Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[CH:20]=2)[CH:12]=1)[CH3:9].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]([CH3:28])([CH3:27])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=2)[CH:12]=1)[CH3:9]
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OCc2cccc(C=O)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OCc2cccc(CO)c2)c1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
85 mg of the (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-(3-formylbenzyloxy)benzylamine obtained as above was dissolved in 2 ml of ethanol, and under ice cooling, 8.6 mg of sodium borohydride was added with stirring for 30 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was evaporated. The residue was purified by silica gel column chromatography (Wakogel C-200, 15 g; eluting solvent: hexane/ethyl acetate=10/1→5/1) to give 40 mg (yield 39%) of the captioned compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([Br:10])=[CH:5][C:3]=1[OH:4].[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.O>[Br:1][C:2]1[C:3](=[O:4])[CH:5]=[C:6]([Br:10])[C:7](=[O:9])[CH:8]=1
Reactant: Oc1cc(Br)c(O)cc1Br
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1C=C(Br)C(=O)C=C1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
To a solution of 2,5-dibromohydroquinone (1) (5 g, 18.6 mol) in acetonitrile (250 ml) was added cerium ammonium nitrate (21.4 g, 39.0 mmol), in small portions. The clear orange solution was stirred for 10 min at room temperature, diluted with water (80 ml) and extracted with chloroform (3×200 ml). The combined chloroform layers were dried over sodium sulphate and evaporated, yielding 3.5 g (71%) of the quinone (2).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: BrBr
Reactant: Cc1cnc(N)cn1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cnc(N)c(Br)n1
Yield: 56.4 %

Procedure:
To a suspension of 5-methylpyrazin-2-amine (1.09 g, 10 mmol) in chloroform (100 mL) was added pyridine (0.85 mL, 10.5 mmol). The mixture was stirred in a foil-wrapped flask fitted with an addition funnel, and a solution of bromine (0.54 mL, 10.5 mmol) in chloroform (10 mL) was added dropwise over 10 min. The mixture was allowed to react an additional 20 minutes after addition was complete and then poured into a separatory funnel containing 10 mL water. The phases were separated and the organics washed again with water, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting red oil was purified by silica gel chromatography with 12-100% EtOAc/hexanes. The major UV active peak was collected to give 3-bromo-5-methylpyrazin-2-amine (1.06 g, 5.64 mmol, 56.4% yield) as a cream-colored solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.85 (s, 1H) 6.42 (br. s., 2H) 2.25 (s, 3H). MS (LC/MS) R.T.=0.93; [M+H]+=189.9.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([C:9](=[O:11])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 3,3 diphenylpropionic acid (1.45 g, 6.44 mmol) in dry CH2Cl2 (70 ml) was added mono-boc piperizine (1.32 g, 7.08 mmol) under nitrogen. To the reaction was added EDC (2.71 g, 14.16 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate:water (10:1) (200 ml). The organic was washed with water (50 ml, 2×) and 10% NaOH (50 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (1:1) to give desired product in 76% yield.
Reaction SMILES: [C:1](=[O:8])([O-])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[NH2:9][CH2:10][CH2:11][CH:12]1[CH:17]([NH:18][C:19]2[N:24]=[C:23]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:22]=[C:21]([Cl:32])[N:20]=2)[CH2:16][CH2:15][CH2:14][N:13]1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].O1CCCC1>O.C(N(CC)CC)C>[N:25]1([C:23]2[CH:22]=[C:21]([Cl:32])[N:20]=[C:19]([NH:18][CH:17]3[CH2:16][CH2:15][CH2:14][N:13]([C:33]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[CH:12]3[CH2:11][CH2:10][NH:9][C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:8])[N:24]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: NCCC1C(Nc2nc(Cl)cc(N3CCCCCC3)n2)CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCC1C(Nc2nc(Cl)cc(N3CCCCCC3)n2)CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
tert-Butyl carbonate (165 mg) was added to the compound 18 (245 mg), tetrahydrofuran (2 mL), water (2 mL) and triethylamine (0.11 mL) with stirring at 0° C. The reaction solution was stirred at room temperature for 2 hours, added water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The residue was filtered with hexane and obtained the title compound (225 mg) having the following physical properties.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[K+].[N:21]12[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:25][NH:24][CH2:23][CH2:22]2.[OH-].[K+]>C(OCC)C.O>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:24]2[CH2:25][CH:26]3[N:21]([CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:23]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: C1CC2CNCCN2C1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: N#CC(CCN1CCN2CCCC2C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a stirred mixture of 78.5 parts of 2,2-diphenyl-4-bromobutyronitrile, 19.7 parts of potassium iodide and 30.0 parts of 1,4-diazabicyclo[4.3.0]nonane is added 70 parts of water and 19.3 parts of potassium hydroxide under a nitrogen atmosphere. The mixture is stirred and heated to 75° - 80° C. and then further heated to reflux (108° - 112° C.). After 3.5 hours of heating at reflux, the mixture is cooled to about 25° C. and 180 parts of ethyl ether added. The resulting organic layer is extracted once with a 20% solution of hydrochloric acid in water followed by a further extraction with 6% solution of hydrochloric acid in water. The aqueous extracts are then combined and basified to pH 11.0 with a 50% solution of sodium hydroxide in water. The resulting oil is extracted with three 110 parts portions of ethyl ether. The ether extracts are combined, dried over anhydrous potassium carbonate, and stripped of solvent under reduced pressure. The resulting product, 2,2-diphenyl-4-(1,4-diazabicyclo[4.3.0]non-4-yl)butyronitrile, is obtained in 89% yield. Correction of this yield to reflect the purity of the 1,4-diazabicyclo[4.3.0]nonane (96%) results in a yield of 93% for this reaction. This product boils at about 190° - 210° C. at 0.1 mm. pressure and is represented by the following structural formula. ##STR9##
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](I)=[C:22]([F:27])[CH:21]=1.CC(C)([O-])C.[Na+].O1CCOCCOCCOCCOCCOCC1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(O)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:22]1[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][C:23]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@:10]2([C:9](=[O:18])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]3)[CH2:12][CH2:11]2)[CH2:13]1
Reactant: Cc1ccc(I)c(F)c1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CC[C@]12CCCNC2
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(C)(C)O
Product: Cc1ccc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(F)c1

Procedure:
A mixture of (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00007 mol) which was prepared using procedures analogous to those described in the synthesis of example 472-a and followed by standard hydrogenation to remove the carbobenzyloxy (Cbz) protecting and, 4-methyl-2-fluoro-1-iodobenzene (21 mg, 0.00009 mol), sodium tert-butoxide (9.98 mg, 0.000104 mol), 1,4,7,10,13,16-hexaoxacyclooctadecane (27.4 mg, 0.000104 mol), 2-(di-tert-butylphosphino)biphenyl (0.8 mg, 0.000003 mol), tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.000001 mol), in tert-butyl alcohol (1.0 mL, 0.010 mol) was stirred at rt for 18. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 361.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:28][CH2:29][C:30](=[O:33])[CH2:31][CH2:32]4)=[CH:23][CH:22]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1
Reactant: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Cl)cc2)S1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(CC4SC(=O)NC4=O)cc3)cc2)CC1

Procedure:
The title compound was prepared from 4-(2,4-dioxo-thiazolidin-5-ylmethyl)benzenesulfonylchloride (J. Med. Chem. 1992, 35, 1853) and 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (t, J=6.0 Hz, 4 H), 3.10–3.60 (m, 2 H), 3.44 (t, J=6.0 Hz, 4 H), 4.95 (dd, J=12.3, 6.0 Hz, 1 H), 6.80–7.00 (m, 4 H), 7.27 (d, J=8.1 Hz, 2 H), 7.63 (d, J=8.1 Hz, 2 H), 9.77 (brs, 1 H), 12.09 (brs, 1 H); MS (ES) m/z: 459.9 (MH+); HRMS Calcd. for C21H21N3O5S2 M+): 459.0923. Found: 459.0930.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:3]=1.B(F)(F)F.CCOCC>CCS>[CH3:1][C:2]1[S:6][C:5]([CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:3]=1
Reactant: COC(=O)CC(Cc1ccc(OCc2ccccc2)cc1)c1ncc(C)s1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCS
Product: COC(=O)CC(Cc1ccc(O)cc1)c1ncc(C)s1
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a solution of methyl (±)-3-(5-methylthiazol-2-yl)-4-(4-benzyloxyphenyl)butanoate (0.99 mmole, crude) in EtSH (5 mL) at RT was added BF3 OEt2 (0.6 mL). After 18 hr. additional BF3.OEt2 (0.6 mL) was added. After another 18 hr, the mixture was cooled to 0° C. and carefully quenched with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (50% EtOAc/hexanes) to give the title compound (249 mg, 86% over 3 steps) as a yellow solid: MS (ES) m/e 292 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.O[C:24]1[CH:65]=[CH:64][C:27]([CH2:28][N:29]([CH2:56][C:57]([O:59]C(C)(C)C)=[O:58])[C:30](=[O:55])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:52])[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[C:48]([F:51])([F:50])[F:49])=[CH:33][C:32]=2[O:53][CH3:54])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:54][O:53][C:32]1[CH:33]=[C:34]([NH:37][C:38](=[O:52])[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[C:48]([F:50])([F:51])[F:49])[CH:35]=[CH:36][C:31]=1[C:30]([N:29]([CH2:56][C:57]([OH:59])=[O:58])[CH2:28][C:27]1[CH:64]=[CH:65][C:24]([O:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)=[O:16])=[CH:25][CH:26]=1)=[O:55]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)c(OC)c2)c(C(F)(F)F)c1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(OC(=O)c4ccc(-c5ccc(C)cc5)cc4)cc3)c(OC)c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
Prepared using General Procedures 2 then 8: To a stirring suspension of 4′-methyl-[1,1′-biphenyl]-4-carboxylic acid (57 mg, 0.27 mmol) in DCM (5 mL) were added DMF (2 drops) and oxalyl chloride (25 μL, 0.29 mmol). The reaction mixture was stirred at room temperature for 2 h. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-24 (108 mg, 0.18 mmol) and TEA (62 μL, 0.45 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h then TFA (3 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to provide to afford 23.1 mg (17%) of 2-(2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-((4′-methyl-[1,1′-biphenyl]-4-carbonyl)oxy)benzyl)benzamido)acetic acid 314 as a white powder. LCMS-ESI (m/z) calculated for C41H35F3N2O8: 740; found 741 [M+H]+, tR=10.33 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 10.34 (s, 0.5H), 10.32 (s, 0.5H), 8.25-8.15 (m, 2H), 7.93-7.85 (m, 2H), 7.74-7.64 (dt, J=6.3, 2.3 Hz, 2H), 7.53-7.39 (m, 3H), 7.39-7.07 (m, 9H), 5.01 (br s, 1H), 4.42 (s, 1H), 3.90-3.65 (m, 10H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:55])[CH:3]([C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1)[CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:55][N:2]([CH3:1])[CH:3]([C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1)[CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:27])([CH3:28])[C:16]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:40][CH:41]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCC(c3cccnc3)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CNCC(c3cccnc3)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 13.8 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)-2-(pyridin-3-yl)ethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (125 mg, 0.167 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 4.5 h then was concentrated under reduced pressure. The residue was dissolved in dioxane and MeOH and was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure. Impurities were still present so the residue was purified again by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give the title compound as an off-white solid (16 mg, 13.8%). LCMS: m/e 692.5 (M+H)+, 2.30 min (method 6). 1H NMR (500 MHz, Acetic Acid) δ ppm 8.83-8.98 (m, 2H), 8.27-8.42 (m, 1H), 7.99-8.11 (m, 2H), 7.71-7.84 (m, 1H), 7.27-7.35 (m, 2H), 5.33-5.42 (m, 1H), 5.22-5.30 (m, 1H), 4.79 (d, J=14.34 Hz, 1H), 4.67 (d, J=12.82 Hz, 1H), 4.21-4.38 (m, 2H), 3.34-3.52 (m, 1H), 2.97-3.15 (m, 1H), 2.83 (br. s., 3H), 2.82 (br. s., 3H), 2.43-2.58 (m, 1H), 0.88-2.23 (m, 40H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:37]1[C:42](C)=[CH:41]C=[CH:39][C:38]=1C.C(NCC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](=[O:24])[N:37]([CH2:42][CH3:41])[CH2:38][CH3:39])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, diethylamine (25 μL, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-diethylcarbamoylmethyl-1H-pyrazol-3-yl)-propionamide (66 mg, 59%) as a white solid: ESI-LRMS m/e calcd for C24H33ClN4O4S [M+] 508.19, found 509.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.18 (m, 5H, CH3 and CH2), 1.21 (t, J=7.2 Hz, 3H, CH3), 1.43-1.94 (m, 8H, 4×CH2), 2.18-2.27 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.33 (q, J=7.2 Hz, 2H, CH2), 3.39 (q, J=7.2 Hz, 2H, CH2), 3.54 (t, J=7.6 Hz, 1H, CH), 4.80 (s, 2H, NCH2), 6.71 (d, J=2.4 Hz, 1H, Ar), 7.36 (d, J=2.4 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 7.93 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20]N(CN(C)C)C.C(OC(=O)C)(=O)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[CH2:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CN(C)CN(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
2-[[(4-chlorophenyl)sulfonyl]methyl]-1,4-difluorobenzene (Intermediate 1) (100 g, 0.33 mol) and N,N,N′,N′-tetramethyldiaminomethane (34.2 g, 0.50 mol) were dissolved in dimethyl formamide (1000 mL) at 60° C. Acetic anhydride (68.3 g, 1.00 mol) was added slowly and the reaction mixture was aged for 5 hours. Water (1000 mL) was added dropwise and the resulting slurry was cooled to 5° C. The solids were filtered, and the cake washed sequentially with dimethyl formamide: water (40:60, 200 mL) and water (500 mL). Drying overnight in vacuo at 40° C. under a nitrogen stream furnished 2-[1-[(4-chlorophenyl)sulfony]ethenyl]-1,4-difluorobenzene (98 g, 95%). 1H NMR (CDCl3) 7.64-7.59 (2H, m), 7.43-7.39 (2H, m), 7.27-7.22 (1H, m), 7.08-6.88 (2H, m), 6.88 (1H, s) and 6.09 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.ClC1C(Cl)=NC=CN=1.NN.[C:20](OCC)(OCC)(OCC)[CH2:21][CH3:22]>>[Cl:1][C:2]1[C:3]2[N:4]([C:20]([CH2:21][CH3:22])=[N:9][N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: NNc1nccnc1Cl
Reactant: CCOC(CC)(OCC)OCC
Agent: Clc1nccnc1Cl
Agent: NN
Product: CCc1nnc2c(Cl)nccn12
Temperature: 25 °C

Procedure:
To 3-chloro-2-hydrazinopyrazine (3.0 g, 20.75 mmol), prepared from 2,3-dichloropyrazine and hydrazine using a procedure analogous to that described in the literature (Huynh-Dinh et al, J. Org. Chem. 1979, 44, 1028), was added 8 mL of triethyl orthopropionate. After refluxing for 10 h, the reaction was cooled down to ambient temperature and the precipitate was filtered. The solid was purified by flash chromatography (100% ethyl acetate, then 10% methanol in ethyl acetate) to give 2.73 g of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 1.54 (t, 3H, J=7.6 Hz), 3.16 (q, 2H, J=7.8 Hz), 7.70 (d, 1H, J=4.5 Hz), 7.83 (d, 1H, J=4.8 Hz).
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[C:22](OCC)=[O:23]>O1CCCC1>[C:1]1([N:7]2[C:22](=[O:23])[C:13]3[CH:14]=[N:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ONc1ccccc1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c2cnc3ccccc3c2on1-c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
A solution of 9 g of N-phenylhydroxylamine [described in Organique Synthese, Vol. 1, p. 445]was added dropwise at 0° C. with stirring under an inert atmosphere to a suspension of 3.85 g of 50% sodium hydride in 100 ml of tetrahydrofuran, and after stirring at 5° C. for 30 minutes, a solution of 18.8 g of ethyl 4-chloro-3-quinoline carboxylate in 100 ml of tetrahydrofuran was added at 0° C. The mixture was stirred for 16 hours at ambient temperature and after concentration to dryness under reduced pressure, the residue was taken up in ice. The mixture was extracted with methylene chloride and the organic phase was washed, dried, and concentrated to dryness. The residue was purified by chromatography on silica (eluent: ethyl acetate) to obtain 1.2 g of 2-phenylisoxazolo(4,5-c)quinolin-3-(2H)-one (corresponding to the 3rd eluted fraction) melting at 163° C. after crystallization from isopropyl ether.