Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30].[OH-].[Na+]>CO>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1C(F)(F)F
Yield: 87 %

Procedure:
A solution of the {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (70 mg, 0.153 mM) and 0.21 mL (0.21 mM) of 1 N NaOH in 5 mL of methanol was sonicated for 23 hours at 50-60° C. The methanol was removed in vacuo and the mixture acidified to pH 1.6 with 1 N HCl. The resultant white precipitate was collected by filtration, washed with H2O, small amounts of MeOH and diethyl ether, then dried in vacuo to afford 59 mg (88%) of the {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ 13.0 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.75 (s, 1H), 7.5-7.3 (m, 6H), 7.1 (d, 1H, J=8 Hz), 7.05 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 5.8 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 1737 and 1635. MS (ES) m/e 441, 443.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:13]2[N:12]=1)[CH2:2][CH3:3].[S:27](Cl)([Cl:30])(=[O:29])=[O:28]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:13]2[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.7 g (2 mmol) of 2-(2-propoxyphenyl)-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][12,4]triazin-4-one (Example 17A). This gives 0.8 g (89.3%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[N:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=2)[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: Brc1cc(-n2cccc2)ccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-n2cccc2)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, 2-bromo-4-(1H-pyrrol-1-yl)pyridine (0.20 g, 0.90 mmol) was dissolved in THF (6 mL). The light yellow solution was cooled to 0° C. and isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 0.78 mL, 1.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 40 min and at room temperature for 2 h. The reaction mixture was cooled to 0° C. and tributyltin chloride (0.28 mL, 1.03 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with 50 mL EtOAc (2×). The combined organic layers were washed with ˜5 mL water and ˜5 mL brine then dried over sodium sulfate, filtered and concentrated to provide 4-pyrrol-1-yl-2-tributylstannanyl-pyridine as a light brown oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH-:13].[Na+]>C(OC(=O)C)(=O)C>[OH:13][CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: [OH-]
Reactant: Cc1cc2c([n+]([O-])c1)CCCC2
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1cnc2c(c1)CCCC2O

Procedure:
The N-oxide (60 g.) was dissolved in acetic anhydride (120 ml.) and added to boiling acetic anhydride (120 ml.) and the mixture heated at reflux for 30 minutes. The solvent was removed in vacuo and the residual oil was treated with 10% hydrochloric acid (700 ml.) and the solution heated on a steam bath for 2 hours. The cooled reaction mixture was adjusted to pH 9.0 with sodium hydroxide and extracted with ether (3 × 100 ml). The combined ethereal extracts were washed with saturated brine, dried (MgSO4) and the solvent removed in vacuo. The resultant oil as distilled at 0.15 mmHg to give a colourless oil (22 g.) b.p. 70°-78° C which crystallised from n-hexane to give 8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline as colourless needles m.p. 58° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7](O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C(OCC)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7]([Cl:15])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cc1ccc(Br)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: CCOCC
Product: O=S(=O)(Cl)Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The 4-bromobenzylsulfonic acid, sodium salt (12.9 g, 43.6 mmol) was combined without further purification with phosphorus pentachloride (10.8 g, 52 mmol) to form an intimate mixture. The mixture was heated to 80° C. under a nitrogen atmosphere and became homogeneous after about 30 minutes. The reaction mixture was maintained at this temperature for about 5 hours. It was then cooled, diluted with diethyl ether and added to a large volume of ice. The ether layer was separated, washed with water and a saturated brine solution and dried over magnesium sulfate. The solvent was then removed with a rotary evaporator to obtain 4-bromobenzylsulfonyl chloride (13.3 g), a small quantity of which was recrystallized from hexane for analysis. The m.p. was about 114° C. to about 116° C. and the 1H NMR spectrum confirmed that the reaction product was 4-bromobenzylsulfonylchloride. The theoretical elemental analysis for bromobenzylsulfonylchloride is: C, 31.19%; H, 2.24%; S, 11.89% and the actual analysis was: C, 31.23%; H, 2.41%; S, 11.73%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:19])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCCC(=O)O)C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(CCCCC(=O)Cl)C(=O)OCc1ccccc1

Procedure:
1.97 g (7.43 mmol) of 5-[[(benzyloxy)carbonyl](methyl)amino]valeric acid are dissolved in 30 ml of dichloromethane, and 4.9 ml (67.3 mmol) of thionyl chloride are added. The mixture is heated under reflux for 1 h. It is then concentrated in vacuo, and the residue is again mixed with dichloromethane and concentrated once again. A viscous oil remains and is dried under high vacuum. 2 g (95% of theory) of the target compound are obtained and are reacted further without further purification and characterization.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:19][CH3:20].[Cl:21]Cl>Cl.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:19][CH3:20])[Cl:21]
Reactant: CCC1Cc2cc(OC(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: ClCl
Agent: Cl
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OC(C)C(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
By following substantially the procedure described in Example 12, Step B, and using as the reactants 2-(1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)propionic acid (3.17 g., 0.01 mole), glacial acetic acid (50 ml.), chlorine (710 mg., 0.01 mole) and concentrated hydrochloric acid (1 drop) there is obtained 2-(1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)-propionic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[CH:27][C:26]=1[CH3:35]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:17][C:25]1[C:26]([CH3:35])=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][C:30]=1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1OCc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 3-benzyloxy-4-methoxyphenol (3 g) in DMSO (2 mL) was added potassium t-butoxide (1.6 g). After 30 min, 4-chloro-3,5-dimethylnitrobenzene (2 g) was added and the resulting solution was heated at 80° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and 1N aqueous NaOH, and the organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to afford 4-(3-benzyloxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (1.9 g) as an orange solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([OH:16])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([OH:16])[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1N
Reactant: OC(CN1CCOCC1)c1cccc(Br)n1
Product: NC(=O)c1cc(-c2ccccc2F)sc1Nc1cccc(C(O)CN2CCOCC2)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 1-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (86 mg, 0.30 mmol) and 2-amino-5-(2-fluorophenyl)thiophene-3-carboxamide (72 mg, 0.31 mmol) as the starting materials.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]>S(=O)(=O)(O)O>[I:1][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[C:4]=1[CH3:3])[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: II
Agent: O=S(=O)(O)O
Product: Cc1c(I)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 94.8 %

Procedure:
To a mixture of iodine (19.6 g, 77.3 mmol) in fuming sulfuric acid (35 mL) was added 4-methyl-3-nitro-benzoic acid (10.0 g, 55.2 mmol). The mixture was stirred at 85° C. over night, then cooled to room temperature and poured over ice. The mixture was partitioned between ethyl acetate and aqueous sodium bisulfite, and the organic layer was separated, dried over MgSO4, filterd and concentrated under reduced pressure to give 16.06 g (95%) of 3-iodo-4-methyl-5-nitro-benzoic acid.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[C@H:3]([C:14]([NH:16][C@@H:17]([C:19]([N-:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:20])[CH3:18])=[O:15])[CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[CH3:13].[ClH:38].CO.O1CCOCC1>CO>[ClH:38].[CH3:1][NH:2][C@H:3]([C:14]([NH:16][C@@H:17]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:20])[CH3:18])=[O:15])[CH2:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([OH:12])=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1cc(O)cc(C)c1C[C@@H](C(=O)N[C@H](C)C(=O)[N-]CCCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN[C@@H](Cc1c(C)cc(O)cc1C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
N-methyl-BOC-2,6-dimethyltyrosyl-(D)-alanylphenylpropylamide (iso F) from Example 12 was treated with methanol-HCl/dioxane as described in Example 12, except that no methanol was used after the removal of methanol-HCl/dioxane, so no reduction of volume was necessary before lyophilization. The product is
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc(N)cc2)C1

Procedure:
tert-butyl 1-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (4.12 g, 9.50 mmol) and palladium on carbon (10% w/w, 0.41 g) in methanol was stirred in an hydrogen atmosphere at room temperature for 18 hours. After filtering through a Celite (10 g) and evaporating to dryness the residue was dried under vacuum overnight to give tert-butyl 1-(4-aminophenylsulfonyl)1,2,3,4-tetrahydroquinolin-3-ylcarbamate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[C:24]([CH:26]=[O:27])[CH:23]=[C:22]([Cl:28])[C:21]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:31][CH:30]=1>O1CCCC1>[Cl:19][C:20]1[CH:25]=[C:24]([CH:26]=[O:27])[CH:23]=[C:22]([Cl:28])[C:21]=1[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](Oc1ccc(-c2c(Cl)cc(C=O)cc2Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)c(-c2ccc(O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 ml of a 1M solution of tetrabutylammonium fluoride were added under an inert gas atmosphere to a solution of 1.5 g of the dichlorinated product of Stage C in 5 ml of tetrahydrofuran and the mixture was stirred at ambient temperature for 30 minutes to obtain the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:27])[O:4][C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=[C:20]4[C:24](=[O:25])[NH:23][C:22](=[O:26])[S:21]4)=[CH:15][C:13]=3[CH:14]=2)=[C:6]([CH3:9])[C:7]=1[OH:8].CCO.[H][H]>[Pd].O1CCOCC1>[CH3:1][C:2]1[C:3](=[O:27])[O:4][C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]4[C:24](=[O:25])[NH:23][C:22](=[O:26])[S:21]4)=[CH:15][C:13]=3[CH:14]=2)=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: Cc1c(-c2cc3cc(C=C4SC(=O)NC4=O)ccc3o2)oc(=O)c(C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1c(-c2cc3cc(CC4SC(=O)NC4=O)ccc3o2)oc(=O)c(C)c1O

Procedure:
To 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene) methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one (350 mg) in a mixed solvent of EtOH (10 ml) and 1,4-dioxane (10 ml) there was added 10% Pd/C (70 mg), and the mixture was stirred for one day in a hydrogen gas atmosphere. The reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (CH2Cl2/MeOH=5/1) to obtain 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:15](I)[CH:16]=[CH2:17]>C1CCCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:17][CH:16]=[CH2:15])[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC=CCC1
Reactant: C=CCI
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C=CCN(C(=O)OC(C)(C)C)C1CC=CCC1
Yield: 55 %

Procedure:
Cyclohex-3-enyl-carbamic acid tert-butyl ester (Kampferer, P.; Vasella, A. Helvetica Chimica Acta 2004, 87, 2764-2789) (3 g, 15.2 mmol) and allyl iodide (1.4 ml, 15.2 mmol) were treated overnight according to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=10/1) the title compound (Rf=0.55, 2.0 g, 55% yield) was obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[Na+].Cl>CO.O1CCCC1>[CH:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[CH:2]/[C:1]([C:4]2[N:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:3])=[CH:12][CH:13]=1
Reactant: CC(=O)c1ccccn1
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To solution of 2-acetylpyridine 1a (10 mmol, 1 equiv.) and tetrahydrofuran (25 mL) is added benzaldehyde 1b (10 mmol, 1 equiv.). Sodium methoxide (12 mmol, 1.2 equiv.) in methanol (24 mL, 0.5M) is introduced into the reaction and is agitated for 15 hours at room temperature. Hydrochloric acid (1N) is added until a neutral pH is obtained. The solution is extracted with dichloromethane twice, and washed once with water. The combined organic layers are dried over MgSO4, and concentrated under reduced pressure. The residue is purified by flash column chromatography on SiO2 (33% ethyl acetate/hexanes) to give the 3-phenyl-1-pyridin-2-yl-propenone 1c as a pale yellow solid. See Hollinshead, S. P., Tetrahedron Letters, Vol 37, pp. 9157-9160 (1996).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19](OC3C=CC([N+]([O-])=O)=CC=3)=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[C:33]([O:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([NH:31][C:32]3[C:33]([O:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ncccc1N
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc2C1
Solvent: CC#N
Product: COc1ncccc1NC(=O)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Yield: 54.7 %

Procedure:
A mixture of 6-(4-nitro-phenoxycarbonylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.46 g) obtained in Example (24a), 3-amino-2-methoxypyridine (441 mg), and acetonitrile (20 mL) was heated to reflux for 5 hours and concentrated. The residue was diluted with ethyl acetate, then washed with a saturated aqueous solution of sodium bicarbonate (twice) and brine, and then concentrated. The residue was purified by chromatography (dichloromethane/ethyl acetate) to obtain the title compound (770 mg, 55%) as an off-white foam.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([Mg]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(OCC)C>[CH2:8]([C:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(Cc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66 %

Procedure:
To 3.00 g (30.57 mmol) of cyclohexanone in 102 mL of tetrahydrofuran at 0° C. was added 36.68 mL (36.68 mmol) of a 1 M solution of benzyl magnesium chloride in diethyl ether and the mixture was allowed to warm to RT and stirred for 17 h. The reaction was quenched with methanol, followed by water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 3.84 g (66%) of 1-benzylcyclohexanol. Then, 2.23 g (11.69 mmol) of the compound was dissolved in 5.8 mL of toluene and 2.00 g (11.69 mmol) of methyl(2S)-2-isocyanatohexanoate was added. The mixture was heated at 85° C. for 12 d. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:6) to give 1.90 g (45%) of methyl(2S)-2-({[(1-benzylcyclohexyl)oxy]carbonyl}amino)hexanoate. Rf=0.39 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.36 (d, J=8 Hz, 1H), 7.25-7.10 (m, 5H), 4.02-3.97 (m, 1H), 3.65 (s, 3H), 3.12 (s, 2H), 1.72-1.06 (m, 16H), 0.87 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[NH:17])[NH2:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl([O-])(=O)(=O)=O.[CH3:23][NH2+:24][CH3:25].C[O-].[Na+]>C(O)CC.CO>[CH3:23][N:24]([CH:10]=[N:9][C:6]1[CH:5]=[N:17][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:16][CH:7]=1)[CH3:25]
Reactant: COc1ccc(N2CCN(C(=N)N)CC2)cc1
Reactant: C[NH2+]C
Agent: C[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCO
Solvent: CO
Product: COc1ccc(N2CCN(c3ncc(N=CN(C)C)cn3)CC2)cc1
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a mixture of 20 g of 4-(4-methoxyphenyl)-1-piperazinecarboximidamide and 21 g of N-[3-(dimethylamino)methylene]amino]-2-propenylidene]-N-methylmethanaminium perchlorate in 200 ml of 1-propanol were added dropwise 70 ml of a solution of sodium methoxide in methanol (1M). After stirring for 2 hours there were added dropwise again 70 ml of a solution of sodium methoxide in methanol (1M). Then the mixture was stirred and refluxed for 2 hours. After cooling, the reaction mixture was evaporated and the residue was purified by column chromatography (eluent: CH2Cl2 /CH3OH 97:3). The eluent of the desired fraction was evaporated, yielding 15 g (62.5%) of N-[(dimethylamino)methylene]-2-[4-(4-methoxyphenyl)-1-piperazinyl]-5-pyrimidinamine (interm. 24);
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[C:11](=O)([O:15]CC)[O:12][CH2:13][CH3:14].[H-].[Na+].Cl>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:11]([O:12][CH2:13][CH3:14])=[O:15])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-bromoacetophenone (80 g, 0.40 mol), ethanol (1 ml) and diethyl carbonate (350 ml) was added sodium hydride (32 g, 60% in oil) by small portions under ice-cooling and the mixture was stirred at room temperature for 4 hrs. The reaction solution was cooled to 0° C. and 6N hydrochloric acid (200 ml) was added. The mixture was extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1-5:1) to give the objective substance (108.9 g, quantitative) as an oil.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[N:18]#CN>ClCCl>[NH2:18][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: N#CN
Solvent: ClCCl
Product: Nc1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.7 %

Procedure:
To a cooled solution of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (2.00 g, 8.08 mmole) in 25 mL dichloromethane, cyanamide (0.728 g, 16.2 mmole) was added in one portion and the mixture was stirred for 48 h at room temperature. The resulting precipitate was filtered, slurried in methanol and subsequently washed with dichloromethane to give 1.01 g (66%) of 3-amino-1,2,4-thiadiazolo[4,5-a]benzimidazole as colourless crystals: mp 255-256 ° C.; 1H NMR (DMSO-d6) δ 8.23 (d, 1H), 7.71 (d, 1H), 7.43 (t, 1H), 7.54 (s, 2H), 7.32 (t, 1H) ppm; IR (KBr) ν 3302, 3151, 1661, 1577, 1487, 1473, 1251, 1207, 810 cm-1 ; HRMS calcd for C8H6N4S 190.0313, found 190.0293. Anal. Calcd for C8H6N4S: C, 50.51; H, 3.18; N, 29.45. Found: C, 50.26; H, 3.26; N, 29.38.