Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl[C:14]1=[C:15]([CH:40]=[CH:41][C:42]2[C:50]([CH3:52])([CH3:51])[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([S:53]([O-:56])(=[O:55])=[O:54])[CH:48]=3)[N+:43]=2[CH2:57][CH2:58][CH2:59][S:60]([O-:63])(=[O:62])=[O:61])[CH2:16][CH2:17][CH2:18]/[C:19]/1=[CH:20]\[CH:21]=[C:22]1/[C:23]([CH3:39])([CH3:38])[C:24]2[C:25](=[N:37]/1)[N:26]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])[CH:27]=[CH:28][CH:29]=2.[Na+:64].[Na+]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2/[C:15](=[CH:40]/[CH:41]=[C:42]3/[N:43]([CH2:57][CH2:58][CH2:59][S:60]([O-:63])(=[O:62])=[O:61])[C:44]4[C:49]([C:50]/3([CH3:51])[CH3:52])=[CH:48][C:47]([S:53]([O-:56])(=[O:54])=[O:55])=[CH:46][CH:45]=4)/[CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=[CH:21][C:22]2[C:23]([CH3:39])([CH3:38])[C:24]3[C:25]([N:37]=2)=[N+:26]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])[CH:27]=[CH:28][CH:29]=3)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Na+:64].[Na+:64]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC1(C)C2=CC=CN(CCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCCC(C=CC2=[N+](CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl
Agent: CC1(C)C(/C=C/C2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]
Agent: CC1(C)C2=CC=CN(CCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCCC(/C=C/C2=[N+](CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl
Agent: [Na+]
Product: CC1(C)C(C=CC2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 17 is prepared analogously to compound 10 (Example 10), except that 4-carboxyphenylboronic acid and compound 16 are used as starting materials.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:14]([Si:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:18][CH2:19][CH2:20][CH:21]1[CH2:24][CH:23]([O:25][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)[CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](OCCC1CC(O)C1)(c1ccccc1)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OCCC1CC(OC2CCCCO2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105 %

Procedure:
3-(2-{[Tert-butyl(diphenyl)silyl]oxy}ethyl)cyclobutanol (3.58 g, 10.1 mmol) was dissolved in dry tetrahydrofuran (50 mL) and 2,3-dihydro-4H-pyran and 4-toluenesulfonic acid pyridine salt were added and the reaction was stirred at room temperature for 48 hours. The reaction was concentrated in vacuo and purified on silica gel with a heptane-ethyl acetate gradient (5% ethyl acetate, then 20% ethyl acetate) to give crude tert-butyl(diphenyl){2-[3-(tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethoxy}silane (4.66 g, 105%) as a milky oil. Partial 1H NMR indicated a ˜4:1 mix of unknown cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.05 (m, 0.80H), 4.30 (m, 0.20H), 4.52 (m, 0.20H), 4.56 (m, 0.80H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]([C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:17][C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:29][C:30]([NH2:32])=[NH:31])=[N:5][CH:4]=1.Cl.NC(N)=N.[C:38](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)[C@H](C1C=CC=CC=1)C)([CH3:41])([CH3:40])[CH3:39]>COCCOC>[C:38]([O:19][C:18](=[O:20])[CH2:17][N:16]([S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:11][CH:10]=1)(=[O:14])=[O:15])[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@@H](c1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reactant: C[C@@H](c1ccccc1)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: COCCOC
Product: C[C@@H](c1ccccc1)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 57.5 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1S)-1-phenylethyl]glycine hydrochloride ##STR29## NaH (30 mg, 80% dispersion by wt in mineral oil, 1.01 mmol) was added in one portion to a stirred suspension of guanidine hydrochloride (154 mg, 1.61 mmol) in DME (6.0 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-[(1S)-1-phenylethyl]glycine t-butyl ester (200 mg, 0.40 mmol) in DME (3.0 mL) was added and the mixture heated at 95° C. for 5 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using pentane-EtOAc (50:50 to 33:66) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1S)-1-phenylethyl]glycine t-butyl ester (128 mg, 0.23 mmol) as pale yellow foam after repeated evaporation from CH2Cl2.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[NH:35][CH:36]=[N:37][C:30]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:37]1[C:30]2[C:31](=[N:32][CH:33]=[CH:34][C:29]=2[NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[C:13](=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:27])[N:6]=2)[CH2:3][CH3:4])[NH:35][CH:36]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Reactant: Clc1ccnc2[nH]cnc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ccnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 7-chloro-3H-imidazo[4,5-b]pyridine (23 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=3)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.C(P(CCCC)CCCC)CCC.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([CH:17]=[C:18]([CH3:20])[CH:19]=3)[O:21][CH2:35][CH2:36][CH2:37][OH:38])(=[O:11])=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of 3-(benzo-2,1,3-thiadiazole-4-sulfonyloxy)-5-methylphenol (645 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a pale yellow oil (615 mg, 82%). 1H-NMR (300 MHz, CDCl3) δ 8.35 (d, J=8.7 Hz, 1H), 8.26 (d, J=7.1 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 6.59 (s, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.80 (t, J=6.0 Hz, 2H), 2.21 (s, 3H), 1,96 (m, 2H), 1.65 (br s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:16][C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18]1
Reactant: F[C@@H]1CCNC1
Reactant: CCOC(=O)c1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(OCCN2CC[C@@H](F)C2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-[(2-bromoethyl)oxy]benzoate D46 (200 mg) and (3R)-3-fluoropyrrolidine (129 mg, 1.025 mmol) in Acetonitrile (10 ml) was added K2CO3 (213 mg, 1.538 mmol). The reaction mixture was stirred at 60° C. overnight. The reaction mixture was filtered and the filtrate was concentrated to give the expected product D48 in 220 mg. LCMS: rt=1.63 min, M+H=282.1 (5 min run)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:12]1([CH2:18][CH2:19][CH2:20]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[C:12]1([CH2:18][CH2:19][CH2:20][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
2.77 g of 4-hydroxybenzaldehyde were dissolved in 30 ml of DMF, and 0.95 g of 60% NaH were further added to the resultant solution. The solution was then stirred for 1 hour after elevating the temperature of the solution up to room temperature. After cooling the solution with ice, 4.3 g of 3-phenyl-1-bromopropane were fed dropwise thereto and the solution was then further stirred for 1 hour at room temperature and subsequently for a night at 50-60° C. The solution reacted was poured into ice-water, extracted with ethyl acetate, then the organic layer resulted was dried with anhydrous magnesium sulfate. Then, the solvent used was distillated under reduce pressure, and the residue obtained was purified by using silica gel column chromatography, for which a mixture of hexane and ethyl acetate (mixing ratio, 4:1) was used for the developer, thereby affording 4.9 g of 4-(3-phenylpropyloxy)benzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([OH:19])[CH2:16][CH:15]2[C:20](=[O:29])[N:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])[CH3:22])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:40][O:41][CH2:42][CH3:43]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][CH2:40][O:41][CH2:42][CH3:43])[CH2:16][CH:15]2[C:20](=[O:29])[N:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])[CH3:22])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reactant: CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)C1CC(OCOCC)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the diene 1c (7.94 g, 0.02 mol) in DCM and DIPEA (9.7 ml, 6 eq) at 0° C. (ice-bath) was added chloromethylethyl ether (2.79 g, 3 eq). The reaction mixture was stirred at room temperature overnight, concentrated by rotary evaporation and purified by column chromatography on silica gel (EtOAc/petroleum ether 1:1→1:0) which gave the pure title compound as slightly yellow syrup (6.67 g, 74%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].CN(C)C(N(C)C)=N.Cl>O1CCCC1.C(OCC)(=O)C>[C:7]1([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]2[C:20](=[O:22])[CH2:21][O:17][C:18]2=[O:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1COC(=O)N1
Reactant: BrCCCCOc1cccc2ccccc12
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1COC(=O)N1CCCCOc1cccc2ccccc12
Yield: 60.2 %

Procedure:
A solution of 3.1 g (11.1 mmol) of 1-[(4-bromobutyl)oxy]naphthalene (Eur. J. Med. Chem. 1997, 32, 175-179) and 1.35 g (13.3 mmol) of 1,3-oxazolidine-2,4-dione (J. Med. Chem. 1991, 34, 1542-1543) in 30 ml of tetrahydrofuran is admixed dropwise with a solution of 2.55 g (22.2 mmol) of 1,1,3,3-tetramethylguanidine in 15 ml of tetrahydrofuran. The mixture is heated at reflux for 8 hours. 0.28 g (2.7 mmol) of 1,3-oxazolidine-2,4-dione and 0.32 g (2.7 mmol) of 1,1,3,3-tetramethylguanidine are added and the mixture is heated at reflux for 4 more hours. The reaction mixture is cooled using an ice bath, and 100 ml of ethyl acetate and then 50 ml of 1M aqueous hydrochloric acid are added. The system is decanted and the aqueous phase is extracted with 2×80 ml of ethyl acetate. The organic phases are subsequently washed with 80 ml of water and then with 80 ml of saturated aqueous sodium chloride solution. They are dried over sodium sulfate and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate, to give 2.0 g of product, which is used as it is in the following step.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:26])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:8][CH:9]=1)=[O:4].[OH-].[K+]>CO.O>[C:22]([O:21][C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:10]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)=[O:26])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
To a suspension of 18.5 g (50 mmol) 5-(2-tert-Butoxycarbonylamino-phenyl-carbamoyl)-thiophene-2-carboxylic acid methyl ester in 500 ml MeOH was added within 20 minutes a solution of 5.6 g (100 mmol) potassium hydroxide in 100 ml water. The reaction mixture was stirred at room temperature for 2 d. The MeOH was evaporated and the remaining aqueous solution was extracted three times with ethylacetate and acidified with a 3N aqueous HCl solution. The precipitation was filtered off, washed with water and dried at 45° C. in high vacuum to yield 14.5 g (40 mmol) 5-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-thiophene-2-carboxylic acid., 1H-NMR (D6-DMSO) δ=1.45 (s, 9H), 7.14 (m, 1H), 7.22 (m, 1H), 7.46 (m, 1H), 7.59 (m, 1H), 7.90 (m, 2H), 8.72 (s, 1H), 9.99 (s, 1H), 13.54 (s, 1H).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:69][N:70]1[CH2:75][CH2:74][S:73][CH2:72][CH2:71]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:68])[S:59]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:68][N:58]([C:52]1[CH:53]=[CH:54][CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:69][N:70]3[CH2:71][CH2:72][S:73][CH2:74][CH2:75]3)[CH2:45][N:46]=1)=[CH:57]2)[S:59]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=1)(=[O:60])=[O:61]
Reactant: CN(c1cccc2cc(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 0.33 h
Yield: 5.3 %

Procedure:
To a solution of triphenylphosphine oxide (0.79 g) in dichloromethane (5 mL) was slowly added trifluoromethanesulfonic anhydride (0.38 mL) under ice-cooling, and the mixture was stirred for 20 min. A solution of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (0.67 g) in dichloromethane (5 mL) was added dropwise, and the mixture was stirred for 1 hr under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=4:6-6:4). The obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (29 mg, yield: 5%) as colorless crystals. MS: 488 (MH+). melting point 142-144° C.
Reaction SMILES: [CH2:1]([O:13][CH:14]([CH3:17])[CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>O>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:16][CH2:15][CH:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:17])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCCCOC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 9 h

Procedure:
6.6 g of 2-dodecyloxypropanol and 20 ml of dry pyridine were mixed and cooled with NaCl-ice. 8.0 g of p-toluenesulfonic acid chloride was added little by little, and the reaction was continued for 9 hours. The reaction mixture returned to room temperature was mixed with a mixture of 30 ml of conc. hydrochloric acid added to 110 g of water, and the mixture was extracted with benzene and dried over anhydrous Na2SO4. Evaporation of benzene gave (2-dodecyloxypropyl) p-toluenesulfonate as an oily product. Yield: 10.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14]([C:20]#[C:19][C:21]4[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: Fc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Product: Nc1ncc(C#Cc2cnc3c(F)cc(-c4ccc(Cl)cc4)cn23)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-fluoro-3-iodo-imidazo[1,2-a]pyridine (example C.30 step 2) (300 mg, 0.8 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (115 mg, 0.8 mmol) according to general procedure II. Obtained as an off-white solid (101 mg, 34%). MS (ISP) 364.1 [(M+H)+],366 [(M+2+H)+]; mp 279–280° C.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.N1CC[O:27][CH2:26][CH2:25]1.C(Cl)(=O)C>C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:26](=[O:27])[CH3:25])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 3 h

Procedure:
To a solution of cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone [Enantiomer C] (CC-039) (0.150 g, 0.45 mmol) in DCM (2 mL) was added polymer supported morpholine (2.5 equivalents) and acetyl chloride (0.51 mmol). The reaction mixture was stirred for 3 hours, filtered and then the solvent evaporated. The product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.095 g). LCMS m/z 375.27 [M+H]+ RT=9.71 min (Analytical Method 2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1)[CH:8]=[CH:7]2)([O-])=O>ClCCl.CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2nc(C3CCCCN3)ccc2c1
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc2nc(C3CCCCN3)ccc2c1

Procedure:
Prepared analogously to Example 3.1.b. from 6-nitro-2-piperidin-2-yl-quinoline. Yield: 0.79 g (59.6% of theory); C14H17N3 (M=227.31); calc.: molecular ion peak (M+H)+: 228; found: molecular ion peak (M+H)+: 228; Rf value: 0.37 (silica gel, dichloromethane/methanol (19:1)).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:3]=1.[N:18]([CH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[CH3:22])=[N+]=[N-].C(C1C=CC(C#N)=CC=1)(=O)C.C1([Se][Se]C2C=CC=CC=2)C=CC=CC=1.C(P(CCCC)CCCC)CCC>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:18][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])=[C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:3]=1
Reactant: O=C(O)c1sc(Cl)cc1Cc1cccc(Cl)c1
Reactant: CC(N=[N+]=[N-])c1ccc(C#N)cc1
Agent: CC(=O)c1ccc(C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: c1ccc([Se][Se]c2ccccc2)cc1
Solvent: CC#N
Product: CC(NC(=O)c1sc(Cl)cc1Cc1cccc(Cl)c1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 5-chloro-3-(3-chlorobenzyl)thiopbene-2-carboxylic acid from Example 1, Step 6 (230 mg, 0.801 mmol), 4-(1-azidoethyl)benzonitrile (146 mg, 0.848 mmol) [prepared according to Thompson et al. J. Org. Chem. 1993, 58, 5886, after reduction of commercially available 4-acetylbenzonitrile] and diphenyl diselenide (549 mg, 1.76 mmol) in acetonitrile at r.t. under N2 was added tributylphosphine (217 μL, 0.881 mmol, 1.1 eq) dropwise (suspension dissolved, slightly exothermic) and the mixture was stirred at r.t. for 6 h, quenched with saturated NaHCO3 and extracted with ether. The crude was purified by Combi Flash chromatography system (10-40% EtOAc/hexane) to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.O.[C:8]([OH:12])(=[O:11])[CH:9]=[O:10].[OH-].[Na+].C>>[OH2:10].[OH:10][CH:9]([C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)[C:8]([OH:12])=[O:11]
Reactant: Nc1nccs1
Reactant: O=CC(=O)O
Agent: N=c1[nH]ccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(C(O)C(=O)O)s1
Reaction time: 1.5 h

Procedure:
A mixture of 2-amino-1,3-thiazole, which can be represented as 2-imino-2,3-dihydro-1,3-thiazole, (36.3 g.), glyoxylic acid hydrate (50 g.) and 1N sodium hydroxide (543 ml.) was stirred for 1.5 hours at 90° to 93° C. After the reaction, the reaction mixture was treated with an activated charcoal and then adjusted to pH 3. The mixture was allowed to stand overnight under ice-cooling. The precipitates were collected by filtration, washed with water and then dried to give 2-hydroxy-2-(2-amino-1,3-thiazol-5-yl)acetic acid hydrate, which can be represented as 2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetic acid hydrate (48.1 g.), mp. 140° to 200° C. (dec.).