Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][N:9]([C:13]([C:15]34[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:18][C:17](=O)[CH2:16]4)=[O:14])[CH2:10][C:11]=2[CH:12]=1.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[C:26]1([CH:32]2[CH2:33][CH2:34][N:35]([CH:17]3[CH2:16][C:15]4([C:13]([N:9]5[CH2:8][CH2:7][C:6]6[N:5]=[CH:4][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:12][C:11]=6[CH2:10]5)=[O:14])[CH:19]([CH2:20][CH2:21][CH2:22]4)[CH2:18]3)[CH2:36][CH2:37]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1CC2CCCC2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)C12CCCC1CC(N1CCC(c3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)hexahydropentalen-2(1H)-one (0.175 g, 0.497 mmol) in DCE (4.3 mL) was added 4-phenylpiperidine (0.080 g, 0.50 mmol). The reaction mixture was stirred at ambient temperature for about 2 h then sodium triacetoxyborohydide (0.158 g, 0.745 mmol) and acetic acid (0.043 mL, 0.74 mmol) were added. The reaction mixture was then stirred at ambient temperature for about 18 h. Saturated aqueous sodium bicarbonate was added to the reaction mixture and the product was extracted into DCM (3×10 mL). The solvent was removed under reduced pressure and the crude material was purified by RP-HPLC to provide [2-(4-phenyl-piperidin-1-yl)-hexahydro-pentalen-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone as a mixture of four diastereomers (0.075 g). RP-HPLC (Table A, Method c) Rt 2.05 min; m/z: (M+H)+498. In addition, the diastereomers were separated using a two-step chiral HPLC method (Step 1: Diastereomer separation: Isocratic using 85% heptane, 7.5% methanol, 7.5% ethanol with 0.2% diethylamine on a Daicel OD-H column (20×250 mm) at 35 deg C. and 12 mL/min flow rate (UV wavelength monitored=265 nm). Step 2: Enantiomer separation: 10-70% gradient over 19 min of isopropanol in heptane with 0.2% diethylamine on a Daicel AD-H column (20×250 mm) at 35 deg C. and 16 ml/min flow rate (UV wavelength monitored=265 nm)) to provide the four enantiomers—the absolute configuration of each compound was not determined Isomer 1: RP-HPLC (Table A, Method d) Rt 12.66 min. Isomer 2: RP-HPLC (Table A, Method d) Rt 13.57 min. Isomer 3: RP-HPLC (Table A, Method d) Rt 8.46 min Isomer 4: RP-HPLC (Table A, Method d) Rt 11.76 min.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[N:3]=1.[NH2:23][C@H:24]([CH3:34])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH2:14][S:13][C:4]2[N:3]=[C:2]([NH:23][C@H:24]([CH3:34])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[C:11]3[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=3[N:5]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Reactant: C[C@@H](N)CNC(=O)OC(C)(C)C
Product: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(SCc2cccc(Cl)c2F)nc2[nH]c(=O)cnc12
Yield: 89.8 %

Procedure:
The titled compound (83 mg) was prepared by the method of Example 6, step (f) using the product from Example 6, step (e) (75 mg) and the product from example 9, step (d) (72 mg).
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=12)=[O:2].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:13]([N:4]1[CH:5]=[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]2=[C:3]1[CH:1]=[O:2])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=Cc1[nH]cc2c1OCCO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc2c(c1C=O)OCCO2
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of aldehyde 19 (0.8 g, 5.2 mmol) in dichloromethane was added (BOC)2O (1.1 g, 5.2 mmol), triethylamine (1.1 g, 10.4 mmol), and 4-dimethylaminopyridine (DMAP) (61 mg, 0.5 mmol). The reaction mixture was stirred for 3 h and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexane/ethyl acetate (3:1) as eluent to yield a colorless crystalline product (1.2 g, 90%): mp 94-95° C.; 1H NMR (300 MHz, CDCl3) δ10.24 (s, 1H), 6.88 (s, 1H), 4.38 (m, 2H), 4.22 (m, 2H), 1.60 (s, 9H); 13C NMR (75 MHz, CDCl3) δ180.9, 148.8, 143.2, 134.2, 116.6, 107.9, 85.1, 66.1, 64.9, 27.9; FT-IR (CDCl3) 2930, 2859, 1653, 1544, 1460, 1380, 1322 cm−1; Anal. Calcd for C12H15NO5: C, 56.91; H 5.97; N, 5.53. Found: C, 56.90; H, 5.80; N, 5.73.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5](Cl)=[O:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]3=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]3[NH:18][C:17]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[CH:27]=2)=[CH:12][CH:11]=1.[Cl-].[NH4+]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([NH:32][C:28]1[CH:27]=[C:26]([C:17]2[NH:18][C:19]3[C:20](=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=3)[C:16]=2[C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[CH:31]=[CH:30][N:29]=1)=[O:6]
Reactant: COC(=O)CC(=O)Cl
Reactant: Cc1cnc2c(-c3ccc(F)cc3)c(-c3ccnc(N)c3)[nH]c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: COC(=O)CC(=O)Nc1cc(-c2[nH]c3cc(C)cnc3c2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 15.4 %

Procedure:
Chlorocarbonyl-acetic acid methyl ester (129 mg, 0.9 mmole) is added to a solution of 200 mg (0.62 mmole) of 4-[3-(4-Fluoro-phenyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridin-2-ylamine (prepared following the procedure for example 7) in 3 mL of pyridine at room temperature. After 30 hours at room temperature, Chlorocarbonyl-acetic acid methyl ester (129 mg, 0.9 mmole) is added again to the reaction mixture stirred 12 more hours at room temperature. The reaction mixture is then poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the solid residue is purified by chromatography on silica gel (ethyl acetate) to give 40 mg of N-{4-[3-(4-Fluoro-phenyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridin-2-yl}-malonamic acid methyl ester as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.Br[C:17]1[CH:18]=[C:19]2[C:23]3=[C:24]([CH2:26][S:27][CH2:28][CH2:29][N:22]3[C@H:21]3[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][C@@H:20]23)[CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:17]2[CH:18]=[C:19]3[C:23]4=[C:24]([CH2:26][S:27][CH2:28][CH2:29][N:22]4[C@H:21]4[CH2:30][CH2:31][NH:32][CH2:33][C@@H:20]34)[CH:25]=2)=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C(F)(F)F)c1

Procedure:
Using 4-methoxy-2-(trifluoromethyl)phenyl boronic acid and following the procedures described in EXAMPLE 9, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 12. 1H NMR(CDCl3, 300 MHz): δ 7.20 (m, 3H), 7.05 (m, 2H), 6.89 (s, 1H), 6.79 (s, 1H), 3.84 (s, 3H), 3.81 (m, 2H), 3.59 (m, 1H), 3.45 (m, 1H), 3.21 (m, 2H), 3.0 (m, 2H), 2.92 (m, 3H), 2.60 (m, 1H), 1.80 (m, 2H). LRMS (ES+): 421 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]#[CH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]=[O:10]>CCOCC>[CH:1]1([C:7]#[C:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CC1CCCCC1
Reactant: C=O
Solvent: CCOCC
Product: OCC#CC1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethyl magesium bromide (prepared from 2.5 g of magnesium turning and 11.3 g of bromoethane) in ether was added dropwise a solution of 10.2 g of cyclohexylacetylene in ether and the reaction mixture was refluxed for 2 hours. The reaction mixture was cooled to ambient temperature and anhydrous formaldehyde (prepared from the thermal decomposition of 50 g of paraformaldehyde for 20 minutes) was bubbled into the mixture. After cooling, the reaction was quenched with saturated ammonium chloride and extracted with ether (2×100 ml). The combined ether extracts were washed with brine, dried over magnesium sulfate and evaporated to yield the product which was distilled under high vacuum at 68°-74° C. to yield 6.4 g as a colorless liquid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].F[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:12][C:11]=1[N+:29]([O-:31])=[O:30]>O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:12][C:11]=2[N+:29]([O-:31])=[O:30])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Reactant: Oc1ccc(O)cc1
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1

Procedure:
A solution of hydroquinone was heated under a nitrogen atmosphere. A solution of the product from Example 114A was added dropwise. The mixture was then stirred, cooled, poured into water, and adjusted the pH. The mixture was extracted, washed, and concentrated to provide N-[4-(4-Hydroxy-phenoxy)-3-nitro-phenyl]-3-trifluoromethyl-benzamide which was reduced to provide the title product.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C@H:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8]C(C)(C)C)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C@H:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([OH:8])=[O:7]
Reactant: CN(C)C(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ((R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate (0.86 g, 3.10 mmol) in CH2Cl2 (250 mL) was added TFA (15 mL) dropwise and the resulting solution was stirred at rt for 3 hours. The desired compound was then precipitated out of solution with a mixture of EtOAC:Hexanes (5:20), filtered off and dried under reduced pressure. (R)-2-(3,3-dimethylureido)-2-phenylacetic acid was isolated as a white solid (0.59 g, 86%) and used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.82 (s, 6H) 5.22 (d, J=7.32 Hz, 1H) 6.58 (d, J=7.32 Hz, 1H) 7.28 (t, J=7.17 Hz, 1H) 7.33 (t, J=7.32 Hz, 2H) 7.38-7.43 (m, 2H) 12.65 (s, 1H). LC-MS: Anal. Calcd. for C11H14N2O3: 222.24; found: 223.21 (M+H)+. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=0.75 min, 93% homogeneity index.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([O:9][CH:10](OCC)OCC)[CH3:8]>>[CH2:7]([O:9][CH:10]1[O:5][CH:2]([CH2:3][OH:4])[CH2:1][O:6]1)[CH3:8]
Reactant: CCOC(OCC)OCC
Reactant: OCC(O)CO
Product: CCOC1OCC(CO)O1

Procedure:
To 59.72 grams (0.655 moles) of anhydrous 1,2,3-propanetriol in a 500 milliliter 3-necked borosilicate flask equipped with a stirrer, a nitrogen inlet and a Vigreaux column, was added with constant stirring under a nitrogen atmosphere 97.9 (0.660 moles) of anhydrous triethylorthoformate and the reactants permitted to react for 6 hours. The reaction was carried out at atmospheric pressure, and at 130° C. ± 2° C. During the reaction, approximately a stoichiometric amount of ethanol was distilled from the reaction vessel. Next, the product was transferred to a 250 milliliter Bantam flask for vacuum fractionation over CaO, with the main fraction collected at 67°-85° C. under 0.5 millimeters of mercury. The fraction as analyzed by gas chromatography had a purity of 90% and it contained both the cis and trans isomers. An infrared analysis did not show any carbonyl peaks. Finally, the product was redistilled from triethylamine to yield pure monomer, 2-ethoxy-4-hydroxymethyl-1,3-dioxolane.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:17]([C:19]1[CH:20]=[C:21]([CH3:31])[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:23][CH:24]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:20]=[C:21]([CH3:31])[C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:4]([C:3]3[CH:7]=[CH:8][C:9]([N:11]4[CH2:15][CH2:14][CH2:13][C:12]4=[O:16])=[N:10][C:2]=3[CH3:1])=[O:6])[CH2:29][CH2:30]2)=[N:23][CH:24]=1)[CH3:18]
Reactant: Cc1nc(N2CCCC2=O)ccc1C(=O)O
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)nc3C)CC2)c(C)c1

Procedure:
Using a crude product (0.605 mmol) of 2-methyl-6-(2-oxopyrrolidin-1-yl)nicotinic acid which is an intermediate described in Example 791, and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (124 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Example 93, the title compound (4 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17]O>OS(O)(=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: Cc1cc(C(=O)O)cc(-c2ccccc2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)cc(-c2ccccc2)c1
Yield: 94 %

Procedure:
A solution of 3-methyl-5-phenylbenzoic acid (3.5 g; 16.5 mmol) and concentrated H2SO4 (30 drops) in methanol (25 ml) was heated at reflux overnight. After evaporation to dryness, the residue was extracted with ether. The organic phase was evaporated and purified by flash chromatography eluting with petroleum ether/ethyl acetate (90/10) to give methyl 3-methyl-5-phenylbenzoate as an oil. Yield=94%.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([CH3:17])[C:5](=[O:18])[CH2:4][N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:38]1([C:44]#[CH:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CC#N.Cl[Pd]Cl.[Cu]I>[CH3:16][O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7]2[N:6]([CH3:17])[C:5](=[O:18])[CH2:4][N:3]=[C:2]([C:45]#[C:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:8]=2[CH:9]=1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2Cl
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc2c(cc1OC)N(C)C(=O)CN=C2C#Cc1ccccc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of 240 mg (0.89 mmol) of 5-chloro-7,8-dimethoxy-1-methyl-1,3-dihydro-1,4-benzodiazepin-2-one XVIIIaa in 7 ml of CH3CN, add under an inert atmosphere 17 mg (0.1 mmol) of PdCl2, 30 mg (0.16 mmol) of CuI. Stir for 5 minutes, then add 68 mg (0.23 mmol) of PPh3, 185 μl of Net3 and 150 μl of phenylacetylene. Heat the mixture at 55° C. for 3 hours. Evaporate to dryness and purify by silica chromatography (AcOEt 1/hexane 1, then AcOEt). Recrystallize in EtOH. Yield: 45%. 1H-NMR (DMSO, 200 MHz): d 3.33 (s, 3H, NCH3), 3.70–3.91 (m, 7H, 1HCH2+20CH3), 4.50–5.60 (m, 1HCH2), 7.06 (s, 1H Ar), 7.32 (s, 1H Ar), 7.48–7.68 (m, 5H Ar). Mass: (M+H)+=335.16.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]([C:33](=[O:35])[CH3:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:42](Cl)([CH3:44])=[O:43]>C(Cl)Cl>[C:42]([O:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[C:26]([C:33](=[O:35])[CH3:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1)(=[O:43])[CH3:44]
Reactant: CC(=O)c1cnc(N2CCn3c(cc4cc(CO)c(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2cc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)C3C(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (132 mg, 0.26 mmol) in CH2Cl2 (5 mL) was added pyridine (1 mL) and AcCl (130 μL, 1.3 mmol). The mixture was stirred at rt for 10 h. The reaction was quenched with water (5 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, and then dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (1/1) to give (2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methyl acetate. LC-MS m/z 553 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1ccc(O)c(F)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(O)c(F)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
To a solution of 3-fluoro-4-hydroxybenzoic acid (Aldrich, 4.0 mmol, 624 mg) in ethanol (10 mL), was added thionyl chloride (2 mL, Aldrich). The reaction mixture was heated at 80° C. for 4 h, and concentrated in vacuo to remove the solvent and excess thionyl chloride to afford the desired product (736 mg, 100% yield) as a white solid. MS(ESI+) m/z 185.33 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:20]=1[F:35]>C1COCC1>[F:35][C:20]1[C:21]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
Sodium hydride (60% oil dispersion) (3.75 g, 94 mmol) was added in portions to a solution of di-t-butyl malonate (10.49 ml, 46.9 mmol) in THF (200 mL). After gas evolution subsided, a solution of 1,2-difluoro-4-nitro-3-(phenyloxy)benzene (10.70 g, 42.6 mmol) in THF (100 mL) was added. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. Chromatography of the residue (ethyl acetate:hexanes) gave the desires product (2.38 g, 12.5%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.81 (dd, 1H), 7.53 (dd, 1H), 7.27-7.35 (m, 2H), 7.09 (t, 1H), 6.93 (d, 2H), 4.80 (s, 1H), 1.48 (s, 18H). ES MS: m/z 470 (M+23).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>>[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([S:59]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])(=[O:61])=[O:60])=[CH:55][CH:54]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 38 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-chlorobenzenesulfonyl chloride as described in example 2, affording the title compound in 38% yield.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:14])[CH2:13][Br:26])[CH2:3]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Solvent: CO
Solvent: O
Product: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@H]1C(=O)CBr

Procedure:
3α-Hydroxy-16α-methyl-5α-pregnane-11,20-dione (5 g.) was dissolved in dry methanol (350 ml.) and treated at 0° with a solution of bromine (1 ml.) in dry methanol (24 ml.) at such a rate that the yellow colour disappeared before further addition. After completion of the addition the mixture was poured into water. The precipitated product was dried and dissolved in chloroform (20 ml.) and put onto a column of silica gel MFC (700 g.). Elution with benzene:ethyl acetate (21/2:1) gave the title compound (3.6 g.) as a foam, [α]D + 112.4°.
Reaction SMILES: [C:1]1([N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N([O-])=[O:16].[Na+].Cl>CN(C)C=O>[N:8]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=NN(c1ccccc1)c1ccccc1

Procedure:
The compound 1,1-diphenylhydrazine is commercially available. The substituted 1,1-diphenylhydrazines can be made by reacting the corresponding 1,1-diarylamine with sodium nitrite and hydrochloric acid in dimethylformamide at about 10° C. to produce an N-nitrosodiphenylamine, then adding the N-nitroso compound in tetrahydrofuran to a suspension of lithium aluminum hydride in dry ether under nitrogen and maintaining the temperature at 25°-35° C. for about 11/2 hours. The procedure is analogous to that given for preparation of N-amino-iminodibenzyl in Cohen et al., U.S. Pat. No. 3,457,271.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:12]=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5]2.[O-:15]Cl=O.[Na+].[OH-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:15])=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5]2
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c(O)ccc2cc(Br)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1c(O)ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.4 %

Procedure:
To a ice-cooled mixture of 6-Bromo-2-hydroxy-1-naphthaldehyde (24.0 g) and aqueous NaH2PO4 solution (3.2 g in 30 mL of water) in DMSO (160 mL) was added dropwise a solution of NaClO2 (80%; 15.1 g) in water (150 mL) over 1 h. After being stirred for 5 h at room temperature, a solution of NaClO2 (80%; 2.16 g) in water (20 mL) was added, and the reaction mixture was further stirred for 2 h at room temperature. The mixture was alkalized with 1N-NaOH, and the precipitate was filtered off. The filtrate was washed with AcOEt and iPr2O, and then the aqueous phase was acidified with conc. HCl. The precipitate was filtered, washed with water, and dried in vacuo to give the title compound (22.3 g) as a brown powder.