Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH:8](Br)[CH3:9].CO[CH:13](OC)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCl>C1(C)C=CC=CC=1.BrCC>[CH:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][CH2:8][CH3:9]
Reactant: CC(Br)Br
Reactant: COC(CCCCCCCCCl)OC
Reactant: C1CCOC1
Agent: [Mg]
Solvent: CCBr
Solvent: Cc1ccccc1
Product: CCC=CCCCCCCCCCC=O
Reaction time: 8 h

Procedure:
To 0.85 gm of magnesium in a thoroughly dried flask equipped with condensor and magnetic stirrer was added 5 mls of anhydrous tetrahydrofuran and 0.5 ml of dibromo ethane. A solution of 4.5 gms of 1,1-dimethoxy-9-chlorononane in 40 mls of toluene was added dropwise. When addition was half complete, a few drops of bromoethane were added and the addition was continued. The temperature was maintained at 75°±5° for two hours. The Grignard reagent was decanted into another flask and 100 mgs of cuprous chloride (CuCl) catalyst was added, followed by dropwise addition of 3.0 gms of a mixture (approximately 60:40) of 1-chloro-2-pentene and 3-chloro-1-pentene dissolved in 15 mls of toluene. The reaction flask was cooled in a water bath at 20°±5°. Magnesium chloride began to precipitate after ten minutes. The reaction stood overnight at room temperature. 50 mls of 3 N hydrochloric acid was added and the reaction mixture was stirred and heated at reflux for 1 hour. The aqueous layer was separated and washed two times with toluene. The organic layer and the toluene washes were combined and dried over sodium sulphate. The solvents were removed on the rotary evaporator and the residue was distilled at 83° at 0.10 torr yielding 2.3 gms of crude 11-tetradecenal. GLC analysis showed that the contaminating 10-ethyl-11-dodecenal was present in only 11.5%. For physical constants see Example 5.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:63]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@H:64]([C:81](O)=[O:82])[CH2:65][CH2:66][CH2:67][CH2:68][NH:69][C:70]([O:72][CH2:73][C:74]1[CH:80]=[CH:79][CH:78]=[CH:77][C:75]=1[Cl:76])=[O:71].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:63]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@H:64]([C:81]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:82])[CH2:65][CH2:66][CH2:67][CH2:68][NH:69][C:70]([O:72][CH2:73][C:74]1[CH:80]=[CH:79][CH:78]=[CH:77][C:75]=1[Cl:76])=[O:71]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2Cl)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
At 0° C. the solution of 746 mg (0.81 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 50 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 340 mg (0.82 mmol) of Boc-Lys(ClZ)-OH, 110 mg (0.82 mmol) of 1-hydroxybenzotriazole and 170 mg (0.82 mmol) of dicyclohexylcarbodiimide in 40 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 16 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 100 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 50 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated. The residue was purified on sinica gel chromatography (CHCl3/CH3OH, 30/1) to provide 850 mg (81%) of the title compound as a glassy mass. Mp 78–88° C., FAB-MS (m/e) 1111.3[M+H]+, 1132.5[M+Na]+, 1010.0[M-Boc]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[C:6]([CH:7]=[O:8])=[C:2]([Cl:1])[N:3]=[C:4]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:18][CH:17]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Yield: 71.5 %

Procedure:
3.0 g of 4-chloro-5-formyl-2-phenylimidazole (Chem. Pharm. Bull. 1976, 24(5), 960), 7.0 g of 4-bromobenzyl bromide and 11.7 g of K2CO3 are stirred at RT for 20 h in 200 ml of DMF. The reaction mixture is then poured onto 500 ml of water, and the precipitate is filtered off with suction and chromatographed on silica gel using DIP. 3.9 g of an amorphous foam are obtained.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:22]S(C2C=CC(C)=CC=2)(=O)=O)=[N:7][N:8]2[C:13]=1[CH:12]=[N:11][N:10]=[C:9]2[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34]1[C:38]([CH2:39]O)=[N:37][CH:36]=[N:35]1.[H-].[Na+]>CN(C)C=O>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:9]1[N:8]2[N:7]=[C:6]([O:22][CH2:39][C:38]3[N:34]([CH3:33])[N:35]=[CH:36][N:37]=3)[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:13]2[CH:12]=[N:11][N:10]=1
Reactant: Cn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4cc(F)ccc4F)nncc3c2C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3cc(F)ccc3F)nncc2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Example 21, step e) (0.4 g, 0.0009 mol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (0.12 g, 0.0011 mol) were dissolved in dry N,N-dimethylformamide (10 ml) under nitrogen and sodium hydride (60% wt in oil) (0.035 g, 0.0009 mol) was added. The solution was stirred at room temperature for 3 h after which solvent was removed in vacuo and the residue was purified using silica gel chromatography with 0%→60% ethyl acetate/dichloromethane as eluent. Trituration with isohexane and recrystallisation from ethyl acetate/isohexane gave the required product (0.137 g, mp=144° C.). Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 1.50 (9H, s), 3.84 (3H, s), 5.48 (2H, s), 7.18-7.26 (1H, m), 7.27-7.35 (1H, m), 7.47 (1H, m), 7.87 (1H, s), 9.41 (1H, s); MS (ES+) m/e 400 [MH]+; Anal. Found: C, 57.30; H, 4.64; N, 24.64%. C19H19F2N7O requires: C, 57.14; H, 4.79; N, 24.55%.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.Br[C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:23]([CH3:36])[CH:22]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][N:15]([C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[C:23]([CH3:36])[CH:22]=1)[CH2:14][CH2:13]2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Reactant: COc1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCN(c1cc(C)c(NC(=O)CC(C)(C)C)c(C)c1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (134 mg, 0.67 mmol) and N-(4-bromo-2,6-dimethyphenyl)-3,3-dimethylbutanamide (200 mg, 0.67 mmol) were then added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, filtered through a pad of silica gel, and recrystallized from toluene to afford the title compound as a solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].C([N:15](C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:44][N:45]1[CH2:50][CH2:49][CH:48](N)[CH2:47][CH2:46]1>CN(C)C=O.O>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50][N:45]2[CH3:44])=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1I
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCCCN2C)ccc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
A solution of 4-iodo-3-methoxybenzoic acid (250 mg, 0.90 mmol) in anhydrous dimethylformamide (8 mL) was treated with N-ethyl-N,N-diisopropylamine (0.63 mL, 3.6 mmol) and TBTU (404 mg, 1.26 mmol). The mixture was then treated with 1-methylpiperidin-4-amine (0.160 ml, 1.26 mmol). The reaction was stirred at room temperature for 24 h. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (250 mg, 71% yield).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6](Cl)=[O:7])[CH3:4].Cl.Cl.[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH:32]4[CH2:37][CH2:36][N:35]([C:6](=[O:7])[CH2:5][N:3]([CH3:4])[CH3:2])[CH2:34][CH2:33]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)CN(C)C)CC1
Yield: 44.9 %

Procedure:
N,N-Dimethylaminoacetyl chloride hydrochloride (100 mg) was added portionwise to a stirred solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (250 mg, 0.57 mmol) and diisopropylethylamine (300 μl) in methylene chloride (25 ml) at 0° C. The reaction mixture was allowed to stir for 2 hours to room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4), filtered and evaporated. The residues were purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10), followed by methylene chloride/methanol (saturated with ammonia) (90/10). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a white foam (0.125 g, 45%); 1H NMR Spectrum: (DMSO d6) 1.50-1.65 (m, 1H); 1.65-1.80 (m, 1H); 1.95-2.15 (m, 2H); 2.25 (s, 6H); 3.10-3.50 (m, 4H); 3.75-4.05 (m, 2H); 3.95 (s, 3H); 4.90 (m, 1H); 7.30 (m, 1H); 7.35 (s, 1H); 7.40-7.60 (m, 2H); 7.85 (s, 1H); 8.40 (s, 1H); 9.65 (s, 1H); Mass Spectrum: (M+H)+ 488.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(Cl)(=O)=O)=C[CH:2]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)(C)(C)C.C(OCC)C>[C:1]([O:20][C:19]([C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][N:17]=1)=[O:21])([CH3:11])([CH3:6])[CH3:2]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(Br)cn1
Temperature: 40 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
para-Toluene sulfonyl chloride (262 mg, 1.38 mmol) was added to a solution of 5-bromo-2-carboxypyridine (118 mg, 0.58 mmol) and pyridine (0.3 mL, 0.39 mmol) in tert-butanol (1 mL) and the mixture was stirred at 40° C. for 10 minutes and room temperature for 2 hours. Saturated sodium hydrogen carbonate solution (4 mL) was then added and the mixture was stirred for 5 minutes. Diethyl ether was next added and the bi-phasic mixture was stirred for a further 10 minutes. The organic layer was then separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0 to 80:20, afforded the title compound as a colourless solid in 73% yield, 110 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][CH2:21]O)=[CH:14][CH:13]=1)[C:7]([CH3:23])=[CH:6]2.[CH2:24]([N:26](CC)[CH2:27][CH3:28])[CH3:25].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][CH2:20][CH2:21][N:26]3[CH2:27][CH2:28][CH2:25][CH2:24]3)=[CH:16][CH:17]=1)[C:7]([CH3:23])=[CH:6]2
Reactant: COc1ccc2c(c1)cc(C)n2-c1ccc(C#CCCO)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: COc1ccc2c(c1)cc(C)n2-c1ccc(C#CCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 4.1 %

Procedure:
To a solution of 4-[4-(5-Methoxy-2-methylindol-1-yl)phenyl]but-3-yn-1-ol (60 mg, 0.19 mmol) in methylene chloride (1 mL) at 0° C. was added triethylamine (54 μL, 0.39 mmol) and methanesulfonylchloride (18 μL, 0.39 mmol). After the solution was stirred at 0° C. for 2 hours, pyrrolidine (163 μL, 1.95 mmol) was added and the reaction was allowed to warm to room temperature overnight. After the reaction was quenched with water, the organic layer was dried over MgSO4, and concentrated. The residue was purified by HPLC to give the desired indole (2.8 mg). LC-MS (C24H26N2O calc'd 358) m/z 359 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.03 (d, J=2.4 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.73 (dd, J=2.7, 9.0 Hz, 1H), 6.32 (s, 1H), 3.85 (s, 3H), 2.92-2.83 (m, 4H), 2.76 (m, 4H), 2.28 (s, 3H), 1.88 (m, 4H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:17][CH2:16][CH:15]([C:18](OC)=[O:19])[C:14]1=O.CO>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:14]2[N:1]=[C:2]([OH:3])[N:4]=[C:18]([OH:19])[C:15]=2[CH2:16][CH2:17]1
Reactant: NC(N)=O
Reactant: COC(=O)C1CCC(c2ccccc2OC)C1=O
Solvent: O
Solvent: CO
Product: COc1ccccc1C1CCc2c(O)nc(O)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a melt of urea (6.07 g, 101 mmol) (bath temp 150° C.) was added methyl 3-(2-methoxyphenyl)-2-oxocyclopentanecarboxylate (5.3 g, 20.21 mmol) dropwise. After stirring overnight, the reaction was cooled to rt. Added MeOH (30 ml), and broke up the solid mass with a spatula and stirred for 1 h. Added water (600 ml), and stirred for 3 hr. The mixture was added to a Buchner funnel, and washed with water. Dried overnight in the vacuum oven (45° C.) to obtain 7-(2-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol (4.03 g, 15.60 mmol, 77% yield) as a tan solid. LC-MS (M+H)+=259.1.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.ClC([O-])=[O:34].CCN(CC)CC.O>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.[CH2:23]([O:24][C:4](=[O:5])[O-:34])[CH2:6][CH2:7][CH2:8][CH2:22][CH2:21][CH2:20][CH2:19][CH2:9][CH2:10][CH2:11][CH2:12][CH2:18][CH2:17][CH2:16][CH3:14]
Reactant: O=C([O-])Cl
Agent: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(=O)[O-]
Temperature: 25 °C

Procedure:
To the solution of budesonide (431 mg, 1.0 mmol) in DCM (4.5 mL) was added heaxdecyl chloroformate (655 μL, 2.0 mmol) and Et3N (512 μL, 3.7 mmol) at room temperature. After reaction mixture was stirred at room temperature over night, it was poured into water (20 mL) and DCM (10 mL); the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude budesonide hexadecylcarbonate. The product was purified by chromatography, eluted with Hexane:AcOEt=9:1 to 3:1 to provide 432 mg of 1:1 mixture of epimers (originated from budesonide) (99.38 area % purity on HPLC). 1H NMR (CDCl3) δ 0.80-2.40 (m, 53H), 2.56 (dt, 1H, 13.1 and 4.6 Hz), 4.30 (t, 2H, 6.7 Hz), 4.5-5.2 (m, 7H), 6.00 (s, 1H), 6.26 (d, 1H, 10.1 Hz), 7.3 (d, 1H, 10.1 Hz). 13C NMR (CDCl3) δ 14.16, 14.18, 14.34, 17.10, 17.27, 17.39, 17.71, 21.21, 22.88, 25.81, 28.79, 29.41, 29.56, 29.70, 29.76, 29.87, 30.54, 31.19, 32.11, 33.08, 33.59, 34.23, 35.19, 37.28, 40.68, 40.98, 44.37, 46.08, 47.52, 50.00, 53.07, 55.39, 55.49, 68.98, 69.73, 69.83, 69.95, 70.04, 82.10, 83.38, 97.71, 98.58, 104.70, 108.51, 122.57, 127.91, 155.08, 156.85, 170.48, 170.59, 186.84, 186.88, 202.10 and 203.38. Mass spectrum (m/e) 699 (M+).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[S:16][C:15]([CH3:17])=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[S:16][C:15]([CH3:17])=[N:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Cc1nnc(S)s1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nnc(C)s2)s1
Temperature: 120 °C
Yield: 61.6 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (1.76 g), 5-mercapto-2-methyl-1,3,4-thiadiazole (1.3 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (40 ml) was heated at 120° C. for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and water was added to this residue. The mixture was extracted with a mixture of tetrahydrofuran and ethyl titrate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(2-methyl-l,3,4-thiadiazol-5-ylthio)thiazole (1.65 g, yield: 60.7%).
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH:10](Cl)([CH3:12])[CH3:11].C(N(CC)CC)C.O>CC(C)=O>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1.[CH:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1)([CH3:12])[CH3:11]
Reactant: C#Cc1ccc(O)cc1
Reactant: CC(C)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)C)cc1
Temperature: 52.5 °C
Reaction time: 5 h

Procedure:
In 100 mL of acetone were dissolved 16.2 g of poly(p-hydroxystyrene) and isopropyl chloride. To this reaction mixture was added 1.8 g of triethylamine. This mixture was stirred at 50 to 55° C. for 5 hours. The resultant reaction mixture was transferred to 1,000 mL of water, and the upper layer was removed by decantation. The viscous resinous substance obtained was dissolved in 75 mL of acetone, and this solution was transferred to 500 mL of water. The rubbery resin precipitated was dried under vacuum. Thus, 15.4 g of poly(p-hydroxystyrene/p-isopropoxystyrene) was obtained as a white powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[CH:22]1[C:27]([C:28]([NH2:30])=O)=[C:26]([CH3:31])[N:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:24](=[O:42])[NH:23]1)(=[O:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[CH:22]1[C:27]([C:28]#[N:30])=[C:26]([CH3:31])[N:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=2)[C:24](=[O:42])[NH:23]1)(=[O:13])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)CCO[Si](C)(C)C(C)(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(=O)(=O)CCO[Si](C)(C)C(C)(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The reaction was carried out under argon. (rac)-4-{2-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]-4-cyanophenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (740 mg, 1.18 mmol) was initially charged in dry THF (30 ml), methoxy-carbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 1.699 g, 7.13 mmol; 6 eq.) was added and the mixture was stirred at RT. After 75 min, HPLC control showed complete conversion. The reaction mixture was then taken up in ethyl acetate (150 ml). The organic phase was washed with saturated sodium chloride solution (3×50 ml), dried over solid sodium sulfate, filtered and concentrated. The residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). The title compound was obtained as a colorless solid (550 mg, 77% of theory).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=2)[NH2:35])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:33]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(Nc5ccccc5CN(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 3-(4-methylpiperazin-1-yl)aniline (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.033 g, 31%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.98 (d, J=6.5 Hz, 1H), 7.45-7.39 (m, 2H), 7.35 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.18-7.11 (m, 3H), 6.96 (s, 1H), 6.81 (d, J=7.9 Hz, 1H), 6.77 (s, 1H), 6.70 (t, J=7.0 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 4.36 (s, 2H), 3.28-3.23 (m, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.61-2.56 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+.