Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:44][CH3:45])[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN1C(=O)N(C)CC1>[CH3:45][O:44][C:37]1[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:36]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCC2
Reactant: NNc1ncccn1
Solvent: CN1CCN(C)C1=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 27 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 128 mg of [2-(7-methoxy-2,3-dihydrobenzofuran-5-yl) -2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMI, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[O:10](CC)[C:11]([S-:13])=[S:12].[K+].[CH2:17](O)[CH3:18]>>[O:10]([CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3])[C:11]([S:13][CH2:17][CH3:18])=[S:12]
Reactant: CCO
Reactant: CC(Br)c1ccccc1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Product: CCSC(=S)OC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500 mL round bottom 3 neck flask was fitted with a magnetic stirrer, nitrogen inlet, and a temperature probe, 1-bromoethyl benzene (20.5 mL) and 200 mL absolute ethanol were added. The reaction flask was placed in an ice/water bath at 0° C. Potassium O-ethyl xanthate was added slowly using a powder funnel rinsed into the reaction flask with an additional 100 mL ethanol. The reaction flask was allowed to stir for an additional 24 hours at room temperature and then 250 mL of purified water was added. The crude mixture was extracted 4 times with 200 mL of 2:1 heptane:ethyl ether retaining the organic layers. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to yield 31.42 grams of crude product. A portion, 15 grams, of the crude product was eluted from a silica gel column using hexane to give 12.81 grams of the pure product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.O>C(Cl)Cl>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH:2]([S:17]([CH3:16])(=[O:19])=[O:18])[NH2:1])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(N)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
To a solution of t-butyl 4-(aminomethyl)tetrahydropyridine-1(2H)-carboxylate (1.50 g, 7.0 mmol, 1 eq) in DCM (anhydrous) (20 mL) is added methanesulfonyl chloride (569 μL, 7.35 mmol, 1.05 eq). To this add triethylamine (2.05 ml, 14.7 mmol, 2.1 eq), dropwise over 15 min. Stir at room temperature for 3 hr. and then add water (20 mL) with stirring. The organic phase is isolated then washed with 2 M aqueous hydrochloric acid (20 mL), and saturated aqueous sodium hydrogen carbonate solution (20 mL). Dry the organic layer (magnesium sulphate) and concentrate to give 4-(methanesulfonyl-aminomethyl)-piperidine-1-carboxylic acid t-butyl ester (2.1 g, 102%). MS (ES): m/z=315.1 [M+Na]+. To a solution of this compound (2.1 g, 7.2 mmol, 1 eq) in 1,4-dioxane (25 mL) add 4 M hydrogen chloride in dioxane (17.95 mL, 72 mmol, 10 eq). Stir at room temperature for 29 hr., basify with 2 M aqueous sodium hydroxide, and then add DCM (20 mL). Separate the layers and extract the aqueous twice with DCM (20 mL), dry the combined organics over magnesium sulphate, filter and concentrate. Extract the aqueous layer a further four times with 3:1 chloroform:isopropanol (25 mL). Concentrate the aqueous layer to less than 10 mL volume and extract again with four times with 3:1 chloroform:isopropanol (25 mL). Combine with all the previous organic extracts to give N-piperidin-4-ylmethyl-methanesulfonamide (703 mg, 50%). MS (m/z): 193 (M+1).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N:20]=[C:19]([NH:30][CH2:31][CH2:32][OH:33])[N:18]=1)[CH2:27][CH2:26][CH2:25]3.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N+:20]([O-:4])=[C:19]([NH:30][CH2:31][CH2:32][OH:33])[N:18]=1)[CH2:27][CH2:26][CH2:25]3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(NCCO)nc2cc3c(cc21)CCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1nc(NCCO)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
H2O2 (70%, 0.5 mL, ca. 10 mmol) was added dropwise to a stirred solution of TFAA (1.4 mL, 10 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 24 (246 mg, 1.0 mmol) and TFA (0.28 mL, 2.0 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 1 h and then at 20° C. for 30 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-4%) of MeOH/DCM, to give 1,4-dioxide 25 (106 mg, 40%) as a red solid: mp (MeOH/DCM) 187-188° C.; 1H NMR [(CD3)2SO] δ 7.99 (s, 1H, H-9), 7.92-7.98 (m, 2H, NH, H-5), 4.84 (t, J=6.0 Hz, 1H, OH)), 3.61 (q, J=6.0 Hz, 2H, CH2O), 3.46 (q, J=6.0 Hz, 2H, CH2N), 2.98-3.10 (m, 4H, H-6, H-8), 2.05-2.14 (m, 2H, H-7); 13C NMR [(CD3)2SO] δ 154.5, 149.4 144.9, 137.6, 129.0, 115.0, 110.9, 59.1, 43.1, 32.6, 31.7, 25.1. Anal. calcd for C12H14N4O3: C, 55.0; H, 5.4; N, 21.4. Found: C, 54.8; H, 5.4; N, 21.1%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](O)(=O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[OH:13][CH2:12][C:11]1[NH:1][C:2]2=[N:3][C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[C:7]2[N:8]=1
Reactant: Cc1cc(C)c(N)c(N)n1
Reactant: O=C(O)CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2nc(CO)[nH]c2n1
Yield: 15.2 %

Procedure:
A mixture of 13.72 g of 2,3-diamino-4,6-dimethylpyridine and 25 g of glycolic acid in 200 ml of toluene was heated under reflux for 3.5 hours, whilst distilling off azeotropically the water formed in the course of the reaction. At the end of this time, the reaction mixture was freed from the toluene by decantation and the oily residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethanol and ethyl acetate in ratios ranging from 2:3 to 1:1 by volume as a eluent, to give 2.7 g of the title compound, melting at 244-246° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([CH3:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O>C(N(CC)CC)C>[Cl:8][C:3]1[C:2]([N:1]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:29])[CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(C)CCCNc1ccccc1C(=O)c1ccccc1
Reactant: Nc1cccnc1Cl
Solvent: CCN(CC)CC
Product: CN(C)CCCNc1ccccc1C(=Nc1cccnc1Cl)c1ccccc1

Procedure:
To a mixture of 2.82 g (0.01 mole) of [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone and 1.29 g (0.01 mole) of 3-amino-2-chloropyridine, 6.2 ml (0.048 mole) of triethylamine and 20 ml of methylene chloride stirred in an ice bath under nitrogen atmosphere was added 2.28 g (0.012 mole) of titanium tetrachloride in 10 ml of methylene chloride during a 5 minute period. The mixture was then stirred at room temperature for 2 days during which time mass spec-CI showed little change in relative intensity of M.W. 129 (starting pyridine) and M.W. 393 (title product). Water was added to the reaction mixture and stirring was continued for 1.5 hr. The mixture was filtered to remove solid and the filter cake was rinsed with methylene chloride. Saturated sodium chloride solution was added to facilitate separation of layers. The methylene chloride layer was washed once with more sodium chloride solution. The aqueous layer having a pH of about 6 was basified to about pH 8-9 with potassium carbonate and then extracted twice with methylene chloride. The latter methylene chloride layers were washed with sodium chloride solution. All the methylene chloride extracts were combined, dried and evaporated to give 4.8 g of semi-solid product. TLC of the product showed it contained very little starting 3-amino-2-chloropyridine. Mass Spec. analysis showed the presence of compounds with molecular weight corresponding to title product (393), 3-amino-2-chloropyridine (129) and triethylamine (102) but no [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone. 1HNMR spectrum in CDCl3 containing 1% TMS indicated the product was mostly title compound and some triethylamine. No 3-amino-2-chloropyridine was seen. The chemical shifts, multiplicities and assignments are given below.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:14][C:15]1[CH:22]=[C:21](O)[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-:25].[Cs+].[Cs+]>CN(C=O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:25][C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:19][C:16]=1[CH:17]=[O:18]
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1Br
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(Br)c(C=O)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 972.7 %

Procedure:
A flask was charged with 2-fluoro-4-(triflouromethyl)benzonitrile (3.78 g, 2 mmol), 2-bromo-4-hydroxybenzaldehyde (4.02 g, 2 mmol), cesium carbonate (6.5 g, 2 mmol) and DMF (40 ml). The mixture was stirred overnight at 40° C. The DMF was evaporated off and the residue was partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate. The organic layer was dried with MgSO4. Evaporation yielded a brown oil which solidified to give a brown solid (7.2 g, 97%).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])C.Cl>C(O)C>[Cl:29][C:25]1[N:24]=[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:10]3[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:19]=2)[C:26]=1[CH:27]=[O:28]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
1.9 g of 4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acid dimethylaminomethylenamide were dissolved in 20 ml of ethanol and 20 ml of a saturated aqueous HCl solution were added. The mixture was heated under reflux for 2 hours, then the volatile constituents were removed in vacuo, the residue was taken up using 200 ml of water, the solution was adjusted to pH−7 using aqueous NaOH solution and stirred for 1 hour, and the precipitate was filtered off with suction. The product was dried in vacuo, and 1.7 g of a colorless solid were obtained,
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].[Cl:33][CH2:34][C:35]1[N:36]=[C:37]([NH:40][C:41]([CH2:43][CH2:44][O:45][CH3:46])=[O:42])[S:38][CH:39]=1.C(=O)([O-])O.[Na+].O>CN(C)C=O>[ClH:33].[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][C:35]2[N:36]=[C:37]([NH:40][C:41](=[O:42])[CH2:43][CH2:44][O:45][CH3:46])[S:38][CH:39]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: COCCC(=O)Nc1nc(CCl)cs1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCC(=O)Nc1nc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cs1
Product: Cl
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (120 mg), 4-chloromethyl-2-(2-methoxyethylcarbonylamino)thiazole (70 mg) and powdered sodium hydrogen carbonate (27 mg) in dry dimethylformamide was stirred for 5 hours and 20 minutes at 60° C. The reaction mixture was powered into water and the resulting precipitate was collected by filtration. The crude product was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (30:1). The eluate was evaporated under reduced pressure and treated with 17.6% hydrogen chloride in ethanol (0.12 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[[2-(3-methoxypropanoylamino)thiazol-4-yl]methyl]piperazine hydrochloride (140 mg).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9]2(=[O:11])=[O:10])[CH:6]=[CH:5]C=CC=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.[H-].[Na+].[CH2:34]([O:41][C:42]1[CH:53]=[CH:52][C:45]([O:46]CCCCBr)=[CH:44][CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([O:41][C:42]1[CH:43]=[CH:44][C:45]([O:46][CH2:5][CH2:6][CH2:1][CH2:7][N:8]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9]2(=[O:10])=[O:11])=[CH:52][CH:53]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: BrCCCCOc1ccc(OCc2ccccc2)cc1
Reactant: O=C1c2ccccc2S(=O)(=O)N1Cc1ccccc1
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1ccc(OCc2ccccc2)cc1
Yield: 66 %

Procedure:
The synthesis was carried out analogous to the preparation of 83.1 using 82 (0.307 g, 1.5 mmol), NaH (0.036 g, 1.5 mmol) and 4-(4-benzyloxy-phenoxy)-butyl bromide (0.2 g, 0.6 mmol) in DMF (5 mL). Purification by flash column chromatography on silica gel gave 83.3 (0.150 g, 66% yield) as a white solid (m p 82-84° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH:7]=[C:6]([C:26]([OH:28])=[O:27])[C:5]2=[O:29].[CH2:30]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:30])[CH2:14][CH2:13]1)[N:8]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[CH:7]=[C:6]([C:26]([OH:28])=[O:27])[C:5]2=[O:29]
Reactant: O=C(O)c1cn(-c2ccc(O)cc2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: C=O
Solvent: O=CO
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(O)cc4)c3c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6,8-Difluoro-1-(4-hydroxyphenyl)-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.80 g) is added slowly to a mixture of 90% formic acid (4 ml) and 37% formaline (4 ml) under ice-cooling. After the addition, the mixture is refluxed for 5 hours. The reaction mixture is distilled to dryness under reduced pressure. The residue is suspended in saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture is stirred at room temperature for 30 minutes. The precipitated crystals are separated by filtration, washed with water, dried, and then recrystallized from DMF to give 6,8-difluoro-1-(4-hydroxyphenyl)-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.52 g) as pale yellowish white crystals, m.p. 300° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=[CH:17][CH:16]=2.C(C1C(C2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH2:44]C(Cl)=O)=CC=CC=3)=C(C)ON=1)C.CNC.N1CCCC1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24]([N:35]1[CH2:36][CH2:41][CH2:42][CH2:43][CH2:44]1)=[O:25])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)Cl
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1CCC(=O)Cl
Agent: CNC
Solvent: C1CCNC1
Product: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)N1CCCCC1

Procedure:
Also, following the above procedure and using in place of 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indole propionyl chloride an equivalent amount of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole propionyl chloride and using in place of dimethylamine an equivalent amount of pyrrolidine there is obtained
Reaction SMILES: NCC1C=CC(S([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=O)=O)=CC=1C.Br[C:19]1[CH:20]=[C:21]([S:29](Cl)(=[O:31])=[O:30])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.[CH3:33][N:34]1C(=O)CCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:34][CH2:33][C:19]1[CH:20]=[C:21]([S:29]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:31])=[O:30])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CN1CCCC1=O
Reactant: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1CN
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cc(CN)cc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
3-Aminomethyl-N-tert-butyl-5-trifluoromethyl-benzenesulfonamide was synthesized in a manner analogous to 4-Aminomethyl-N-tert-butyl-3-methyl-benzenesulfonamide in Example 4, using 3-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride in place of 4-bromo-3-methylbenzene-1-sulfonyl chloride. In the second step NMP was used as the solvent, Pd(dppf)Cl2 alone was used as catalyst and the reaction mixture was stirred at 150° C. for 30 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[N:8][C:9]([O:16][CH2:17][CH3:18])=[C:10]([NH2:15])[C:11]=1[NH:12][CH2:13][CH3:14])=[O:5])[CH3:2].C(O)(=O)C.[N:24]([O-])=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[N:12]([CH2:13][CH3:14])[N:24]=[N:15][C:10]=2[C:9]([O:16][CH2:17][CH3:18])=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2]
Reactant: CCNc1c(N)c(OCC)nc(C)c1C(=O)OCC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc(OCC)c2nnn(CC)c12
Reaction time: 8 h
Yield: 75 %

Procedure:
26.7 g. of 5-amino-4-ethylamino-6-ethoxy-2-methylpyridine-3-carboxylic acid ethyl ester (0.1 mol.) are dissolved in 100 ml. of acetic acid. At room temperature 7.5 g. of sodium nitrite in 20 ml. of water are added dropwise with continual stirring. The temperature is kept below 20°. The mixture is stirred overnight and then evaporated to dryness. 100 ml. of water are added to the residue which is then extracted three times with 50 ml. portions of ether. The organic layer is collected, dried over sodium sulfate, filtered and the solvent distilled off. The residue of 4-ethoxy-1-ethyl-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester is recrystallized from ligroin, yield 75%, m.p. 56°-58°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].C(OC(C)C)(C)C>ClCCl>[Cl:13][CH2:14][C:15]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:2][CH:3]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: COC(=O)CCc1ccc(C(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 50 g of methyl 3-phenylpropionate, 51.6 g of chloroacetyl chloride and 250 ml of dichloromethane was cooled to 0° C. Then at 0° to 10° C. with stirring, 122 g of aluminum chloride was added slowly, stirred at a room temperature for 2 hours and allowed to stand overnight. The reaction mixture was poured into an ice-concentrated hydrochloric acid and extracted with chloroform, then the chloroform layer was washed with water, dried and the chloroform was removed by distillation to obtain the residue, then isopropyl ether was added to the residue to effect crystallization. The crystals were collected by filtration, and recrystallized from ethanol to obtain 53.4 g of methyl 3-(4-chloroacetylphenyl)-propionate. Colorless needle-like crystals. Melting point: 90°-92° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([Cl:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)CC1
Solvent: C1COCCO1
Product: O=C(Cl)C1CCN(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-4-piperidinecarboxylic acid (0.1 g, 0.45 mmol) was stirred in dioxane (5 mL) and thionyl chloride (0.165 mL, 2.25 mmol) was added drop-wise. After stirring for 1 h the solvent was removed by evaporation, DCM was added to the residue which was then re-concentrated to give 1-(4-fluorophenyl)-4-piperidinecarbonyl chloride which was used directly in step 2. Step 2: The acid chloride from step 1 was taken up in DCM (2.5 mL) and added drop-wise to 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.121 g, 0.38 mmol) in DCM (2.5 mL), followed by triethylamine (0.080 mL, 0.57 mmol). The reaction mixture was stirred for 3 h under argon, then the solvent was removed by evaporation. The residue was partitioned between DCM (30 mL) and water (30 mL). The aqueous was re-extracted with DCM (30 mL) and the combined organic layers were dried and concentrated to yield the title compound as a yellow oil. δH (CDCl3, 400 MHz) 7.40 (2H, d), 7.15 (2H, d), 6.89 (2H, m), 6.80 (2H, m), 4.20 (1H, br.s), 3.82 (1H, d), 3.50 (4H, m), 3.27 (3H, s), 3.10 (1H, m), 2.76 (1H, d), 2.58 (1H, d), 2.35 (3H, m), 2.17 (1H, m), 2.00 (3H, m), 1.70 (2H, d), 1.46 (9H, s), 1.22 (3H, d). MS (ES): MH+ 525.4. Description 60