Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:4]2[N:11]=[N:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:5]2=[N:6][C:7]=1[CH3:8].[Li][CH2:28]CCC.CI>C1COCC1.CCCCCC>[Br:1][C:2]1[C:3]([N:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:28])=[C:4]2[N:11]=[N:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: [Li]CCCC
Reactant: CCC(CC)Nc1c(Br)c(C)nc2c1nnn2-c1c(C)cc(C)cc1C
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)N(C)c1c(Br)c(C)nc2c1nnn2-c1c(C)cc(C)cc1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [6-bromo-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine (50 mg, 0.12 mmol) in dry THF )1.5 ml) was added 2.5 M n-BuLi in hexane (0.14 ml) at −78° C. After stirring at −78° C. for 10 min, 0.5 ml of methyl iodide was added at that temperature then allowed to warmed to room temperature and stirred for 15 min for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 46 mg of brown oil. The residue was purified through silica gel coliumn chromatography using 1:1 chloroform:hexane as eluent to give the title compound as a golden oil. 1H NMR (CDCl3) ä 7.04(s, 2H), 4.35(m, 1H), 3.32(s, 3H), 2.70(s, 3H), 2.38(s, 3H), 1.94(s, 6H), 1.7-2.0(m, 4H), 1.01(t, 6H)ppm.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH:10]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:50]1[O:53][CH:51]1[CH3:52]>CO.Cl>[OH:53][CH:51]([CH3:52])[CH2:50][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC1CO1
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CN1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.30 g, 0.5 mmol) from Example 2 in MeOH (10 mL) was added DIEA (0.17 mL, 1.0 mmol) and propylene oxide (1 mL, 13 mmol). The solution was stirred for 18 h at ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3:0.3 CH2Cl2 :MeOH:NH4OH as eluant. The free base was dissolved in MeOH containing 1.5 equivalents of 3 N aqueous HCl. The resulting solution was evaporated under reduced pressure and the residue was lyophilized from CH3CN:H2O to give the hydrochloride salt of the title compound as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[C:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
30 g of 4-bromobenzonitrile, 13.4 g of 3-methyl-1-butyn-3-ol, 0.7 g of triphenylphosphine and 0.3 g of bis(triphenylphosphine) palladium(II) chloride were dissolved in 140 ml of triethylamine in nitrogen atmosphere, and 0.1 g of copper(I) iodide was added thereto. This was stirred for one hour at room temperature and then for 5 hours at 90° C. The crystals as precipitated were filtered out and, after triethylamine was removed by distillation, extracted with chloroform. The crystals were washed two times with 10% hydrochloric acid and two times with water, and chloroform was removed by distillation. The residue was distilled under reduced pressure (b.p. 140° to 160° C./5 mmHg) to obtain 23.5 g of 3-methyl-1-(4'-cyanophenyl)-1-butyn-3-ol.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[CH:1]1([NH:5][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A solution of 20.00 g (0.28 mol) cyclobutylamine in 50 ml tetrahydrofuran was added dropwise to a solution of 22.00 g of diketene (0.26 mole) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 24.60 g (0.16 mol, 61% yield) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[N+:8]([O-])([OH:10])=[O:9]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]([CH3:7])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1ccc(Cl)n1
Agent: O=S(=O)(O)O
Product: Cn1cc([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-methylpyrazole (Maybridge, Basel, Switzerland, 953 mg, 8.18 mmol) in concentrated sulfuric acid (1.4 ml), cooled with an ice-bath, was added over 30 min fuming nitric acid (1.19 mL, 28.6 mmol). The reaction mixture was stirred at rt for 2 h before being poured on ice/water and extracted with EtOAc (2×). The organic layers were washed with saturated aqueous NaHCO3 (2×) and brine, dried over Na2SO4, filtered, evaporated and dried over vacuum to give the title compound as a white solid (HPLC tR 2.24 min (Method A); M+H=162 MS-ES)
Reaction SMILES: [F:1][S:2]([F:23])([F:22])([F:21])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.[N+:24]([O-:27])([OH:26])=[O:25]>>[N+:24]([C:8]1[CH:7]=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])=[CH:4][C:3]=1[S:2]([F:1])([F:20])([F:21])([F:22])[F:23])([O-:26])=[O:25].[N+:24]([C:6]1[CH:7]=[CH:8][C:3]([S:2]([F:23])([F:1])([F:20])([F:21])[F:22])=[CH:4][C:5]=1[N:9]1[C:10](=[O:19])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]1=[O:18])([O-:27])=[O:25]
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=[N+]([O-])O
Product: O=C1c2ccccc2C(=O)N1c1cc(S(F)(F)(F)(F)F)ccc1[N+](=O)[O-]
Product: O=C1c2ccccc2C(=O)N1c1ccc([N+](=O)[O-])c(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1 g (2.863 mmol) of 2-(3-pentafluorosulfanylphenyl)isoindole-1,3-dione was dissolved at 0° C. in 3.29 ml of concentrated nitric acid, and the mixture was stirred at 0° C. for 2 h. Afterward, the mixture was left to stand at room temperature overnight. The reaction solution was added to 50 g of ice-water and the mixture was stirred for 1 h; then the precipitate was filtered off with suction, washed with water, dried and purified chromatographically on silica gel using toluene as the eluent. 2-(4-Nitro-3-pentafluorosulfanylphenyl)isoindole-1,3-dione having a melting point of 200-203° C. and 2-(2-nitro-5-pentafluorosulfanylphenyl)isoindole-1,3-dione having a melting point of 175-177° C. were obtained in a ratio of 1:2.
Reaction SMILES: [F:1][C@H:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](F)[N:11]=1)[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[N:26][C:27]([C@@H:30]([NH2:32])[CH3:31])=[N:28][CH:29]=2)=[CH:20][C:19]=1[CH3:33].CCN(C(C)C)C(C)C.O>CS(C)=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[N:28][C:27]([C@@H:30]([NH:32][C:12]3[N:11]=[C:10]([N:5]4[C@@H:4]([C@@H:2]([F:1])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])[CH:15]=[CH:14][N:13]=3)[CH3:31])=[N:26][CH:25]=2)=[CH:20][C:19]=1[CH3:33]
Reactant: Cc1cc(-c2cnc([C@H](C)N)nc2)ccc1F
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cnc([C@H](C)Nc3nccc(N4C(=O)OC[C@@H]4[C@H](C)F)n3)nc2)ccc1F
Yield: 95.8 %

Procedure:
(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (50 mg, 0.218 mmol), (S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanamine (60.5 mg, 0.262 mmol), and DIPEA (57 ul, 0.327 mmol) were taken up in 3 mL DMSO. Heated to 110 C for 1 h. The reaction mixture was poured into 30 mL water and extracted with EtOAc (2×30 mL). Organics were washed with 20 mL each water, brine, and dried over Na2SO4, and filtered and concentrated on silica gel. Column chromatography (25-100% EtOAc/hept) gave the desired product (92 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 2H), 8.25 (d, J=5.7 Hz, 1H), 7.51 (d, J=5.7 Hz, 1H), 7.42-7.31 (m, 2H), 7.21-7.12 (m, 1H), 6.15 (s, 1H), 5.28 (s, 2H), 4.80 (dddd, J=26.6, 9.0, 3.5, 1.6 Hz, 1H), 4.57 (dd, J=8.8, 3.4 Hz, 1H), 4.44 (td, J=9.0, 1.3 Hz, 1H), 2.39 (d, J=1.9 Hz, 3H), 1.66 (d, J=6.9 Hz, 3H), 1.35-1.24 (m, 3H). HRMS (A) m/z 441.1849 (M+H)+. Anal. RP-HPLC tR=3.10 min. Purity 100%/100%.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1>O.CCO.C1COCC1.[Ni]>[NH2:15][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CNc1cccc(Br)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CNc1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Raney 2800 nickel, in water (Aldrich; 8 mL) was added to a solution of ethyl 2-((3-bromo-2-nitrophenyl)amino)acetate (14.12 g, 46.6 mmol) in EtOH (290 ml) and THF (290 ml); the mixture was placed under an atmosphere of H2 and was stirred at RT for 20 h. The mixture was filtered through a pad of wet Celite, topped with sand, and washed with DCM to give ethyl 2-((2-amino-3-bromophenyl)amino)acetate (210c) as a brown liquid. MS (ESI, pos. ion) m/z: 273.0/275.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:26]1C=C(C2NN=C(NC(C3CC4C(=CC=CC=4)C3)=O)C=2)C=C[CH:31]=1>>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:16]1[C:14]([NH:13][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[C:3]([CH:26]=[CH2:31])[CH:4]=2)[NH:12][N:11]=1)=[O:15]
Reactant: O=C(Nc1cc(-c2cccc(Br)c2)[nH]n1)C1Cc2ccccc2C1
Reactant: O=C(Nc1cc(-c2ccc(Br)cc2)[nH]n1)C1Cc2ccccc2C1
Product: C=Cc1cccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)c1

Procedure:
The title compound was prepared in the same manner as that described in Example 33 except that 5-(4-bromophenyl)-3-(2-indanyl)carbonylaminopyrazole used in Example 33 was replaced with 5-(3-bromophenyl)-3-(2-indanyl)carbonylaminopyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[CH3:19])=[CH:17][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([O:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=1>>[ClH:1].[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([CH3:19])[C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:29][C:30]5[CH:31]=[C:32]([O:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=5)[N:21]=4)=[CH:17][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Cl)n1
Reactant: CS(=O)(=O)Oc1cccc(N)c1
Product: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Nc2cccc(OS(C)(=O)=O)c2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-(4-Chloro-benzyl)-N5-(2-chloro-pyrimidin-4-yl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (103 mg, 0.25 mmol) and methanesulfonic acid 3-amino-phenyl ester (56 mg, 0.25 mmol) as a white solid (87 mg, 58%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.40 (s, 1H), 8.00 (s, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.50 (t, J=5.7 Hz, 1H), 7.36-7.44 (m, 4H), 7.23-7.29 (m, 2H), 7.08 (s, 1H), 6.84 (d, J=8.1 Hz, 2H), 5.65 (d, J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz, 2H), 3.58 (s, 3H), 3.43 (s, 3H), 3.34 (s, 3H). MS (ESI) m/z=564 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]=[CH:6][C:7]1[C:12](F)=[CH:11][CH:10]=[CH:9][C:8]=1F)[CH2:2][CH2:3][CH3:4].[CH2:15]([Mg]Br)[CH3:16].[CH3:19][CH2:20]OCC>C1COCC1>[CH2:1]([N:5]=[CH:6][C:7]1[C:12]([CH2:19][CH3:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCOCC
Reactant: CCCCN=Cc1c(F)cccc1F
Solvent: C1CCOC1
Product: CCCCN=Cc1c(CC)cccc1CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of butyl-(2,6-difluoro-benzylidene)-amine (1.10 g; 5.58 mmol) in THF (25 mL) was added dropwise a solution of ethylmagnesium bromide in Et2O (4.1 ml; 3.00 mol/l; 12.3 mmol) at −10° C. After the addition was completed the reaction mixture was stirred at RT for 4 hours. The reaction mixture was quenched by dropwise addition of a 5% aqueous NaHCO3-solution, and then extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to afford butyl-(2,6-diethyl-benzylidene)-amine (1.10 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([NH:21][C:22]([O:24]C3C=CC=CC=3)=O)[S:20][C:14]=2[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([NH:21][C:22]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:24])[S:20][C:14]=2[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)Oc3ccccc3)sc2C1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCNC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.3 %

Procedure:
45 mg allylamin was added to 200 mg 2-phenoxycarbonylamino-6,7-dihydro-4H-thiazolo (5,4-c) pyridine-5-carboxylic acid tert-butyl ester in 25 mL DMF. The reaction was stirred for 12 h at RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and concentrated. The residue was purified by column chromatographie (silica gel, eluent: 40% ethylacetate in hexane) to give 179 mg of desired product. (M+H)+: 339
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.CN(C)C(=O)C>O>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 77 %

Procedure:
A mixture of 17.6 parts of 1-(phenylmethyl)piperazine, 8.4 parts of ethyl 4-fluorobenzoate and 45 parts of N,N-dimethylacetamide was stirred and refluxed for 22 hours. The reaction mixture was cooled and poured onto 500 parts of water. The product was extracted three times with benzene. The combined extracts were washed three times with a lot of water, dried, filtered and evaporated. The residue was stirred in hexane. The product was filtered off, washed with hexane and dried in vacuo, yielding 12.5 parts (77%) of ethyl 4-[4-(phenylmethyl)-1-piperazinyl]benzoate (intermediate 2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=1)=[O:4].[F:14][C:15]([F:31])([F:30])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]2)[N:17]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:18]3[N:17]=[C:16]([C:15]([F:31])([F:30])[F:14])[CH:21]=[CH:20][N:19]=3)[CH2:23][CH2:24]2)=[O:11])=[CH:7][N:6]=1)=[O:4]
Reactant: NCC1CCN(c2nccc(C(F)(F)F)n2)CC1
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of 6-(methoxycarbonyl)nicotinic acid (250 mg, 1.39 mmol) and 1-{1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methanamine (INTERMEDIATE 6, 361 mg, 1.39 mmol) in dimethylformamide (5.0 ml) were added hydroxybenzotriazole (225 mg, 1.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg, 1.67 mmol), and N,N-diisopropylethylamine (291 μl, 1.67 mmol). The reaction was allowed to stir at ambient temperature for 18 h. After removal of the solvent by evaporation, the residue was purified by flash chromatography on a silica gel column, eluting with a gradient of 0-100% ethyl acetate in hexanes to give the title compound as a white solid (272.2 mg). Mass spectrum (ESI) 425 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.13 (s, 1H), 8.49 (d, 1H, J=4.8 Hz), 8.33 (d, 1H, J=8.0 Hz), 8.24 (d, 1H, J=8 Hz), 6.73-6.77 (m, 2H), 4.87 (d, 2H, J=13.5 Hz), 4.05 (s, 3H), 3.44-3.47 (m, 2H), 2.90-2.98 (m, 2H), 1.90-2.00 (m, 1H), 1.90 (d, 2H, J=12.6 Hz), 1.27-1.36 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:24])=[CH:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.N1C=CC=CC=1.[CH3:31][C:32](OC(C)=O)=[O:33]>O1CCOCC1.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:24])=[CH:3][CH2:4][N:5]([C:6]1[CH:7]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:32](=[O:33])[CH3:31]
Reactant: FC(F)=CCNc1cc(OCc2ccccc2)c2ccccc2c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)N(CC=C(F)F)c1cc(OCc2ccccc2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.9 %

Procedure:
A solution of 210 (149 mg, 0.46 mmol) in dioxane (5 mL) under Ar was treated with DMAP (50 mg, 0.40 mmol), pyridine (0.37 mL, 4.6 mmol) and Ac2O (0.2 mL, 2.3 mmol) and stirred at 25° C. for 19 h. The reaction solution was quenched by the addition of 10% aqueous HCl (10 mL) and EtoAc (10 mL). The aqueous layer was removed and extracted with EtOAc (3×5 mL). The organic solutions were combined, washed with saturated aqueous NaCl (15 mL), dried (MgSO4), and concentrated under reduced pressure. Chromatography (SiO2, 15% EtOAc-hexane) afforded 211 (162 mg, 169 mg theoretical, 96%) as a pale yellow oil: 1H NMR (CDCl3, 400 MHz) δ8.33 (dd, 1H, J=1.6, 8.1 Hz, C8-H), 7.77 (dd, 1H, J=1.7, 7.5 Hz, C5-H), 7.52 (m, 5H, C6H5), 7.38 (m, 2H, C6 and C7-H), 7.20 (d, 1H, J=1.6 Hz, C4-H), 6.57 (d, 1H, J=1.6 Hz, C2-H), 5.25 (s, 2H, CH2Ph), 4.43 (dtd, 1H, J=1.9, 7.9, 24.8 Hz, C2'-H), 4.32 (dd, 1H, J=1.6, 1.6 Hz, C1'-H), 4.30 (m, 1H, C1'-H), 1.82 (s, 3H, CH3CO); 13C NMR (CDCl3, 100 MHz) δ170.0, 160.0, 157.1, 155.1, 139.4, 135.9, 133.8, 128.2, 127.7, 127.2, 127.1, 126.9, 125.7, 124.7, 121.9, 118.6, 105.0, 74.9 (dd, J=75.2, 91.6 Hz), 69.8, 41.8 (d, J=28 Hz), 22.0; 19F NMR (CDCl3, 376 MHz) δ-87.0 (d, J=40.0 Hz), -89.1 (dd, J=24.8, 40.0 Hz); IR (film) vmax 2928, 1745, 1660, 1413 cm-1 ; FABHRMS (NBA-NaI) m/z 368.1740 (M+H+, C22H19F2NO requires 368.1470).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])[CH3:4].C[O-].[Na+].CO[CH:21](OC)[CH2:22][NH2:23]>ClCCl.CO>[CH3:2][N:3]([CH3:4])[CH2:5][CH2:6][CH:7]([C:8]1[NH:9][CH:21]=[CH:22][N:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCC(C#N)c1ccccc1
Reactant: COC(CN)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCC(c1ccccc1)c1ncc[nH]1
Reaction time: 8 h

Procedure:
Hydrogen chloride was passed into a solution of α-(N,N-dimethylaminoethyl)benzeneacetonitrile (18.8 g) and dry methanol (6.3 ml) in dry dichloromethane (200 ml) for 8 h at 5°-15°. Solvent was removed to give a colourless oil which was taken up in dry methanol (150 ml) and treated with 2 M sodium methoxide solution (65 ml). Aminoacetaldehyde dimethyl acetal (10.6 g) was added and the mixture left to stand overnight. Methanol was then removed and the residue dissolved in 2 N hydrochloric acid (200 ml) and heated at 80° for 30 min. The mixture was cooled, adjusted to pH 9.5 with potassium carbonate and extracted with ethyl acetate (3×200 ml). The extracts were washed with brine (200 ml), concentrated and dried in vacuo to give the title compound, m.p. 135°-136° (16.3 g).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)=O)=CC=1.O[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([OH:40])=[O:39]>>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:35]2[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=2)[C:38]([OH:40])=[O:39])=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:19]1(=[O:28])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: O=C(O)c1cccc(O)c1
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(C(=O)O)c2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate and 3-hydroxybenzoic acid in a similar manner as described for Example 12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH2:23][OH:24])[CH:9]=2)=[CH:4][CH:3]=1.CC(C)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][C:23]([OH:27])=[O:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Reactant: CC(C)=O
Product: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of the alcohol 2 [(0.92 g, 2.68 millimoles (mM)] in acetone (25 ml) was added a 2N H2Cr2O7 (Jones Reagent) solution (3.02 ml, 6.04 mM) dropwise over a 10 minute time period. After stirring for 1 hour the reaction solution was decanted from the chromium precipitates on the sides of the reaction vessel. The reaction solution was concentrated in vacuo and taken up into ethyl acetate (EtOAc) (100 ml), washed with distilled H2O until the washes were clear, dried (MgSO4), filtered, and concentrated in vacuo. Crystallization from Et2O: hexane afforded 12 (0.88 g, 92%) as an off-white crystalline solid, mp=126°-128° C.