Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:13]([O:15][C:16]([CH2:18][C:19]1([CH3:36])[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([CH3:35])[C:23]([CH3:34])=[C:24]([S:30](Cl)(=[O:32])=[O:31])[C:25]=2[CH3:29])[O:20]1)=[O:17])[CH3:14].Cl>CC(C)=O.CCOC(C)=O.O>[CH2:13]([O:15][C:16]([CH2:18][C:19]1([CH3:36])[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([CH3:35])[C:23]([CH3:34])=[C:24]([S:30]([NH:9][C:2](=[NH:10])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)(=[O:31])=[O:32])[C:25]=2[CH3:29])[O:20]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)CC1(C)CCc2c(C)c(S(=O)(=O)Cl)c(C)c(C)c2O1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C)CCc2c(C)c(S(=O)(=O)NC(=N)c3ccccc3)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.2 %

Procedure:
To a suspension of benzamidine hydrochloride (2.72 g) in acetone (70 ml) was added 1N aqueous sodium hydroxide (1N NaOH) (17.3 ml) under ice-cooling. To the mixture of a solution of 2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman-6-sulfonyl chloride (3.25 g) in acetone (15 ml) was added dropwise over 15 minutes under ice-cooling, and stirred at room temperature for 20 hours. Acetone was removed under reduced pressure to give a residue. To the residue was added a mixture of water and AcOEt and the mixture was acidified with 1N HCl. The separated organic phase was washed with water and brine, and dried over MgSO4. After filtration, the filtrate was evaporated and purified by chromatography over silica gel (AcOEt-hexane 50:50 as eluent) to give N-(2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman-6-sulfonyl)benzamidine as a glass (1.60 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:13]3[C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=3[CH2:11][CH2:10][C@H:9]([NH:24][C:25](=[O:27])[CH3:26])[C:8]=2[CH:28]=1)([OH:3])=O.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:25]([NH:24][C@@H:9]1[C:8]2[CH:28]=[C:4]([C:1]([NH:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:3])[CH:5]=[CH:6][C:7]=2[C:13]2[C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10]1)(=[O:27])[CH3:26]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(C(=O)O)cc1[C@@H](NC(C)=O)CC2
Reactant: NCCN1CCCCC1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(C(=O)NCCN3CCCCC3)cc1[C@@H](NC(C)=O)CC2
Yield: 43 %

Procedure:
Using an analogous procedure to that described for Example 10, N-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide was reacted with 1-(2-aminoethyl)piperidine to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-N-(2-piperidinoethyl)-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carboxamide.
Reaction SMILES: NC1C=C(C=CC=1O)C[N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:7]1.C1CCNCC1.C(OC(=O)C)(=O)C>ClCCl>[C:30]([O:29][C:27]([NH:26][C:19]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=1[C:17]([NH:16][CH2:15][C:14]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1)=[O:35])=[O:34])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 143.6 %

Procedure:
To a mixture of 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (27 mg, 0.049 mmol), (piperidinomethyl)polystyrene (2.7 mmol/g, 60 mg, 0.15 mmol) and dichloromethane (2 mL) was added acetic anhydride (0.12 mmol) in dichloromethane (0.12 mL). The reaction mixture was stirred at room temperature for 3 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to give 1-(3-acetylamino)-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (30 mg, quant.): ESI/MS m/e 590.4 (M++H, C29H37F2N5O6).
Reaction SMILES: C(O)(=O)C1C(=CC=CC=1)O.C(OO)(C)(C)C.C1(C)C=CC=CC=1.[C:24]1([S:30]([CH:33]([CH2:44][CH:45]=[C:46]([CH3:54])[CH2:47][CH2:48][CH:49]=[C:50]([CH3:53])[CH:51]=[O:52])[CH:34]=[C:35]([CH3:43])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:42])[CH:40]=[O:41])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([S:30]([CH:33]([CH2:44][CH:45]=[C:46]([CH3:54])[CH2:47][CH2:48][CH:49]=[C:50]([CH3:53])[CH2:51][OH:52])[CH:34]=[C:35]([CH3:43])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:42])[CH2:40][OH:41])(=[O:32])=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C=O)=CCCC(C)=CCC(C=C(C)CCC=C(C)C=O)S(=O)(=O)c1ccccc1
Agent: CC(C)(C)OO
Agent: O=C(O)c1ccccc1O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=CCCC(C)=CCC(C=C(C)CCC=C(C)CO)S(=O)(=O)c1ccccc1)CO
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a stirred suspension of SeO2 (0.54 g, 4.82 mmol, 2 equiv) and salicylic acid (0.34 g, 2.41 mmol, 1 equiv) in CH2Cl2 (20 mL) at 0° C. was added a 3.0 M solution of t-butyl hydrogen peroxide (TBHP) in toluene (5.0 mL, 14.46 mmol, 6 equiv). The mixture was stirred at that temperature for 1.5 h, and a solution of the compound (J) (1.00 g, 2.41 mmol, 1 equiv) in CH.sub.2Cl.sub.2 (5 mL) was slowly added for 10 min. The reaction mixture was stirred at 0° C. for 3 h, diluted with CH2Cl2 (30 mL), washed with 10% NaOH solution (10 mL×3) and then saturated Na2S2O3 solution (10 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the diol compound (K) (0.47 g, 1.06 mmol) in 44% yield, together with the hydroxyl-aldehyde (0.13 g, 0.29 mmol, 12% yield), which was derived from further oxidation. Both of these two compounds can provide the dialdehyde of the Chemical Formula 3 after the Swern oxidation reaction.
Reaction SMILES: [CH2:1]([CH:9]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:10][O:11][C:12]1[C:13]2[C:21]([CH:22]=[C:23]3[CH:27]=[CH:26][S:25][C:24]=13)=[C:20]([O:28][CH2:29][CH:30]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16]1[S:17][CH:18]=[CH:19][C:15]=1[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[CH3:64][Sn:65](Cl)([CH3:67])[CH3:66].O>C1COCC1>[CH3:64][Sn:65]([CH3:67])([CH3:66])[C:26]1[S:25][C:24]2[C:12]([O:11][CH2:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[C:13]3[C:21](=[CH:22][C:23]=2[CH:27]=1)[C:20]([O:28][CH2:29][CH:30]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:16]1[S:17][C:18]([Sn:65]([CH3:67])([CH3:66])[CH3:64])=[CH:19][C:15]1=[CH:14]3
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCC(CCCCCCCC)COc1c2cc3ccsc3c(OCC(CCCCCCCC)CCCCCCCCCC)c2cc2ccsc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCC(CCCCCCCC)COc1c2cc3cc([Sn](C)(C)C)sc3c(OCC(CCCCCCCC)CCCCCCCCCC)c2cc2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Compound (4a) (0.350 g, 0.420 mmol) was solubilized in anhydrous THF (17 mL) and cooled at −78° C. under N2. n-Butyllithium (0.42 mL, 2.5M) was then added and the stirring was continued for 30 minutes at this temperature and then 30 minutes at room temperature. The reaction mixture was cooled to −78° C. again before adding trimethylstannyl chloride (1.1 mL, 1.0 M). The reaction was warmed up to room temperature and stirred overnight. The reaction was stopped by adding water, and the mixture was extracted with diethyl ether, dried over MgSO4, filtered, and concentrated in vacuo. The crude monomer was solubilized in 5 mL of THF and then dropped in methanol (200 mL). The product was allowed to precipitate in the freezer overnight before filtering and washing with cold methanol to afford a yellow fluffy powder as the title compound (0.420 g, 86%). 1H NMR (500 MHz, CDCl3, 298 K): 8.43 (s, 2H); 7.51 (s, 2H); 4.29 (d, J=5.4 Hz, 4H); 2.00 (quintet, J=6.0 Hz, 2H); 1.74 (m, 4H); 1.45 (m, 60H); 0.88 (m, 12H); 0.47 (s, 18H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): 149.22; 142.73; 141.25; 132.62; 130.19; 124.51; 109.71; 75.50; 39.37; 31.99; 31.97; 31.42; 30.23; 29.83; 29.82; 29.78; 29.75; 29.47; 29.42; 27.08; 22.74; 14.19; 14.18; 8.40 ppm. HRMS (ESI-TOF-MS): m/z calcd for C60H104O2S2Sn2 1158.5516. found 1158.5543.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][C:17]([O:19][C@@H:20]1[CH2:33][C:32]2[C@@:23]([CH3:39])([C@@H:24]3[C@@H:29]([CH2:30][CH:31]=2)[C@@H:28]2[CH2:34][CH2:35][C:36](=O)[C@@:27]2([CH3:38])[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)=[O:18].C([C:44]1[CH:49]=[C:48](C)[CH:47]=[C:46](C(C)(C)C)[N:45]=1)(C)(C)C.O1CCCC1>C(Cl)Cl>[CH3:16][C:17]([O:19][C@@H:20]1[CH2:21][C:22]2[C@@:23]([CH3:39])([C@@H:24]3[C@@H:29]([CH2:30][CH:31]=2)[C@@H:28]2[CH2:34][CH:35]=[C:36]([C:47]4[CH:48]=[CH:49][CH:44]=[N:45][CH:46]=4)[C@@:27]2([CH3:38])[CH2:26][CH2:25]3)[CH2:32][CH2:33]1)=[O:18]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
Trifluoromethanesulphonic anhydride (45.4 mL) is dropped into a solution of prasterone acetate (100 g) and 2,6-di-tert-butyl-4-methylpyridine (58 g) in methylene chloride (1 L) at −5° C., maintaining the temperature between −5° C. and 0° C. and stirring at said temperature for about 5 h. The mixture is then concentrated under vacuum, and the concentrate is taken up in n-hexane (about 1500 mL) to obtain a precipitate which is isolated by filtration. The filtered solution is washed with a 1N hydrochloric acid solution (about 1.5 L) and then with a sodium chloride saturated aqueous solution (500 mL). The organic phase is added with potassium carbonate (50 g), and the resulting suspension is stirred for about 15 h at room temperature, then filtered. After removal of the solvent under vacuum an oil (about 110 g) is obtained, which is taken up with tetrahydrofuran (1.5 L). The solution is degassed and diethyl(3-pyridyl)borane (54.5 g), bis(triphenylphosphine)palladium II chloride (1.8 g) and a 2M sodium carbonate aqueous solution (500 mL) are added in sequence in an inert gas environment. The resulting mixture is refluxed for about 1 h, then cooled to room temperature, and ethyl acetate (1 L) and water (1 L) are added. The aqueous phase is back-extracted with ethyl acetate (0.5 L), and the combined organic phases are concentrated under vacuum to obtain crude abiraterone acetate as oil (230 g; purity about 88%; assay 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[CH3:25].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:9](=[O:11])[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[S:32][CH:33]=1)[CH3:25]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
A solution of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (252 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with a 2.0M solution oxalyl chloride in methylene chloride (0.6 mL, 1.2 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 2 h. The reaction mixture was then treated with (2-amino-thiazol-4-yl)-acetic acid ethyl ester (409 mg, 2.2 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.4 mmol). This solution was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded {2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (254 mg, 60.3%) as a white solid: mp 121-125° C.; EI-HRMS m/e calcd for C21H25ClN2O3S (M+) 420.1274, found 420.1268.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[C:42]([Cl:45])(=[O:44])[CH3:43]>CN1C(=O)CCC1>[C:42]([N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)(=[O:44])[CH3:43].[ClH:45]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and acetyl chloride (0.022 mL, 0.3 mmol). The mixture was stirred at RT for 15 min and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C26H28FN5O2: 462.5. NMR (CD3OD): 8.12 (1H, s), 7.37 (1H, m), 7.34 (2H, d, J=8.4 Hz), 7.28 (1H, m), 7.18 (1H, m), 7.15-7.10 (3H, m), 5.88 (1H, s), 4.69 (1H, m), 4.51 (2H, s), 4.06 (1H, m), 3.24 (1H, m), 2.89 (1H, m), 2.73 (1H, m), 2.15 (3H, s), 1.92 (2H, m), 1.66 (2H, m) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=O)[CH2:9][O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[S:22])[CH2:9][O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(COc1c(Cl)cc(Cl)cc1Cl)Nc1cccnc1
Solvent: Cc1ccccc1
Product: S=C(COc1c(Cl)cc(Cl)cc1Cl)Nc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-3-pyridyl-2,4,6-trichlorophenoxyacetamide, 33.4 gm, is added to 200 ml of toluene. 22.2 gm of phosphorus pentasulfide (P2S5) is then added to the system. The system is exposed to microwave radiation throughout in order to aid in the dispersion of the phosphorus pentasulfide. The reaction is stirred for 16 hours at ambient temperature. The reaction is then stopped and the solution filtered. The toluene is removed by stripping to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.[CH2:22]=[C:23]([CH3:25])[CH3:24].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]2[C:5]=1[NH:11][CH:17]([C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=1)[CH2:22][C:23]2([CH3:25])[CH3:24])=[O:12]
Reactant: C=C(C)C
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: O=Cc1cccc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a stirred solution of 2-amino-5-fluoro-benzoic acid methyl ester (8.46 g, 50 mmol) and 3-bromobenzaldehyde (6.4 mL, 55 mmol) in acetonitrile (200 mL) were added isobutene (14 mL, 200 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.65 g, 7.5 mmol). The resulting mixture was stirred at 85° C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (10 g, 51%) as a light yellow solid: MS (ESI) M+1=392.0 & 394.0.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH2:20][CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])O.[Na+].[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:20]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]2[CH:3]1[CH2:2][N:33]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6]2=[O:8])[CH3:21]
Reactant: CCOC(=O)C1C(CCl)C1(CC)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCN1CC2C(C1=O)C2(CC)c1cccc([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 33.1 %

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-ethyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 16, 4.0 g, 12.8 mmol), was added sodium hydrogen carbonate (1.3 g, 15.4 mmol) and hexylamine (15.3 g, 20 ml, 151 mmol). The mixture was heated to 150° C. for 12 h, then cooled to room temperature and partitioned between hydrochloric acid (2N, 500 ml) and ethyl acetate (2×500 ml). The combined organic layers were washed with water (500 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with a gradient of dichloromethane/ethyl acetate 100:0 to 90:10. Product-containing fractions were combined and concentrated in vacuo to give the title compound as an orange oil (1.4 g, 32%).
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:25][C:26]([O:28]CC)=[O:27])[C:5]([CH3:24])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:7]=1[CH3:8])#[N:2].O.[OH-].[Li+].Cl>C1COCC1.CO>[C:1]([C:3]1[N:4]([CH2:25][C:26]([OH:28])=[O:27])[C:5]([CH3:24])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:17])=[O:18])[C:7]=1[CH3:8])#[N:2]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C)c1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C)n(CC(=O)O)c1C#N
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(2-cyano-3,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (40.0 mg, 0.093 mmol) in THF (1.1 ml), MeOH (372 μl), and Water (372 μl) at 0° C., was added lithium hydroxide (5.2 mg, 0.217 mmol). The mixture was stirred for 1 hour. This mixture was left standing over the course of 2 days at room temperature. To this mixture, was added HCl (214 μl, 0.214 mmol), then, the mixture was concentrated under vacuum, diluted in dichloromethane (50 ml) and washed with water (20 ml×3). The organic layer was dried, filtered, and evaporated to give 2-(2-cyano-3,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid as a solid. 1H NMR (CDCl3/400 MHz) δ (ppm) 7.95-7.90 (m, 1H), 7.43-7.37 (m, 1H), 7.34-7.28 (m, 1H), 6.92-6.86 (m, 1H), 4.77 (s, 2H), 4.19 (s, 2H), 3.44-3.33 (m, 4H), 2.07 (s, 3H), 2.02 (s, 3H), 1.98-1.93 (m, 4H). MS m/z: 402.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]([N+:16]([O-])=O)=[C:8]2[C:3]=1[NH:4][C:5](=[O:20])[C:6](=[O:19])[NH:7]2.Cl[Sn]Cl>CCO>[NH2:16][C:9]1[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[NH:7][C:6](=[O:19])[C:5](=[O:20])[NH:4]2
Reactant: O=c1[nH]c2c(Cl)cc(C(F)(F)F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c(C(F)(F)F)cc(Cl)c2[nH]c(=O)c(=O)[nH]c12
Temperature: 75 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
A mixture of 5-chloro-8-nitro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione (25 mg, 0.08 mmol), SnCl2 ·2H2O (97 mg, 0.34 mmol) and EtOH (3 mL) was heated at 75° C. with stirring for 12 h. Work-up as above gave 21 mg (93%) of the title compound as a yellow powder. Mp>360° C. 1H NMR (DMSO-d6) 11.441 (s, 1H), 11.324 (s, 1H), 7.241 (s, 1H), 5.916 (s, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][C@H:8]2[NH2:13].CCN(C(C)C)C(C)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1>C(Cl)Cl>[Cl:23][C:24]1[N:29]=[C:28]([NH:13][C@H:8]2[C:7]3[C:12](=[C:3]([F:2])[CH:4]=[CH:5][CH:6]=3)[O:11][CH2:10][CH2:9]2)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1
Reactant: N[C@@H]1CCOc2c(F)cccc21
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H]1CCOc2c(F)cccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution of (R)-8-fluorochroman-4-amine hydrochloride (1.02 g) and DIEA (2.6 mL) in DCM (10 mL) was slowly added to a solution of 2,4-dichloro-5-nitropyrimidine (0.97 g) THF (25 mL) at −78° C. The reaction mixture was stirred for 30 min at −78° C. then allowed to warm to RT overnight. The reaction was quenched with the addition of sat. NH4Cl (1 mL), the solvent volume was reduced in vacuo, and the resulting mixture partition between EtOAc and water then separated. The crude material was purified via column chromatography, elution with 30% EtOAc/Hex gave the titled product (1.43 g). 1H-NMR (300 MHz, CDCl3) δ 9.1 (s, 1H), 8.6 (br d, 1H), 7.1-6.8 (m, 3H), 5.6 (dd, 1H), 4.4 (m 1H), 4.3 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][C@@:7]1([CH2:46][OH:47])[O:11][C@@:10]([SiH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[C@H:9]([OH:33])[C@@H:8]1[O:34][CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)([CH3:4])([CH3:3])[CH3:2].[C:48]1([CH3:58])[C:49]([S:54](Cl)(=[O:56])=[O:55])=[CH:50][CH:51]=[CH:52][CH:53]=1.CCO[C:62]([CH3:64])=O>N1C=CC=CC=1.C(Cl)Cl>[C:1]([O:5][CH2:6][C@@:7]1([CH2:46][O:47][S:54]([C:49]2[C:62]([CH3:64])=[CH:51][CH:52]=[CH:53][CH:48]=2)(=[O:56])=[O:55])[O:11][C@@:10]([SiH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[C@H:9]([O:33][S:54]([C:49]2[C:48]([CH3:58])=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:56])=[O:55])[C@@H:8]1[O:34][CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC[C@@]1(CO)O[C@](n2ccc(=O)[nH]c2=O)([SiH](c2ccccc2)c2ccccc2)[C@H](O)[C@@H]1OCc1cccc2ccccc12
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)OC[C@]1(COC(C)(C)C)O[C@](n2ccc(=O)[nH]c2=O)([SiH](c2ccccc2)c2ccccc2)[C@H](OS(=O)(=O)c2ccccc2C)[C@@H]1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
Dried Compound 46 (29.24 g, 44.79 mmol) was dissolved in a mixture of anhydrous pyridine (82 mL) and anhydrous CH2Cl2 (82 mL). To this solution was added toluenesulfonyl chloride (21.3 g, 112 mmol). After stirring at room temperature for 10 hours, the mixture was poured into EtOAc (1 L), washed with saturated aqueous NaHCO3 (2×0.8 L), then with 1% (v/v) aqueous AcOH (2×0.8 L). Dried over anhydrous Na2SO4, filtered, and evaporated to a brown oil. Purification by silica gel chromatography (2:1 hexanes:EtOAc) yielded Compound 47 (32.36 g, 75%) as a pale yellow foam.