Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])=[CH:16][C:10]=3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:25]=[CH:24][CH:23]=[C:19]([C:20](=[O:21])[NH:40][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:39][CH2:38]5)[CH:18]=4)=[CH:16][C:10]=3[C:9]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:6][CH:7]=1
Reactant: NC1(c2ccccc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.154 mmol) and 1-phenylcyclopropanamine hydrochloride (0.038 g, 0.22 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.36 (s, 1H), 8.41 (d, J=4.58 Hz, 1H), 8.22 (s, 1H), 8.17 (d, J=8.24 Hz, 1H), 7.98 (d, J=1.53 Hz, 1H), 7.93 (d, J=7.63 Hz, 1H), 7.89 (d, J=7.94 Hz, 1H), 7.83 (dd, J=8.39, 1.68 Hz, 1H), 7.66-7.68 (m, 1H), 7.65 (d, J=5.19 Hz, 1H), 7.61 (t, J=7.78 Hz, 1H), 7.37 (t, J=8.70 Hz, 2H), 7.29 (t, J=7.63 Hz, 2H), 7.22-7.26 (m, 2H), 7.15-7.19 (m, 1H), 2.77 (d, J=4.58 Hz, 3H), 1.31 (d, J=11.90 Hz, 4H). LCMS: retention time: 3.250 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 521 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[OH:43][CH:44]1[CH2:47][NH:46][CH2:45]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[OH:43][CH:44]1[CH2:47][N:46]([C:18]([CH:14]2[CH2:15][CH2:16][CH2:17][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:12][CH2:13]2)=[O:20])[CH2:45]1
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)CC1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCC(C(=O)N2CC(O)C2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
To a stirred solution of 1-[(benzyloxy)carbonyl]azepane-4-carboxylic acid (317 mg, 1.14 mmol) in DMF (5 ml) was added HOBt (154 mg, 1.14 mmol) followed by EDCI (218 mg, 1.14 mmol). After 5 minutes, a solution of 3-hydroxyazetidine hydrochloride (138 mg, 1.26 mmol) and DIPEA (0.44 ml, 2.51 mmol) in DMF (1 ml) was added and the resulting solution was stirred for 12 hours at room temperature. The mixture was diluted with EtOAc (30 ml) and washed with saturated aqueous NaHCO3 (3×15 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica FCC (using a gradient of eluents; 99:1 to 92:8 DCM/MeOH) to give the title product as colourless oil (265 mg, 70%).
Reaction SMILES: [P:1]([O-:8])([O:5]CC)[O:2]CC.O.[NH2:10][C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>C(O)C>[CH2:13]([P:1](=[O:2])([O-:5])[O-:8])[CH3:14].[N:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][C:11]=1[NH3+:10].[N:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][C:11]=1[NH3+:10]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CCOP([O-])OCC
Solvent: O
Solvent: CCO
Product: CCP(=O)([O-])[O-]
Product: [NH3+]c1nc2ccccc2[nH]1

Procedure:
To a mixture of 27.62 g. (0.02 moles) of diethyl phosphite and 20 ml. of water 13.31 g. (0.1 moles) of 2-amino-benzimidazole and 150 ml. of ethanol are added. The reaction mixture is refluxed for 5 hours. The solvent and the excess of diethyl phosphite are evaporated in vacuo. The crystalline substance obtained is dried over phosphorus pentoxide. Yield of the title compound is 95%.
Reaction SMILES: N1(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C2C=CC=CC=2N=N1.Cl.Cl.[F:24][CH:25]([F:34])[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.CN(C)C=O.C(N(CC)CC)C>ClCCl>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:33][CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][CH:25]([F:34])[F:24])[CH2:32][CH2:31]2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: NC1CCN(CC(F)F)CC1
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(CC(F)F)CC2)ccc1N
Reaction time: 20 h
Yield: 88.6 %

Procedure:
To a mixture of 1.07 g (3.78 mmole) of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester, 0.90 g (3.78 mmole) of 1-(2,2-difluoro-ethyl)-piperidin-4-ylamine dihydrochloride and 5 mL of dimethylformamide was added 2.63 mL of triethylamine. The mixture was stirred for 20 hours, then taken up in dichloromethane and washed twice with 100 mL of saturated aqueous sodium bicarbonate, once with 50 mL water, once with 50 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) to give 1.05 g of 4-amino-N-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(OC(C)C)(C)C>ClC1C=CC(Cl)=CC=1Cl>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)[CH2:22][CH2:21]2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(CN2CCNCC2)cc1
Reactant: Clc1cc(-c2ccccc2)ccn1
Solvent: CC(C)OC(C)C
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Cc1ccc(CN2CCN(c3cc(-c4ccccc4)ccn3)CC2)cc1
Temperature: 100 °C
Yield: 38.9 %

Procedure:
A solution of 2-chloro-4-phenylpyridine (11.4 g) and 4-(4-methylbenzyl)piperazine (11.4 g) in 1,2,4-trichlorobenzene (40 cc) is heated for 5 hours at 170° C. After the mixture is cooled to a temperature in the region of 20° C., isopropyl ether (200 cc) is added. The precipitate formed is separated by filtration, washed with isopropyl ether (50 cc) and then dissolved in ethyl acetate (250 cc). 5N aqueous sodium hydroxide solution (16 cc) is added, followed by distilled water (100 cc). The organic solution is decanted and the aqueous phase washed with ethyl acetate (2×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in 2-propanol (75 cc); decolorizing charcoal (0.5 g) is added and the mixture is heated to 100° C. for 30 minutes, filtered on diatomaceous earth and cooled to 10° C. for 1 hour. The precipitate formed is separated by filtration and washed with 2-propanol (2×10 cc). 2-[4-(4-Methylbenzyl)-1-piperazinyl]-4-phenylpyridine (8 g), m.p. 103° C., is thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8]N)([CH3:4])([CH3:3])[CH3:2].C([N:13](CC)CC)C.[Cl:18][CH2:19][O:20][C:21](Cl)=[O:22]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:10])[CH:7]([NH:13][C:21]([O:20][CH2:19][Cl:18])=[O:22])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCCl
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)CCN
Solvent: ClCCl
Product: CC(NC(=O)OCCl)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
β-alanine t-butylester (316 mg) was dissolved in methylene chloride (2 ml). To this solution were added triethylamine (333 μl: 1.1 molar equivalent) and chloromethylchloroformate (309 mg: 1.1 molar equivalent). The mixture was stirred for 20 minutes while cooling with ice. The reaction solution was concentrated under reduced pressure and was then dissolved in chloroform (20 ml), followed by washing well with water and a saturated solution of sodium chloride. Anhydrous sodium sulfate was applied to dry the chloroform layer which was then concentrated under reduced pressure. The concentrate was purified by silica gel chromatography using a solvent system of chloroform/methanol (200:1 v/v) to obtain the desired substance (394 mg) with a yield of 76%.
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.[CH2:29]([O:32]/[N:33]=[C:34](/[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)\[C:35](O)=[O:36])[CH:30]=[CH2:31].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(OCC)(=O)C>[CH2:29]([O:32]/[N:33]=[C:34](/[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)\[C:35]([NH:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12)=[O:36])[CH:30]=[CH2:31]
Reactant: C=CCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Compound V (1.35 g, 3 mmoles) in methylene chloride (20 ml) was added BSA (1.1 ml, 4.5 mmoles), and the mixture was stirred for 30 minutes at room temperature to become a clear solution. A mixture of (Z)-2-allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVd) (1.40 g, 3.0 mmoles) and phosphorus pentachloride (690 mg, 3.3 mmoles) in methylene chloride (20 ml) was stirred for 15 minutes at room temperature and poured in one portion into the solution of the trimethylsilylated Compound V. The mixture was stirred for 20 minutes at room temperature and diluted with ethyl acetate (200 ml), washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wakogel, C-200, 30 g). The column was eluted with chloroform and the fractions containing the desired product were combined. Evaporation under reduced pressure afforded the title compound (VId) as an amorphous powder, yield 2.32 g (89%). Mp. 100°-115° C. (dec.).
Reaction SMILES: C1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)CCCCC=1.[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.N1CCOCC1>C1CCCCC1>[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][C:17]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:16][CH2:15]1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CC1(C)CCC(=O)CC1
Solvent: C1CCCCC1
Solvent: C1COCCN1
Product: CC1(C)CC=C(N2CCOCC2)CC1

Procedure:
Compound III″ (brown liquid) is obtained quantitatively according to Example 1, from 4,4-dimethylcyclohexanone (350.03 g, 2.76 mol), morpholine (327.01 g, 3.75 mol) and cyclohexane (330 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]=[CH:17][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=3)=[CH:10][C:9]2=[O:39])[CH:5]=[CH:6][CH:7]=1.O[CH2:41][C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[C:44]([O:50][CH3:51])[CH:43]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([CH2:41][C:42]4[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[C:44]([O:50][CH3:51])[CH:43]=4)[CH:17]=[N:18][CH:19]=3)=[CH:10][C:9]2=[O:39])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CO)ccc1C#N
Reactant: O=c1cc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)ccn1-c1cccc(Cl)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(Cn2cncc2Cc2ccn(-c3cccc(Cl)c3)c(=O)c2)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-Chloro-phenyl)-4-(1-trityl-1H-imidazol-4-ylmethyl)-1H-pyridin-2-one (272 mg, 0.527 mmol) from step 6 and 4-hydroxymethyl-2-methoxy-benzonitrile (90.3 mg, 0.55 mmol) in CH2Cl2 cooled to -78° C. over dry ice/acetone bath was added N,N-diisopropylethylamine (192 μl, 1.1 mmol) and trifluoromethane-sulfonic anhydride(93 μl, 0.55 mmol). The reaction was allowed to slowly warm to room temperature and stirred overnight. The reaction was diluted with methanol (10 mL), heated to reflux for 2 h, cooled and the solvent evaporated in vacuo. The residue was partitioned between sat. Na2CO3 (20 ml) and CH2Cl2 (2×50 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH2Cl2 3:97 to 4:96 to 10:90 gradient elution) to afford the free base which was converted to the hydrochloride salt to afford the title compound as an off white solid.
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:26]#[N:27]>CN(C)C=O>[CH2:28]([CH:25]([N:20]1[CH:21]=[C:17]([C:15]([NH:14][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[N:18]=[CH:19]1)[C:26]#[N:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCC(Br)C#N
Reactant: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCC(C#N)n1cnc(C(=O)NC(c2ccccc2)c2ccccc2)c1
Yield: 49.8 %

Procedure:
To a solution of 1.67 g of 4-{[(diphenylmethyl)amino]carbonyl}-1H-imidazole in 100 ml of dimethylformamide were added 5.03 g of potassium fluoride on alumina. With stirring, 1.35 g of α-bromooctanonitrile were added. The solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. NMR indicated a mixture of starting material with desired product, so the residue was dissolved in 200 ml of acetonitrile, and 1 g of α-bromooctanonitrile and 5 g of potassium fluoride on alumina was added. After stirring at room temperature for 2 days, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over SiO2 and the appropriate fractions combined and concentrated in vacuo to provide 1.2 g of the desired titled intermediate, oil. MS: M+ =400
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:13].[F:16][C:17]1[C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=[CH:19][N:18]=1.ClC1C(Cl)=CC=CC1(N=[C:35]=[S:36])F>>[F:1][C:2]([F:14])([F:15])[C:3]1[C:8]([C:9]([F:11])([F:12])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:13][C:35]([NH:24][CH2:23][C:22]1[C:17]([F:16])=[N:18][CH:19]=[CH:20][CH:21]=1)=[S:36]
Reactant: Nc1cccc(C(F)(F)F)c1C(F)(F)F
Reactant: FC1(N=C=S)C=CC=C(Cl)C1Cl
Reactant: NCc1cccnc1F
Product: Fc1ncccc1CNC(=S)Nc1cccc(C(F)(F)F)c1C(F)(F)F
Yield: 90 %

Procedure:
Prepared in 90% yield from the product of Example 197A and the product of Example 193C according to the procedure described for the product of Example 192D and Example 192G.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)=[C:31]([CH3:33])[CH:32]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([C:34]2[CH2:35][CH2:36][N:37]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:38][CH:39]=2)=[C:31]([CH3:33])[CH:32]=1)=[O:25]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(S(=O)(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Isopropylsulfonyl chloride (72 μl) was added to a suspension of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (221 mg) described in Reference Example 170 and potassium carbonate (138 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 5 hours. Water was added and the precipitated solid was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (62 mg) as a white solid.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-])([CH3:3])[CH3:2].[CH3:13][N:14](C)C(Cl)=O>ClCCl>[CH:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCc1cccc[n+]1[O-]
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)OCc1cccc(C#N)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2-(isopropoxymethyl)pyridine-N-oxide (17.8 g, 0.11 mol) in dichloromethane (200 mL) at room temperature was treated with trimethylsilyl cyamide (17.65 mL, 0.132 mol) and dimethylcarbamyl chloride (12.18 mL, 0.132 mol), heated to 40° C. for 18 h, quenched with 2-M aqueous Na2CO3 solution (400 mL) and stirred for 2 h. The mixture was extracted with dichloromethane (2×200 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as an orange oil; NMR δH (400 MHz, CDCl3) 1.17-1.18 (6H, d, J 6 Hz), 3.67-3.76 (1H, sept J 6 Hz), 4.58 (2H, s), 7.74-7.76 (1H, d, J 8 Hz), 7.92-7.94 (1H, d, J 7.5 Hz) and 8.04-8.08 (1H, t, J 7.5 Hz)
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(Cl)(Cl)[Cl:16].C(=O)([O-])[O-].[Na+].[Na+].[C:25](Cl)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[C:25]([N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([Cl:16])=[O:14])=[CH:9][CH:10]=1)([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26]
Reactant: C=CCNc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCN(C(=O)OCc1ccccc1)c1ccc(CC(=O)Cl)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. 4-(allylamino)phenylacetic acid in 200 ml. warm chloroform is added a solution of 12 g. sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1N hydrochloric acid, dried, and evaorated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time ultimately to yield 4-(N-carbobenzyloxy-allylamino)phenylacetyl chloride as a viscous, orange oil.
Reaction SMILES: CS[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]1=[O:19].S(Cl)([Cl:23])(=O)=O>ClCCl>[Cl:23][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]1=[O:19]
Reactant: CCOC(=O)c1nc2ccccc2n(CSC)c1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1nc2ccccc2n(CCl)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.1 g (7.5 mmol) of ethyl 1-(methylthiomethyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in dichloromethane (10 mL), and 1.3 g (9.8 mmol) of sulfuryl chloride was added dropwise at or below 10° C. The mixture was stirred for 2 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, to obtain ethyl 1-(chloromethyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate. The chloromethylation product thus obtained was used in the subsequent reaction without purification.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH3:10][O:11][CH:12]([O:29][CH3:30])[C:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]([C:24]([NH2:27])([CH3:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[N:15]([CH3:28])[N:14]=1.CCN(CC)CC>C(Cl)Cl>[CH3:30][O:29][CH:12]([O:11][CH3:10])[C:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]([C:24]([NH:27][S:4]([CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:6])=[O:5])([CH3:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[N:15]([CH3:28])[N:14]=1
Reactant: COC(OC)c1cc(-c2cccc(C(C)(C)N)c2)n(C)n1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1cc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
2,2,2-Trifluoroethylsulfonyl chloride (253 mg, 1.4 mmol) was added dropwise to a stirred solution of the amine from Step 2 (267 mg, 0.92 mmol) and Et3N (193 □L, 1.4 mmol) in CH2Cl2 (25 mL) at RT under N2. The mixture was stirred at RT for 30 min and then diluted with CH2Cl2 (25 mL), washed with NaHCO3 solution (20 mL) and concentrated under reduced pressure to yield the crude sulfonamide (213 mg, 53%). 1H NMR (CDCl3, 360 MHz) δ 7.60-7.53 (2H, m), 7.49 (1H, t, J=7.6 Hz), 7.37 (1H, d, J=7.6 Hz), 6.38 (1H, s), 5.50 (1H, s), 5.02 (1H, s), 3.88 (3H, s), 3.47 (2H, q, J=8.8 Hz), 3.44 (6H, s), 1.81 (6H, s). MS (ES+) C18H24F3N3O4S requires: 435, found: 404 (M-OCH3+, 100%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15][CH2:16][CH2:17]C.IC(C)C.OC1O[C@@H](CO)[C@H](O)[C@H](O)[C@H]1O>>[CH:16]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH3:17])[CH3:15]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Agent: OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: CC(C)I
Product: CC(C)C1c2ccccc2-c2ccccc21

Procedure:
Fluorene (15.0 g, 90.4 mmol), n-BuLi (48.1 ml, 120 mmol, 2.5 M in hexane), RX=2-iodopropane (14.0 ml, 139.6 mmol). 42 was isolated as a yellowish solid (18.7 g, quant.). The analytical data were identical with these to be found in the literature (M. A. Schmidt, H. G. Alt, W. Milius, J. Organomet. Chem. 1996, 525, 15).