Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].[C:26](OC(C)=C)(=[O:28])[CH3:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23][C:26](=[O:28])[CH3:27])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=C(C)OC(C)=O
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(OC(C)=O)=CC[C@H]3[C@@H]1CC2

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17-one (8.84 g, 26 mM), isopropenyl acetate (132 g, 1320 mM) and p-toluenesulfonic acid monohydrate (1.34 g, 7 mM) is heated at 120° in a distilling flask equipped with a 5 inch Vigreaux column to insure slow distillation. After heating at 120° for 16 hrs, 5 ml of distillate is collected. The temperature is increased to 140° and after 45 mins an additional 60 ml of isopropenyl acetate is collected. The residue is poured into 750 ml of ether and the ether solution is extracted with saturated NaHCO3 solution and H2O. The ether extract is dried over MgSO4 and evaporated in vacuo to give a residue containing the enol acetate and recovered starting material as the major components. The residue is chromatographed on 300 g of neutral silica gel and the column is eluted with 0.5% acetone:petroleum ether to give 1,17-diacetoxy-3 -methoxyestra-1,3,5(10),16-tetraene, yield 6.1 g (61%); m.p. 118° (petroleum ether).
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[C:6]([C:11]([O:13]C)=O)=[N:7][CH:8]=[CH:9][N:10]=1>C(O)C>[NH2:4][C:5]1[C:6]([C:11]([NH:2][NH2:3])=[O:13])=[N:7][CH:8]=[CH:9][N:10]=1
Reactant: NN
Reactant: COC(=O)c1nccnc1N
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nccnc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
Hydrazine monohydrate (34 mL, 1094.95 mmol) was added portionwise to a stirred suspension of methyl 3-aminopyrazine-2-carboxylate (21.3 g, 139.09 mmol) in ethanol (65 mL) at r.t. The resulting slurry was stirred at 60° C. for 2 hours, cooled to room temperature and filtered. The solid was washed with cold ethanol (2×25 ml) and dried to a constant weight to afford 3-aminopyrazine-2-carbohydrazide (20.75 g, 97%) as a beige solid: 1H NMR Spectrum; (DMSO-d6) 4.49 (2H, d), 7.46 (2H, br s), 7.78 (1H, d), 8.17 (1H, d), 9.79 (1H, t); Mass Spectrum [M+H]+=154.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:12])[C:10](=[O:11])[C:5]2=[C:4]([O:13][CH3:14])[C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Li]CCCC.CCCCCC.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:37](OC)=[O:38].Cl>C1COCC1>[CH3:14][O:13][C:4]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([C:37]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][N:31]=2)=[O:38])[N:6]2[CH2:7][CH2:8][N:9]([CH3:12])[C:10](=[O:11])[C:5]=12
Reactant: CCOC(=O)c1c(OC)c2n(c1Br)CCN(C)C2=O
Reactant: COC(=O)c1cnccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1c(OC)c2n(c1C(=O)c1cnccn1)CCN(C)C2=O
Temperature: 25 °C

Procedure:
To a cold (−78° C.) solution of ethyl 6-bromo-8-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (0.5 g, 1.51 mmol; Example 7, steps 1 to 6, substituting benzyl bromide with iodomethane in step 5) in anhydrous THF (15 mL) under an atmosphere of dry nitrogen, a solution of n-BuLi in hexane (1.81 mL, 1.81 mmol, 1 M) was added. The resultant mixture was stirred at −78° C. for 15 minutes, and treated with methyl pyrazine-2-carboxylate (0.21 g, 1.51 mmol). The reaction mixture was allowed to warm up to room temperature, treated with dilute hydrochloric acid, and concentrated under vacuum. The residue was extracted with ethyl acetate. The organic extracts were combined, washed with aqueous sodium carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 0 to 10% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[CH:7][C:6]([CH2:18][N:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]2=[O:27])=[CH:5][CH:4]=1.Cl.[OH-:29].[Na+]>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[CH:7][C:6]([CH2:18][N:19]2[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:29])=[CH:21][C:20]2=[O:27])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ccc(C#N)cc2=O)cc1-c1cccc([N+](=O)[O-])c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(Cn2ccc(C(N)=O)cc2=O)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
Into a 20 mL vial with a stir bar was added P-196 (132 mg, 0.37 mmol) and concentrated HCl (2 mL). The reaction was stirred at rt for 18 hours, basified with 4N aqueous NaOH, and the product was extracted with ethyl acetate (3×5 mL). The combined organics were concentrated to half their original volume and 5 mL of hexane was added. The resulting solids were filtered, washed with hexane, and triturated with ether to afford 29.8 mg (22%) of P-207 as a tan solid. 1H NMR (400 MHz, DMSO-d6) 8.28 (s, 1H), 8.20 (dd, J=1.4, 8.3 Hz, 1H), 8.05 (br. s., 1H), 7.93 (t, J=7.4 Hz, 2H), 7.72 (t, J=8.0 Hz, 1H), 7.61 (br s, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.42 (dd, J=2.1, 8.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 6.54 (dd, J=1.8, 7.0 Hz, 1H), 5.10 (s, 2H), 3.79 (s, 3H) ppm. MS: 380.1 (APCI+).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=3)[C:23]=2[OH:24])=[C:15]([CH3:34])[CH:14]=1)#[N:12].C(O)=O>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:29]([C:28]2[CH:32]=[CH:33][C:25]([N:22]3[C:23]([OH:24])=[C:19]([C:16]4[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[CH:14][C:15]=4[CH3:34])[CH:20]=[N:21]3)=[N:26][CH:27]=2)=[O:30])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CC(C)(C)N1CCNCC1
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C(C)(C)C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using 1-t-butyl piperazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (53 mg, 0.119 mmol, 76%) as a white solid. MS: 445 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (s, 9 H) 2.43 (s, 3 H) 2.71 (br. s., 4 H) 3.57 (br. s., 4 H) 7.56-7.62 (m, 1 H) 7.65 (s, 1 H) 7.94 (d, J=8.1 Hz, 1 H) 7.98-8.07 (m, 2 H) 8.42 (d, J=8.6 Hz, 1 H) 8.52 (d, J=1.5 Hz, 1 H) 12.42 (br. s., 1 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 57.7 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (55 mg, 0.128 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.3 eq) and methyl chloroacetate (25 mg, 0.227 mmol, 1.7 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had gone to completion. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-55% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (37 mg, 57%). MS(ES)+ m/e 501.1 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:41]=[CH:40][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:32][CH:33]=3)=[O:27])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:32][CH:33]=3)=[O:27])=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:40][CH:41]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)nc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccccc4)nc3)cc2)C(=O)O)cc1
Yield: 78.5 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-isopropylphenoxy)-3-[4-[2-(2-phenylpyridine-5-carbonylamino)ethoxy]phenyl]propionate (169 mg), which is the product of Example 96, was reacted with aqueous sodium hydroxide solution (1N, 0.60 ml) and the reaction mixture was treated to give the title compound (126 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28](=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:26][O:27][C:28](=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)Cc1ccc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid, Example 26, step 3, was reacted with methyl-(4-aminophenyl)acetate and HBTU at 80° C. 4 h to give the title compound as a white solid. MS (m/e)=541.3 [M+H+].
Reaction SMILES: [Na].C(O[CH:7]=[CH:8][C:9](=O)[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])CCC.[C:18]([NH2:24])(=[O:23])[CH2:19][C:20]([NH2:22])=[O:21]>C(O)C>[O:21]=[C:20]1[C:19]([C:18]([NH2:24])=[O:23])=[CH:7][CH:8]=[C:9]([C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[NH:22]1
Reactant: NC(=O)CC(N)=O
Reactant: CCCCOC=CC(=O)C(F)(F)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1ccc(C(F)(F)C(F)(F)F)[nH]c1=O

Procedure:
0.22 g (9.7 mmol) of sodium was dissolved in 50 ml of ethanol, 2 g (8.1 mmol) of 1-butoxy-4,4,5,5,5-pentafluoropent-1-en-3-one and 0.86 g (8.1 mmol) malonamide were added and the mixture was heated under reflux for 7 h. The mixture was concentrated, and 1N hydrochloric acid was added. The resulting precipitate was filtered off with suction and dried. This gave 1.9 g (94% of theory) of a yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][C:12](OCCCC)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)CCOc1ccc(C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(OCCCO)cc1
Temperature: -5 °C

Procedure:
This ester 21.0 g was dissolved in 500 ml dry ether and cooled to -5° C. in an ice/acetone bath. To the cold solution was added, cautiously, a slurry of 3.5 g lithium aluminum hydride in 100 ml dry ether. After one hour the excess lithium aluminum hydride was destroyed by the cautious addition of 200 ml ethyl acetate, then 50 ml water. The solution was filtered and the filtrated partitioned between 200 ml ether-200 ml water. The organic layer was removed, dried, and evaporated to a yellow oil which was vacuum distilled (116° C./0.35 mm) over potassium carbonate to a clear colorless oil, 3-p-t-butylphenoxypropanol, 10.1 g (64%).
Reaction SMILES: [H-].[Na+].S([O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]([CH:21]=1)=[N:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([OH:22])[CH:17]=1)[CH:12]=2)(O)(=O)=O.[Cl:23][CH2:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[ClH:23].[Cl:23][CH2:24][CH2:25][CH2:26][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]([CH:21]=1)=[N:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH2:26][CH2:25][CH2:24][Cl:23])[CH:17]=1)[CH:12]=2
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reactant: O=S(=O)(O)Oc1ccc2cc3ccc(O)cc3nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 11.80 g. of sodium hydride (61.14% oil dispersion) and 26.0 g. of 3,6-acridinediol sulfate (2:1) is added 250 ml. of dry N,N-dimethylformamide. The mixture is stirred at room temperature for 1.5 hours, then 49.8 g. of 3-chloropropyl-p-toluene sulfonate are added. This mixture is stirred at room temperature for 3 hours and 20 minutes, then at 50° C. for 2 hours. The volatile materials are removed under reduced pressure at 35°-40° C. and the residue is quenched with 1200 ml. of ice-cold saturated aqueous sodium bicarbonate solution. The resulting tan crystals are collected and dissolved in 500 ml. of chloroform. A 30 ml. portion of 6 N hydrochloric acid in isopropanol is added and the mixture is diluted with ether. The solid is collected and recrystallized from ether, giving the desired product as tan crystals, m.p. 211°-213° C.
Reaction SMILES: ClC[C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.[SH:27][C:28]1[N:32]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[N:31]=[N:30][N:29]=1.[CH:40](O)(C)C>>[CH3:9][C:8]1[C:3]([SH:27]([CH3:40])[C:28]2[N:32]([C:33]3[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=3)[N:31]=[N:30][N:29]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: Oc1ccc(-n2nnnc2S)cc1
Reactant: CC(C)O
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1[SH](C)c1nnnn1-c1ccc(O)cc1
Temperature: 0 °C
Yield: 75 %

Procedure:
0.61 g (1.5 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine and 0.30 g (1.5 mmol) of 4-(5-mercaptotetrazol-1-yl)phenol in 30 ml of isopropanol are heated under reflux for 2 h under a nitrogen atmosphere. The mixture is then concentrated. The residue is taken up in 30 ml of water, adjusted to pH 9 using 2N sodium hydroxide solution and extracted with 4×30 ml of dichloromethane. The organic extracts are washed with water, dried over magnesium sulfate and concentrated. The residue is taken up in 200 ml of hot acetonitrile, clarified with active carbon, filtered, concentrated to a volume of 50 ml and cooled to 0° C. The precipitate is filtered off, washed with acetonitrile and dried. 0.64 g (75%) of the title compound is isolated as a pale beige solid. M.p. 92° C. (dec.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:3].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:12]=1[CH2:13][OH:14].N1C=CC=CC=1>ClCCl>[OH:14][CH2:13][C:12]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]=1[NH:10][C:2](=[O:3])[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: Cc1cccc(N)c1CO
Reactant: COC(=O)COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)COC(=O)Nc1cccc(C)c1CO
Yield: 35.1 %

Procedure:
Starting from methoxycarbonylmethyl chloroformate (11.7 g), 2-amino-6-methylbenzyl alcohol (10.5 g) and pyridine (6.2 ml) in dichloromethane (230 ml), 6.8 g (20%) of the title compound, m.p. 70-74° C., are obtained according to the procedure indicated in Example C1, after chromatography on silica gel (eluent: ethyl acetate/petroleum ether 50/70=1:1) and crystallization from diisopropyl ether.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]1[O:24][C@@H:23]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO.C(Cl)(=O)C.[Cl-].[NH4+]>[CH2:28]([O:27][P:25]([O:30][CH2:31][CH3:32])([C@H:23]1[S:22][CH2:21][C@H:20]([CH2:19][OH:18])[O:24]1)=[O:26])[CH3:29].[CH2:28]([O:27][P:25]([O:30][CH2:31][CH3:32])([C@H:23]1[S:22][CH2:21][C@@H:20]([CH2:19][OH:18])[O:24]1)=[O:26])[CH3:29]
Reactant: CCOP(=O)(OCC)[C@@H]1O[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CS1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: CO
Product: CCOP(=O)(OCC)[C@@H]1O[C@@H](CO)CS1
Product: CCOP(=O)(OCC)[C@@H]1O[C@H](CO)CS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of cis and trans-5-t-butyldimethylsilyloxymethyl-2-(diethyloxyphosphinoyl)-1,3-oxathiolane (example 25) (4.00 g, 10.8 mmol) in MeOH (30 mL) was added a few drops of acetyl chloride (200 μL) at 0° C. The mixture was stirred at 0° C. for 1 hr. and at room temperature for 18 hr. A few drops of ammonium chloride was added and the solvent was evaporated under reduced pressure. The crude material was purified by several flash chromatography with a mixture of dichloromethane and methanol (96:4) to give 382 mg of the cis isomer , 1.19 g of the trans isomer and 332 mg of the mixture in a total yield of 80% after the first purification. ##STR52## 1H NMR (300 MHz, CDCl3) δ: 1.37 (t, 6H, J=7.0 Hz, CH3), 3.03 (dd, 1H, J=5.4 Hz, 10.8 Hz, H-4a), 3.31 (dd, 1H, J=9.0 Hz, 10.9 Hz, H-4b), 3.74 (dd, 1H, J=4.0 Hz, 12.3 Hz, CHAHBOH), 3.98 (dd, 1H, J=2.9 Hz, 12.4 Hz, CHAHBOH), 4.24 (m, 4H, CH2), 4.40 (m, 1H, H-5), 5.30 (d, 1H, 2JHP =9.6 Hz, H-2). ##STR53## 1H NMR (300 MHz, CDCl3) δ: 1.37 (m, 6H, CH3), 2.05 (bs, 1H, OH), 3.00 (dd, 1H, J=7.0 Hz, 10.2 Hz, H-4a), 3.25 (dd, 1H, J=6.3 Hz, 10.4 Hz, H-4b), 3.69 (dd, 1H, J=4.9 Hz, 11.9 Hz, CHAHBOH), 3.85 (dd, 1H, J=3.9 Hz, 11.9 Hz, CHAHBOH), 4.23 (m, 4H, CH2), 4.65 (m, 1H, H-5), 5.36 (d, 1H, 2JHP =8.6 Hz, H-2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=C(O)c1cn2cc(Cl)ccc2n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(=O)c3cn4cc(Cl)ccc4n3)CC2)cc1
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid (0.170 g) and 1-(4-methoxyphenyl)piperazine (Aldrich; 0.165 g) in dichloromethane (4mL) are added diethyl cyanophosphonate (Aldrich; 0.157 mL) and triethylamine (0.144 mL), followed by DMF (2 mL). After stirring overnight, the mixture is quenched with aqueous sodium bicarbonate and then partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are filtered through sodium sulfate and concentrated, and the residue is chromatographed on silica gel using methanol/dichloromethane (2/98) to give 0.212 g of 1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)carbonyl]-4-(4-methoxyphenyl)piperazine, mp 180-181° C.; IR (mineral oil) 1620, 1517, 1237, 1246, 1230 cm-1. 1HNMR (CDCl3) δ 3.16, 3.78, 3.97, 4.47, 6.86, 6.94, 7.21, 7.56, 8.10, 8.20.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)[CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O.C(O)C>[N:28]1([CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[CH:15]=4)[C:10](=[O:27])[C:9]=3[CH:8]=2)=[O:5])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(CCCl)Nc1ccc2c(=O)c3cc(NC(=O)CCCl)ccc3[nH]c2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(CCN1CCCC1)Nc1ccc2c(=O)c3cc(NC(=O)CCN4CCCC4)ccc3[nH]c2c1
Temperature: 0 °C

Procedure:
2,6-Bis(3-chloropropionamido)-9(10H)-acridone (AR-ACO-9, 3.00 g, 7.38 mmol) and KI (0.10 g, 0.60 mmol) were suspended in a mixture of dimethylformamide (45 mL) and ethanol (45 mL). Pyrrolidine (12 mL, 10.22 g, 144 mmol) was added in one lot and the whole stirred at reflux for 21 hr. The flask was cooled and all the solvents removed under reduced pressure. Dimethylformamide (100 mL) was added to the flask and this was in turn removed under reduced pressure. The process was repeated with toluene (2×100 mL) and propan-2-ol (2×100 mL). The solid in the flask was dissolved in water (60 mL) and 0.88 s.g. ammonia (10 mL) was added dropwise with stirring to yield an orange-brown precipitate. The flask was chilled with ice-water and the product collected, washed with dilute ammonia (2×10 mL, 1% dilution of 0.88 s.g. ammonia) and ice-cold water (2×10 mL). The product was dried in air and over P2O5 under vacuum to yield a yellow solid AR-ACO-10 (3.11 g, 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.C(O[C:16](=O)[N:17]([C:19]1[CH:24]=[CH:23][C:22](Br)=[C:21]([O:26][CH3:27])[CH:20]=1)C)(C)(C)C>>[N:9]1[O:8][N:7]=[C:6]2[CH:10]=[C:2]([C:22]3[CH:23]=[CH:24][C:19]([NH:17][CH3:16])=[CH:20][C:21]=3[O:26][CH3:27])[CH:3]=[CH:4][C:5]=12
Reactant: Brc1ccc2nonc2c1
Reactant: COc1cc(N(C)C(=O)OC(C)(C)C)ccc1Br
Product: CNc1ccc(-c2ccc3nonc3c2)c(OC)c1

Procedure:
The starting compound is obtained according to the procedure described in Example 7 from 5-bromo-benzo[1,2,5]oxadiazole and (4-bromo-3-methoxy-phenyl)-methyl-carbamic acid tert-butyl ester, as a yellow powder. MS(ES+): 378 (M+23).
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([CH2:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:33][C:34]1([NH:38][CH3:39])[CH2:37][NH:36][CH2:35]1>>[CH2:18]([N:8]1[C:7]2[N:6]=[C:5]3[CH:20]=[C:21]([N:36]4[CH2:37][C:34]([CH3:33])([NH:38][CH3:39])[CH2:35]4)[C:2]([F:1])=[CH:3][C:4]3=[CH:13][C:12]=2[C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9]1)[CH3:19]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CNC1(C)CNC1
Agent: CS(=O)(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(C)(NC)C4)cc3nc21
Yield: 61.4 %

Procedure:
1-Ethyl-7-fluoro-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.52 g of 7,8-difluoro-1-ethyl-4-oxo-1,4-dihydrobenzo[b]-[1,8]naphthyridine-3-carboxylic acid and 2.34 g of 3-methyl-3-(methylamino)azetidine dimethanesulphonate. 1.18 g of 1-ethyl-7-fluoro-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 338° C.