Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:13][C:14]1[C:15]2[N:16]([C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]=2)[CH:17]=[C:18]([CH3:20])[CH:19]=1.O>CN(C=O)C>[CH3:24][C:22]1[N:23]=[C:15]2[C:14]([O:13][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]2[C:21]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CC(C)CCI
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCCC(C)C)cc(C)cn12
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
1.23 ml (9.4 mmol) of 1-iodo-3-methylbutane and 6.12 g (18.8 mmol) of caesium carbonate were added to 2.0 g (8.5 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 239A in 122.3 ml of DMF, and the mixture was stirred at 60° C. for 40 min. 900 ml of water were added to the reaction mixture, which had cooled to RT, and the mixture was stirred at RT for 1 h, and the precipitated solid was filtered off, washed with water and dried under high vacuum. This gave 2.25 g (84% of theory; purity 97%) of the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42][C:43]#[C:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:42][C:43]#[C:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(C#CCBr)(CC)O[Si](CC)(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#CCO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 71.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (58.9 mg, 0.105 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol), 15-crown-5(10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=19:1, developed once) to give the title compound as a colorless oil (60.2 mg, 72%).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([OH:14])[CH:6]=1.N1C=CN=C1.[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)C>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH:6]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=Cc1ccc([N+](=O)[O-])c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzaldehyde O-methyloxime (5.0 g, 25 mmol) in N,N-dimethylformamide (40 mL) is added imidazole (1.8 g, 27 mmol), followed by triisopropylsilyl chloride (6.0 mL, 28 mmol), and 4-(dimethylamino)pyridine (catalytic amount). After stirring overnight at room temperature, the reaction mixture is diluted with diethyl ether (200 mL) and then washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase is then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude solid is purified by flash chromatography (hexanes/ethyl acetate) to give 4-nitro-3-[(triisopropylsilyl)oxy]benzaldehyde O-methyloxime as a white solid (6.2 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)Cc1ccccc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)Cc4ccccc4)cc3c2C1
Yield: 85.1 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.1 μL (0.051 mMol) phenylacetyl chloride, 13.6 mg (85%) of the title compound were recovered as a grey-brown solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].[F:18][C:19]([F:26])([F:25])[C:20](SCC)=[O:21]>CO>[F:18][C:19]([F:26])([F:25])[C:20]([NH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])=[O:21]
Reactant: N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: CCSC(=O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a suspension of 2'-amino,2'-deoxyuridine (2.0 g, 8.22 mmoles) in methanol (150 ml) was added S-ethyl trifluorothioacetate (1.6 ml, 12.48 mmoles, 1.5 eq.). This mixture was stirred at room temperature overnight. Nitrogen was bubbled through the reaction mixture for 2 h to remove volatile thio-byproducts. The mixture was evaporated to dryness and the solid was recrystallized from methanol/chloroform to yield 2.3 g (82%) of 2'-trifluoroacetylamino,2'-deoxyuridine. The analytical data agreed with the literature (Imazawa and Eckstein (1979) supra).
Reaction SMILES: O(C)[Na].Cl.[NH2:5][OH:6].[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[C:10]([Cl:20])[CH:9]=1>CO>[NH2:7][C:8]1[CH:9]=[C:10]([Cl:20])[C:11]([C:15]([CH3:18])([CH3:19])[C:16](=[N:5][OH:6])[NH2:17])=[C:12]([Cl:14])[CH:13]=1
Reactant: CC(C)(C#N)c1c(Cl)cc(N)cc1Cl
Reactant: NO
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CC(C)(C(N)=NO)c1c(Cl)cc(N)cc1Cl
Temperature: 25 °C
Yield: 26 %

Procedure:
NaOCH3 30% (0.592 mole) was added to a solution of hydroxylamine hydrochloride (0.1085 mole) in CH3OH (200 ml), stirred at RT. The mixture was stirred for 10 minutes. Intermediate (3) (0.0542 mole) was added portionwise and the resulting reaction mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was partitioned between CH2Cl2 and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE, filtered off, washed with DIPE, and dried, yielding 3.7 g (26%) of 4-amino-2,6-dichloro-N′-hydroxy-α,α-dimethylbenzeneethanimidamide (intermediate 17).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7](=[O:25])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[CH:17]4)[C:11]([CH3:23])=[C:10]([F:24])[CH:9]=2)[CH2:5][CH2:4]1.Br[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1>CN(C=O)C>[CH:3]1([NH:6][C:7](=[O:25])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[N:18]=[CH:17]4)[C:11]([CH3:23])=[C:10]([F:24])[CH:9]=2)[CH2:4][CH2:5]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Reactant: BrCC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC2CCCO2)c1
Yield: 29.7 %

Procedure:
The procedure for Example 1 was followed using sodium hydride (60% in mineral oil, 12 mg), N-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide (Intermediate 3, 45 mg) and 2-(bromomethyl)tetrahydrofuran (26 mg) in DMF (5 ml) to give the title compound as a colourless glass (17 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH2:18][CH3:19])=[C:16]([CH2:20][N:21]2[CH:30]([CH2:31][OH:32])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)[C:15]([CH2:33][CH3:34])=[N:14]1.[H-].[Na+].[CH3:37]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH2:18][CH3:19])=[C:16]([CH2:20][N:21]2[CH:30]([CH2:31][O:32][CH3:37])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)[C:15]([CH2:33][CH3:34])=[N:14]1
Reactant: CI
Reactant: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1CN1Cc2ccccc2CC1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1CN1Cc2ccccc2CC1COC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A solution of 200 mg (0.39 mmol) of the compound of step A in 5 mL of THF was treated with 10 mg (0.42 mmol) of sodium hydride and stirred for 30 minutes at room temperature. Then 0.1 mL (1.6 mmol) of methyl iodide was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with water and the product was extracted into ethyl acetate which was dried and evaporated. The crude product was flash chromatographed on silica gel to give the desired product in 26% yield as a colorless oil. 1H-NMR (CDCl3) δ0.90 (3H, t, J=7), 1.20 (3H, t, J=7), 2.39 (2H, q, J=7), 2.65 (2H, q, J=7), 2.88-2.96 (1H, m), 3.16-3.20 (1H, m), 3.32 (3H, s), 3.55-3.78 7H, m), 6.90-7.24 (4H, m), 7.65 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]2[C:11]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][C:12]=3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1.C(Cl)Cl>C(C(O)=O)(F)(F)F>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:10]2[C:11]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:12]=3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(-c4c(F)cccc4F)c3c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(F)c1-c1cccc2[nH]c3c(c12)CCNCC3
Yield: 87.2 %

Procedure:
tert-Butyl 10-(2,6-difluorophenyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.700 g, 1.76 mmol) was dissolved in CF3CO2H (4 mL) and CH2Cl2 (14 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was cooled in an ice bath and quenched with cold 1N NaOH (100 mL). The resulting mixture was extracted with 3% CH3OH in CH2Cl2 (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product (0.51 g) was chromatographed (SiO2 30 g, eluted with 90:10:1 CH2Cl2:CH3OH:conc. NH4OH) to yield 10-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.458 g) in 87% yield. 1H NMR (400 MHz, Acetone-d6) δ 2.35-2.38, 2.74-2.77, 2.95-2.98, 6.84, 7.08, 7.12, 7.36, 7.50; MS (ESI+) for C18H16F2N2 m/z 299.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:4][CH2:5][CH:6]1OCC[O:7]1.Cl.O>C1COCC1>[CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:4][CH2:5][CH:6]=[O:7]
Reactant: COC(CCC1OCCO1)c1ccccc1C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(CCC=O)c1ccccc1C
Reaction time: 12 h

Procedure:
To a solution of 2-(3-Methoxy-3-o-tolyl-propyl)-[1,3]dioxolane (285.0 mg, 1.2 mmol) in 14 mL THF was added 7 mL 1M aqueous HCl at room temperature. After stirring the mixture for 12 h, water was added and the solution extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×10 mL) and dried over Na2SO4. Evaporation of solvent provided the desired product as an oil which was used directly in the next experiment without further purification.
Reaction SMILES: [Zn](C)[CH3:2].[C:4]1([CH:10]=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1>>[C:4]1([C@@H:10]([OH:11])[CH3:2])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1
Reactant: O=CC1=CCCCC1
Reactant: C[Zn]C
Product: C[C@H](O)C1=CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A 10 mL Schlenk flask was charged with bis(sulfonamide) ligand 2 (3.8 mg, 0.01 mmol), Ti(OtBu)4 (193 μL, 0.50 mmol), and 0.5 mL hexanes and stirred for 30 min at room temp. A hexanes solution of Me2Zn (0.32 mL, 0.63 mmol) was then added, and after stirring for 10 min, cyclohexenecarboxaldehyde (28 μL, 0.25 mmol) was added. The reaction was stirred at room temp for 19 h and quenched with a saturated solution of aq NH4Cl. The organic and aqueous layers were separated, and the aqueous layer was extracted with hexanes. The combined organic layers were then washed with brine and H2O and dried over MgSO4. The filtrate was concentrated in vacuo and the residue was chromatographed on silica (10% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 94% yield (30 mg, 0.23 mmol). 1H NMR (CDCl3, 500 MHz) δ.1.20 (d, 3H, J=6.2 Hz), 1.51 (m, 4H), 1.61 (br s, 1H), 1.99 (m, 4H), 4.10 (q, 1H, J=6.2 Hz), and 5.61 (br t, 1H) ppm; 13C{1H} NMR (CDCl3; 125 MHz) δ.21.4, 22.5, 22.6, 23.6, 24.8, 72.0, 121.3, and 141.2 ppm. 1H NMR and 13C NMR spectra for this compound compare with previously reported literature data.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=O.CN>O1CCCC1>[CH3:20][NH:22][C:17](=[O:19])[CH2:16][N:15]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccccn2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.44 g, 0.0096 mole), 1,1'-carbonyldiimidazole (1.56 g, 0.0096 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 5 hours. A solution of 1M monomethylamine in tetrahydrofuran (15 ml) was added and the reaction stoppered and stirred overnight. The tetrahydrofuran was evaporated in vacuo and the residue triturated in water (30 ml) and filtered. The filter cake was again triturated in water (30 ml) and filtered, giving 1.94 g (76%) of solid, mp 228°-230° C. Recrystallization from tetrahydrofuran-methanol gave 1.49 g of a white solid, mp 228.5°-230° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:7](=[O:13])[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:29]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:29][C:8]1[C:7](=[O:13])[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH2:11][CH3:12]
Reactant: BrBr
Reactant: CCCCc1nc(CC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 4′-[(2-butyl-4-ethyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.67 g) in acetic acid (20 mL) was added bromine (0.46 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.26 g, 62%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:7]2[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[N:9][C:2]([S:38][C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)=[C:3]([CH:6]=2)[C:4]#[N:5])=[CH:19][CH:20]=1
Reactant: Fc1ccc(S)cc1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Sc1ccc(F)cc1
Temperature: 100 °C

Procedure:
An oven-dried round bottom flask was charged with 60.0 mg (0.152 mmol) of the product of Example 36 and Cs2CO3 (250.0 mg, 0.767 mmol), toluene (1.0 mL) and 4-fluorobenzene thiol (97.5 mg, 0.761 mmol) were added sequentially. The reaction was heated to 100° C. for 23 hours and then allowed to cool to room temperature at which point the reaction was filtered and concentrated. The residue was purified by preparative thin layer chromatography (20 cm×20 cm, 1000 μm, silica gel) eluting with 10:90 EtOAc-hexane affording a white solid). MS (electrospray) m/e 487 MH+.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>C1COCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: OCc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
Powdered KOH (1.74 g, 30.65 mmol) was added to a vigorously stirred solution of pyridin-2-yl-methanol (2 mL, 20.72 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred for 15 minutes and tosyl chloride (5.13 g, 26.90 mmol) was then added. The reaction mixture was allowed to warm to RT and stirring was continued overnight. The reaction mixture was quenched with saturated NaHCO3 and the product was extracted with EtOAc (3×50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo to give a yellow oil. The residue was purified by flash column chromatography using EtOAc: hexane (1:4) to yield the title compound (4.6 g, 85%) as a yellowish solid.
Reaction SMILES: CO.O.[OH:4][C:5]1[CH:6]=[C:7]([C:11]2([CH3:30])[CH2:16][CH2:15][N:14](CC(CC3C=CC=CC=3)C(O)=O)[CH2:13][CH:12]2[CH3:29])[CH:8]=[CH:9][CH:10]=1>O>[CH3:29][C@@H:12]1[C@@:11]([C:7]2[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=2)([CH3:30])[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: CC1CN(CC(Cc2ccccc2)C(=O)O)CCC1(C)c1cccc(O)c1
Solvent: CO
Solvent: O
Product: C[C@H]1CNCC[C@@]1(C)c1cccc(O)c1

Procedure:
A beaker was charged with methanol (0.4 kg), water (0.5 L), and Compound 7(100 g). The mixture was charged to the reactor and rinsed forward with a solution of water (0.3 L) and methanol (0.2 kg) to seed the reaction mixture.
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=O)[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28]>CO.[OH-].[K+].O>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: NNC(N)=O
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1(C)CC(=NNC(N)=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-4-oxopiperidine prepared according to DE 199 09 767 A1 is dissolved in methanol containing 10% by weight of KOH and stirred for 5 hours at room temperature. Methanol is evaporated, the residue is washed with water and dried in vacuo. To a solution of 6.4 g (0.02 mol) 2,6-diethyl-2,3,6-trimethyl-1-(1-pheyl-ethoxy)-piperidine-4-one in 20 ml methanol are added 3.3 g (0.03 mol) semicarbazide hydrochloride and 1.67 g (0.025 mol) KOH (85%). The mixture is stirred under reflux 5 h and then diluted with 200 ml water. The precipitate is extracted into 100 ml of dichloromethane, the organic layer is washed with water, dryied over MgSO4 and evaporated to give 7.8 g (98.8%) of the title compound as a slightly yellow resin.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Yield: 100.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-3-chlorobenzoic acid (2.4 g) and 1-(2,4-dimethylphenyl)piperazine (1.9 g), the title compound (4.1 g) was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[Si:18]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl 4-hydroxycyclohexanecaboxylate (3.44 g, 20.0 mmol) was dissolved in DMF (7 mL), and imidazole (3.40 g, 50.0 mmol) and tert-butyldimethylsilyl chloride (3.62 g, 24 mmol) were added thereto, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=10:1) to afford ethyl 4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylate (5.73 g, 100%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCOC(=O)Cl
Agent: Cl
Product: CCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 34 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-butyl chloroformate. Yield: 34% of theory, C33H39N7O5 (613.7) ##EQU90##