Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:35][C:36]([C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1)=[O:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH2:35][C:36]([C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)=[O:37])[CH2:17][CH2:18]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(C(=O)CCl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(CC(=O)c2ccc(C#N)cc2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
To a solution of (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoic acid amide (Example 126, 0.050 g, 0.12 mmol) and Et3N (0.040 mL, 0.30 mmol) in CH2Cl2 (2.0 mL) was added 4-(2-chloro-acetyl)-benzonitrile (55 mg, 0.30 mmol). The reaction was stirred at rt for 18 h and then was concentrated to residue. The residue was purified on a Biotage system (eluted with 80% EtOAc/hexanes) to produce 29 mg (48%) of the desired product as a white solid. MS (ESI), (M+H)+ 545.16; 1H NMR (CDCl3, 500 MHz) δ 7.72 (d, 2H, J=8.5), 7.50-7.65 (m, 2H), 7.50 (d, 2H, J=7.0), 7.35-7.45 (m, 2H), 6.67 (s, 1H), 5.32 (s, 1H), 4.14 (dd, 1H, J=5.0, 9.0), 3.52 (br s, 1H), 3.28 (t, 1H, J=14), 2.97 (dd, 1H, J=3.5, 14), 2.82 (br s, 1H), 1.00-2.00 (m, 10H), 0.71 (d, 3H, J=6.5), 0.66 (d, 3H, J=6.5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:31][Si:32]([CH3:41])([CH3:40])[C:33]#[C:34][C:35](OCC)=[O:36]>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[C:35](=[O:36])[C:34]#[C:33][Si:32]([CH3:41])([CH3:40])[CH3:31])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OC)c(Cc2ccc(Cl)nn2)c1
Reactant: CCOC(=O)C#C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(C(C(=O)C#C[Si](C)(C)C)c2ccc(Cl)nn2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-[(6-chloropyridazin-3-yl)methyl]-4-methoxybenzoate (10.03 g, 34.2 mmol) in THF (400 mL) was added LHMDS (100 mL, 1M solution in THF) and ethyl 3-(trimethylsilyl)propynoate (6.66 mL, 35.5 mmol) at −78° C. The reaction was warmed to 0° C. and stirred for 0.5 hr until the reaction was complete by LCMS analysis. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with 0.5 N HCl, brine, dried over MgSO4, and condensed in vacuo to yield an oil. The crude material was purified via silica gel chromatography (CH2Cl2) to yield the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[CH3:20].[B:21](OC)([O:24]C)[O:22]C.Cl>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[C:8]([CH3:20])[C:7]([B:21]([OH:24])[OH:22])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
n-Butyl lithium (1.6 M solution in hexanes, 37.5 ml, 0.060 mol) is added dropwise to a solution of 4-bromo-4′-chloro-3-methylbiphenyl (11.5 g, 0.041 mol) in tetrahydrofuran (120 ml) at −78° C., under an atmosphere of nitrogen, and the mixture is stirred at −78° C. for 30 minutes. Trimethyl borate (27.4 ml, 0.245 mol) is added slowly at −78° C. and the mixture is stirred for 1 hr. The reaction mixture is allowed to warm to room temperature over 2-3 hours and then stirred at room temperature for 1 hr. 0.1N Aqueous hydrochloric acid (320 ml) is added and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate (3×300 ml) and the organic extracts are combined, dried with anhydrous sodium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4′-chloro-3-methylbiphen-4-ylboronic acid (6.0 g) as white solid.
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([C:12]2[N:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]3=[N:14][C:13]=2[NH2:22])[CH2:11][CH2:10]1.N1C=CC=CC=1>C(#N)C>[CH:9]1([C:12]2[N:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]3=[N:14][C:13]=2[NH:22][C:6](=[O:7])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1nc2ccc(F)cn2c1C1CC1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)CC(=O)Nc1nc2ccc(F)cn2c1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl acetyl chloride (0.040 mL, 0.00029 mol) was added to a solution of 3-Cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-ylamine (compound f, 0.054 g, 0.00027 mol) in acetonitrile (5.00 mL) containing pyridine (0.0637 g, 0.00081 mol) and the mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and crude product purified by column chromatography (50% ethyl acetate/hexanes to neat ethyl acetate) to give N-(3-cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-3,3-dimethyl-butyramide as a yellow solid. Rf 0.41, 5% methanol/dichloromethane; MS m/z 289 (M+H). SH-SY5Y_EC50 (μM): 2.5464.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:12])([O-:11])[CH3:10].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:9]([O:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:10])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 96.2 %

Procedure:
A typical procedure is given for the reaction of Entry 1 in Table 1. A 4 mL vial was charged with bromobenzene (63 mg, 0.40, mmol), Pd(dba)2 (11.5 mg, 0.02 mmol), Ph5FcP(t-BU)2 (14.2 mg, 0.02 mmol) and sodium t-butoxide (47 mg, 0.48 mmol). Anhydrous toluene (2 mL) was added, and the vial was sealed with a cap containing a PTFE septum and removed from the drybox. The reaction mixture was stirred at room temperature for 23 h. The reaction solution was then adsorbed onto silica gel, and the product was isolated by eluting with ethyl acetate/hexanes (0 to 10% gradient) to give 58 mg (97%) of t-butoxybenzene.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([Cl:13])[C:11]=1[F:12])[C:6](F)=[O:7]>O>[Cl:2][C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([Cl:13])[C:11]=1[F:12])[C:6]([NH2:1])=[O:7]
Reactant: O=C(F)c1cc(Cl)c(F)c(Cl)c1F
Reactant: N
Solvent: O
Product: NC(=O)c1cc(Cl)c(F)c(Cl)c1F
Reaction time: 0.5 h
Yield: 90 %

Procedure:
620 ml of concentrated aqueous ammonia solution and 600 ml of water are initially introduced, 458 g (2 moles) of 3,5-dichloro-2,4-difluorobenzoyl fluoride are added dropwise at 40°-50°, and then the mixture is stirred at 50° for 30 minutes. The precipitate is filtered off with suction, washed with water and dried. 408 g (90% of theory) of 3,5-dichloro-2,4-difluorobenzamide of melting point 163°-164° are obtained.
Reaction SMILES: C(OC([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[N:9][N:10]=1)=O)C.[Li+].[OH-].Cl>C1COCC1.O>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:8]1[O:7][CH:6]=[N:10][N:9]=1
Reactant: CCOC(=O)c1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnco1
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of 5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester (200 mg, 0.44 mmol) in THF-H2O (1:1)(5 mL) LiOH (32 mg, 1.32 mmol) was added. The reaction mixture was stirred for 2 hrs and then the pH was adjusted to 5 with 1N HCl. Upon dilution with water a solid precipitated. Filtration afforded the desired product (89 mg). LC/MS (Method A) [0.48 min; 383(M+1)]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(OC(=O)C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1ccc(Br)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC(=O)c1ccc(Br)cn1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
tert-Butyl (3-(5-bromopyridin-2-yl)-3-hydroxypropyl)carbamate(224 mg, 0.68 mmol) in ethylacetate (4.5 mL, 0.15 M) had 1.2 equivalents of Dess-Martin periodinane (344 mg, 0.81 mmol) added to it and stirred for 1 hour. The reaction mixture is then filtered and washed with sodium hydrogen carbonate and evaporated to give the title compound (220 mg): MS (ESI+) m/z 273.0 [M−But+H].
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][CH3:24]>O>[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][N:23]([CH3:24])[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([N:23]([CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])[CH3:24])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNCCN(C)C
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Solvent: O
Product: CN(C)CCN(C)c1cccc2c1C(=O)c1cccc(N(C)CCN(C)C)c1C2=O
Temperature: 25 °C

Procedure:
A mixture of 1,5-dichloroanthraquinone (5.5 g, 20 mmol) and N,N,N′-trimethylethylenediamine (40 ml) was refluxed for 18 h. The mixture was cooled to room temperature, diluted with water (400 mL) and extracted with chloroform (2×200 mL). The combined organic layer was washed with water, brine, dried over MgSO4 and evaporated to dryness. The residue thus obtained was purified by silica gel flash chromatography [CHCl3/MeOH/Et3N (44:5:1)] to provide Compound 9. Abs (max, PBS pH 7.4)=508 nm. The structure of Compound 9 is given below:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Brc1ccccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1cc(-c2ccccn2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.91 min; Mass spectrum (ESI+): m/z=262/264 (Br) [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7]2.CO[CH:23](OC)[CH2:24][C:25]([CH3:28])(O)[CH3:26]>N1C=CC=CC=1>[CH3:26][C:25]1([CH3:28])[O:1][C:2]2[C:3]3[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7][C:8]=3[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:10]([OH:12])[C:11]=2[CH:23]=[CH:24]1
Reactant: COC(CC(C)(C)O)OC
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12
Solvent: c1ccncc1
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Yield: 79.1 %

Procedure:
A mixture of 3 (2.60 g, 9.42 mmol) and 4,4-dimethoxy-2-methylbutan-2-ol (5.54 g, 37.7 mmol) were dissolved in anhydrous pyridine (6.5 mL). The mixture was refluxed under nitrogen for three days. After removal of the solvent in vacuo, the residue was dissolved in ethyl acetate. The ethyl acetate was washed several times with 1N HCl and brine. It was then dried over Na2SO4. The crude product obtained by evaporation in vacuo was purified by silica gel column chromatography, eluting with 25% ethyl acetate/hexane to afford 2.55 g of 4 in 78.6% yield, mp 96°-98° C. 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.3 Hz, CH3); 1.22 (3H, t, J=7.5 Hz, CH3); 1.53 (6H, s, 2 CH3); 1.75 (2H, m, CH2); 2.92 (2H, t, J=7.1 Hz, CH2); 3.35 (2H, q, J=7.1 Hz, CH2); 5.56 (1H, d, J=10.0 Hz, H3); 5.98 (1H, s, H9); 6.72 (1H, d, J=10.0 Hz, H4); MS (EI): 343 (5.7, M+1); 342 (22.5, M+); 327 (100, M--CH3); IR (KBr): 1728 (vs, C=O) cm-1; Anal. calcd. for C20H22O5 : C, 70.16; H, 6.48; Found: C, 70.45; H, 6.92.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[N:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O1CCOCC1>[CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:34](=[O:35])[O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:25][CH:26]=2)[N:9]=1)(=[O:5])=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
(4-{4-[(Isopropylsulfonyl)methyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}phenyl)amine (1.5 g, 3.84 mmol) was dissolved in dioxane (10 mL). Sodium bicarbonate (485 mg, 5.76 mmol) was added, followed by phenyl chloroformate (0.484 mL, 3.84 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 10 mL DCM and 10 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (1.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]C#N)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:3][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:6][C:5]=23)=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccn2)cc1
Reactant: N#CCc1ccc(F)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccn4)cc23)cc1

Procedure:
The title compound, light green solid (65 mg, 49%), MS (ISP) m/z=357.1 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 1 from 2-[5-(4-Nitro-phenyl)-pyrazol-1-yl]-pyridine (intermediate K) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccnc(Cl)c1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 133 mg of (2-Amino-5-chloro-phenyl)-(2-chloro-pyridin-4-yl)-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.26 (s, 9H), 7.18 (dd, 5.2 Hz, 1.6 Hz), 7.25 (m, 1H), 7.32 (m, 1H), 7.41 (d, 2H, J=6.4 Hz), 7.54 (dd,1H, J=9.2 Hz, 2.4 Hz), 7.67 (m, 2H), 7.77 (d,1H, J−8.8 Hz), 8.55 (d, 1H, J=5.2 Hz), 10.09 (s, 1H). MS: m/z463.0 (M++1).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].[OH:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>C1(C)C=CC=CC=1>[C:8]([O:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: OC1c2ccccc2-c2ccccc21
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1c2ccccc2-c2ccccc21

Procedure:
With stirring and ice cooling, 111 g of triethylamine was added to a mixture of 120 g of methacrylic acid chloride, 182 g of 9-hydroxyfluorene, and 1500 g of toluene. The mixture was stirred at room temperature for 16 hours. By standard aqueous work-up and solvent distillation, a crude product was obtained. It was purified by column chromatography, yielding the target compound, 9-fluorenyl methacrylate.
Reaction SMILES: Cl[CH2:2][Cl:3].C(Cl)(=O)C(Cl)=O.[C:10]([C:13]1[CH:21]=[CH:20][C:16](C(O)=O)=[C:15]([CH3:22])[CH:14]=1)(=[O:12])[CH3:11]>CN(C)C=O>[C:10]([C:13]1[CH:21]=[CH:20][C:16]([CH2:2][Cl:3])=[C:15]([CH3:22])[CH:14]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(C(=O)O)c(C)c1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CCl)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
28 ml of dichloromethane, 4 ml of oxalyl chloride, and a drop of N,N-dimethylformamide were added to 5.0 g of 4-acetyl-2-methylbenzoic acid, and the mixture was stirred for 3 hours at room temperature. After removing the solvent by distilling under reduced pressure, 5.6 g of crude 4-acetyl-2-methylbenzyl chloride was obtained.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)=[C:5]([CH3:30])[CH:4]=1.[OH-].[Na+].O>C(O)C>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)=[C:5]([CH3:30])[CH:4]=1
Reactant: Cc1ccccc1C(=COCCN1CCC[C@@H](C(=O)O)C1)c1ccc(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[2-[[2-(4-Fluoro-2-methylphenyl)-2-(2-methyl-phenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid methyl ester (0.74 g, 0.0018 mol) (prepared as described in Method C) was dissolved in ethanol (15 ml) and 10N sodium hydroxide solution (1.8 ml) was introduced. After stirring the reaction mixture for 2 h at room temperature TLC indicated that saponification was incomplete, so further 10 N sodium hydroxide solution (1.8 ml) was added, and the reaction mixture was heated for 10 min. at 40° C. Water (400 ml) was added, and the solution was extracted with diethyl ether (100 ml). The aqueous layer was acidified to pH 5 with 2N hydrochloric acid solution and extracted with dichloromethane (4×50 ml). The combined extracts were dried (MgSO4) and evaporated to a residue (0.61 g) which was dissolved in toluene (50 ml). Methanol (0.2 ml) and chlorotrimethylsilane (0.216 ml) were added, and after mixing, a layer of cyclohexane (ca. 30 ml) was added. After storing this mixture at 4° for 18 h, the title compound was collected by filtration (0.60 g, 77%), m.p. 190°-201° (after drying in vacuo).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@@H:12]2[O:22][CH2:23][CH3:24])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[O:22][CH2:23][CH3:24])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)N1CC[C@@H](NC(=O)c2cc(Cl)c(C)[nH]2)[C@@H](OCC)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCO[C@H]1CNCC[C@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Yield: 37.5 %

Procedure:
A solution of ethyl (3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate (Intermediate 34, 1.6 g, 4.48 mmol), potassium hydroxide (1.76 g, 31.37 mmol), and hydrazine hydrate (1.6 mL, 31.37 mmol) in ethylene glycol (180 mL) was stirred for 40 h at 120° C. The reaction mixture was poured in to water (120 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated in vacuo to yield the crude product which was triturated with water (30 mL) to afford 4-chloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide 480 mg (37%) as solid.
Reaction SMILES: FC(F)(F)CC(O[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17])=O.[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([N:37]([CH3:64])[C:38]([CH3:63])([C:40]([NH:42][C@H:43]([C:47]([N:49]([C@@H:51]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:52]([O:57][CH3:58])[CH2:53][C:54]([OH:56])=[O:55])[CH3:50])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[CH:29]1[C:30]2[CH:31]([CH2:33][O:34][C:35]([N:37]([CH3:64])[C:38]([CH3:63])([C:40]([NH:42][C@H:43]([C:47]([N:49]([C@@H:51]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:52]([O:57][CH3:58])[CH2:53][C:54](=[O:56])[O:55][C:7]3[C:8]([F:17])=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=3[F:13])[CH3:50])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:41])[CH3:39])=[O:36])[C:32]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(CC(F)(F)F)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Yield: 98.3 %

Procedure:
Pentafluorophenyl 3,3,3-trifluoropropanoate (2.44 mL, 13.4 mmol, 2.0 eq.) was added to a solution of #128 (4.18 g, 6.70 mmol, 1.0 eq.) in 50 mL of dichloromethane followed by pyridine (1.61 mL, 20.1 mmol, 3.0 eq.). Reaction was allowed to stir at room temperature for -12 hours. Reaction was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-70% acetone in heptanes) producing #135 (5.2 g, 98%) as a white foam. LC-MS (Protocol Q1): m/z 812.1 [M+Na+] retention time=1.24 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:18]([N:17]([CH3:21])[CH3:16])=[O:19])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(O)cc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OC(=O)N(C)C)cc(C)n1
Temperature: 80 °C

Procedure:
30,8 g (0,25 mole) of 2,6-dimethyl-4-hydroxypyridine were suspended in 500 ml of acetonitrile, 69 g (0,5 mole) of potassium carbonate were added and the mixture was heated to reflux temperature for 2 hours. Subsequently 47 g (0,44 mole) of dimethylcarbamic acid chloride were added at an interior temperature of approximately 60°-70° C. and the mixture was maintained for two hours at about 80° C.