Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24]([O:31][C:32](=[O:36])[C@@H:33]([CH3:35])[NH2:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)[Cl:60]>>[ClH:60].[CH2:24]([O:31][C:32](=[O:36])[C@@H:33]([CH3:35])[NH:34][C:10](=[O:11])[CH2:9][NH2:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCCl
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)CN)C(=O)OCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a cold (0° C.) solution of 100 ml. methylene chloride containing 10 g. (57 mmol) of N-t-butyloxycarbonylglycine, 20 g. (57 mmol) of D-alanine benzyl ester p-toluene sulfonic acid salt and 5.77 g. (57 mmol) of triethylamine was added 12.3 g. (60 mmol) of dicyclohexylcarbodiimide and the resulting reaction mixture allowed to warm to room temperature. After 18 hours the mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in 200 ml. of ethyl acetate and the organic layer washed with 2.5% hydrochloric acid, water, a saturated sodium bicarbonate solution and a brine solution. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. To the resulting oil 200 ml. of dioxane saturated with hydrogen chloride was added. After 30 minutes 400 ml. of diethyl ether was added and the product filtered under nitrogen, 10.9 g. (70% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:23]=[C:22]([O:34][CH3:35])[N:21]=3)[CH2:16][CH:15]2C(O)=O)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].CN[CH:41]=[CH:42][CH2:43][CH2:44][CH2:45]C.CCN(C(C)C)C(C)C.[CH3:56][N:57]([CH:59]=[O:60])[CH3:58]>>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:23]=[C:22]([O:34][CH3:35])[N:21]=3)[CH2:16][CH:15]2[C:59](=[O:60])[N:57]([CH2:58][CH2:45][CH2:44][CH2:43][CH:42]=[CH2:41])[CH3:56])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccc(OC)cc3)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Reactant: CCCCC=CNC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3ccc(OC)cc3)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Yield: 82 %

Procedure:
The acid 16c (1.2 g, 2 mmol) was reacted with N-methylhexeneamine (340 mg, 3.0 mmol) and DIEA (1.29 g, 10.0 mmol) in dry DMF (30 ml) according to the procedure described in Example 13 step c. Purification by column chromatography on silica gel gave the title compound, (1.02 g, 82%), (M+H)+621.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:4]=1.Cl.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl>CN(C=O)C.CCOC(C)=O.O>[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:24][CH2:23][CH2:22][N:21]([CH3:26])[CH3:20])=[CH:16][CH:17]=2)([CH3:10])[CH3:11])[CH:4]=1
Reactant: CN(C)CCCCl
Reactant: CC(C)(c1ccc(O)cc1)c1cc(Br)ccn1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCCOc1ccc(C(C)(C)c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
Sodium hydroxyde (pellets are finely grinded, 0.488 g, 12.2 mmol, 5 eq) is added to a solution of 4-[1-(4-bromo-pyridin-2-yl)-1-methyl-ethyl]-phenol (Step 31.2) (0.714 g, 2.44 mmol) in DMF (5 mL). The mixture is stirred for 20 min at rt. 3-Dimethylamino-1-propylchloride hydrochloride (0.611 g, 3.87 mmol, 1.6 eq) is added. The reaction mixture is heated to 90° C., stirred for 10 h, allowed to cool, diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 0.398 g of the title compound as an impure brown oil which is used without further purification: ESI-MS: 377.1/379.0 [M+H]+; TLC: Rf=0.22 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@@H:12]([OH:20])[C:11]1=[CH2:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:22]([Zn]CC)C.ICI>CCOCC>[Si:1]([O:8][CH2:9][C@H:10]1[C:11]2([CH2:22][CH2:21]2)[C@H:12]([OH:20])[C@@H:13]2[O:17][C:16]([CH3:19])([CH3:18])[O:15][C@H:14]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC[Zn]CC
Reactant: C=C1[C@H](O)[C@@H]2OC(C)(C)O[C@@H]2[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CCOCC
Solvent: ICI
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)C1(CC1)[C@@H]2O
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To a solution of 12 (3 g, 9.5 mmol) in anhydrous ether (50 mL) was added diethyl zinc (1.0 M solution in hexane, 24.2 mL, 28.6 mmol) followed by diiodomethane (4.6 mL, 57.3 mmol) at 0° C. The reaction mixture was allowed to room temperature and was refluxed for 8 hr. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl solution (20 mL) and extracted with ether (2×60 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (5% EtOAc/hexane) to afford 13 (3.0 g, 93%) as an oil. [α]24D−86.03° (c 2.01, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.55 (m, 1H), 4.49 (m, 1H), 4.08 (m, 1H), 3.59 (dd, J=3.0 & 9.5 Hz), 3.50 (dd, J=4.5 & 10.5 Hz, 1H), 2.22 (d, J=10.5 Hz, D2O exchange OH, 1H), 1.57 (m, 1H), 1.44 (s, 3H), 1.31 (s, 3H), 0.84 (m, 10H), 0.43 (m, 1H), 0.32 (m, 1H), 0.24 (1H), −0.06 (s, 6H). 13C NMR (125 MHz, CDCl3) 159.01, 115.9, 115.4, 86.85, 84.85, 79.48, 71.63, 57.21, 32.13, 31.54, 30.33, 29.24 23.83, 7.14, 0.015; HR-MS Calcd. For (C17H32O4Si)+ 328.2070. found 328.2195.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[C:5](/[CH:20]=C/C3C=CC=CC=3)[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:29].[K+].[K+].[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH:20]([C:5]1[CH:6]=[CH:7][C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[C:9]2[C:4]=1[CH2:3][N:2]([CH3:1])[C:10]2=[O:11])=[O:29]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CN1Cc2c(/C=C/c3ccccc3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2c(C=O)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl {2-methyl-3-oxo-7-[(E)-2-phenylethenyl]-2,3-dihydro-1H-isoindol-4-yl}carbamate (Compound 109D, 1.0E2 mg, 0.27 mmol) was added in one portion to a pre-stirred mixture (room temperature, 45 min) of potassium osmate dihydrate (1.0 mg, 0.0027 mmol) and potassium monopersulfate (170 mg, 1.1 mmol) in DMF (1.35 mL). After stirring overnight at room temperature, the reaction mixture was treated with 1.35 mL of saturated aqueous Na2SO3. The resulting slurry was extracted with EtOAc (3×) and the combined organic layers were washed with 1N HCl (3×) and brine and concentrated in vacuo. The desired product was obtained after chromatography using an ISCO Combiflash unit (0-15% EtOAc in Heptane) as 23 mg of a tan solid (29% yield). 1H NMR (400 MHz, DMSO-d6) δ=1.51 (s, 9 H), 3.08 (s, 3 H), 4.74 (s, 2 H), 8.12 (d, J=8.6 Hz, 1 H), 8.21 (d, J=8.6 Hz, 1 H), 9.95 (s, 1 H), 10.01 (s, 1 H). MS (ES+): m/z 291.28 (100) [MH+]; HPLC: tR=1.27 min (UPLC, Analytical).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:6][CH:7]=1.[Cl:22]C1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[ClH:22].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N+:6]([O-:30])[CH:7]=1
Reactant: CC1(C)C=C(c2ccc(N)cn2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)C=C(c2ccc(N)c[n+]2[O-])c2cc(C#N)ccc2O1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
1 g of 4-(5-amino-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile was dissolved in 15 ml of dichloromethane and 1 g of m-chloroperbenzoic acid was added. After stirring at room temperature for 1 hour a further 0.5 g of m-chloroperbenzoic acid was added. After stirring at room temperature overnight the mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using firstly 10% (v/v) methanol/ethyl acetate and then 20% (v/v) methanol/ethyl acetate for the elution. The product, 5-amino-2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine, was converted into the hydrochloride salt which was recrystallized from isopropanol. There were obtained 238 mg of 5-amino-2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide hydrochloride of melting point 235°-237° C.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C1NC(C(=O)CCCCCCC(=O)C)=NC=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]1[N:38]=[CH:39][N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=1.[Li]CCCC.[CH2:55]([C:57]1([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67](N(OC)C)=[O:68])[O:61][CH2:60][CH2:59][O:58]1)[CH3:56]>C1COCC1.CCCCCC.O>[CH2:55]([C:57]1([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]([C:39]2[N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=[C:37]([C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:27]=3)[N:38]=2)=[O:68])[O:58][CH2:59][CH2:60][O:61]1)[CH3:56]
Reactant: CCC1(CCCCCC(=O)N(C)OC)OCCO1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc3ccccc3c2)c1
Agent: CC(=O)CCCCCCC(=O)c1ncc(-c2ccc3ccccc3c2)[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCC1(CCCCCC(=O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Reaction time: 0.5 h

Procedure:
To a solution of Example 5, E2 (1.0 eq.) in THF (0.1 M solution) at −78° C. was added a solution of n-BuLi (1.3 eq.) in hexane. The solution was stirred for 30 min and then a solution of 6-(2-ethyl-1,3-dioxolan-2-yl)-N-methoxy-N-methylhexanamide (1.5 eq.) in THF was slowly added. The reaction mixture was stirred for 1 hr at −78° C. and then 1 hr at RT. Then water was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was used without purification in the next step. MS (ES) C30H42N2O4Si requires: 523, found: 524 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1.S(O)(O)(=O)=O.CS[C:20](=[NH:22])[NH2:21]>[OH-].[Na+]>[NH:1]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1)[C:20]([NH2:22])=[NH:21]
Reactant: CSC(=N)N
Reactant: NCc1cc(CCC(=O)O)no1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)NCc1cc(CCC(=O)O)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6.8 g (0.04 mol) of the product from Example 12 are dissolved in 40 ml of 1 N sodium hydroxide solution and 5.56 g of S-methylisothiourea hydrogen sulfate (=0.04 mol of urea) in solid form are added. The mixture is stirred at room temperature for 24 hours, during which the product slowly crystallizes out, and is filtered off with suction and washed thoroughly with water. Yield: 2.8 g; melting point >297° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=3[OH:27])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C=O)C.[H-].[Na+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>O>[C:1]12([C:11]3[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=3[O:27][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
2.1 g (5.79 mmol) of benzyl 3-(1-adamantyl)-4-hydroxybenzoate and 20 ml of DMF were introduced into a three-necked flask and 191 mg (6.34 mmol) of sodium hydride (80% in oil) were added portionwise. The mixture was stirred until the evolution of gas had ceased, then 565 μl (5.79 mmol) of methyl bromoacetate were added and the mixture was stirred at room temperature for twelve hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The solid was triturated from hexane, filtered off and dried. 2.36 g (94%) of the expected compound, having a melting point of 134°-5° C., were recovered.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10]([C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)=O)[CH2:3]1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:22]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[C:10]([C:12]3[N:16]([CH3:17])[C:15]4[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=4[N:13]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)C(CC(=O)c2nc3ccccc3n2C)C1
Reactant: Nc1ccc(C(=O)O)cc1
Product: CC1CCc2c(cc(-c3nc4ccccc4n3C)n2-c2ccc(C(=O)O)cc2)C1
Yield: 60 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-[2-(1-methyl-1H-benzimidazol-2-yl)-2-oxoethyl]cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 60% yield (98% purity by HPLC). MS(ESI+): 386.6; MS(ESI−): 384.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[CH:7]2.I[CH3:13]>>[CH3:13][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[CH:7]2
Reactant: Oc1cccc2cncnc12
Reactant: CI
Product: COc1cccc2cncnc12

Procedure:
According to the procedure previously described in Example 6, 8-hydroxy-quinazoline (A1) (20 mmol) and iodomethane gave 8-methoxy-quinazoline (111). 8-Methoxy-quinazoline (111) (10 mmol) was then treated with m-chloroperbenzoic acid which gave the N-oxide 112. Subsequent treatment of the N-oxide 112 with Ac2O and phosphorus oxychloride according to Example 14 afforded 2-chloro-8-methoxy-quinazoline (113).
Reaction SMILES: C1COCC1.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[N:13][OH:14])[CH:7]=1.ClN1C(=O)CCC1=O.[CH3:23][Si:24]([CH3:32])([CH3:31])[C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28]>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:23][Si:24]([CH3:32])([CH3:31])[C:25]1[C:12]([C:8]2[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=2)=[N:13][O:14][C:26]=1[Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: ON=Cc1cccnc1
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1onc(-c2cccnc2)c1[Si](C)(C)C
Temperature: 65 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of anhydrous THF (250 ml) containing 3-pyridinealdoxim (61) (18.87 g, 154.7 mmol) were added 20.57 g (1.0 eq) of N-chlorosuccinimide. After the addition, the resulting solution was stirred for 18 hours at 65° C. Then the temperature of the reaction mixture was lowered to −30° C. and 1,2-bis-trimethylsilanyl-ethyne was added (26.4 g, 170.4 mmol), subsequently followed by triethylamine (2 eq, 42 ml, dropwise), while keeping the temperature <−25° C. After stirring for another 30 minutes, the mixture was allowed to warm to ambient temperature, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-(4,5-bis-trimethylsilanyl-isoxazol-3-yl)-pyridine (62) as an oil (4.45 g, 17%). 1H-NMR (400 MHz, CDCl3): δ 8.70 (dd, J=5 Hz, 2 Hz, 1H), 8.68 (d, J=2 Hz, 1H), 7.76 (dt, J=8 Hz, 2 Hz, 1H), 7.41-7.37 (m, 1H), 0.46 (s, 9H), 0.011 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=[CH:5][N:6]=1.C(Cl)(=O)CCCCC[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]CC.[C:35](Cl)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[O:41]=[C:35]([N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH2:1][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH2:10][CH2:11]1)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: Cc1nccn1CCC1CCNCC1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCC(=O)Cl
Product: CCCCCCCCCCCc1nccn1CCC1CCN(C(=O)CCCCC)CC1

Procedure:
Following essentially the last step of the procedure for preparing the compound of Example 1, and using in place of 4-[2-(2-methyl-1H-imidazol-1-yl)ethyl]piperidine and stearoyl chloride, approximately equivalent amounts of the compound of Example (5A) and hexanoyl chloride, respectively, the title compound was obtained as a liquid, b.p. 167°-170° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:18]=1[C:19]([NH2:21])=[O:20]>>[CH2:1]([N:8]1[C:12]([C:13]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:18]=2[C:19](=[O:20])[NH2:21])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1c(N)cccc1N1CCOCC1
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Product: NC(=O)c1c(NC(=O)c2nnnn2Cc2ccccc2)cccc1N1CCOCC1

Procedure:
In a manner similar to Example 1, 1-benzyl-1H-tetrazole-5-carbonyl chloride is condensed with 2-amino-6-(4-morpholinyl) benzamide to give 1-benzyl-N-[2-carbamoyl-3-(4-morpholinyl)phenyl] 1H-tetrazole-5-carboxamide.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[CH2:9]Cl.CCCCCC.C1C=CC=CC=1>C(O)(=O)C>[C:1]([O:4][CH2:9][C:8]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=1[CH3:6])(=[O:3])[CH3:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=O)OCc1cc([N+](=O)[O-])ccc1C
Temperature: 115 °C

Procedure:
A slurry of anhydrous sodium acetate (60.0 g; 0.73 mol) in acetic acid (400 ml) is stirred and 2-methyl-5-nitrobenzyl chloride (45.3 g; 0.24 mol) added. The resulting reaction mixture is heated to reflux and is heated overnight at 115° C., after which time tlc (silica gel; 75/25 hexane/benzene) indicates that no starting material is present. The mixture is cooled down, concentrated in vacuo, and diluted with water. The precipitated solid (48.9 g; 95.8%) is collected and dried. A sample recrystallized from hexane has a melting point of 52°-53.5° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]1[CH:42]=[CH:41][C:11]([C:12]([NH:14][C:15]2[C:16]3[CH:29]=[C:28]([C:30]([NH:32][N:33]([CH3:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[S:27][C:17]=3[N:18](C(OC(C)(C)C)=O)[N:19]=2)=[O:13])=[CH:10][CH:9]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:40][N:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:30]([C:28]1[S:27][C:17]2[NH:18][N:19]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:41]=[CH:42][C:8]([CH2:7][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[C:16]=2[CH:29]=1)=[O:31]
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: C1CCNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide and then 93 μL (1.11 mmol) of pyrrolidine are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 25 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-pyrrolidin-1-ylmethylbenzamide are thus obtained in the form of a yellow powder melting from 172 to 178° C. LC-MS-DAD-ELSD: 475(+)=(M+H)(+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]2=[N:4][CH:3]=1.CS[C:17]1[N:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[CH:20]=[CH:19][N:18]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:36]([NH:39][C:17]1[N:18]=[C:19]([C:2]2[N:6]3[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]3=[N:4][CH:3]=2)[CH:20]=[CH:21][N:22]=1)([CH3:38])[CH3:37]
Reactant: CC(C)N
Reactant: OCCNc1nccn2c(Br)cnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Product: CC(C)Nc1nccc(-c2cnc3c(NCCO)nccn23)n1

Procedure:
2-[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol was prepared by a process analogous to that described in Example 12 starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (from Example 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and isopropylamine. LC-MS: [M+H]+ 314.3.
Reaction SMILES: [CH:1]1([SH:4])[CH2:3][CH2:2]1.C1(Br)CC1.[H-].[Na+].Br[C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CS(C)=O.CCOCC>[CH:1]1([S:4][C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: SC1CC1
Agent: BrC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)SC1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
An ether solution of cyclopropyl mercaptan synthesized from cyclopropyl bromide (50.0 g, 413 mmol) in accordance with the process described in literature (J. Am. Chem. Soc., 114, 3492 (1992)) was added dropwise to a solution of 60% sodium hydride (5.4 g, 135 mmol) in dimethyl sulfoxide (100 ml) under cooling with ice, and the mixture was stirred at room temperature for 10 minutes. A solution of ethyl bromodifluoroacetate (27.4 g, 135 mmol) in dimethyl sulfoxide (200 ml) was added dropwise to this solution under cooling with ice, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water to conduct extraction with ether. The solvent was distilled out of the resultant extract under reduced pressure. The resultant residue was distilled under reduced pressure to obtain the intended product (12.3 g; yield: 46.0%) as a colorless oil.