Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([C:16]#[N:17])[CH2:13][C@H:12]1[C:18]1[NH:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[CH:65]=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[C:63](Br)=[CH:62][C:61]=3[Cl:72])=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[C:61]([Cl:72])=[CH:62][C:63]([C:26]4[CH:27]=[CH:28][C:23]([C:21]5[N:22]=[C:18]([C@@H:12]6[CH2:13][C@H:14]([C:16]#[N:17])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[NH:19][CH:20]=5)=[CH:24][CH:25]=4)=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[CH:65]=3)=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C#N)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C#N)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C
Yield: 7.5 %

Procedure:
A solution of [(S)-1-((2S,4S)-4-cyano-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.10 g, 0.19 mmol), (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (113.9 mg, 0.19 mmol) and potassium carbonate (119.3 mg, 0.86 mmol) in toluene (0.46 mL) and water (0.24 mL, 13.56 mmol) was degassed with nitrogen for 20 min and then Pd(dppf)Cl2CH2Cl2 (6.27 mg, 0.0076 mmol) was added and the reaction was degassed with nitrogen for 15 min. The reaction mixture was heated at 100° C. for 12 h, concentrated under vacuum, and purified by reverse phase HPLC. The pure fractions were combined and concentrated under vacuum to afford the di-TFA salt of the title compound (13 mg, 6% yield). (m/z): [M+H]+ calcd for C44H49ClF3N9O7 908.34. found 908.7.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=C(OC)C=C(F)C=1C[N:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17](=[O:25])(=[O:24])[N:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:15]1=[O:36]>>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([N:16]2[C:15](=[O:36])[N:14]([CH2:8][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17]2(=[O:24])=[O:25])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3ccccc32)c(Cl)c1
Reactant: OCc1ncccc1F
Product: COc1ccc(N2C(=O)N(Cc3ncccc3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (152 mg, 0.34 mmol) was prepared from (IntA1) (167 mg, 0.50 mmol), and (3-fluoropyridin-2-yl)methanol (95 mg, 0.75 mmol) using the methods of (113).
Reaction SMILES: C(O)[CH:2]([OH:13])[CH:3]([OH:12])[CH:4]([OH:11])[CH:5]([OH:10])[CH:6]([OH:9])[CH:7]=[O:8].[H-].[Na+]>C(COC)OC>[CH2:2]([OH:13])[C@H:3]([C@H:4]([C@@H:5]([C@@H:6]([CH2:7][OH:8])[OH:9])[OH:10])[OH:11])[OH:12]
Reactant: O=CC(O)C(O)C(O)C(O)C(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
In Method B, 3,6-anhydro-2-deoxy-4,5,7-tris-O-(phenylmethyl)-D-gluco (and D-manno) heptose mixture 4 is reacted with a tetrasubstituted bisphosphonate, where and R' and R" may be any of the aliphatic substituents listed in Table II, and sodium hydride in dimethoxy ethane, giving the isomeric mixture 2,5-anhydro-1-deoxy-1-C-(disubstituted phosphinyl)-3,4,6-tris-O-(phenylmethyl)-D-glucitol and D-mannitol 12' which are then reacted as described in Method A giving 2,5-anhydro-1-deoxy 1-(disubstituted phosphinyl)-D-mannitol, 6-(disubstituted phosphate) 14' and the corresponding D-glucitol derivative 23'. ##STR16##
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[OH:8][N:9]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]1([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:18]([O:17][CH:12]1[CH2:13][C:14]([CH3:16])([CH3:15])[N:9]([O:8][C:6](=[O:7])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]([CH3:27])([CH3:26])[CH2:11]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Temperature: 50 °C
Yield: 29.2 %

Procedure:
A solution of 4.66 g (40 mmol) of n-butyl isocyanate in 10 ml of toluene is added over 10 minutes to a suspension of 10.6 g (38.2 mmol) of 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine in 40 ml of toluene. The reaction mixture is heated at 50° C. for 30 minutes. The reaction mixture is then filtered, and the residue from evaporation of the filtrate is crystallized from hexane to give 4.2 g (29% yield) of a white solid, m.p. 126-27° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:34]=1[C:35]#[N:36]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:34]=2[C:35]#[N:36])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: N#Cc1ccc([N+](=O)[O-])cc1OCCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc([N+](=O)[O-])cc1OCCCCNc1nc(Cl)nc2c1CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation of R, 1.1 g, 4.163 mmol) in acetonitrile (40 mL) was added diisopropylethylamine (0.807 g, 6.245 mmol) followed by 2-(4-aminobutoxy)-4-nitrobenzonitrile (Preparation O, 1.174 g, 4.99 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, with 50% ethyl acetate in pet-ether) to get 2-(4-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)butoxy)-4-nitrobenzonitrile (0.9 g, 47%) as a light yellow solid. LC-MS (M+H)+=464.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (1H, d, J=8.4 Hz), 7.98 (1H, s), 7.91 (1H, d, J=8.8 Hz), 7.57 (1H, m), 7.32-7.13 (5H, m), 4.39-4.35 (2H, t, J=6.4 Hz), 4.19-4.15 (1H, t, J=8.0 Hz), 3.46-3.33 (2H, m), 2.85-2.75 (1H, m), 2.60-2.50 (2H, m), 1.99-1.00 (1H, m), 1.88-1.75 (4H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[Cl:11][C:12]([Cl:19])([Cl:18])[CH2:13][O:14][C:15](Cl)=[O:16]>CC(C)=O.O>[Cl:11][C:12]([Cl:19])([Cl:18])[CH2:13][O:14][C:15]([NH:1][CH2:2][CH2:3][OH:4])=[O:16]
Reactant: NCCO
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCO)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Aminoethanol (20 g.) and sodium carbonate (27.8 g.) is dissolved in acetone-water (4:1) (500 ml.) and 2,2,2-trichloroethylchloroformate (104.2 g.) is added dropwise to the stirred solution at 0° C. over a period of 0.5 hours. The mixture is stirred at 0° C. for a further 3 hours. The solids are filtered off and washed with acetone and the filtrate is evaporated to dryness. The resulting gum is taken up in chloroform (500 ml.) and washed with water (3×100 ml.). The chloroform solution is evaporated to dryness to give 2-(2,2,2-trichloroethoxycarbonylamino)ethanol; ν max (film), 3300, 2910, 1700, 1520, 1240, 1140, 1055, cm-1 ; δ (CDCl3) 3.43 (2H, t, J 7.5 Hz, HOCH2CH2NH--), 3.77 (2H, t, J 7.5 Hz, HOCH2CH2NH--) and 4.77 ppm (2H, s, --COOCH2CCl3).
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:28][CH2:27][CH2:26][C@H:14]1[C:15]([O:17]C(C1C=CC=CC=1)=O)=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4].[OH-].[K+]>O.C1COCC1>[NH:1]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:28][CH2:27][CH2:26][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Boc-Gly-Nleu-Pro-OBz (7.9 g, 0.0166 mol.) was dissolved in a mixture of 50 ml H2O and 80 ml THF. The solution was chilled to 0° C. KOH (1.9 g, 0.033 mol.) dissolved in 30 ml H2O was added while stirring the solution. The stirring was continued at room temperature for one hour. The THF was removed under reduced pressure. The aqueous solution was chilled to 0° C. and acidified to about pH=3 by addition of concentrated HCl (swirling the solution vigorously at the same time). The product was extracted from the aqueous solution by ethyl acetate. The combined organic layer was dried using Na2SO4 and the ethyl acetate was removed under reduced pressure to obtain the product (5.7 g, 89%). TLC Rf=0.38 (developing solvents: CMA, 85:15:3). FAB-MS, observed (M+H)+=386. 1H-NMR (500 MHz, DMSO-d6, 27° C., assignment by TOCSY) δ6.69 (m, Gly-NH), 6.57 (m, Gly-NH), 4.56 (m, Pro-α), 4.28-4.14 (m, Pro-α), 4.14-3.97 (m, Nleu-α), 3.83-3.62 (m, Gly-α), 3.62-3.44 (m, Gly-α, Pro-δ), 3.44-3.28 (m, Pro-δ), 3.12-2.92 (m, Nleu-β), 2.23-1.58 (m, Pro-β, Pro-γ, Nleu-γ), 1.34 (m, Boc-CH3), 0.85 (m, Nleu-δ), 0.78 (m, Nleu-δ).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Al+3].[O-]CC.[O-]CC>C(O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: CC[O-]
Agent: [Al+3]
Solvent: CCO
Product: OCc1cccc(Oc2ccccc2)c1
Yield: 98.9 %

Procedure:
To a solution of 198 g. of m-phenoxy-benzaldehyde in 1 liter of absolute ethanol 60 g. of aluminum ethoxide are added. The reaction mixture is allowed to stand at room temperature. The reaction mixture is then evaporated under atmospheric pressure. From the residue following the procedure of Example 1 198 g. (98.9%) of m-phenoxybenzyl alcohol are prepared in a purity over 95% (according to gas chromatography).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[CH2:9]([O:11][C:12]([C:14]1[C:15](Cl)=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][C:20]([Cl:30])=[CH:19][CH:18]=2)=[O:13])[CH3:10]>CN(C=O)C>[CH2:9]([O:11][C:12]([C:14]1[C:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][C:20]([Cl:30])=[CH:19][CH:18]=2)=[O:13])[CH3:10]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To the stirred solution of 2,2,2-trifluoro-ethanol (0.051 ml, 0.69 mmol) in 4 ml of DMF, was added NaH (28 mg, 0.69 mmol) portion wise at 0° C. The mixture was stirred for 30 min at room temperature and then a solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (200 mg, 0.58 mmol) in 2 ml dry DMF was added. The resulting reaction mixture was stirred for 5 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl solution and then diluted with further water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5% ethyl acetate in hexane) to obtain 6-chloro-4-phenyl-2-(2,2,2-trifluoro-ethoxy)-quinoline-3-carboxylic acid ethyl ester (140 mg, 59%) as off white solid. LC-MS: 410 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:44](C)=O.[Na+]>C(Cl)Cl>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH3:44])[C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1N=C(N2CCN[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 4 mL of CH2Cl2 was added 5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)-piperazin-1-yl]-1,3-thiazol-4(5H)-one (Example 139, 50 mg), followed by 50 mg of 37% HCHO. The mixture was stirred at room temperature for 20 min, then 50 mg of NaBH(OAc)3 was added. The reaction mixture was kept stirring for 1 h and partitioned between CH2Cl2 and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc to MeOH/EtOAc (10/90) to afford the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].S(=O)(=O)(O)O.[O-:16][C:17]#[N:18].[Na+]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:17]([NH2:18])=[O:16]
Reactant: COc1ccccc1CN
Reactant: N#C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccccc1CNC(N)=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To an aqueous solution (13 ml) containing 2-methoxybenzylamine (13.7 g, 0.1 mol.) was added dropwise dilute sulfuric acid (prepared from 2.8 ml of conc. sulfuric acid and 6.7 ml of refined water) at room temperature. After completion of the dropwise addition, an aqueous solution (70 ml) containing sodium cyanate (7.65 g, 0.12 mol.) was added to the reaction mixture at room temperature taking 15 minutes. The suspension obtained as reaction mixture was heated at 80° C. for one hour. The reaction mixture was cooled, then resulting crystalline precipitates were collected by filtration, followed by recrystallization from ethanol to give 17 g (yield 94%) of colorless prisms.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([OH:40])=O)[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:75][CH2:76][CH2:77][NH:78][CH3:79]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:27])([CH3:28])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([N:78]([CH2:77][CH2:76][OH:75])[CH3:79])=[O:40])[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCC(CC(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CNCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCO)C(=O)CC1CCN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac {1-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (77 mg, 0.28 mmol) and DIPEA (94 uL, 0.54 mmol) were added followed by 2-hydroxy-ethyl-methyl amine (Oakwood, 20 mg, 0.27 mmol) and the mixture was stirred at rt overnight. The reaction was quenched with water and the mixture was extracted with methylene chloride (3×10 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 46 mg.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:3][C:4]2[C:10]([N+:12]([O-:14])=[O:13])=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)ccc2nc(Cl)sc12
Temperature: 17 °C

Procedure:
4.76 g (23 mmol) of 2,6-dichlorobenzothiazole, in solution in 10 ml of concentrated sulphuric acid, are introduced into a 100 ml round-bottomed flask. The mixture is cooled to 17° C. in order to add a solution of 1.62 g (26 mmol) of nitric acid in 10 ml of sulphuric acid and then the temperature is allowed to rise to ambient temperature.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][C:10]([C:13]1[CH:14]=[C:15]([SH:23])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[CH3:12][C:10]([C:13]1[CH:14]=[C:15]([S:23][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:8])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:9])[CH3:11]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1
Reactant: O=C1CCCCC1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(SC2CCCCC2=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Chlorocyclohexanone (0.6 g, 0.0045 moles) was added to a cold (+5° C.) solution of 3,5-bis (1,1-dimethylethyl)benzenethiol (Example 2)(1.0 g, 0.0045 moles) in tetrahydrofuran (50 ml). The solution was stirred for 15 minutes. Triethylamine (1.25 ml) was added, the cold bath was removed and the mixture was stirred at room temperature for 20 hours and then at 50° C. for 2 hours. The mixture was cooled to room temperature and filtered to remove a white solid. The filtrate was concentrated to an oil. The product was purified by silica gel chromatography to give a white solid which was recrystallized from hexane (DSC 81.49° C.). The structure was supported by NMR and Ir.
Reaction SMILES: [CH2:1]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C[Mg]Br.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26].[Cl-].[NH4+]>CCOCC>[CH2:1]([C:15]1[NH:16][C:17]([C:23]([O:24][CH2:25][CH3:26])=[O:27])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccc[nH]1
Reactant: CCOC(=O)Cl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccc(C(=O)OCC)[nH]1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
Into 20 ml of anhydrous ether was dissolved 4.00 g (15 mmol) of 2-tetradecylpyrrole obtained in Synthetic Example 2, and then 7 ml (21 mmol) of ca. 3M ethereal solution, of methylmagnesium bromide was added thereto at room temerature. The resulting mixture was heated under reflux for 30 minutes. Under cooling with ice water, 2 ml (21 mmol) of ethyl chlorocarbonate was added to the mixture. After heating under reflux for 10 hours, the resulting mixture was cooled to room temperature, poured into ice water containing ammonium chloride, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous megnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain 1.89 g (37% yield) of ethyl 5-tetradecylpyrrole-2-carboxylate, m.p. 60°-63° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([CH3:16])([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:6].[OH:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:10]1([S:7]([C:5]([CH3:16])([CH3:6])[CH2:4][CH2:3][CH2:2][N:20]2[CH2:21][CH2:22][CH2:23][CH:18]([OH:17])[CH2:19]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC1CCCNC1
Reactant: CC(C)(CCCBr)S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Yield: 97.4 %

Procedure:
(5-Bromo-2-methylpentane-2-sulfonyl)benzene (5 g, 16.4 mmol), 3-hydroxypiperidine (2 g, 20 mmol) and potassium carbonate (4.5 g, 33 mmol) in acetonitrile (50 ml) were stirred at 50° C. for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 120:8:1 dichloromethane/methanol/ammonia, to give the title compound (5.2 g, 98%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([N:43]2[CH2:46][CH:45]([F:47])[CH2:44]2)=[N:41][CH:42]=1>>[F:47][CH:45]1[CH2:46][N:43]([C:40]2[N:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)[CH2:44]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: FC1CN(c2ncc(Br)cn2)C1
Product: C[C@@H](c1ccc(-c2cnc(N3CC(F)C3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to Example 31 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidine. LC (method 5): tR=1.55 min; Mass spectrum (ESI+): m/z=505 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.25 (s, 3H), 1.54 (d, 3H), 2.12 (s, 2H), 2.20 (m, 1H), 2.44 (m, 2H), 3.03 (m, 1H), 4.21 (m, 2H), 4.46 (m, 2H), 5.45-5.60 (m, 2H), 7.03 (d, 2H), 7.25-7.40 (m, 7H), 8.53 (s, 2H).