Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18]O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40].C(Cl)(Cl)Cl>ClCCl>[Br:40][CH2:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(CC1CCCCC1)Nc1ccccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1ccccc1CCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of 2-cyclohexyl-N-[2-(2-hydroxyethyl)phenyl]acetamide (780 mg) in dichloromethane (20 mL) were added triphenylphosphine (938 mg) and carbon tetrabromide (1.12 g) at room teperature. The solution was stirred at room temperature for 1 hour. Chloroform was added and the solution was washed in turn with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=7:3) to give the title compound (450 mg).
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[CH3:6])=[O:4].C1N2CN3CN(C2)C[N:23]1C3.[Br-].[NH4+].C(O)(C)C>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:7]2[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][N:23]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:17]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Br-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
Reflux 1.8 g. (0.005 moles) of 2-(2-bromo-N-methylacetamido)-5-chlorobenzophenone, 2.8 g. (0.020 moles) of hexamethylenetetramine and 1.96 g. (0.020 moles) of ammonium bromide together for 2 hours in 14 ml. of 85% (v/v) aqueous isopropyl alcohol. Pour the reaction mixture into water and extract the product with benzene. Wash the benzene solution with water, dry over anhydrous sodium sulfate, filter and evaporate to dryness. After recrystallization, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained. The material gives a single spot by thin layer chromatography, and after drying under vacuum at 110° C., shows no depression on mixed melting point with an authentic sample (M.P. 129.5°-130.5° C.).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14](=[O:15])[C:13]2[N:12]=[C:11]([CH:16]=O)[CH:10]=[CH:9][C:8]=2[C:7](=[O:18])[CH:6]=1)(=[O:3])[CH3:2].[CH2:19]([O:24][C:25](=[O:38])[C@H:26]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH2:27])[CH2:20][CH:21]([CH3:23])[CH3:22]>C1(C)C(C)=CC=CC=1>[CH3:23][CH:21]([CH2:20][CH2:19][O:24][C:25]([C:26]1[CH:28]=[C:29]2[C:30](=[C:16]([C:11]3[CH:10]=[CH:9][C:8]4[C:7](=[O:18])[CH:6]=[C:5]([NH:4][C:1]([CH3:2])=[O:3])[C:14](=[O:15])[C:13]=4[N:12]=3)[N:27]=1)[NH:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:37]2=1)=[O:38])[CH3:22]
Reactant: CC(=O)NC1=CC(=O)c2ccc(C=O)nc2C1=O
Reactant: CC(C)CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1C
Product: CC(=O)NC1=CC(=O)c2ccc(-c3nc(C(=O)OCCC(C)C)cc4c3[nH]c3ccccc34)nc2C1=O
Yield: 429 %

Procedure:
7-Acetamido-2-formylquinoline-5,8-dione (23) (prepared as described in Example 23) (244 mg, 0.1 mmol), L-tryptophan isoamyl ester (37) (prepared as described in Example 37) (239 mg, 1 mmol) and xylene (64 ml) were mixed. The mixture was stirred and slowly heated in an oil bath from room temperature to 110° C. over a one-hour period, and then from 110° C. to 140° C. over a 3-hr period. The hot reaction mixture was filtered to remove the brown impurity. The filtrate was evaporated under vacuum. The residue was treated with ethylacetate/hexane to give an orange solid (213 mg, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.Br[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2nccn2n1
Reactant: Brc1ccsc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Clc1ccc2ncc(-c3ccsc3)n2n1
Yield: 65.6 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (200 mg, 1.30 mmol, 1.0 equiv) in toluene (5.00 mL) was added 3-bromothiophene (0.18 mL, 1.95 mmol, 1.5 equiv), potassium carbonate (360 mg, 2.60 mmol, 2.0 equiv), triphenyl phosphine (68 mg, 0.260 mmol, 0.20 equiv) and potassium acetate (29 mg, 0.130 mmol, 0.1 equiv). The reaction mixture was heated to reflux for 24 h. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 201 mg of the white solid, 85%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21].COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:26]3[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
For example, N—BOC-piperazine and methanesulfonyl chloride were reacted together in dichloromethane and triethylamine to yield 4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester. Cleavage of the BOC protecting group using HCl (2M) in dichloromethane yielded 1-methanesulfonyl-piperazine. HCl salt. A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.00 g), 1-methanesulfonyl-piperazine (750 mg) and trimethylorthoformate (3.80 mL) was stirred in 1,2-dichloroethane (30 mL) for 6 hrs at room temperature. To this was added sodium triacetoxyborohydride (900 mg) and the reaction mixture was stirred for 24 hours at room temperature. The mixture was then quenched with brine, extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with hot ethyl acetate to yield 2-chloro-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine as a white solid (1.01 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8].[C:23](Cl)(=[O:25])[CH3:24]>>[C:23]([O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)ccc1O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1Cl
Yield: 34 %

Procedure:
Using 5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2 hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CON(C)C(=O)c1ccc(O)c(CN2CCOCC2)c1
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1ccc(O)c(CN2CCOCC2)c1
Reaction time: 2 h

Procedure:
Bis(cyclopentadienyl)zirconium chloride hydride (4.29 g, 16.27 mmol) was added portionwise over 10 min to a solution of 4-hydroxy-N-methoxy-N-methyl-3-(morpholinomethyl)benzamide (3.8 g, 13.56 mmol) in THF (50 mL), under N2 whilst maintaining the temperature below 20° C. Stirred for 2 h, quenched with saturated potassium sodium tartrate, extracted with EtOAc (3×100 mL), washed with more saturated potassium sodium tartrate and brine, dried (Na2SO4), filtered and evaporated in vacuo. Purified by flash chromatography with EtOAc as eluent to give the sub-title compound as a colourless oil. Yield: 2.1 g
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[NH3:18]>C(O)C>[NH2:18][CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@H]2CO2)CC1
Reactant: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@H](O)CN)CC1
Reaction time: 12 h

Procedure:
Tert-butyl 4-[[(2S)-oxiran-2-yl]methyl]piperazine-1-carboxylate 20a (9.20 g, 38 mmol) was dissolved in 60 mL of ethanol followed by the addition of 50 mL of aqueous ammonia. The reaction solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound tert-butyl 4-[(2R)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 20b (9 g, as a white solid), which was used in the next step without further furification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[CH:33]1[CH:34]=[CH:35][C:36]2[N:41]([OH:42])[N:40]=[N:39][C:37]=2[CH:38]=1.[H-].[Na+]>CN(C=O)C>[N:41]1([O:42][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[C:8](=[C:18]4[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[O:25])[CH2:20][CH2:19]4)[C:9]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=4[CH2:11][CH2:12][C:3]=23)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=2[N:39]=[N:40]1
Reactant: On1nnc2ccccc21
Reactant: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(On4nnc5ccccc54)ccnc32)CC1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of the title compound from Example 261 (1.0 grams) in dry DMF (60 mL) was added HOBT (1.4 grams), sodium hydride (0.2 grams, 60% in mineral oil) and distilled water (0.5 mL). The solution was stirred at 25° C. under nitrogen while being irradiated with a 200 Watt lamp for 20 hours. The reaction mixture was concentrated in vacuo, diluted with CH2Cl2 and saturated aqueous sodium bicarbonate and after two hours, the organic phase was separated, dried over MgSO4 and concentrated. Purification by flash column chromatography (silica gel) using 3-5% MeOH--CH2Cl2 afforded the title compound (Yield 1.1 grams, 87%, MH+564).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].Cl.C(=O)([O-])[O-].[K+].[K+].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20](=[O:19])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][NH:9]1
Reactant: Cc1ccccc1NN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2ccccc2C)c1=O
Yield: 86.3 %

Procedure:
In the same manner as in Reference Example 63 and using (2-methylphenyl)hydrazine•hydrochloride (5 g, 32 mmol), water (100 mL), potassium carbonate (9.7 g, 70 mmol) and diethyl ethoxymethylenemalonate (8.3 g, 38 mmol) as starting materials, the title compound (6.8 g, 87%) was obtained as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[F:15][C:16]1[C:21](B(O)O)=[CH:20][CH:19]=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=2)[N:17]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=2)=[CH:20][CH:19]=[C:18]([C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:30]=2)[N:17]=1
Reactant: CCCCCCCc1ccc(Br)cc1
Reactant: CCCCCCCCCc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccc(-c2ccc(-c3ccc(CCCCCCC)cc3)c(F)n2)cc1
Yield: 39.1 %

Procedure:
A solution of 48 mmol of 1-bromo-4-heptylbenzene in 155 ml of toluene is admixed with 48 mmol of 2-fluoro-6-(4-nonylphenyl)pyridine-3-boronic acid, 77 ml of ethanol, a solution of 96 mmol of sodium carbonate in 77 ml of water and 0.5 mmol of tetrakis(triphenylphosphine)palladium(0) at room temperature. The mixture is heated at the boil for 7 h. After cooling, the phases are separated, the aqueous phase is extracted with tert-butyl methyl ether and the combined organic phases are washed with water and saturated sodium chloride solution and dried with sodium sulfate. The solvents are then removed under reduced pressure and the raw product is purified by column chromatography over silica gel 60 using n-heptane as eluent and recrystallization from acetone, giving 8.9 g (39%) of 2-fluoro-3-(4-heptylphenyl)-6-(4-nonylphenyl)pyridine; X 42 S3 56 SC 136.1 S2 136.7 N 137 I.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]([C:16]([CH2:18]Cl)=[O:17])([CH3:15])[CH3:14]>CC(C)=O>[CH3:12][C:13]([CH3:15])([CH3:14])[C:16](=[O:17])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)C(=O)CCl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Cn1cncn1
Temperature: 25 °C
Yield: 72 %

Procedure:
138 g (2 moles) of 1,2,4-triazole were added in portions to 276.4 g (2 moles) of ground potassium carbonate and 296.2 g (2 moles) of α-chloropinacolin in 500 ml of acetone at room temperature, whereupon the internal temperature rose to the boiling point. The reaction mixture was stirred under reflux for 5 hours and then cooled to room temperature. It was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. The oily residue crystallized after adding benzine. 240.8 g (72% of theory) of 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 62°-64° C. were obtained. ##STR79##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.C1C[O:17][CH2:16]C1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:16]=[O:17])[N:3]=1
Reactant: C1CCOC1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Product: O=Cc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 23.7 g (100 mmol) of 2,6-dibromopyridine in 150 mL of anhydrous, degassed THF cooled to −78° C. was added dropwise under N2 a solution of 11.0 mL (110 mmol) of 10.0 M n-BuLi in 150 mL anhydrous, degassed Et2O. After 2 hours at −78° C., 24.2 mL (300 mmol) of anhydrous degassed DMF was added dropwise with rapid stirring. This solution was stirred at −78° C. for 2 hours, and was then allowed to warm to room temperature (RT) overnight. The solution was cooled to −78° C. and 100 mL of 1.0 M aq. HCl was added slowly. The organic phase was separated and the aqueous phase was washed with 3×50 mL Et2O. The organic washes were combined and washed with 3×50 mL H2O and 3×50 mL brine, then dried over Na2SO4. The volatiles were removed in vacuo to provide an orange oil. The oil was triturated with hexanes to give 2-bromo-6-formylpyridine as a pale orange solid that was washed with cold pentanes and dried under vacuum overnight.
Reaction SMILES: [P:1]([O-:32])([O:28][CH2:29][CH2:30]Br)([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2].[CH3:33][N:34]([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[P:1]([O-:32])([O:28][CH2:29][CH2:30][N+:34]([CH3:36])([CH3:35])[CH3:33])([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2]
Reactant: CN(C)C
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCCCOP(=O)([O-])OCCBr
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCNC(=O)OCCCOP(=O)([O-])OCC[N+](C)(C)C
Temperature: 60 °C

Procedure:
The entire amount of the phosphate ester obtained in Example 3 is dissolved in 70 ml of toluene containing 14 g of trimethylamine under anhydrous state and heated at 60° C. for 48 hours. The reaction mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in 40 ml of methanol, vigorously stirred in the presence of 2.7 g of silver carbonate and heated under reflux for 1 hour. After filtration, the filtrate is evaporated to dryness, and the product is separated and purified by silica gel chromatography [eluent: chloroform-methanol-water (65:25:4)] and crystallized from chloroform-acetone. By this procedure is obtained 0.9 g of the above-indicated compound as colorless crystalline powder.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[CH:17]=[C:18]4[C:25](=[O:26])[NH:24][CH2:23][CH:22]([CH3:27])[N:19]4[C:20]=3[CH:21]=2)=[O:12])=[CH:6][CH:5]=1.[OH-].[K+]>CCO>[CH3:27][CH:22]1[N:19]2[C:20]3[CH:21]=[C:13]([C:11]([NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=4)=[O:12])[CH:14]=[CH:15][C:16]=3[CH:17]=[C:18]2[C:25](=[O:26])[NH:24][CH2:23]1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3cc4n(c3c2)C(C)CNC4=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1CNC(=O)c2cc3ccc(C(=O)Nc4ccc(C(=O)O)cc4)cc3n21
Temperature: 80 °C
Yield: 55 %

Procedure:
To a suspension of 1b (Example 1) (33 mg, 0.09 mmol) in EtOH (2 mL) was added 10% of aqueous KOH (174 uL, 0.35 mmol). The mixture was heated to 80° C. for 3 h. The reaction was cooled to room temperature and concentrated. The resulting residue was dissolved in water (7 mL) and acidified with 6 N HCl to pH ˜2. A large amount of white precipitate formed which was filtered and rinsed with ether and dried in the vacuum oven (50° C.) to provide 18 mg of the title compound, yield 57%. ESI-MS m/z 362.37 [M−H]−.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:12][CH2:13][CH2:14][O:15][C:16]([C:18]1[CH:19]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=2)[C:20]([C:26]([O:28][CH3:29])=[O:27])=[C:21]([CH3:25])[NH:22][C:23]=1[CH3:24])=[O:17].O>CN(C)C=O>[C:1]([S:3][CH2:12][CH2:13][CH2:14][O:15][C:16]([C:18]1[CH:19]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=2)[C:20]([C:26]([O:28][CH3:29])=[O:27])=[C:21]([CH3:25])[NH:22][C:23]=1[CH3:24])=[O:17])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCSC(C)=O)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
To a solution of 0.30 g of thioacetic acid in 20 ml of N,N-dimethylformamide cooled on ice was added 0.50 g of potassium carbonate, and the mixture was stirred for 10 minutes. Then, 0.90 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(3-bromopropyl) ester was added , and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine successively,m and dried over magnesium sulfate.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH2:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:26])[CH:3]=1.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:32]=CC=C[CH:28]=1.C([Sn](CCCC)(CCCC)CCCC)C=C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:32]([C:2]1[C:10]2[N:9]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH2:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:26])[CH:3]=1)[CH:27]=[CH2:28]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=C(Cn1c2c(c3cc(C)cc(Br)c31)CN(C)CC2)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Product: C=CCc1cc(C)cc2c3c(n(CC(=C)c4ccc(F)cc4)c12)CCN(C)C3
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6-Bromo-5-(2-(4-fluorophenyl)allyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (185 mg, 0.23 mmol) and tetrakis(triphenylphosphine (5.3 mg, 0.046 mmol) were charged in a reaction bottle, which was evacuated and backfilled with nitrogen. Dry toluene (2 mL) was added under nitrogen and the flask purged with nitrogen for 2 min. Allyltributyltin (151 mg, 0.46 mmol) was added dropwise. The reaction mass was stirred at 100° C. overnight. The reaction mixture was concentrated under vacuum and purified on silica gel (100-200 mesh) using 0-3% MeOH:DCM as eluent. Yield: 30 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:34][CH:35]([F:37])[F:36])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(OC(C)(C)C)=O)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:34][CH:35]([F:36])[F:37])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(N)cc1
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of [3-(4-tert-butoxycarbonylaminobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.11 g) in dichloromethane (2.5 mL) was treated with trifluoroacetic acid (0.25 mL) and the resulting mixture was allowed to stand at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a yellow gum (0.051 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[CH:19][C:18]=1[O:28][CH3:29]>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:23]=[C:21]([C:20]3[CH:25]=[C:26]([CH3:27])[C:17]([OH:16])=[C:18]([O:28][CH3:29])[CH:19]=3)[N:22]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: COc1cc(C(=N)NO)cc(C)c1O
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(O)c(OC)c3)no2)cc1C
Yield: 35.3 %

Procedure:
The title compound (16 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and 4,N-dihydroxy-3-methoxy-5-methyl-benzamidine (23 mg, 117 μmol) according to Method A; LC-MS: tR=0.57 min; [M+1]+=387.78.