Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].[H-].[Na+].[N+]([C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1)([O-])=O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[S:10][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Sc1nc2ncccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3ncccc3[nH]2)o1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
1H-Imidazo[4,5-b]pyridine-2-thiol (1.51 g, 10.0 mmol) is suspended into 80 mL of tetrahydrofuran under argon. Then, 0.72 g (15.0 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (1.41 g, 10.0 mmol) is then added and the reaction mixture is stirred at room temperature for 2.5 h, upon which it is poured on ice and extracted 3 times with ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate, filtered, washed with ethyl acetate and dried under reduced pressure. 1.34 g of 5-(1H-imidazo[4,5-b]pyridin-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a crystalline light-brown powder. mp: 188° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Product: Clc1c(NCCNCc2ccccn2)ccc2ccccc12
Yield: 52 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and pyridine-2-carbaldehyde in 52% yield as a yellow oil.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][CH:6]([N:8]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)C)C.[C:25](O)(=O)C>[Fe]>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:4](=[O:24])[CH:5]([CH3:25])[CH2:6][N:8]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)[C:14]=2[N:15]=1
Reactant: CCOC(=O)CC(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Reactant: CC(=O)O
Agent: [Fe]
Product: CC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reaction time: 0.17 h

Procedure:
To a solution of 1.07 g (0.030 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butanoic acid ethyl ester in 20 mL of acetic acid was added 1.0 g (0.018 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hrs and then filtered while hot. 50 mL of water and 50 mL of ethyl acetate were added and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-96:4) gave 0.584 g of (rac)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)([O-:8])=[O:7].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=2)[CH:12]=[N:13]1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)n1ncc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
Methanesulfonyl chloride (887 μl, 7.20 mmol) was added to a suspension of 5-nitroindazole (979 mg, 6.00 mmol) and triethylamine (2.0 ml, 14.3 mmol) in dichloromethane (20 ml) at 0° C., and the resulting mixture was stirred at room temperature for 3 hours. Methanesulfonyl chloride (222 μl, 1.80 mmol) was further added thereto, followed by stirring for another 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution to terminate the reaction, followed by extraction with chloroform. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by washing with methanol to obtain 1-(methylsulfonyl)-5-nitro-1H-indazole (1.16 g, 80%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: COCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COCOc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
4-Methoxymethoxy-2-nitroaniline (7.69 g (38.8 mmol)) was dissolved in 19.0 ml of pyridine. To this, p-toluenesulfonyl chloride (8.14 g (42.7 mmol)) was added with stirring at room temperature and the mixture was stirred at room temperature for 18 hours. Then, water (200.0 ml) was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with chloroform-ethanol (100:1) as eluent, to give 9.46 g (63%) of 4′-methoxymethoxy-2′-nitro-p-toluenesulfonanilide as a yellow oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:30]([NH:40][CH2:41][C:42](O)=[O:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl>[C:30]([NH:40][CH2:41][C:42]([NH:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nn1cccc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)Nn1cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.7 %

Procedure:
N,N'-Dicyclohexylcarbodiimide (2.32 g, 11.2 mmol) was added in one portion to a stirred solution of 1-amino-2-benzoylpyrrole (2.1 g, 11.2 mmol) and carbobenzyloxyglycine (2.36 g, 11.2 mmol) in 70 ml of dichloromethane. The reaction mixture was stirred rapidly for 2.5 hours at room temperature and thereafter filtered to remove the precipitated dicyclohexylurea. Evaporation of the filtrate left 4.7 g of a semi-solid which was flash chromatographed (silica gel, 1:1 ethyl acetate-hexane) to give 3.75 g (88%) of powder, m.p. 96°-98°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14].[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C(Cl)Cl.N1C=CC=CC=1>[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14])(=[O:34])[CH2:32][CH3:33]
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(N)c3)n2)cc1F
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1N1CCCCC1C
Temperature: 40 °C

Procedure:
Methyl 4-{5-[3-amino-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate, prepared as in example 67, Steps 1 and 2, (100 mg; 0.24 mmol) was suspended in a DCM/Pyridine mixture (4 mL, 1:1). Propionyl chloride (25 μL, 0.29 mmol) was added and the mixture was heated to 40° C. for 18 h. After this time, solvents were removed under vacuum and title compound was obtained as an off-white powder after trituration with MeOH (96 mg; 83%). LC/MS (Method B): 467.4 (M+H)+. HPLC (Method A) Rt. 5.69 min (purity: 93.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[CH2:5].O([CH2:16][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][Si](C)(C)C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:4]1([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:5][CH2:16][N:17]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:18]1)=[O:13]
Reactant: C=C(CN1CCOCC1)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(CN2CCOCC2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a stirred cold solution (0° C.) of 2-morpholin-4-ylmethyl-acrylic acid methyl ester (110 mg, 0.594 mmols) and N-(methoxylmethyl)-N-(trimethylsilylmethyl)-benzylamine (182 μl, 0.71 mmols) in dichloromethane (2 ml) was added slowly trifluoroacetic acid (9 μl, 0.12 mmols). The resulting solution was allowed to stir at rt overnight and directly purified by column chromatography eluting with ethyl acetate to provide title compound as clear oil (86 mg, 45%).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.O>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccnc1Oc1cccc(Cl)c1

Procedure:
A solution 2-Chloro-nicotinonitrile (5.0 grams, 36.1 mmole), cesium carbonate (23.5 grams, 72.2 mmole) and 3-chlorophenol (4.65 grams, 36.1 mmole) in dimethylformamide (100 ml) was heated to 80° C. over night. The mixture was cooled and poured into 500 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a white solid (8.21 g). M.P. 88-90° C.; Anal. calcd. for C12H7N2OCl: C, 62.49; H, 3.06; N, 12.15. Found: C, 62.43; H, 3.00; N, 12.13.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C([Li])CCC.[C:14](=[O:16])=[O:15]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:14]([OH:16])=[O:15])=[C:2]1[C:6]([OH:8])=[O:7]
Reactant: O=C=O
Reactant: O=C(O)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccsc1C(=O)O
Temperature: -78 °C
Yield: 82 %

Procedure:
A dry, 2 L, 3-necked, round-bottomed flask was equipped with a mechanical stirrer and addition funnel. To the flask was added 2-thiophenecarboxylic acid (25 g, 195 mmol) in anhydrous THF (500 mL) under argon. The mixture was cooled to −78° C. with a dry ice-isopropanol bath and allowed to stir for 30 min. n-Butyllithium in Hexanes (2.5 M, 172 mL) was added dropwise over 30 min. The reaction was kept at −78° C. for an additional hour with stirring then placed under an atmosphere of dry carbon dioxide. With addition of the carbon dioxide the reaction became thick. The reaction remained at −78° C. for an additional hour before warming to −10° C. The reaction was quenched with 2 N HCl (213 mL) and allowed to reach rt. The layers were separated and the aqueous layer was extracted with EtOAc (3×200 mL). The organic layers were combined, dried (Na2SO4) and concentrated by rotary evaporation. The brown solid was crystallized from hot isopropanol and dried overnight under vacuum. Desired thiophene-2,3-dicarboxylic acid was obtained (27.3 g, 159 mmol; 82% yield); 1H NMR (DMSO-d6) 7.69 (d, J=1.5, 1), 7.38 (d, J=4.8, 1); ES MS (M+H)+=173; TLC (Chloroform-MeOH-water, 6:4:1); Rf=0.74.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]1[CH2:15][CH:14]1[C:16](O)=O.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:32][N:33]1[C:38]([CH3:39])=[CH:37][N:36]=[C:35]([CH3:40])[C:34]1=[NH2+:41].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:39][C:38]1[N:33]2[N:32]=[C:16]([CH:14]3[CH2:15][CH:13]3[C:3]3[N:2]([CH3:1])[CH:6]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]=3)[N:41]=[C:34]2[C:35]([CH3:40])=[N:36][CH:37]=1
Reactant: Cc1ncc(C)n(N)c1=[NH2+]
Reactant: Cn1cc(-c2ccccc2)nc1C1CC1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(C)n2nc(C3CC3c3nc(-c4ccccc4)cn3C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylic acid (70 mg, 0.289 mmol) in DMF (2.0 mL) was added 1-amino-3,6-dimethylpyrazin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (98 mg, 0.289 mmol) followed by O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (93 mg, 0.289 mmol) and triethylamine (0.040 mL, 0.289 mmol) at rt. After 2 h stirring at rt, the reaction mixture was stirred at 70° C. for 12 h. The crude was purified by prep HPLC using Phenomenex column and MeOH—H2O-TFA as eluent (20% to 100% over 12 min gradient; flow: 40 mL/min). Collected the pure fractions and removed solvent. Obtained 5,8-dimethyl-2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrazine in 44% yield. Prepared hydrochloride salt by adding 1.0 M HCl (3 mL) and MeOH (3 mL) and removing solvent. 1H NMR (500 MHz, METHANOL-d4) δ 6.63 (s, 1H), 6.24 (s, 1H), 6.15-6.11 (m, 2H), 5.90-5.85 (m, 2H), 5.84-5.79 (m, 1H), 2.33 (s, 3H), 1.74-1.71 (m, 1H), 1.50-1.44 (m, 4H), 1.28 (s, 3H), 0.63-0.58 (m, 1H), 0.56-0.51 (m, 1H); MS (ESI) 345 (M+H); Rf=1.61 (Condition A).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:20])[CH2:14][CH:15]([OH:19])[C:16]=1OC)([O:3][CH2:4][CH3:5])=[O:2].C([Al](CC)CC)C.[CH:28]#[N:29].C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:20])[CH2:14][CH:15]([OH:19])[C:16]=1[C:28]#[N:29])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCCCCC1=C(OC)C(O)CC1=O
Reactant: C#N
Agent: CC[Al](CC)CC
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCC1=C(C#N)C(O)CC1=O
Yield: 44.4 %

Procedure:
The procedure similar to that of Step 3 (a) of Example 1 was repeated using 9.4 g of 2-(6'-carbethoxyhexyl)-3-methoxy-4-hydroxy- 2-cyclopenten-1-one, 8.2 g of triethyl aluminum, 2.0 g of hydrocyanic acid, and a mixed solvent of benzene and toluene to provide 4.1 g of oily 2-(6'-carbethoxyhexyl)-3-cyano-4-hydroxy-2-cyclopenten-1-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][C:17]([C:19]1[C:28]2[O:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:25]([CH3:35])[C:24](=[O:36])[C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[ClH:43]>CO.CC(C)=O>[ClH:43].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][C:17]([C:19]2[C:28]3[O:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:25]([CH3:35])[C:24](=[O:36])[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)CBr)cccc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: COc1ccccc1N1CCN(CC(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Reaction time: 4 h

Procedure:
A solution of 11.5 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of methanol was added dropwise at 20°-25° C. to a stirred mixture consisting of 21.4 g of Intermediate VI and 4.1 g of potassium carbonate in 120 ml of methanol. After 4 hours stirring at the same temperature, the reaction mixture was stripped in vacuo. The residue was extracted with chloroform and the organic solution was washed with water, dried on anhydrous sodium sulfate/calcium chloride, filtered and stripped in vacuo. The obtained crude product was dissolved in acetone and a slight excess of ethanolic hydrogen chloride was added. After collection by suction filtration and recrystallization from 95% ethanol, 16.3 g of the title compound was obtained (m.p. (189) 195°-199° C.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].[NH:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=2[S:11]([OH:14])(=[O:13])=[O:12])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CCCc1ccc(F)c(S(=O)(=O)O)c1
Reactant: C1CNCCNC1
Product: CCCc1ccc(N2CCCNCC2)c(S(=O)(=O)O)c1
Yield: 37.2 %

Procedure:
According to the same method as in Example 2, from 0.61 g of 2-fluoro-5-n-propylbenzenesulfonic acid and 2.80 g of homopiperazine, 0.31 g (yield: 37.2%) of the above title product having the following physical property was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[N:3]1.[I:16]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[I:16][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=1)[NH:5][CH:4]=[N:3][C:2]2=[O:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cccc2c(=O)nc[nH]c12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc(I)cc2c(=O)nc[nH]c12
Temperature: 40 °C
Reaction time: 192 h
Yield: 56 %

Procedure:
To a solution of Methyl 4-oxo-1,4-dihydroquinazoline-8-carboxylate (6.0 g, 0.0294 mol) in sulphuric acid (48 mL) was added N-Iodosuccinimide (53 g, 0.2382 mol; 4 equiv of NIS was added at the beginning of reaction and the remaining NIS was added at day-2, day-3 and day-4 of the reaction in equal portions). The reaction mixture was stirred at 40° C. for 8 days and cooled to room temperature. (The completion of reaction was monitored by LCMS). The reaction mixture was carefully poured on-to ice cold solution of saturated potassium carbonate and maintained a basic pH. The precipitate was filtered, washed with water and dried. This solid was further suspended in saturated sodium bicarbonate (100 mL) containing methanol (20 mL). After stirring for 30 min, the insoluble solid was collected by filtration. This material was further slurred in a mixture of chloroform and methanol (1:1) and filtered and dried under vacuum to afford (5.5 g, 56%) of the title compound as an off white solid. TLC—: Chloroform/Methanol: (9/1): Rf=0.25. LCMS: Mass found (M+1, 331.0).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[N+:11]([C:14]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([O:24][CH3:25])[CH:18]=[CH:17][C:15]=1[NH2:16])([O-:13])=[O:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[C:20]([N+:21]([O-:23])=[O:22])[C:14]=2[N+:11]([O-:13])=[O:12])=[O:7])=[CH:9][CH:10]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2,3-dinitro-4-methoxyaniline as a white solid as described in Example 1. 1H NMR (CDCl3): 9.99 (s, 1H), 8.96 (d, J=2.4, 1H), 8.77 (d, J=9.3, 1H), 8.18-8.14 (m, 1H), 7.53 (d, J=9.0, 1H), 7.45 (d, J=9.3, 1H), 4.02 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:15]([Mg]Cl)[CH2:16][CH2:17][CH3:18].BrC1C=C2C(C(C(C)C)=CC(C)(C)O2)=CC=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)c2ccc(Br)cc2O1
Reactant: CCCC[Mg]Cl
Agent: CC(C)C1=CC(C)(C)Oc2cc(Br)ccc21
Product: CCCCC1=CC(C)(C)Oc2cc(Br)ccc21

Procedure:
7-bromo-2,2-dimethyl-chroman-4-one (Compound 65, 1.58 g, 6.20 mmol) was treated by the procedure described above (using n-butyl magnesium chloride) for the preparation of Compound 66 to produce the title compound as a clear oil: (1.07 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH2:18]([N:20]1[N:24]=[N:23][C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[N:21]1)[CH3:19]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:22]3[N:23]=[N:24][N:20]([CH2:18][CH3:19])[N:21]=3)=[CH:26][CH:27]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CCn1nnc(-c2ccc(C(=O)Cl)cc2)n1
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nnc(-c2ccc(C(=O)N[C@@H]3CCCC[C@@H]3c3ccc(OC)c(OC)c3)cc2)n1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
3.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene (compound C2) are dissolved in 100 ml of methylene chloride and 3.0 ml of triethylamine. A solution of 3.0 g of 4-(2-ethyl-2-H-tetrazol-5-yl)benzoyl chloride in 50 ml of methylene chloride is added dropwise at RT and the mixture is extracted, after stirring for 2 h, with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again. The organic phase is dried using sodium sulphate and concentrated. The residue is taken up in petroleum ether (low)/ethyl acetate in the ratio 2/1, filtered off with suction and dried. 5.2 g of the title compound of m.p. 188-192° C. are obtained.
Reaction SMILES: [CH3:1][SiH:2]([CH3:11])[O:3][Si:4]([CH3:10])([CH3:9])[O:5][SiH:6]([CH3:8])[CH3:7].[CH3:12][NH:13][C:14](=[O:16])[CH3:15]>[Pt].C1(C)C=CC=CC=1>[CH3:12][N:13]([Si:2]([CH3:11])([CH3:1])[O:3][Si:4]([CH3:9])([CH3:10])[O:5][SiH:6]([CH3:7])[CH3:8])[C:14](=[O:16])[CH3:15]
Reactant: C[SiH](C)O[Si](C)(C)O[SiH](C)C
Reactant: CNC(C)=O
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(=O)N(C)[Si](C)(C)O[Si](C)(C)O[SiH](C)C
Temperature: 100 °C

Procedure:
To a 1000 ml 3-necked flask was added 208.5 grams (1 mole) purified 1,1,3,3,5,5-hexamethyltrisiloxane prepared in Example 1, 153.3 grams (2.1 moles) of N-methylacetamide, 173.2 grams of toluene and about 120 ppm of platinum containing catalyst (as Pt) prepared in accordance with the teaching of U.S. Pat. No. 3,220,970 to Lamoreaux (hereinafter Lamoreaux catalyst). To the flask was attached a mechanical stirrer, a thermometer and a reflux condenser. The reaction mixture was heated at 100° C. for 20 hours and thereafter heated at 130° C. for 24 hours. At the end of the 44 hour period, analysis by infrared spectroscopy showed no Si--H present in the reaction mixture. The solvent was removed by distillation and the residue filtered through Celite R to give 317.5 grams (90.6% theoretical) of 1,5-bits (N-methylacetamido)-1,1,3,3,5,5-hexamethyltrisiloxane.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]2[CH2:9][C@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:3]1.[Li+].[OH-:18]>C1COCC1.O>[C:13]([O:12][C:10]([C@H:7]1[CH2:6][CH2:5][C@H:4]([OH:3])[CH2:9][C@@H:8]1[C:2]([OH:18])=[O:1])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](O)C[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl(1S,2S,5S)-7-oxo-6-oxabicyclo(3,2,1)octane-2-carboxylate was dissolved in THF—H2O. At 0° C., LiOH (3 eq.) was added and the resulting mixture was stirred at 0° C. for 2 hours. TLC showed starting material was consumed. The mixture was then acidified to pH of about 2. The product was extracted with EtOAc (×3). The combined extracts were washed with brine (×1); dried over MgSO4. After filtration, the filtrate was concentrated to give (1S,2S,5S)-2-(tert-butoxycarbonyl)-5-hydroxycyclohexanecarboxylic acid (quantitative).