Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([N:30]2[C:34](=[O:35])[C@@H:33]3[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][C@@H:32]3[CH2:31]2)=[CH:26][CH:25]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:23][C:24]4[N:29]=[CH:28][C:27]([N:30]5[C:34](=[O:35])[C@@H:33]6[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][C@@H:32]6[CH2:31]5)=[CH:26][CH:25]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc(N)nc3)C(=O)[C@@H]2C1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CN(C(=O)OC(C)(C)C)C[C@H]5C4=O)cn3)nc2n1C1CCCCCC1
Yield: 95.1 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50.4 mg, 0.157 mmol) was combined with cis-tert-butyl 5-(6-aminopyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (50 mg, 0.157 mmol, 1.0 eq), gave after silica gel chromatography, cis-tert-butyl 5-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (90 mg) in 94% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.76 (s, 1H), 8.65 (d, J=9.6 Hz, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 6.46 (s, 1H), 4.54 (m, 1H), 4.13 (dd, J1=9.85 Hz, J2=6.82 Hz, 1H), 3.97 (d, J=10.61 Hz, 1H), 3.89 (t, J=9.85 Hz, 1H), 3.62-3.76 (m, 2H), 3.06-3.40 (m, 9H), 2.65 (q, J=10.95 Hz, 2H), 2.02 (m, 2H), 1.89 (m, 2H), 1.74 (m, 4H), 1.60 (m, 2H), 1.49 (m, 9H). MS m/z 603.6 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:26]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([S:32]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[N:12]=[C:11]([CH2:13][O:14][C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH:25]=[N:24][N:23]=[N:22]5)=[N:19][CH:20]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: Cl
Product: O=S(=O)(C1CCCCC1)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and cyclohexanesulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.08 (1H, s), 8.42 (1H, d), 8.01 (1H, d), 7.95 (1H, s), 7.86 (1H, dd), 3.52 (2H, s), 4.74 (1H, m), 3.68 (2H, m), 3.11 (3H, m) 2.51 (1H, m), 2.17 (2H, m) 1.92 (3H, m), 1.73 (1H, m), 1.23 (7H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=NNC(N)=S)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C[OH:22].NNC(N)=S>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)NN=C(c1cccc(Br)c1)c1cccc(Br)c1
Reactant: CO
Agent: NNC(N)=S
Solvent: CC(=O)O
Product: O=C(c1cccc(Br)c1)c1cccc(Br)c1
Yield: 18 %

Procedure:
Bis(3-bromophenyl) ketone thiosemicarbazone (14) Into a round bottom flask containing the appropriate ketone (1.044 g, 3.07 mmol), 35 mL of anhydrous methanol were added and the solution was refluxed for about 15 minutes. To the warm ketone solution, thiosemicarbazide (0.294 g, 3.23 mmol) and 1% solution of HOAc (1.5 mL) were added. The reaction mixture was refluxed under nitrogen atmosphere for 46 h, at which point, the solvent was evaporated and, the crude reaction mixture was purified by flash chromatography (20% EtOAc/80% hex) to obtain 0.231 g (0.559 mmol) of the product in an 18% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](N)[CH:4]=1.N([O-])=O.[Na+].[C:14]1(=[O:20])[NH:18][C:17](=[O:19])[CH:16]=[CH:15]1.C(=O)=O.C([O-])(=O)C.[Na+]>Cl.O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[C:17]([NH:18][C:14](=[O:20])[CH:15]=2)=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1cccc(N)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C=O
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(C2=CC(=O)NC2=O)c1
Reaction time: 0.5 h

Procedure:
A 61.5 g portion of m-anisidine in 150 ml of 12N hydrochloric acid and 150 ml of water was cooled in an ice-salt bath. A 35 g portion of sodium nitrite in 80 ml of water was added dropwise, with stirring over 1/2 hour. A solution of 48.5 g of maleimide in 400 ml of acetone was added together with 50 g of dry-ice. A 125 g portion of sodium acetate was added, followed immediately by 12.75 g of cupric chloride dihydrate. The mixture was allowed to stand 18 hours, then the solid was collected and dried. A 90 g portion of this solid and 51 g of 2,4-lutidine in 250 ml of isopropanol was heated on a steam bath for 1/2 hour, then poured into 1200 ml of water. The solid was collected, dried and then recrystallized, first from isopropanol then from ethyl acetate:ethanol, giving 29.0 g of 2-(m-methoxyphenyl)maleimide as yellow crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:24])[CH:17]=[CH:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].O.[C:26](OCC)(=O)C>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:24])[CH2:17][C@@H:18]1[CH3:26])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(C)=O
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.3 g (10 mmol) of 17β-acetoxy-5α-androst-1-en-3-one in 15 ml of ethyl acetate and 143 mg (0.1 mmol) of CuBr are added to solution a). It is stirred for 16 hours at 25° C. The reaction solution is hydrolyzed with 1 ml of water, stirred for 15 minutes more and the inorganic solid is filtered off. The solid is washed with ethyl acetate. After evaporation of the solvent, 3.5 g of substance is obtained that is recrystallized from acetone. After suctioning off of the crystals, 2.9 g of 17-acetoxy-1α-methyl-5α-androstan-3-one of a melting point of 179-180° C. is obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:32]=[C:33]([NH:34][C:35]([CH3:37])=[O:36])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)[CH:32]=[C:33]([NH:34][C:35]([CH3:37])=[O:36])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(NC(C)=O)cc(C3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(NC(C)=O)cc(C3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-cyclohexylacetamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:10][C:11]1[N:16]([CH3:17])[C:15](=[O:18])[NH:14][C:13](=[O:19])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:10][C:11]1[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:13](=[O:19])[CH:12]=1
Reactant: Cn1c(Cl)cc(=O)[nH]c1=O
Reactant: CCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCn1c(=O)cc(Cl)n(C)c1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Next 5.4 ml of n-octyl bromide was added to a solution consisting of 5 grams of 6-chloro-1-methyl-uracil obtained as described above, 5.2 grams of potassium carbonate and 50 ml of N,N-dimethylformamide and the mixture was heated to 90° C. and stirred for a period of 5 hours. After cooling, the reaction mixture was added slowly to a solution of 10 ml of concentrated hydrochloric acid and 300 ml of water. The resulting solution was extracted twice with 100 ml of chloroform and, after drying over magnesium sulfate, the chloroform layer was concentrated under reduced pressure. The concentrate was then refined using silica gel column chromatography, whereupon 3.1 grams of 6-chloro-1-methyl-3-n-octyl-uracil was obtained in the form of white crystals.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16](S(C)=O)[S:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.[NH2:23][C@@H:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][C@H:25]1[OH:33].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16]([NH:23][C@@H:24]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH2:26][C@H:25]5[OH:33])[S:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cncnc43)cc2s1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cncnc43)cc2s1
Temperature: 150 °C
Yield: 21.4 %

Procedure:
To a mixture of 6-((9H-purin-9-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (270 mg, 0.8 mmol) from Step 2 of the this Example and (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (246 mg, 1.6 mmol) in NMP (1.5 mL) was added DIEA (570 μL, 3.3 mmol). The reaction vessel was sealed and the mixture was heated at 150° C. in the Biotage microwave reactor for 1.5 h. The mixture was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-1-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (71 mg, 21%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.97 (s, 1H), 8.77 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.74 (d, J=1.3 Hz, 1H), 7.37 (m, 1H), 7.30 (m, 1H), 7.11-7.25 (m, 4H), 5.45-5.57 (m, 3H), 5.18 (t, J=7.1 Hz, 1H), 4.28 (m, 1H), 3.16 (dd, J=6.9, 15.5 Hz, 1H), 2.74 (m, 1H). LCMS (ESI) m/z 415 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]([C:37]5[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=5)=[N:29][N:28]=4)=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[N:11][CH:10]=1)C1C=CC=CC=1.CO.[H][H]>C(Cl)Cl.[Pd]>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([NH:26][C:23]3[CH:22]=[CH:21][C:20]([O:19][C:13]4[CH:14]=[CH:15][N:16]=[C:17]5[C:12]=4[N:11]=[CH:10][C:9]([OH:8])=[CH:18]5)=[CH:25][CH:24]=3)=[N:28][N:29]=2)=[CH:38][CH:39]=1
Reactant: Clc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OCc6ccccc6)cnc45)cc3)c3ccccc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Oc1cnc2c(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)ccnc2c1
Reaction time: 8 h

Procedure:
A round bottom flask was charged with N-(4-(7-(benzyloxy)-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine (400 mg, 687 μmol), 10% Pd/C (73.1 mg, 687 μmol) and 3.4 mL MeOH. The flask was fitted with a hydrogen-filled balloon and the mixture was stirred overnight. The mixture was diluted with DCM and filtered through Celite. The filtrate was concentrated and the crude material was purified by reverse phase chromatography, Gilson, 10-90% 0.1% TFA/ACN in water over 15 min to provide 8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-3-ol as a light yellow solid. MS: [M+H]=492.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][CH2:10][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Fc1ccc([C@H]2CO2)cc1
Reactant: NCc1ccccc1
Product: O[C@H](CNCc1ccccc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
Charge a 10 L round bottom flask with (S)-2-(4-fluorophenyl)oxirane (880 g, 6.38 mol) under a nitrogen atmosphere. Add benzylamine (2047 g, 19.13 mol) while the mixture is maintained at 20° C. Heat the mixture to 80° C. and stir it at that temperature for 5 h. Cool to 22° C. and stir for 16 h. Add H2O (3 L) to quench the reaction. Filter and wash the filter cake with water (2×1 L). Slurry the solid obtained with heptane (2 L) and filter to give the title compound (1216 g, 77%). MS (m/z): 246 (M+1); ee value: 99.0% (AD-H 250 mm×4.6 mm×5 μm column using 90:10 hexanes (with 0.02% diethylamine):EtOH at 25° C. with a flow rate of 1.0 mL/min).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:3]([OH:22])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1
Yield: 59.6 %

Procedure:
A solution of 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (1.00 g, 3.08 mmol) in ethanol (15 mL) was treated with a 1N aqueous sodium hydroxide solution (6 mL). The solution was heated at 45–50° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (20 mL) and extracted with diethyl ether (1×40 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid (570 mg, 60%) as a white solid: mp 139–143° C.; EI-HRMS m/e calcd for C16H22O4S (M+) 310.1239, found 310.1241.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([C:36](O)=[O:37])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)(=[O:23])=[O:22]>>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:36]([C:26]4[CH:25]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:29]=[CH:28][C:27]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:37])[CH2:17][CH2:18]3)=[C:9]([F:19])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(N2CCNCC2)c(F)c1)C1CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ccc(S(=O)(=O)C4CC4)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(4-Cyclopropanesulfonyl-2-fluoro-phenyl)-piperazine (Example W) and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 543.3 MH+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[O-]CC.[Na+].[CH3:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25]>C(O)C>[CH3:21][O:22][C:23](=[O:27])[CH:24]([CH3:26])[CH2:25][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: C=C(C)C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C(C)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 94.5 %

Procedure:
1-(4-Trifluoromethyl-phenyl)-piperazine (460 mg; 2.0 mmol) and sodium ethoxide (150 mg; 2.21 mmol) are dissolved in ethanol (2 mL) and irradiated for 5 minutes in a mono-mode microwave oven at 60° C. 2-Methyl-acrylic acid methyl ester (400 μL; 4.0 mmol) is then added and the resulting mixture is irradiated for 50 minutes in a mono-mode microwave oven at 100° C. The reaction is concentrated under reduced pressure, diluted in ethylacetate (10 mL) and extracted with water (2×5 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product (623 mg; 1.89 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.C1COCC1.[CH3:15][S:16]SC>O.C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:16][CH3:15])[CH:3]=1
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CSSC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CSc1cccc(C)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
Add 1M 3-methyl-phenylmagnesium bromide in THF (25 mL, 25 mmol) to −30° C. diethyl ether (50 mL). Add dimethyl disulfide (1.8 mL, 20 mmol) to the reaction over 3 minutes allowing the reaction to warm to room temperature. Dilute the reaction in H2O (75 mL) and diethyl ether (50 mL). Separate and extract the cloudy aqueous layer with diethyl ether (25 mL). Combine the organic layers and wash with H2O (25 mL). Dry the organic layer with Na2SO4 (30 g), filter over Celite 501 (10 g) and concentrate in vacuo to give 3.0 g of crude material. Combine with another batch of crude title compound that yielded 6.0 g crude. Chromatograph the entire 9.0 g crude on a SiO2 column in hexanes to give 7.2 g (70%) of 1-methyl-3-methylsulfanyl-benzene.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH:20][C:21]([O:23]C1C=CC(Cl)=CC=1)=O.CCN(C(C)C)C(C)C.[CH3:41][S:42]([NH:45][NH2:46])(=[O:44])=[O:43]>O1CCOCC1>[CH3:15][N:13]1[CH:14]=[C:10]([C:8]2[CH:9]=[C:4]3[C:5](=[CH:6][C:7]=2[C:16]([F:19])([F:18])[F:17])[NH:20][C:21](=[O:23])[N:46]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])[C:3]3=[O:2])[N:11]=[N:12]1
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(-c2cn(C)nn2)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)nn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
2-(4-Chloro-phenoxycarbonylamino)-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-4-trifluoromethyl-benzoic acid methyl ester (260 mg, 0.57 mmol) was dissolved in dioxane (15 mL). After addition of i-Pr2NEt (294 μL, 3 equiv) and CH3SO2NHNH2 (126 mg, 2 equiv), the solution was stirred for 2 h at 100° C. The solvent was removed in vacuo and the crude product was dried in vacuo for 2 h. DCM (5 mL) was then added and, after sonication, the solution was put in the freezer for 16 h. The resulting solid was filtered off, washed with DCM and dried to afford N-[6-(1-methyl-1H-[1,2,3]triazol-4-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (180 mg, 78%) as an off-white solid. (ESI-MS: m/z 446.5 [M+CH3CN+H]+, rt 3.71 min) 1H-NMR (DMSO-d6, 400 MHz) 8.33 (s, 1H), 8.28 (s, 1H), 7.64 (s, 1H), 4.13 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)#[N:24]>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=3)=[O:33])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Product: N#Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Yield: 53 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-cyanophenyl isocyanate in a yield of 53%, according to the procedure for the synthesis of example 42.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[Br:31][CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36]>O1CCCC1.C(OCC)(=O)C>[Cl:19][CH:18]([Cl:20])[C:16]([NH:15][CH:12]([CH2:13][F:14])[CH:11]([O:21][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][Br:31])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)=[O:17]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: O=C(Cl)CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(OC(=O)CCCBr)C(CF)NC(=O)C(Cl)Cl)cc1
Yield: 44.9 %

Procedure:
Upon stirring a mixture of florfenicol (8.8 g, 1 equivalent), diisopropylethylamine (5 mL, 1.2 equivalents), and 4-N,N-dimethylaminopyridine (1.2 g, 0.4 equivalent) in tetrahydrofuran (90 mL) at −20° C., a solution of 4-bromobutyryl chloride (5 g, 1.1 equivalent) in tetrahydrofuran (15 mL) was added via a syringe. The solution was stirred at room temperature under a nitrogen atmosphere overnight and diluted with ethyl acetate. The resulting solution was washed with 1 M HCl(aq) and the organic layer was separated and concentrated to give a brown oil. The crude oil was purified by gel column chromatography to give 4-bromo-butyric acid 2-(2,2-dichloro-acetyl amino)-3-fluoro-1-(4-methanesulfonyl-phenyl)-propyl ester (5.6 g, 45% yield) as a brown foam; H1-NMR (DMSO-d6), δ=2.1 ppm (p, 2H), 2.6 ppm (t, 2H), 3.2 ppm (s, 3H), 3.5 ppm (t, 2H), 4.2-4.6 (m, 3H), 6.0 ppm (d, 1H), 6.4 ppm (s, 1H), 7.6 ppm (d, 2H), 7.9 ppm (d, 2H), 8.9 ppm (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6](C2C(C(OC)=O)=CC([N+]([O-])=O)=CC=2)[CH:7]=1.Br[C:24]1[C:33]([CH3:34])=[CH:32][C:31]([N+:35]([O-:37])=[O:36])=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].FC1C=CC(OC)=C(B(O)O)C=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[CH:6][C:7]=1[C:24]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][C:31]([N+:35]([O-:37])=[O:36])=[CH:32][C:33]=1[CH3:34]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(F)cc1B(O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1cc(OC)ccc1F
Yield: 38 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5′-fluoro-2′-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2-bromo-3-methyl-5-nitrobenzoate (1.73 g, 6.31 mmol), (PPh3)4Pd (0.22 g, 0.19 mmol), and 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) (1.50 g, 8.8 mmol) to afford 0.77 g (38%) of methyl 2′-fluoro-5′-methoxy-6-methyl-4-nitro-2-biphenylcarboxylate. Data for 2′-fluoro-5′-methoxy-6-methyl-4-nitro-2-biphenylcarboxylate: 8.61 (d, J=2.3, 1H), 8.27 (d, J=2.4, 1H), 7.09 (m, 1H), 6.91 (dd, J=9.0, 4.3, 1H), 6.73 (dd, J=8.2, 3.0, 1H), 3.70 (s, 3H), 3.69 (s, 3H), 2.19 (s, 3H).