Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[N:29][C:30]=1[F:31]>O>[Cl:24][C:25]1[C:30]([F:31])=[N:29][CH:28]=[C:27]([O:32][CH2:2][CH2:3][CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[CH:26]=1
Reactant: Oc1cnc(F)c(Cl)c1
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Fc1ncc(OCCCOC2CCCCO2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
2-(3-Bromopropoxy)tetrahydro-2H-pyran (12.93 g, 57.9 mmol) and cesium carbonate (39.5 g, 121.0 mmol) were added to an N,N-dimethylacetamide solution (80 ml) of 5-chloro-6-fluoropyridin-3-ol (8.14 g, 55.2 mmol), and stirred overnight under a nitrogen atmosphere at 100° C. The reaction solution was cooled with ice, water was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Moritex NH, hexane:ethyl acetate=18:1 to 11:1) to obtain 3-chloro-2-fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (10.84 g, yield: 68%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C[Li].Cl.[C:15](=O)([O-])O.[Na+]>O1CCCC1.ClCCl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Li]C
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-methylbenzoic acid (1.71 g, 10.0 mmol) in anhydrous tetrahydrofuran (10 ml), at 0° C. and under nitrogen, was added methyllithium (1.6M in diethyl ether, 13.1 ml, 21.0 mmol), via syringe. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to room temperature over 1 h. To the reaction mixture was added cold hydrochloric acid (1M, 100 ml) and dichloromethane (110 ml). The mixture was adjusted to pH 7 by addition of saturated aqueous sodium hydrogen carbonate solution and the two layers were separated. The aqueous layer was extracted with further dichloromethane and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (1.19 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:33][CH:34]=[CH2:35])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([NH:31][CH3:32])=[O:30])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH2:23][CH2:24][CH3:25])=[C:12]([CH:20]=[CH:21][CH:22]=1)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[OH-].[K+].S(OC)(O[CH3:42])(=O)=O>C1COCC1>[CH3:42][O:1][C:2]1[C:3]([CH2:33][CH:34]=[CH2:35])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([NH:31][CH3:32])=[O:30])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH2:23][CH2:24][CH3:25])=[C:12]([CH:20]=[CH:21][CH:22]=1)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(=O)NC)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(=O)NC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 51 (120 mg, 0.247 mmol), potassium hydroxide (16.6 mg, 0.285 mmol) and dimethyl sulfate (46.7 mg, 0.37 mmol) were added to 5.0 ml of THF, and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and 10 ml of water was added. The solution was extracted three times with ethyl acetate, the combined extracts were dried, and the solvent was removed under vacuum to give an oil. Chromatography of the oil on silica gel using 50/50 ethyl acetate/hexane as eluant gave the product as a colorless gum.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][N:13]=1.C([Li])CCC.[I:24]I>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:24])=[CH:14][N:13]=1
Reactant: II
Reactant: Fc1cccc(F)c1Nc1ccc(Br)cn1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Nc1ccc(I)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirred solution of sodium hydride (2 eq.) in rigorously degassed THF (approximately 50 mL/g) at 0° C., was added dropwise a solution of (2,6-difluorophenyl)-(5-bromopyridin-2-yl)-amine (1 eq.) in THF (approximately 15 mL/g). The solution was allowed to warm slowly to room temperature over 1 hour, after which time the solution was cooled to −78° C. n-Butyllithium (approximately 1.6 M in hexanes, 1.1 eq.) was added dropwise over 15 minutes and the resultant solution was stirred at −78° C. for 1 hour. Zinc chloride/TMEDA complex (prepared as described by Isobe et al., Chem. Lett., 1977, 679) was added as a solid in a single portion and the solution was allowed to warm to 0° C. over 30 minutes, and was stirred at 0° C. for a further 1 hour. A solution of iodine (1.1 eq.) in THF (approximately 10 mL/g) was added and the solution was allowed to warm to room temperature. After stirring at room temperature for at least 1 hour, the reaction was quenched with a saturated aqueous solution of ammonium chloride. The solution was extracted with diethyl ether (3 times approximately 50 mL/g of 5-Bromopyridin-2-yl)-(2,6-difluorophenyl)-amine used). The combined organic layer was washed successively with 10% aqueous sodium sulfite solution (approximately 50 mL/g), saturated aqueous sodium thiosulfate solution (approximately 50 mL/g) and water (approximately 50 mL/g), dried over MgSO4 and concentrated in vacuo to give the crude reaction product as an orange oil. Purification by column chromatography, using 10% ethyl acetate:hexane as eluant, provided (2,6-Difluoro-phenyl)-(5-iodo-pyridin-2-yl)-amine (Rf 0.22) in approximately 50% yield.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[I:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.O>CN(C)C=O>[I:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][Si:5]([CH3:7])([CH3:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:11]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
387 mg of irdidazole and 411 mg of tertbutyldimethylsilyl chloride is added at ambient temperature and under an inert atmosphere to 500 mg of para-iodo-phenol in 4 ml of dimethylformamide and the mixture is maintained under agitation for 15 hours at ambient temperature then for 1 hour at 40° C. The reaction medium is poured into water, and the aqueous phase is extracted with dichloromethane. The organic phase is then dried and evaporated under reduced pressure. In this way 636 mg of expected product is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[C:7]1[CH2:12][CH:11]=[CH:10][C:9](=[CH:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:8]1Br)[CH2:4][CH3:5])[CH3:2].C([Li])CCC.[Cl-].[CH2:26]([In+:28][CH2:29][CH3:30])[CH3:27]>CCCCCC>[CH2:1]([N:3]([CH:6]=[C:7]1[CH2:12][CH:11]=[CH:10][C:9](=[CH:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:8]1[In:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(C=C1C=CCC(=CN(CC)CC)C1Br)CC
Reactant: CC[In+]CC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCN(C=C1C=CCC(=CN(CC)CC)C1[In](CC)CC)CC

Procedure:
2.4 g (7.3 mmol) of 2,6-bis(diethylaminomethylene)phenyl bromide in 40 ml of hexane, 4.6 ml of butyllithium (7.3 mmol; 1.6 mol/l in hexane) and 1.5 g (7.3 mmol) of diethylindium chloride in 20 ml hexane are reacted analogously to Example 1 to give [2,6-bis(diethylaminomethylene)phenyl]diethylindium, which is obtained as a colorless liquid, b.p. 115° C./0.04 mbar, by vacuum distillation.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][CH:30]3[CH2:31][CH2:32]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)NC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
TFA (0.5 mL, 7.20 mmol) was added to a solution of 1-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3-cyclopropylurea (10 mg, 0.024 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (6 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.53 (s, 1H), 7.69-7.67 (m, 2H), 7.59 (d, 1H, J=8.8 Hz), 7.27 (m, 3H), 3.91 (t, 2H, J=5.6 Hz), 3.62 (m, 1H), 2.64 (t, 2H, J=6.0 Hz); ESI-MS [M+H]+: 333.1.
Reaction SMILES: Br[C:2]1[C:3](=O)[C:4](Br)=[CH:5][C:6]([Br:9])(Br)[CH:7]=1.[O:12]1C2C=CC=CC=2[N:14]=[C:13]1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[C:27]([O:29][CH3:30])=[O:28]>ClCCl>[Br:9][C:6]1[CH:7]=[CH:2][C:3]2[N:14]=[C:13]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]3[C:27]([O:29][CH3:30])=[O:28])[O:12][C:4]=2[CH:5]=1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: COC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCCN1c1nc2ccc(Br)cc2o1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
2,4,4,6-Tetrabromo-2,5-cyclohexadien-1-one (4.7 g) was added to a solution of methyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (3.0 g) [see Preparation 2] in dichloromethane (60 ml) at −10° C. over a period of 10 minutes. The reaction mixture was then warmed to room temperature and diluted with dichloromethane. The organic layer was washed with saturated sodium hydrogen carbonate, then with 1N sodium hydroxide solution, dried over sodium sulphate and the solvent removed under reduced pressure to afford methyl (2S)-1-(6-bromo-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (3.7 g) as a purple coloured oil.
Reaction SMILES: N=C=N.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[CH3:23][N:24]([S:53]([CH3:56])(=[O:55])=[O:54])[C:25]1[C:30]([CH2:31][NH:32][C:33]2[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][N:36]=[C:35]([NH:43][C:44]3[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=3)[C:47]([OH:49])=O)[N:34]=2)=[CH:29][CH:28]=[CH:27][N:26]=1.CC[N:59]([CH:63]([CH3:65])[CH3:64])C(C)C.C1(N)CC1>C(#N)C>[CH:63]1([NH:59][C:47](=[O:49])[C:46]2[CH:50]=[CH:51][CH:52]=[C:44]([NH:43][C:35]3[N:34]=[C:33]([NH:32][CH2:31][C:30]4[C:25]([N:24]([CH3:23])[S:53]([CH3:56])(=[O:54])=[O:55])=[N:26][CH:27]=[CH:28][CH:29]=4)[C:38]([C:39]([F:42])([F:40])[F:41])=[CH:37][N:36]=3)[CH:45]=2)[CH2:65][CH2:64]1
Reactant: CN(c1ncccc1CNc1nc(Nc2cccc(C(=O)O)c2)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: CCN(C(C)C)C(C)C
Agent: N=C=N
Agent: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(c1ncccc1CNc1nc(Nc2cccc(C(=O)NC3CC3)c2)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
A polymer supported carbodiimide (PS-CDI) (0.326 mmol) was allowed to swell in acetonitrile (volume of 500 μL). The resultant suspension was treated with 10 (100 mg, 0.164 mmol) and DIEA (29 μL, 0.164 mmol). The resultant solution was then treated with cyclopropylamine (19 μL, 0.164 mmol). The resultant suspension was then mixed on a shaker plate for 16 hours. The mixture was then filtered, and the solids washed with 10% MeOH in chloroform. The combined filtrates were concentrated under reduced pressure, and the resultant residue was purified over silica (99:1:0.1 CHCl3:CH3OH:NH4OH) to provide 11 as a white foam. Yield: 14.3 mg, 16%. LC Ret. Time (standard)=2.1 min., m/z 536.2 (MH+); 1H NMR (CD3OD) : 8.42 (d, J=7.8 Hz., 1H), 8.20 (s, 1 h), 7.97 (t, J=7.8 Hz., 1H), 7.81 (d, J=7.8 Hz., 1H), 1.68 (d, J=7.8 Hz., 1H), 7.39-7.34 (m, 2H), 7.26 (t, J=7.8 Hz., 1H), 4.94 (s, 2H), 3.23 (s, 3H), 3.14 (s, 3H), 2.82 (m, 1H), 0.79 (m, 2 h), 0.60 (m, 2H) ppm. FAK IC50: 0.00186 μM
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]([CH3:29])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Reactant: CC(N)CO
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NC(C)CO)cn1
Temperature: 50 °C
Yield: 70.6 %

Procedure:
A mixture of 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (500 mg, 1.1 mmol), rac-2-amino-1-propanol (95 mg, 1.3 mmol) and TBD (44 mg, 0.31 mmol) was heated at 50° C. for 15 h under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 5% methanol in dichloromethane) to give the title compound (290 mg, 73%) as a white solid. MS: m/e=374.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15]([NH:17][CH2:18][CH2:19]O)[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11].[ClH:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15]([NH:17][CH2:18][CH2:19][Cl:21])[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: Cl
Reactant: Cc1cccc(C)c1N(CC(C)NCCO)S(C)(=O)=O
Product: Cc1cccc(C)c1N(CC(C)NCCCl)S(C)(=O)=O
Yield: 87 %

Procedure:
The title compound is prepared as described in Example 50, with the difference that 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-(2-hydroxy-ethylamino)-propane, prepared according to Example 46, is applied as starting substance. The product is obtained with a yield of 87%; its hydrochloride melts at 185°-190° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[OH-].[K+].[CH3:13][C:14]([CH3:16])=O>CO>[CH3:13][C:14]([CH3:16])=[C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)[C:8]#[N:9]
Reactant: Cc1ccc(CC#N)cc1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=C(C#N)c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
p-Tolylacetonitrile (18.5 g, 0.14 mol) is dissolved in a mixture of acetone (50 ml) and methanol (6.7 ml) and KOH (3.33 g, 0.05 mol) is added. The resulting mixture is heated to 65° C. (oilbath) and stirred for 3 h. The volatiles are removed in a rotary evaporator, the residue is dissolved in toluene and washed 3 times with half saturated aq. NaCl-solution. The organic layer is dried over MgSO4, the solvent removed under reduced pressure and the residue distilled over a short-path apparatus at 0.06 mbar. The fraction distilling at 77° C. is collected (11 g) and subjected to a fine distillation over a Widmer-column to yield 3.54 g (15%) of 3-methyl-2-p-tolyl-but-2-ene nitrile as colourless oil (b.p. 90-95° C./0.05 mbar).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([NH:23][C:24]5[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=5)[CH:19]=[C:20]([CH3:22])[CH:21]=4)[CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1.CCOC(C)=O>[CH3:22][C:20]1[CH:21]=[C:16]([C:14]2[CH:13]=[N:12][N:11]([CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)[CH:15]=2)[CH:17]=[C:18]([NH:23][C:24]2[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=2)[CH:19]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCC4(CC3)OCCO4)c2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCC(=O)CC3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-{3-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (62.4 mg, 0.14 mmol) was dissolved in THF (1 mL) and hydrochloric acid (0.45 mL, 2.72 mmol) was added. The reaction mixture was stirred at room temperature for two hours. The mixture was diluted with EtOAc, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10-80% EtOAc/hexanes) to afford 4-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]cyclohexanone as a colorless foam. MS ESI calcd. for C21H21F3N5O [M+H]+ 416. found 416. 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.80 (d, J=4.7 Hz, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 7.27 (d, J=4.7 Hz, 1H), 7.08 (s, 1H), 4.77-4.68 (m, 1H), 2.61-2.48 (m, 4H), 2.35-2.17 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])[CH2:6]1)([CH2:3][CH3:4])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH:1]([CH:5]1[CH2:6][C:7](=[O:12])[CH:8]([C:24](=[O:25])[NH:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)(=[O:22])=[O:21])[C:9](=[O:11])[CH2:10]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)C1CC(=O)CC(=O)C1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CCC(C)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-sec.-butyl-1,3-cyclohexanedione with p-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-sec.-BUTYL-2-(N-p-CHLOROBENZENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 106°-107° C. (corr.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:19][CH2:20][CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:22][CH2:21][CH2:20][CH2:19][N:11]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18])(=[O:33])=[O:32]
Reactant: O=C(OCc1ccccc1)N(CCCO)c1cccc[n+]1[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCN(C(=O)OCc1ccccc1)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a stirred solution of 3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)-amino] propanol (3 g, 9.92 mmol) and triethylamine (1.2 g, 11.91 mmol) in anhydrous dichloromethane, kept at 0° C. under nitrogen atmosphere, methanesulfonyl chloride (1.36 g, 11.91 mmol) was added, the reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was washed with ice-water, dried with sodium sulfate, filtered and concentrated to give 2.17 g (61%) of 3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]-propyl methanesulfonate which, when required, was purified by flash chromatography (dichloromethane/methanol 95:5).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)=[O:4].[I-].[K+].C(N(CC)CC)C.Cl.[F:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=1>C(#N)C>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([CH2:2][C:3]([NH:5][C:6]3[CH:15]=[CH:14][C:9]4[NH:10][C:11](=[O:13])[O:12][C:8]=4[CH:7]=3)=[O:4])[CH2:36][CH2:37]2)=[CH:38][CH:39]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)oc2c1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2[nH]c(=O)oc2c1
Yield: 26.1 %

Procedure:
A mixture of 0.91 g (4 mmol) of 2-chloro-N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide, 0.7 g (4 mmol) of potassium iodide, 1.2 ml (8 mmol) of triethylamine, 0.7 g (3 mmol) of 4-(4-fluoro-benzyl)-piperidine hydrochloride and 50 ml of acetonitrile is refluxed for 20 hours. The reaction mixture is concentrated and 30 ml of water and 30 ml of chloroform are added to the residue. The organic layer is separated and the water phase is extracted three times with 10 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 adsorbent (Merck) and chloroform methanol=97:3 as eluent to yield 0.3 g (26%) of the title compound. Melting Point: 232-234° C. (diethylether)
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[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[C:24]([NH:31][CH2:32][CH2:33][NH2:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][CH2:33][NH:34][C:19]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)=[O:21])([CH3:30])([CH3:28])[CH3:29]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)NCCN
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCNC(=O)OC(C)(C)C)cn1
Yield: 90 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using N-Boc-ethylenediamine instead of 2-aminoethyl isopropylether, to the title compound (261 mg, 90%) which was obtained as a white solid. MS: m/e=511.5 [M+OAc]−.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[ClH:1].[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)c(Cl)c1
Temperature: -5 °C

Procedure:
A suspension of 2-chloro-4-methyl aniline (10.1 mL, 11.63 g, 82.1 mmol) in 64 mL water and 60 mL 12 N HCl was cooled to −5° C. (internal temperature) and stirred with a mechanical stirrer. A solution of sodium nitrite (8.26 g, 119.7 mmol) in 56 mL water was added over 30 minutes. The solution became more clear but some solid remained. The mixture was stirred at −5° C. for 20 minutes and then cooled to −10° C. A solution of tin(II) chloride dihydrate (53.60 g, 237.6 mmol) in 36 mL 12 N HCl was added dropwise over 30 minutes while maintaining an internal temperature of −5 to −10° C. The resulting pinkish-brown mixture was stirred at −5 to −10° C. for 2 hours and then filtered cold through a pre-chilled fritted glass funnel. The collected solids were washed with cold 1% ethanol in ether (100 mL) followed by cold ether (500 μL) and air dried for 30 minutes. After drying in vacuo, the desired product was obtained as a very pale yellow crystalline solid (7.76 g, 49%). 1H NMR δ (300 MHz, CDCl3) δ 10.09 (bs, 2H), 7.89 (s, 1H), 7.25 (dd, 1H, Jm=1.2 Hz), 7.13 (dd, 1H, Jo=8.4 Hz, Jm=1.2 Hz), 7.02 (d, 1H, Jo=8.4 Hz), 2.24 (s, 3H); MS (CI) m/z 157/159.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][OH:31])=C[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C(#[N:38])C.O>>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][OH:31])=[N:38][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CO)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Reactant: CC#N
Solvent: O
Product: CC(C)(C)[C@@H](CO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F

Procedure:
Alcohol, 32, was synthesized in a manner similar to compound 70a utilizing the same deprotection procedure, starting with compound 54a: 1H NMR (400 MHz, CDCl3) δ 10.77 (brs, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 5.59 (brs, 1H), 4.36 (t, J=8.3 Hz, 2H), 4.11 (m, 1H), 3.72 (m, 2H), 1.06 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 348.13 (M+H) RT=1.83 minutes.