4-dimethoxyphenoxy)methyl)-3-(pyrrolidin-2-yl)isoxazole (35.10 g) to give a crude product (60.10 g), which was combined with the first crude product and further purified by silica gel chromatography (AcOEt/hexane) and NH-form silica gel chromatography (AcOEt/hexane); the purified product was recrystallized (Et2O/pentane) to give the titled compound (134.30 g, colorless powder.)
Reaction SMILES: Cl.[C:2]1(C)C=CC(NN)=CC=1.BrCCC1C=CC(C(F)(F)F)=NC=1.FC(F)(F)C1N=CC(CCN(C2C=CC(C)=CC=2)N)=CC=1.C(OC(OCC)CCCNC)C.[F:57][C:58]([F:82])([F:81])[C:59]1[N:64]=[CH:63][C:62]([CH2:65][CH2:66][N:67]2[C:75]3[C:70](=[CH:71][C:72]([CH3:76])=[CH:73][CH:74]=3)[C:69]([CH2:77][CH2:78][NH:79][CH3:80])=[CH:68]2)=[CH:61][CH:60]=1.C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[F:82][C:58]([F:57])([F:81])[C:59]1[N:64]=[CH:63][C:62]([CH2:65][CH2:66][N:67]2[C:75]3[C:70](=[CH:71][C:72]([CH3:76])=[CH:73][CH:74]=3)[C:69]3[CH2:77][CH2:78][N:79]([CH3:2])[CH2:80][C:68]2=3)=[CH:61][CH:60]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CNCCc1cn(CCc2ccc(C(F)(F)F)nc2)c2ccc(C)cc12
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: Cc1ccc(N(N)CCc2ccc(C(F)(F)F)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CN(C)CC1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using p-tolylhydrazine hydrochloride, 5-(2-bromoethyl)-2-(trifluoromethyl)pyridine, and triethylamine (General Method 1), 1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1-p-tolylhydrazine (Example 2) and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5-methyl-1H-indol-3-yl)-N-methylethanamine (Example 11), formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:28]1([NH:34][N:35]=[C:36]([C:40](Cl)=[O:41])[C:37](Cl)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[O:41]=[C:40]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:37](=[O:38])[C:36]1=[N:35][NH:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Reactant: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)Cn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C

Procedure:
N-isopropyl-N-phenyl-2-(2-phenylaminophenylamino)-acetamide (10 g) and 2-(phenyl-hydrazono)-propanedioyl dichloride (6.83 g), were each dissolved in THF (100 ml) and added simultaneously, with stirring, to a flask containing THF (100 ml) at 0° C., under nitrogen. The reaction mixture was allowed to warm to R.T. and stirred four hours. The THF was evaporated in vacuo and the residue was dissolved in ethyl acetate (200 ml). The ethyl acetate solution was washed with 10% aqueous sodium carbonate (2×200 ml) and water (2×200 ml), dried (Na2SO4), and concentrated in vacuo. The residual foam was treated with diethyl ether (50 ml) to precipitate the title compound as a bright yellow solid (7.5 g). The mother liquor was concentrated to a tan foam (2.5 g). 1H-NMR (300 MHz, CDCl3): d 11.4 and 10.85 (s, 1H), 7.6-6.8 (m, 19 H), 5.05 (m, 1H), 4.4 (m, 2H), 1.05 (m, 6H); MS (FAB)=532 (MH+); TLC, Rf=0.19 (hexane:ethyl acetate, 2:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:5]C(OC(C)(C)C)=O.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20].ClCCl>>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[NH2:5]
Reactant: COC(=O)[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)CC(C)(C)C

Procedure:
The (2S)—N-tert-butoxycarbonyl-3-tert-butyl-L-alanine methyl ester (529 mg, 2.04 mmol) is stirred at RT in TFA/dichloromethane 1:3 (3 ml), and the solution is concentrated on a rotary evaporator and dried under high vacuum. 540 mg (97% of theory) of product are obtained.
Reaction SMILES: BrC1C=C(C2C=NC=C(C=2NC2C=C3C(=CC=2)NC=C3)C#N)C=CC=1.Cl[C:27]1[C:32]([C:33]#[N:34])=[CH:31][N:30]=[CH:29][C:28]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1.[NH2:45][C:46]1[CH:47]=[C:48]2[C:52](=[C:53]([CH3:55])[CH:54]=1)[NH:51][CH:50]=[CH:49]2>>[CH3:44][O:43][C:37]1[CH:36]=[C:35]([C:28]2[CH:29]=[N:30][CH:31]=[C:32]([C:27]=2[NH:45][C:46]2[CH:47]=[C:48]3[C:52](=[C:53]([CH3:55])[CH:54]=2)[NH:51][CH:50]=[CH:49]3)[C:33]#[N:34])[CH:40]=[CH:39][C:38]=1[O:41][CH3:42]
Reactant: Cc1cc(N)cc2cc[nH]c12
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1OC
Agent: N#Cc1cncc(-c2cccc(Br)c2)c1Nc1ccc2[nH]ccc2c1
Product: COc1ccc(-c2cncc(C#N)c2Nc2cc(C)c3[nH]ccc3c2)cc1OC

Procedure:
Following procedures analogous to those described for preparing compound 113 (Example 2, Method B), the title compound was prepared from 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile and 5-amino-7-methylindole. MS: 385.3 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>CCO.CCOC(C)=O>[OH:22][NH:21][C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=[CH:5][CH:4]=1)=[NH:2]
Reactant: CN(C)C(=O)c1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(C(=N)NO)cc1
Temperature: 80 °C
Reaction time: 25 h
Yield: 79 %

Procedure:
4-cyano-N,N-dimethylbenzamide (200 mg, 1.148 mmol), potassium carbonate (952 mg, 6.89 mmol) and hydroxylamine hydrochloride (479 mg, 6.89 mmol) were dissolved in EtOH (11.4 mL). The reaction mixture was stirred at 80° C. for 25 h. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL), water phase extracted with EtOAc (20 mL). Combined organic phases were washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed to give 188 mg of white crystalline needles. The crude material was used without further purification.
Reaction SMILES: C([Li])CCC.CCCCCC.[S:12]1[CH:16]=[CH:15][N:14]2[CH:17]=[N:18][CH:19]=[C:13]12.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:20][Si:21]([CH3:23])([CH3:22])[C:16]1[S:12][C:13]2=[CH:19][N:18]=[CH:17][N:14]2[CH:15]=1
Reactant: C[Si](C)(C)Cl
Reactant: c1cn2cncc2s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)c1cn2cncc2s1
Reaction time: 0.5 h

Procedure:
A 1.6 N n-butyllithium/n-hexane, solution (16.7 ml) was added in an argon atmosphere at −50° C. to a solution of 3.17 g of imidazo[5,1-b]thiazole in 120 ml of dry THF. The mixture was stirred at the same temperature for 30 min. Trimethylsilyl chloride (3.54 ml) was added thereto, and the mixture was stirred for 20 min. A 1.6 N n-butyllithium/n-hexane solution (8.0 ml) was added thereto, and the mixture was stirred for 20 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was then added thereto, followed by washing with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 4.53 g of 2-(trimethylsilyl)imidazo[5,1-b]thiazole.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)[CH3:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CCOc1ccc(N=C=O)cc1
Product: CCOc1ccc(NC(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure P and Scheme AB using 1-ethoxy-4-isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 467.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]4[O:20][C:21]([C:24]5[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=5)=[CH:22][N:23]=4)=[O:18])=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[CH2:37][CH2:36]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCN(C)CC5)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 57.6 %

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (19 mg, 0.043 mmol) and 1-methyl piperazine (0.007 mL, 0.07 mmol) were dissolved in dichloroethane (2 mL) and NaBH(OAc)3 (18 mg, 0.086 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 3.5 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 2.5% Et3N/EtOAc) to furnish methyl 6-(2-(3-(4′-((4-methylpiperazin-1-yl)methyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a clear tan oil (13 mg, 58%): 1H NMR (CDCl3, 600 MHz) δ 8.11 (d, 1H, J=7.7 Hz), 8.02 (d, 2H, J=9.0 Hz), 7.96 (t, 1H, J=7.8 Hz), 7.51 (dd, 4H, J=8.2, 2.2 Hz), 7.36 (d, 2H, J=8.0 Hz), 7.33 (d, 2H, J=8.0 Hz), 4.03 (s, 3H), 3.54 (s, 2H), 3.51 (t, 2H, J=7.6 Hz), 3.15 (t, 2H, J=7.6 Hz), 2.50 (bs, 8H), 2.30 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.7, 139.3, 139.0, 138.3, 137.1, 129.6, 128.9, 128.0, 127.1, 126.8, 125.2, 123.3, 62.6, 55.1, 53.1, 53.0, 45.9, 40.6, 29.3; HR ESI-TOF m/z 525.2493 (M+H+, C31H32N4O4, requires 525.2496).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:32]=[CH:33][C:28]([CH2:27][O:26][CH3:25])=[CH:29][CH:30]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: COCc1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COCc1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Temperature: 120 °C
Yield: 17.1 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(methoxymethyl)phenylboronic acid (16.6 mg, 0.1 mmol). The mixture was heated at 120° C. in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-6-(4-(methoxymethyl)phenyl)-1′-methyl-2-phenylsp-iro[chroman-4,4′-imidazol]-5′(1′H)-one (3.8 mg, 15%). 1H-NMR (MeOD): 2.10 (t, 1H), 2.24 (t, 1H), 3.01 (s, 3H), 3.27 (s, 3H), 4.17 (m, 2H), 5.81 (d, 1H), 6.90 (m, 2H), 7.12 (d, 2H), 7.27 (m, 3H), 7.49 (m, 5H).
Reaction SMILES: [CH2:1]([C:3]1[C:14]([CH:15]([CH3:18])[CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:14]([CH:15]([CH3:18])[CH2:16][NH:17][C:26](=[O:28])[CH3:27])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccc3c(c2c1C(C)CN)CCO3
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nn2ccc3c(c2c1C(C)CNC(C)=O)CCO3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a solution of 2-(2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)propan-1-amine (118 mg, 0.481 mmol) and triethylamine (134 μL, 0.961 mmol) in tetrahydrofuran (5 mL) was added acetyl chloride (90.9 μL, 0.962 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. A saturated aqueous sodium hydrogen carbonate solution (100 μL) was added and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (133 mg, yield 96%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.N1C=CC=CC=1.[N:19]#[C:20][C:21]#[N:22]>C1(C)C=CC=CC=1>[C:20]([C:21]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:22]=1)#[N:19]
Reactant: N#CC#N
Reactant: Cc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c[nH]c(C#N)n2)cc1
Temperature: -78 °C
Yield: 52.4 %

Procedure:
0.93 g (5 mmol) of 2-amino-4'-methylacetophenone hydrochloride was suspended in 30 ml of toluene in a 50-ml stainless steel autoclave. To the suspension was then added 0.79 g (10 mmol) of pyridine. The suspension was then cooled to a temperature of -78° C. To the suspension was then added about 0.5 g (9.6 mmol) of cyanogen which had been cooled and solidified at a temperature of -78° C. The autoclave was then sealed. The suspension was heated at a temperature of 100° C. for 2.5 hours, and then allowed to cool. The content was then taken out of the autoclave. The reaction mixture was then extracted with ethyl acetate and water. The resulting organic phase was dried over anhydrous sodium sulfate, and then subjected to silica gel column chromatography to obtain 0.48 g (yield: 52 %) of 2-cyano-4-(p-tolyl)imidazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[OH:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:10][N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][C:13]=2[O:12][CH3:11])[CH2:32][CH2:31]1
Reactant: Fc1ccc(C2CO2)cc1
Reactant: COc1ccc2ccccc2c1CCCCN1CCNCC1
Solvent: CCO
Product: COc1ccc2ccccc2c1CCCCN1CCN(CC(O)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
0.80 g of the optically active form of 2-(4-fluorophenyl)oxirane was dissolved in ethanol, and 3.2 g of 1-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine was added, followed by reflux with heating or 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1) to give 1.2 g of optically active 1-[2-hydroxy-2-(4-fluorophenyl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin as a solid.
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].NCCC1C=CC([S:17]([NH2:20])(=[O:19])=[O:18])=CC=1.C(Cl)(Cl)Cl.C1(N=C=[N:33][CH:34]2CCCCC2)CCCCC1>C(#N)C.C(=S)=S>[S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].[S:17]([N:33]=[C:34]=[S:1])(=[O:19])(=[O:18])[NH2:20]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Agent: NC(=O)N=S(=O)=O
Solvent: ClC(Cl)Cl
Solvent: S=C=S
Solvent: CC#N
Product: NS(=O)(=O)N=C=S

Procedure:
A sulfonylurea derivative (SUNCS) is synthesized in preparation for making another sulfonylurea-containing initiator polymer. The preparation of SUNCS is achieved according to the synthetic scheme as illustrated in FIG. 3. 4-(2-Amino-ethyl)benzenesulfonamide (AEBS) is first dissolved in acetonitrile (or chloroform). In step 1 the AEBS solution is reacted with carbon disulfide (CS2) and dicyclohexylcarbodiimide (DCC). Dicyclohexylurea (DCU) product is removed from sulfamoyl-isothiocyanate (S-NCS) by filtration. The solvents are then removed to give the S-NCS intermediate. In step 2 the S-NCS, cyclohexyl isocyanate, and tetrabutylammonium bromide (TBAB) are placed in a glass vessel with tetrahydrofuran (THF) and the mixture is stirred under an inert dry atmosphere during the slow addition of sodium hydride (NaH). The SUNCS product (Compound IV, also shown in Table I) is then isolated and purified by flash chromatography.
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[C:51]([O:56][CH3:57])[CH:50]=2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.[Cl-].[Na+].O.O>[C:36]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([C:49]2[CH:54]=[CH:53][C:52]([NH:55][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([Br:1])[N:10]4[N:9]=3)=[C:51]([O:56][CH3:57])[CH:50]=2)[CH2:47][CH2:48]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: Oc1ncc2ccc(Br)n2n1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
In a 10 mL sealed tube, to 7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ol (150.0 mg, 0.701 mmol) and N,N-Diisopropylethylamine (0.488 mL, 2.80 mmol) in 3.8 mL of anhydrous DMF was added N-Phenylbis(trifluoromethanesulfonimide (263 mg, 0.736 mmol). After stirring at room temperature for 2 hours, 4-(4-Amino-3-methoxy-phenyl)-piperidin-1-carboxylic acid tert-butyl ester (214.7 mg, 0.701 mmol) was added. The reaction mixture was heated at 65° C. for 4 hours. The reaction was conc. in vacuo. Water and brine were added and the contents were extracted with DCM. The combined organic layers were dried with sodium sulfate, filtered, and conc. in vacuo. The reaction mixture was purified via silica gel column chromatography using 100:1 DCM:MeOH as the eluant to afford a the title compound as a red oil (52%). 1H NMR (DMSO-d6)-8.89 (s, 1H), 8.23 (d, 1H, J=8.20 Hz), 7.83 (s, 1H), 6.98-6.95 (m, 2H), 6.91 (d, 1H, J=4.72 Hz), 6.85 (d, 1H, J=8.52 Hz), 4.66-4.55 (br s, 1H), 4.16-3.99 (m, 3H), 3.89 (s, 3H), 2.87-2.75 (m, 2H), 1.78 (d, 2H, J=12.93 Hz), 1.70 (d, 1H, J=12.57 Hz), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.Cl[CH2:38][C:39]([NH2:41])=[O:40].CCN(CC)CC>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:7][C:2]4([CH3:1])[CH3:36])[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)n(C)c2n1
Reactant: NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CC(N)=O)CC3(C)C)n(C)c2n1
Reaction time: 84 h
Yield: 47.6 %

Procedure:
A mixture of 8-(2,2-dimethylpiperazin-1-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (120 mg, 0.25 mmol), 2-chloroacetamide (50 mg, 0.54 mmol) and NEt3 (50 μL, 0.36 mmol) in DCM (5 mL) was allowed to stir at r.t. for 5 h before further 2-chloroacetamide (100 mg, 1.07 mmol) and NEt3 (100 μL, 0.72 mmol) was added. The resulting mixture was allowed to stir for 84 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) affording 717 (65 mg, 49%). LCMS (method I): RT 2.54 min, [M+H]+ 547.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.99 (1 H, m), 7.77-7.74 (1 H, m), 7.32-7.22 (2 H, m), 6.95 (1 H, brd s), 5.43 (1 H, brd s), 4.34 (4 H, brd s), 3.90 (3 H, s), 3.86 (6 H, t, J=4.76 Hz), 3.35 (2 H, q, J=7.48 Hz), 2.96 (2 H, s), 2.62-2.45 (4 H, m), 2.38 (2 H, s), 1.45 (3 H, t, J=7.48 Hz), 1.25 (6 H, s)