Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][C:24](F)=[CH:25][C:19]=4[C:18]=3[CH3:27])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[OH-].[K+].CN(C)CC[OH:34]>CS(C)=O.C(OCC)(=O)C.O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][C:24]([OH:34])=[CH:25][C:19]=4[C:18]=3[CH3:27])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CN(C)CCO
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(O)cc4c3C)c(C)nc12
Temperature: 90 °C
Reaction time: 24 h
Yield: 25.1 %

Procedure:
In an oven dried, nitrogen purged pressure tube, 0.040 g (0.105 mmol) of 8-(1-ethyl-propyl)-3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine, 0.012 g (0.21 mmol) of KOH, and 0.019 g (0.210 mmol) of N,N-dimethylethanolamine are combined in 1 mL of dry DMSO and heated at 90° C. After approximately 24 hours, the reaction mixture is diluted with 20 mL of ethyl acetate and 20 mL of water. The layers are separated and the aqueous is extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using Hexane/Ethyl Acetate. The product containing fractions are combined to obtain 0.010 g of the title compound, 25% yield. MS, ES+=380.1 (M+1); 1H NMR (DMSO-d6)=9.518 (s, 1H); 7.760-7.730 (s, 1H); 7.129 (s, 1H); 6.980 (s, 1H); 3.150-3.050 (m, 1H); 2.421 (s, 3H); 2.336 (s, 3H); 2.103 (s, 3H); 1.850-1.760 (m, 4H); 0.789-0.753 (m, 6H) ppm.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>CC(O)(C)C.CC(O)(C)C.CO>[C:12]([C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[CH2:15][C:14]([O:18][CH3:19])=[O:17])#[N:13]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: C=CC(=O)OC
Solvent: CC(C)(C)O
Solvent: CO
Product: COC(=O)CCC(C#N)(CC(=O)OC)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
2-naphthylacetonitrile (3.45 g, 20.6 mmol) and methyl acrylate (9.7 ml, 107 mmol) were suspended in 2-methyl-2-propanol (10 ml). Heat was applied to the reaction vessel until the solution became clear. The mixture was cooled to room temperature, at which time (Bu)4NOH (6.9 mmol, 0.33 equiv.) was added as a solution in 2-methyl-2-propanol:methanol (1:2). The combined reaction mixture was heated to reflux for 4 h under vigorous stirring at which time the reaction appeared complete by GC-MS. After allowing the reaction to cool the mixture was partitioned between H2O (75 ml) and EtOAc (50 ml). The aqueous layer was removed and washed with EtOAc (2×50 ml). The combined organic phases were washed with NaHCO3 (sat. aq.) and brine and dried over MgSO4. After filtration the solvent was removed in vacuo. The crude product was purified by flash column chromatography (25% EtOAc in hexanes) to isolate the title compound as a light yellow oil (5.75 g, 82%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:27]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:28])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CC(NC(=O)C2CCCCC2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (328 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (529 mg, 84%).
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.FC(F)(F)C([O-])=[O:16].[Na+].O>FC(F)(F)C(O)=O>[OH:16][C:9]1[C:4]2[C:3](=[O:10])[NH:2][S:1](=[O:11])(=[O:12])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1NS(=O)(=O)c2cccc(O)c21
Yield: 18.5 %

Procedure:
4.6 g (25 mmol) of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide (Saccharin®) were dissolved in 30 ml of trifluoroacetic acid and mixed with 4 g of sodium trifluoroacetate. The solution was electrolysed analogously to Example 1. After a charge quantity of 0.4 Ah had been used up the solution was added to water. It was extracted with chloroform and worked up as in Example 1. In addition to 3.3 g of starting material, 0.92 g of 4-hydroxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide were obtained after recrystallisation from water. This corresponds to a yield of 61% based on the starting material reacted;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][N:27]([CH3:26])[C:28]4=[O:32])=[CH:3][C:4]=3[O:24][CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: COc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Product: COc1cc(N2CCN(C)C2=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 82 %

Procedure:
Using (4-bromo-2-methoxyphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (404 mg) described in Preparation Example 252 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (347 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:9])=[C:4](C)[CH:5]=[CH:6][CH:7]=1.[C:10]([Cl:14])(Cl)([Cl:12])[Cl:11].Cl[CH2:16]CCl>>[Cl:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:16])=[C:7]([C:10]([Cl:14])([Cl:12])[Cl:11])[C:2]=1[Cl:1]
Reactant: ClC(Cl)(Cl)Cl
Reactant: ClCCCl
Reactant: Cc1cccc(Cl)c1Cl
Product: Cc1ccc(Cl)c(Cl)c1C(Cl)(Cl)Cl

Procedure:
reacting a dichlorotoluene with carbon tetrachloride in 1,2-dichloroethane in the presence of an aluminum halide to thereby obtain crude dichlorotrichloromethyltoluene; and then
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[Br:13][CH2:14][CH2:15]Br.O>CN(C=O)C>[Br:13][CH2:14][CH2:15][NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: BrCCBr
Reactant: CC(=O)c1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(NCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
To a suspension of 60% NaH (5.93 g, 247.08 mmol) in DMF (80 mL) taken in a one liter 2 neck round bottom flask fitted with a pressure equalizing addition funnel and a septum was added a solution of p-aminoacetophenone (20 g, 148.1 mmol) in DMF (60 mL) in drops through the pressure equalizing addition funnel under nitrogen atmosphere at 0° C. and the contents were stirred for 2 hours at 25° C. Then to the stirred solution was added 1,2-dibromoethane (97.48 g, 518.5 mmol) in drops and the contents were further stirred for another 18 hours at 90° C. The reaction mixture was cooled to 25-35° C. and was carefully added to cold water (650 mL) while stirring. The organics were extracted with ethylacetate (3×200 mL) and combined organics were washed with water (2×100 mL) followed by a brine wash. The separated organics were dried over Na2SO4 and concentrated under reduced pressure. The crude was chromatographed over silicagel by using 15-20% ethyl acetate/pet. ether (3 Lit), affording the title compound 5.1 g (14%) as a pale yellow solid. Mp: 92-94° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21]OS(C)(=O)=O)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]([CH3:29])[CH3:28]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][N:27]([CH3:29])[CH3:28])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)CC(=O)OCc1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 24.5 %

Procedure:
In a sealed vial, (R)-benzyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)-butanoate (130.8 mg, 0.34 mmol) was stirred at rt in a THF solution of Me2NH (2.0 M, 10 mL, 20 mmol) for 3 d. Then the reaction was concentrated under reduced pressure and purified by preparative TLC (0.5% MeOH in DCM, and then 5% MeOH/DCM) to afford the title compound as a colorless gum (28 mg, 25%). 1H NMR (300 MHz, CDCl3): δ=7.85-7.25 (m, 5H), 5.25-5.00 (m, 2H), 4.15 (br s, 1H), 2.58-2.50 (m, 4H), 2.41 (br s, 6H), 1.39 (s, 9H); MS ESI [M]+, calcd for [C18H28N2O4+H]+ 336.4 found m/z 337.2 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].IC.[C:15](OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15]
Reactant: Clc1cccc2[nH]ccc12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 0.794 mL (6.60 mmol) of 4-chloroindole in 10 mL of dry dimethylformamide is reacted with 0.260 g (6.60 mmol) of 60% sodium hydride dispersed in mineral oil at room temperature for 4 h. 0.411 mL (6.60 mmol) of iodomethane is added and the reaction is allowed to stir at room temperature 15 h. TLC (2:1 hexanes:ethyl acetate) indicates the starting material is gone and new less polar spot. The reaction is quenched with 50 mL of water, extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated. The crude product is purified by chromatography using hexanes:ethyl acetate as a solvent system to obtain 0.785 g of the title compound, 72% yield. MS, ES=166.1 (M+1); 1H NMR (DMSO-d6) δ 7.431-7.413 (m, 2H); 7.145-7.064 (m, 2H); 6.442-6.432 (m, 1H); 3.795 (s, 3H) ppm.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[C@H:22]([CH2:23][OH:24])[CH2:21][N:20]([CH2:25][C:26]3([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[C@H:22]([CH:23]=[O:24])[CH2:21][N:20]([CH2:25][C:26]3([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCc1ccccc1)C1(CN2C[C@@H](CO)[C@H](c3cccc(F)c3)C2)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C[C@@H]1CN(CC2(C(=O)OCc3ccccc3)CCCCC2)C[C@H]1c1cccc(F)c1
Reaction time: 0.33 h

Procedure:
A solution of oxalyl chloride (0.6 mL, 7 mmol) in 35 mL CH2Cl2 was cooled to −78° C. and DMSO (1 mL, 14.1 mmol) was added dropwise. After stirring for 20 min a solution of Benzyl 1-{[(3R,4S)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]methyl}cyclohexane carboxylate (2.5 g, 5.88 mmol, from Step C) in 35 mL CH2Cl2 was added. The mixture was stirred for 20 min more then triethylamine (4 mL, 29.5 mmol) was added. The cooling bath was removed and the mixture was stirred for 4h. 100 mL CH2Cl2 was added and the mixture was washed with 1 M NaOH then water and sat'd sodium chloride. The organic layer was dried over magnesium sulfate and concentrated. Flash chromatography (90 g silica, 5/1 hexane/EtOAc) gave the desired aldehyde. 1H NMR (500 MHz, CDCl3) δ1.25-1.43 (m, 6H), 1.58-1.63 (m, 4H), 2.15-2.19 (m, 2H), 2.62-2.73 (m, 2H), 2.83-2.87 (m, 1H), 2.92-3.01 (m, 2H), 3.44-3.51 (m, 1H), 5.11-5.21 (dd, 2H), 6.9-6.97 (m, 1H), 6.98-7.13 (m, 2H), 7.23-7.4 (m, 6H), 9.6 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:20][C@H:14]2[C:13](=[O:32])[NH:12][C@:11]2([C:34]([NH:36][S:37]([CH:40]3[CH2:42][CH2:41]3)(=[O:39])=[O:38])=[O:35])[CH2:33][C@H:10]2[CH2:9][C:8]([F:44])([F:43])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.N1C=CC=CC=1.[CH3:52][C:53]1[O:57][N:56]=[C:55]([C:58](O)=[O:59])[CH:54]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH:40]1([S:37]([NH:36][C:34]([C@@:11]23[CH2:33][C@H:10]2[CH2:9][C:8]([F:43])([F:44])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:58]([C:55]2[CH:54]=[C:53]([CH3:52])[O:57][N:56]=2)=[O:59])[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]4[CH:31]=[N:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH2:20][C@H:14]2[C:13](=[O:32])[NH:12]3)=[O:35])(=[O:39])=[O:38])[CH2:42][CH2:41]1
Reactant: Cc1cc(C(=O)O)no1
Reactant: N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3cnc4ccccc4n3)CN2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@@H](Oc4cnc5ccccc5n4)CN3C2=O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 2a, 8.05 mg, 0.012 mmol) in DMF (120 μl) was added pyridine (7 μl, 0.087 mmol) followed by 5-methylisoxazole-3-carboxylic acid (2.28 mg, 0.018 mmol) and then HATU (7.04 mg, 0.019 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, cooled to 0° C. and neutralized with HCl (4 N in dioxane, 22 μl; diluted with ethyl acetate). The mixture was concentrated and purified by prep-TLC (ethyl acetate) to provide the title compound N-((2R,6S,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (7.65 mg, 10.29 μmol, 86% yield) MS (ESI): m/z=744.3 [M+H]. Example 2 provided an IC50 of >1.0 nM in a 1a enzyme assay; an IC50 of >1.0 nM in a 1b enzyme assay; a HLM stability value of <50 μl/min/mg; an EC50 of >5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of >5.0 nM in a replicon cell line assay in a 1b-con1 background.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:17][CH3:18].[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:21][C@H:20]([OH:19])[CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc2c(C3=CCNCC3)c[nH]c2cc1Cl
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Product: COc1cc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2cc1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-chloro-5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.80 g, 3.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.60 g, 3.2 mmol). The product was isolated as a yellow foam. Yield 260 mg (19%). mp 115°-120° C. FDMS m/e=452 (M+ of free base). α[D]589 =+6.62 (c=1.03, dimethylsulfoxide).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:31][CH2:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NCC1CCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC3CCC3)c2c1N

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example Eb) and cyclobutylmethanamine as an off-white solid (67%). MS 414 (MH+).
Reaction SMILES: [CH2:1]([S:19][C:20]1[C:21](=O)[CH:22]=[C:23]([S:27][C:28]2[N:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:31]=[N:30][N:29]=2)[C:24](=[O:26])[CH:25]=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][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1([SH:46])C=CC=CC=1.[CH:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:1]([S:19][C:20]1[CH:25]=[C:24]([OH:26])[C:23]([S:27][C:28]2[N:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:31]=[N:30][N:29]=2)=[C:22]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:21]=1[SH:46])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCSC1=CC(=O)C(Sc2nnnn2-c2ccccc2)=CC1=O
Reactant: c1ccccc1
Reactant: Sc1ccccc1
Product: CCCCCCCCCCCCCCCCCCSc1cc(O)c(Sc2nnnn2-c2ccccc2)c(-c2ccccc2)c1S
Temperature: 20 °C
Reaction time: 6 h

Procedure:
50g of 2-n-octadecylthio-5-(1-phenyl-5-tetrazolylthio)-p-benzoquinone was added to 1 liter of benzene. After adding 11g of thiophenol to this mixture, the mixture was stirred at 20°C for 6 hours. Then benzene was removed by distillation under a reduced pressure, and the resulting crystals were separated by filtration and washed with water. They were recrystallized form n-hexane. Thus 40g of needle-like crystals of 2-n-octadecylthio-5-(1-phenyl-5-tetrazolylthio)-6-phenylthiohydroquinone having a melting point of 96°C was obtained.
Reaction SMILES: [C:1]([NH:8][CH:9]([CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=N[C:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:53][O:54][C:55](=[O:63])[CH2:56]C1CCNCC1>ClCCl>[CH3:53][O:54][C:55](=[O:63])[CH2:56][N:34]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]1[C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[CH:9]([CH2:16][CH2:17][CH2:18][CH3:19])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(C)(C)C(=O)O
Reactant: COC(=O)CC1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(NC(=O)OC(C)(C)C)C(C)(C)C(=O)C1CCCCN1CC(=O)OC
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of N-Boc-β-n-butyl-α,α-dimethyl-β-alanine (1.68 g, 6.13 mmol) in dichloromethane (30 ml) was added HATU reagent (2.8 g, 7.37 mmol) and di-i-propylethylamine (6.58 ml, 36.8 mmol) under cooling with ice. After being stirred for 30 min, to the reaction mixture was added 4-piperidineacetic acid methyl ester (1.45 g, 9.19 mmol) and stirred overnight at room temperature. After the solvent was distilled off, the resulting residue was dissolved into ethyl acetate and washed with 5% aqueous citric acid, 5% aqueous sodium bicarbonate, and brine for three times respectively. The organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was subjected to the silica gel column chromatography (2.2×20 cm) and eluted with hexane:ethyl acetate=2:1 to give powder of N-Boc-β-n-butyl-α,α-dimethyl-β-alanyl-piperidineacetic acid methyl ester (1.70 g, 67.2%).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH:7]([CH3:11])[C:8]([OH:10])=O)[N:4]=[CH:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[NH:2]1[CH:6]=[C:5]([CH:7]([CH3:11])[C:8]([NH:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[O:15])=[O:10])[N:4]=[CH:3]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C(=O)O)c1c[nH]cn1
Agent: Cl
Product: CC(C(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1c[nH]cn1
Yield: 21 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-imidazol-4-yl)propanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 167, (2S)-2-(2-(1H-imidazol-4-yl)propanamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (49 mg, 21%). 1H-NMR (400 MHz, CDCl3): δ 9.80 (s, 1H), 9.46 (s, 1H), 9.38 (br s, 1H), 7.80-7.15 (m, 9H), 7.00-6.79 (m, 6H), 4.82-4.71 (m, 1H), 4.54-4.38 (m, 2H), 4.01-3.59 (m, 3H), 1.45-1.34 (m, 3H). MS (EI) for C28H27FN4O4 found 503 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:4][CH:3]=1.[CH2:26]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][N:34]=[C:33]2I)[CH3:27].C([Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([NH:21][C:19]([C:8]1[C:6]2=[N:7][C:2]([C:33]3[C:32]4[C:36](=[C:28]([CH2:26][CH3:27])[CH:29]=[CH:30][CH:31]=4)[NH:35][N:34]=3)=[CH:3][N:4]=[C:5]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCc1cccc2c(I)n[nH]c12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCc1cccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)n[nH]c12
Temperature: 115 °C
Yield: 12.2 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (320 mg, 749 μmol) and 7-ethyl-3-iodo-1H-indazole (244 mg, 898 μmol) in DMF (2.5 mL) was added 1,1,1,2,2,2-hexabutyldistannane (651 mg, 412 μL, 1.12 mmol) under N2. After 10 min tetrakis(triphenylphosphine)palladium (0) (43.3 mg, 37.4 mmol) was added and the reaction mixture heated to 115° C. After 16 h the reaction was cooled and concentrated. The residue was diluted with 10% methanol/dichloromethane and filtered through a pad of celite. Purification of the filtrate by chromatography (silica, 5-45% ethyl acetate/hexane) gave N-tert-butyl-2-(7-ethyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (45 mg, 91.3 μmol, 12%) as an off-white solid. MS (M+H)+=493.4; 1H NMR (CDCl3) δ: 10.57 (s, 1H), 9.34 (s, 1H), 8.49 (d, J=7.5, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 7.35 (d, J=7.1 Hz, 1H), 7.29 (t, J=7.1 Hz, 1H), 5.77 (s, 2H), 3.62 (t, J=8.3, 2H), 3.07 (q, J=7.5 Hz, 2H), 1.68 (s, 9H), 1.50 (t, J=7.5 Hz, 3H), 0.98 (t, J=8.3, 2H), 0.0 (s, 9H).