Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=4[Cl:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Reaction time: 0.05 h
Yield: 53.5 %

Procedure:
To a solution of 415 mg of 2,4-dichlorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in ethyl acetate, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give a residue which is crystallized from ethyl acetate to give 420 mg of the desired product as a crystalline solid, m.p., 210°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:21]([NH:13][NH:12][C:10]1[CH2:9][N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, prepared in Example 1, in 25 parts by volume of tetrahydrofuran is added 0.62 part by volume of benzoyl chloride, and the mixture is stirred at room temperature for 2 hours to complete the reaction. The reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting white precipitate is separated, washed with water and then with methanol, and dried, whereby 2-(2-benzoylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine is yielded as crystals. Recrystallization from a mixture of chloroform and methanol yields white needles melting at 207° C to 208° C (effervescence).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]([C@@H:11]2[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH2:8][C:9]#[N:10])#[N:2].C(O)C.[SH2:44]>C(N(CC)CC)C>[NH2:10][C:9]1[NH:2][C:1](=[S:44])[C:3]2[N:4]=[CH:5][N:6]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1
Reactant: S
Reactant: N#CCc1c(C#N)ncn1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc2c(ncn2[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=S)[nH]1

Procedure:
A mixture of 8 g of 4-cyano-5-cyanomethyl-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)imidazole, 250 ml of ethanol saturated at 0° C. with hydrogen sulfide, and 2.5 g of triethylamine is kept in a steel bomb for 48 hours at ambient temperature. The reaction solution is evaporated in vacuo to a yellow foam which is coevaporated with ethanol several times to provide 6-amino-1,5-dihydro-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-4H-imidazo[4,5-c]pyridine-4-thione.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1
Reactant: CSc1nc2cccccc-2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2cccccc-2n1

Procedure:
First, 3 g of 2-methylthiocycloheptimidazole as synthesized according to Synthetic example 1 (c) with reference to the method disclosed in Bulletin of the Chemical Society of Japan, volume 33, No. 1, pages 56 to 58 (1960) was added to 50 ml of methanol, and 1 g of sodium methoxide was further added thereto. After reflux with heating for 10 hours, the solvent was distilled away, and 50 ml of benzene was added to the residue. The insoluble matters were filtered out, and the filtrate was concentrated. The resulting crystals were purified by silica gel column chromatography using ethyl acetate as a developing solvent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[OH:24][C@@H:25]1[CH2:29][NH:28][C:27](=[O:30])[CH2:26]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:29][C@@H:25]([OH:24])[CH2:26][C:27]3=[O:30])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1C[C@H](O)CN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@@H](O)CC4=O)cc3)CC2)c(C)c1
Yield: 38.6 %

Procedure:
Using (4-bromophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.87 g) described in Preparation Example 170 and (S)-4-hydroxypyrrolidin-2-one (556 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (760 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:20])[CH:16]([C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])[CH:17]([CH3:19])[CH3:18])[CH3:13]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CCOC(=O)CC(C)C
Product: CCOC(=O)C(C(=O)c1ccc(F)cc1F)C(C)C
Yield: 68 %

Procedure:
2,4-Difluorobenzoyl chloride (4.9 ml) and isovaleric acid ethyl ester (3.0 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(a) to obtain the title compound (3.65 g, 68%) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:17]=[C:18]([N:22]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[CH3:28])[CH:19]=[CH:20][CH:21]=1)#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[CH3:28])[CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1cccc(-n2c(C)ccc2C)c1
Product: CCOC(=O)c1c(C)nc(C#Cc2cccc(-n3c(C)ccc3C)c2)n1C

Procedure:
The title compound, MS: m/e=362.8 (M+H+), was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 1-(3-ethynyl-phenyl)-2,5-dimethyl-1H-pyrrole.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].O.[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:27]
Reactant: CCI
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a mixture of sodium hydride (content, 60%; 36 mg) and anhydrous dimethylformamide (5 ml), a solution of the compound (224 mg) obtained in Example 318 in anhydrous dimethylformamide (3 ml) and ethyl iodide (0.072 ml) were successively added dropwise at 0° C. in a nitrogen atmosphere and stirred at room temperature for 24 h. Water was added to the reaction mixture, which was distilled under reduced pressure; thereafter, ethyl acetate and water were added to the resulting residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane ethyl acetate=1:1) to give 213 mg of the titled compound (yield, 87%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:12][CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(NC2CCNC2)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 102.6 %

Procedure:
To 500 mg (2.87 mmol) 4-fluorophenyl methyl sulfone dissolved in 4 mL DMF was added 247 mg (2.87 mmol) 3-aminopyrrolidine followed by 793 mg (5.74 mmol) potassium carbonate. The mixture was heated to 70° C. and stirred for 48 h. Upon cooling to room temperature, the mixture was partitioned between EtOAc and water, dried over MgSO4 and concentrated to provide 708 mg of 4-(pyrrolidin-3-ylamino)phenyl methyl sulfone, pure by 1H NMR.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].Cl.Cl[CH2:15][CH2:16][N:17]([CH:21]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[CH2:18][CH2:19]Cl>C(O)C>[CH:1]1([N:7]2[CH2:15][CH2:16][N:17]([CH:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[OH:29])[CH2:18][CH2:19]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccccc1CC(c1ccccc1)N(CCCl)CCCl
Reactant: NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1ccccc1CC(c1ccccc1)N1CCN(C2CCCCC2)CC1
Reaction time: 24 h

Procedure:
In ethanol (30 ml) are dissolved in N,N-bis(2-chloroethyl)-1-phenyl-2-(2-hydroxyphenyl)ethylamine hydrochloride (1.9 g) and cyclohexylamine (0.7 g) and thereto is added sodium hydrogen carbonate (1.4 g). The mixture is refluxed with stirring for 24 hours. After the reaction, the solvent is distilled off. To the residue is added a diluted aqueous ammonia and the alkaline solution is extracted with chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The crystalline residue (crude free base) is dissolved in a small amount of ethanol and thereto is added a 25% hydrobromic acid-acetic acid solution and the mixture is allowed to cool. The precipitated crystals are recrystallized from ethanol to give the desired compound as dihydrobromide (1.4 g), melting point: 245.5°-247.5° C.
Reaction SMILES: C([N:4]1[CH2:8][C@@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@H:6]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][C@H:6]3[C@H:7]([C:9]4[CH:13]=[CH:12][S:11][CH:10]=4)[CH2:8][NH:4][CH2:5]3)[CH2:20][CH2:19]2)=[CH:22][CH:23]=1
Reactant: C=CCN1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: Fc1ccc(C2CCN(C[C@@H]3CNC[C@H]3c3ccsc3)CC2)cc1

Procedure:
A mixture of 1.2 g (3.2 mmol) of 1-Allyl-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(R)-(3-thienyl)pyrrolidine and 0.19 g (0.2 mmol) of Wilkinson's catalyst ([Rh(PPh)3Cl] in 20 mL of an 85% solution of CH3CN in water in a flask fitted with a short path distillation head and an addition funnel for added solvent was heated to reflux. As solvent is azeotroped off, more is added to maintain the original concentration. After stirring at reflux for 4 h, the reaction mixture was concentrated. To the residue was added 3 mL of 2 N HCl and this mixture was partitioned between EtOAc and water. The aqueous fraction was washed with EtOAc and was then made basic with 2 N NaOH solution. The aqueous fraction was then extracted with EtOAc. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated to give the title compound which was used without further purification. Mass Spectrum (CI) m/e=345 (M+1)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:23])C.C(O)(=O)C.O>CC(O)(C)C.[Zn]>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C:2](=[O:23])[NH:1]3)[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)CCc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CCO
Agent: [Zn]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of {2-[3-(1H-indol-4-yl)-phenyl]-ethyl}-dimethyl-amine (600 mg, 2.2 mmol) in t-BuOH: ethanol: acetic acid (14.5 mL: 8.8 mL: 10.5 mL) was added pyridiniumn tribromide (2.3 g, 6.6 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (9.24 mL). Water (0.32 mL) and zinc dust (2.2 g, 61.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was dissolved in methanol (10 mL) and hydrogenated using 10% Pd-C for overnight. The reaction was filtered through celite and the filtrate was concentrated. The residue was purified on a silica gel column to give 4-[3-(2-dimethylamino-ethyl)-phenyl]-1,3-dihydro-indol-2-one
Reaction SMILES: C([O:4][C@H:5]([CH2:10][C:11]1[CH:19]=[C:18]([CH3:20])[C:17]2[C:13](=[CH:14][N:15]([CH2:21][O:22][CH3:23])[N:16]=2)[CH:12]=1)[C:6]([O:8]C)=[O:7])(=O)C.O.[OH-].[Li+]>O1CCCC1.CO.O>[OH:4][C@H:5]([CH2:10][C:11]1[CH:19]=[C:18]([CH3:20])[C:17]2[C:13](=[CH:14][N:15]([CH2:21][O:22][CH3:23])[N:16]=2)[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COCn1cc2cc(C[C@@H](OC(C)=O)C(=O)OC)cc(C)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCn1cc2cc(C[C@@H](O)C(=O)O)cc(C)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-methyl 2-acetoxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)propanoate (2.70 g, 8.4 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) at 0° C. was added a solution of lithium hydroxide monohydrate (1.41 g, 4.0 equiv) in water (20 mL). The reaction was stirred at 0° C. for 1 h. The reaction was concentrated, dissolved in water (5 mL), cooled to 0° C., and treated with 1M hydrochloric acid until mildly acidic. The solution was was extracted extensively with ethyl acetate and then dichloromethane. The organics were combined, dried over magnesium sulfate, and concentrated to give 1.40 g (63%) as an oil which solidified to a crystalline solid upon standing. 1H-NMR (CDCl3, 500 MHz) δ 2.40 (s, 3H), 2.78 (dd, J=14.0, 7.9, 1H), 3.00 (dd, J=14.0, 4.0, 1H), 3.18 (s, 3H), 4.24 (dd, J=7.9, 4.3, 1H), 5.47 (s, 2H), 6.85 (s, 1H), 7.22 (s, 1H), 7.90 (s, 1H). Mass spec.: 265.08 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4]([CH2:7][C:8]([OH:10])=[O:9])([OH:6])=[O:5].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[OH-].O>O1CCOCC1.O.C(O)(C)C>[C:18]([NH:1][CH2:2][CH2:3][P:4]([CH2:7][C:8]([OH:10])=[O:9])([OH:6])=[O:5])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCP(=O)(O)CC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(O)CP(=O)(O)CCNC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A suspension of [(2-aminoethyl)hydroxyphosphinyl]acetic acid (0.75 g., 4.49 mmole) in a mixture of dioxane (5 ml.) and water (5 ml.) was cooled in an ice bath and treated with triethylamine (2.0 ml., 14.5 mmole). A clear solution was obtained. The mixture was then treated with benzoyl chloride (0.65 ml., 5.6 mmole) dropwise over a 5 minute period. After stirring at 0° for one hour, the mixture was evaporated to dryness. The residue was taken up in saturated sodium bicarbonate (20 ml.) and washed with ethyl acetate. The aqueous phase was acidified with concentrated hydrochloric acid (pH 1) and extracted with dichloromethane. The dichloromethane extracts were discarded and the aqueous phase evaporated to a small volume. This was then applied to an AG 1-X8 (acetate form) column (30 ml. bed volume) eluting first with water then with 5% acetic acid-water then 1N hydrochloric acid. The product eluted with 1N hydrochloric acid. Fractions containing the product were combined, evaporated to dryness, taken up in water, and lyophilized. The crude product (0.9 g.) was chromatographed on an HP-20 column (1 inch diameter column, 200 ml. bed volume) eluting with a linear gradient of water-acetonitrile (0→100%) at a flow rate of 5 ml./min., collecting 5 ml. fractions. The fractions containing the desired product (Tlc) were combined, evaporated, taken up in water, millipore filtered, and lyophilized to give 0.72 g. of [[(2-benzoylamino)ethyl]hydroxyphosphinyl]acetic acid as a white solid; m.p. 54°-57°; Rf (isopropanol/conc. NH4OH/water; 7:2:1)=0.42.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1>[CH3:14][C:8]1([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC1(NC(=O)CCCCl)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(N2CCCC2=O)CCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
Dissolve 4-chloro-N-(1-methylcyclohexyl)butanamide (1.35 g, 6.20 mmol) in anhydrous THF (100 mL) and add NaH (1.24 g, 31.00 mmol, 60% wt in oil). Heat and stir the reaction mixture at 60° C. overnight then cool it to room temperature. Add water (50 mL) carefully and extract the aqueous with EtOAc (3×200 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-70% of EtOAc-Hexane) to give 0.64 g (57%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 3.41 (t, 2H), 2.34 (t, 2H), 2.26 (m, 2H), 1.92 (m, 2H), 1.32-1.56 (m, 8H), 1.26 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:20]([NH2:23])[C:21]#[CH:22].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([NH:23][CH2:20][C:21]#[CH:22])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: C#CCN
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared in Step II (200 mg; 0.59 mmol; 1 eq) is dissolved in anhydrous DCM (10 ml). The reaction is put under nitrogen. Prop-2-ynylamine (0.08 ml; 1.19 mmol; 2 eq), diisopropylethylamine (0.61 ml; 3.56 mmol; 6 eq) are added successively and the reaction mixture is stirred for 3 hours at room temperature. Solvents are evaporated and the resulting crude product is purified by preparative HPLC. Compound (1) is isolated as a beige powder (25 mg; 12%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:17]C(=O)C)[CH:13]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc2nc(CN3CCCC3)ccc2c1
Agent: Cl
Product: Nc1ccc2nc(CN3CCCC3)ccc2c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To the N-[2-(1-pyrrolidinylmethyl)-6-quinolinyl]acetamide (5.53 g, 20.5 mmol) obtained in 1) of Example 7 was added concentrated hydrochloric acid (100 ml), the mixture was stirred at 110° C. for 1 hour, and the solvent was distilled off under reduced pressure. To the resulting residue was added ethyl acetate, the mixture was washed with an aqueous potassium carbonate solution and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the titled compound (4.56 g) as a powder from ethyl acetate-hexane.
Reaction SMILES: CC[O-].[Na+].[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCO>[F:5][C:6]([F:15])([F:16])[C:7]([CH:8]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:14]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CCOC(=O)CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC(C(=O)OCC)C(=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
To a solution of NaOEt (0.217 mol) in EtOH (prepared from 5.0 g of Na and 220 mL of EtOH) was added ethyl triflouroacetoacetate (40.0 g, 0.217 mol). After 10 min, ethyl 3-bromopropionate (35.0 g, 0.194 mol) was added and the mixture was heated under reflux for 24 h. The reaction mixture was concentrated, taken up in ether, and washed with water. The ether layers were dried (MgSO4) and concentrated to give 50 g of a yellow oil. Distillation (100°-110° C./25 mm) gave 14.0 g (23%) of product as a colorless oil.
Reaction SMILES: Cl.CN.[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([O:25][C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]1[S:17][CH:18]([CH2:21][C:22](O)=[O:23])[CH2:19][N:20]=1)=[CH:12]2)[CH3:5].O[N:37]1[C:41]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([O:25][C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]1[S:17][CH:18]([CH2:21][C:22]([NH:37][CH3:41])=[O:23])[CH2:19][N:20]=1)=[CH:12]2)[CH3:5]
Reactant: On1nnc2ccccc21
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC)S3)[nH]c12
Temperature: 0 °C
Yield: 98.4 %

Procedure:
To an ice-cooled and stirred mixture of methylamine hydrochloride (26 mg) and triethylamine (0.053 mL) in N,N-dimethylformamide (5 mL) were added [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (90 mg), 1-hydroxybenzotriazole (52 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (73 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give a pale yellow amorphous solid, which was crystallized from ethyl acetate-hexane to give the title compound (91 mg, 99%) as pale yellow crystals. MS 489 (MH+). mp 233-235° C.