Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:42][C@@H:43]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C@@H:44]([OH:62])[CH2:45][C@@H:46]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH2:63]([C@H:43]([NH:42][C:7]([C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[C@@H:44]([OH:62])[CH2:45][C@@H:46]([NH:54][C:55]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:61])[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A solution of the product from Example 1F (7.0 g, 37.0 mmol), EDAC (8.5 g, 44.3 mmol), HOBT (6.0 g, 44.4 mmol), and NMM (8.0 mL, 72.8 mmol) in DMF (30 mL) was stirred at 25° C. for 1 hour, treated with a solution of the product from Example 6A (14.15 g, 36.8 mmol) in DMF (30 mL), stirred at 25° C. for 16 hours, concentrated, and partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaHCO3 and brine, and concentrated. The solution of the residue in hot methanol (20 mL) and water (10 mL) was allowed to cool and stand for 16 hours. The solids were collected by filtration and rinsed several times with hexanes, followed by drying under vacuum to give the title compound (16.97 g, 77% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)O[C:9]1[CH:14]=[CH:13][CH:12]=CC=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:26]=[O:27]>C(Cl)(Cl)Cl>[CH2:6]([N:1]([CH2:12][CH2:13][CH2:14][CH3:9])[CH2:2][CH2:19][CH2:20][NH:25][C:26]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:26]=[O:27])=[O:27])[CH2:5][CH2:4][CH3:3]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1CO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCCN(CCCC)CCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine (0.67 ml) and phenyl chlorocarbonate (0.76 ml) were added to a suspension of [2-(hydroxymethyl)phenyl]-N-octadecylformamide (2.20 g), which was synthesized in Example 1-1, in chloroform (22 ml) while being cooled with ice. After being stirred for 2 hours at room temperature, the reaction mixture, with chloroform added thereto, was washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated. 3-(Dibutylamino)propylamine (1.36 ml) was added to the residue. After being stirred for 3 hours at 70° C., the reaction mixture was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=60:1-30:1), thereby yielding 3.11 g of the aimed compound as white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:17]1[N:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(N2CCNCC2)nn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
To an ice cold solution of 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (2.00 g, 6.69 mmol) in dichloromethane (10 mL) was carefully added trifluoroacetic acid (2 mL). The mixture was stirred for 45 minutes at room temperature and then concentrated in vacuo to afford the crude 3-chloro-6-piperazin-1-ylpyridazine (˜1.0 g) which was used in the next reaction without further purification. MS (ES+) m/z 199.1 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:15](=[O:24])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[N:25]1[C:34]2[C:33](=O)[CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.[BH4-].[Na+]>C(O)C.C([O-])(O)=O.[Na+]>[O:24]=[C:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C@@H:2]([NH:1][CH:33]1[C:34]2[N:25]=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:30][CH2:31][CH2:32]1)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)NCc1ccccn1
Reactant: O=C1CCCc2cccnc21
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC1CCCc2cccnc21)C(=O)NCc1ccccn1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 5-amino-6-oxo-6-(pyridin-2-ylmethyl-amino)hexylcarbamate, 28, (2.16 g, 6.43 mmol) in ethanol (14 mL) was added 6,7-dihydroquinolin-8(5H)-one (0.90 g, 6.12 mmol). The mixture was heated in microwave reactor at 150° C. for 13 min. After cooling the reaction to room temp., NaBH4 (0.46 g, 12.24 mmol) was added to the mixture. The reaction mixture was stirred at room temp for 1 h. The mixture was diluted with aqueous saturated NaHCO3, extracted twice with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5% to 25% methanol/CH2Cl2) to afford the desired product 29: 1H NMR (d6-DMSO) δ 8.44 (d, J=4.4 Hz, 1H), 8.40 (m, 1H), 8.32-8.31 (m, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.20 (t, J=4.8 Hz, 1H), 7.13 (dd, J=8.0, 4.2 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 4.32 (d, J=5.6 Hz, 2H), 3.95-3.89 (m, 1H), 3.62-3.57 (m, 1H), 2.69 (d, J=4.8 Hz, 2H), 2.61-2.56 (m, 2H), 1.99-1.95 (m, 1H), 1.89-1.83 (m, 1H), 1.63-1.28 (m, 8H), 1.35 (s, 9H); ESI+ MS: m/z (rel intensity) 468.3 (100, [M+H]+).
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:26](O)=[O:27])=[C:23]([CH3:25])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C>CN(C=O)C>[CH:32]1([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:26]([N:36]([CH3:37])[CH3:35])=[O:27])=[C:23]([CH3:25])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:33][CH2:34]1
Reactant: CNC
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)c(C(=O)O)s3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)c(C(=O)N(C)C)s3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
A mixture of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-methylthiazole-5-carboxylic acid (example 50B, 51 mg, 0.106 mmol), dimethylamine (40% in water, 0.027 mL, 0.213 mmol), HATU (52.6 mg, 0.138 mmol) and 2,6-lutidine (0.025 mL, 0.213 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 2-8% methanol/dichloromethane). The product was further purified by preparative HPLC. 2-(7-(Dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N,N,4-trimethylthiazole-5-carboxamide (17 mg, 0.032 mmol, 30.0% yield) was obtained as a off-white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11](#[N:15])[CH:12]([CH3:14])[CH3:13].[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:18]=1[CH2:19]Br.O>C1COCC1>[CH3:13][C:12]([CH3:14])([CH2:19][C:18]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([F:25])[C:17]=1[F:16])[C:11]#[N:15]
Reactant: Fc1ccc(F)c(CBr)c1F
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)Cc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1M in THF, 26.6 mL, 26.6 mmol) was added to a solution of isobutyronitrile (2.4 mL, 26.6 mmol) in THF at −78° C. and stirred for 25 minutes. 2,3,6-trifluorobenzyl bromide (2.3 mL, 17.8 mmol) was added and the reaction was warmed to room temperature and stirred for 1.5 h. Water was added to quench the reaction and it was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield 2,2-dimethyl-3-(2,3,6-trifluorophenyl)propanenitrile (34) as a white solid.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[N:47]1[N:48]([C:52]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][C:53]=2[C:54](O)=[O:55])[N:49]=[CH:50][CH:51]=1>>[N:47]1[N:48]([C:52]2[CH:60]=[CH:59][C:58]([C:61]([F:62])([F:63])[F:64])=[CH:57][C:53]=2[C:54]([NH:44][C@H:40]2[CH2:41][CH2:42][CH2:43][C@@H:39]2[NH:38][C:35]2[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=2)=[O:55])[N:49]=[CH:50][CH:51]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1-n1nccn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(C(F)(F)F)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a; CAS number 1384066-81-2; 94 mg, 0.37 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1[CH2:50][CH2:49][CH2:48][C@H]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][C@@H:36]([CH3:37])[C:49]([CH3:48])([CH3:50])[CH3:2])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN[C@@H](C)C(C)(C)C)c4)cc23)CC1
Yield: 34.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2S)-3,3-dimethyl-2-butanamine (52 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 19.8 mg of the title compound (34.7%).
Reaction SMILES: CC1[C@@H]2[CH2:8][C@H:9]([O:34]C(/C=C/C3N=CN(C)C=3)=O)[C@@:10]3(C)[O:14][C@@:13]([O:31]C)(C(CO[C@@H]4OC[C@@H](O)[C@@H](O)[C@@H]4OC(C)=O)=C[C@@H]2[C@@H](C(C)C)CC=1)[CH:12]=[CH:11]3.CCN(CC)CC.CC(OC(C)=O)=[O:57]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:9]([CH2:10][C:11]([CH2:12][C:13]([OH:31])=[O:14])=[O:57])=[O:34]
Reactant: CO[C@]12C=C[C@](C)(O1)[C@@H](OC(=O)/C=C/c1cn(C)cn1)C[C@H]1C(C)=CC[C@H](C(C)C)[C@H]1C=C2CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: CO[C@]12C=C[C@](C)(O1)[C@@H](OC(=O)/C=C/c1cn(C)cn1)C[C@H]1C(C)=CC[C@H](C(C)C)[C@H]1/C=C\2CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Bis-Acetoxy Eleutherobin (2800) and Methyl-Ketal Precursors of Eleuthosides A and B (2900+3000) as illustrated in FIG. 27. To a solution of natural eleutherobin (4) (10.0 mg, 0.015 mmol, 1.0 equivalent), Et3N (6.0 mL, 0.043 mmol, 3.0 equivalents), and 4-DMAP (0.40 mg, 0.0033 mmol, 0.2 equivalents) in CH2Cl2 (0.60 mL) at 0° C. was added Ac2O (1.0 M in CH2Cl2, 0.017 mL, 0.017 mmol, 1.1 equivalents) and the reaction was stirred at the same temperature for 1 hour. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (0.50 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide a crude residue which was was purified by flash chromatography (silica gel, 2% MeOH in CH2Cl2) to afford triacetate 2800 (1.8 mg, 16%) along with an inseperable mixture of eleuthosides 2900 and 3000 (7.8 mg, 73%) as well as recovered 1 (0.5 mg, 5%). 2800. Rf=0.44 (silica gel, MeOH-- CH'2Cl2,1:20); [α]D -67.3 (c 1.2, CHCl3); FT-IR (neat) nmax 2962, 1746, 1740, 1644, 1634, 1372, 1226, 1156, 1068, 759, 668, 617 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.O.[C:24](=O)(O)[O-:25].[Na+].C=O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:22])[CH:9]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]#[N:21])[CH2:17][CH2:18]2)=[O:12])[CH2:24][OH:25])=[CH:6][CH:7]=1
Reactant: N#CCN1CCC(C(=O)NCC(=O)c2ccc(F)cc2)CC1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCN1CCC(C(=O)NC(CO)C(=O)c2ccc(F)cc2)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 380.7 %

Procedure:
In a 22-l round bottomed flask, suspend 1-cyanomethyl-piperidine-4-carboxylic acid-[2-(4-fluorophenyl)-2-oxoethyl] amide (1.004 kg, 3.31 moles) in absolute ethanol (5.0 l) and process water (2.5 l). To the suspension is added sodium bicarbonate (55.62 g, 0.662 moles) and 37% formaldehyde (400 ml, 4.93 moles), then the suspension is warmed to 40° C. and the reaction followed by HPLC. Upon completion, the reaction is quenched by added ice water (5.0 l) and brine (5.0 l). The reaction is stirred for three hours, then the crystals are collected by vacuum filtration, washed with process water (1.0 l) and dried at ambient temperature and 25 in Hg to give 1-cyanomethyl-piperidine-4-carboxylic acid-[2-(4-fluorophenyl)-1-hydroxymethyl-2-oxoethyl] amide (839 g, 2.52 moles). 1H NMR (400 MHz, d6 DMSO) d 1.52 (m, 2H), 1.67 (t, 2H), 2.12 (t, 2H), 2.23 (m, 1H), 2.77 (m, 2H), 3.38 (s, 1H), 3.65 (m, 1H), 3.68 (s, 2H), 3.75 (m, 1H), 5.15 (m, 1H), 5.25 (m, 1H), 7.16 (t, 2H), 8.06 (q, 2H), 8.40 (d, 1H).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:12][C:13]1[C:14]([Cl:23])=[N:15][CH:16]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1.I[CH2:25][CH3:26]>O.CN(C)C=O>[Br:12][C:13]1[C:14]([Cl:23])=[N:15][CH:16]=[C:17]([S:19]([CH2:25][CH3:26])(=[O:21])=[O:20])[CH:18]=1
Reactant: CCI
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
Sodium sulfite (4.94 g, 39.2 mmol) and sodium bicarbonate (3.46 g, 41.2 mmol) in water (100 mL) were heated to 75° C. 3-bromo-2-chloropyridine-5-sulfonyl chloride (6.00 g, 20.6 mmol) was added portionwise over 1 hour. The reaction mixture was stirred at 75° C. for 1 hour after complete addition. The mixture was concentrated under vacuum. N,N-Dimethylformamide (37.5 mL), sodium bicarbonate (3.46 g, 41.2 mmol) and iodoethane (1.658 mL, 20.62 mmol) were added. The resulting mixture was heated to 75° C. for 2 hours then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The reaction mixture was purified by flash chromatography (silica gel, 100% heptane to 100% ethyl acetate) to provide the title compound (3.15 g, 53% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br>CC(O)=O.CCOC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Br:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2,4-dinitroaniline (2,2 g, 12 mmol) in 40 ml of AcOH was added 1.0 ml of Br2 dropwise and reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to provide 2.9 g (11 mmol, 92%) of 2,4-dinitro-6-bromo-aniline which was characterized by NMR and used in a following reaction without further purification.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[C@@H:10]([CH3:14])[CH2:9]2)=[CH:3][CH:2]=1.C(OC(=O)[C@H](C)C[C@H:27]([N:41]1[C:45](=O)[CH2:44][CH2:43][C:42]1=O)CC1C=CC(C2C=CC=CC=2)=CC=1)C.C([Li])CCC.[C:55](Cl)(=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57]>C1COCC1>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C:11](=[O:13])[C@@H:10]([CH3:14])[CH2:9]2)=[CH:5][CH:6]=1.[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([CH2:27][N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N1C(=O)CCC1=O
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(CN2CCCC2)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
146 mg (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b, R1=H) [9:1 diastereoisomer mixture [(2S,4S): (2R,4S)]] is added to 10 ml THF. The mixture is cooled to −78° C. and 381 μl butyllithium (1.59 M in hexane) are added. 81 μl Pivaloyl chloride is then added. After 4 h, the mixture is warmed to room temperature. The mixture is then quenched by the addition of saturated ammonium chloride solution and isopropyl acetate. The phases are separated and the organic phase dried (MgSO4) and then concentrated in vacuo. The residue is purified by column chromatography, by eluting with isopropyl acetate/hexane 3:1 to 1:0 to afford (3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (2-b, R1=pivaloyl) and (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (2-a, R1=pivaloyl). Ratio of diastereoisomers determined by 1H NMR to be 4:1 [(3S,5S):(3R,5S)]. 1H NMR (CDCl3) for (2-b, R1=Piv): 1.09, 1.14 (3H), 1.30 (9H), 1.34 (1H), 2.01-2.66 (3H), 3.03, 3.27 (1H), 4.31, 4.50 (1H), 7.21-7.53 (9H). Diastereomeric ratio is determined by integration of the pairs of signals at [3.03 ppm (2-a, R1=Piv) and 3.27 ppm (2-b, R1=Piv)] or those at [4.31 ppm (2-b, R1=Piv) and 4.50 ppm (2-a, R1=Piv)] from the 1H NMR spectrum. Spectroscopic data for (2-a, R1=Piv) as in Example 5.
Reaction SMILES: O[C:2]1[S:3][C:4]([CH2:8][CH2:9][Cl:10])=[C:5]([CH3:7])[N:6]=1.P(Cl)(Cl)([Cl:13])=O.Cl>ClC1C=CC=CC=1>[Cl:13][C:2]1[S:3][C:4]([CH2:8][CH2:9][Cl:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(O)sc1CCCl
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1nc(Cl)sc1CCCl
Temperature: 100 °C
Yield: 73.9 %

Procedure:
A suspension of 177.6 g (1 mole) of 2-hydroxy-4-methyl-5-(2-chloroethyl)-thiazole in 530 cm3 of anhydrous chlorobezene is heated to 100° C. under stirring. 306.6 g (2 moles) of phosphoryl chloride are flown into the solution in 30 minutes, then it is stirred at a temperature of 125°-130° C. until the formation of hydrogen chloride ceases (about 2 hours). The reaction mixture is cooled to 20° C., then it is poured onto 1.5 kg of ice. The phases are separated, the aqueous phase is extracted twice with 200 cm3 of chlorobenzene each. The combined phases containing the chlorobenzene are washed acid-free with water and then with a 5% sodium hydrogen carbonate solution and then evaporated under reduced pressure. The brown residue is fractionated in vacuo. 145 g (74%) of 2-chloro-4-methyl-5-(2-chloroethyl)thiazole are obtained. The boiling point is 102° C. at a pressure of 53.2 Pa, n20D =5512, n30D =1,5468.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)S(=O)(=O)c1cc(C(F)(F)F)ccc1Cl
Reactant: NCc1ccccc1
Product: CN(C)S(=O)(=O)c1cc(C(F)(F)F)ccc1NCc1ccccc1

Procedure:
A solution of 2-Chloro-N,N-dimethyl-5-trifluoromethyl-benzenesulfonamide (2.10 g, 0.00730 mol) in Benzylamine (5 mL, 0.04 mol) was heated at 100° C. for 5 hours. The benzylamine was evaporated under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with water (3×50 mL), dried over magnesium sulfate, filtered and evaporated. The material was purified via silica gel chromatography using 0% 25% Ethyl Acetate:Hexane solvent gradient. 2-Benzylamino-N,N-dimethyl-5-trifluoromethyl-benzenesulfonamide isolated as a pale yellow solid (1.84 g, 70%).
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:15]([OH:17])=O.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22]>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:17]
Reactant: O=C(O)c1cc2c(s1)-c1ccccc1OCC2
Reactant: CNc1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl

Procedure:
Following General Procedure C, 157 is prepared from 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid and 2-chloro-N-methylaniline. MS: (ESI+) 70.1