Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:32]1[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 2.54 (s, 3H), 3.50 (s, 4H), 3.80 (s, 3H), 4.14 (s, 4H), 6.89 (d, J=7.7 Hz, 2H), 7.44 (s, 1H), 7.66 (s, 1H), 7.79 (s, 1H), 7.79 (s, 1H), 7.91 (d, J=7.7 Hz, 2H).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:8]([C:9](=[O:31])[NH:10][C@@H:11]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@@H:8]3[O:7][C@H:6]3[C:4]([OH:5])=[O:3])=[O:31])[CH2:27][CH:28]([CH3:29])[CH3:30])[S:16][CH:17]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)[C@@H]1O[C@H]1C(=O)O)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Yield: 75.6 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 17e (76.4 mg, 0.16 mmol); LiOH (8 mg, 0.34 mmol); after extraction afforded the desired product as a white solid (51 mg, 71.5%). 1H NMR (DMSO-d6, 400 MHz): δ 12.52 (s, 1H); 8.78-8.76 (d, 1H, J=8.0 Hz); 7.94-7.92 (t, 2H); 7.63 (s, 1H); 7.29-7.24 (t, 2H); 4.58-4.57 (m, 1H); 3.62-3.61 (d, 1H, J=1.80 Hz); 3.41-3.40 (d, 1H, J=1.80 Hz); 1.64-1.51 (m, 3H): 0.91-0.88 (dd, 6H). 13C NMR (DMSO-d6, 100 MHz): 171.02, 166.26, 162.88, 160.46, 157.72, 147.81, 130.80, 130.77, 127.62, 127.54, 115.59 (d, J=21.6 Hz); 107.97, 52.36, 52.08, 51.37, 28.89, 24.25, 22.82, 21.19. EST-HRMS (m/z): [M+H+] calcd for C19H20FN3O5S: 422.1180, observed: 422.1186. HPLC Method 1: Rt=23.8 min, purity=95.1%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=O)[C@H:10]([CH3:20])[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[CH3:20][C@H:10]1[C@H:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N1CCCC1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Product: C[C@@H]1CNCC[C@H]1N1CCCC1

Procedure:
The title compound was prepared in analogy to 193B, by reduction of (trans)-3-methyl-4-(2-oxo-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester with lithium aluminium hydride and subsequent deprotection with 4M hydrochloric acid in dioxane. MS: 169.2 (MH+).
Reaction SMILES: C(N(CC)CC)C.[F:8][CH:9]([F:21])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].[CH2:22]([O:24][C:25](=[NH:29])[O:26][CH2:27][CH3:28])[CH3:23]>CC(C)=O>[CH2:22]([O:24][C:25](=[N:29][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH:9]([F:21])[F:8])(=[O:19])=[O:18])[O:26][CH2:27][CH3:28])[CH3:23]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)F
Reactant: CCOC(=N)OCC
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=NS(=O)(=O)c1ccccc1OC(F)F)OCC
Temperature: 25 °C

Procedure:
11.1 g (0.11 mol) of triethylamine are added dropwise at room temperature, with stirring, to a solution of 24.3 g (0.1 mol) of 2-difluoromethoxy-benzenesulfonyl chloride and 11.7 g (0.1 mol) of imidocarbonic acid diethyl ester in 70 ml of acetone. The reaction proceeds slightly exothermically. The reaction mixture is stirred for some hours at room temperature, and the triethylamine hydrochloride is then filtered off. The mother liquor is concentrated by evaporation, and the oil remaining is chromatographed by means of chloroform/ether/petroleum ether (3:3:2) on a silica gel column. After the eluate has been evaporated, there remain 23 g of the above ester, which crystallise (72% of theory), m.p. 80°-81° C.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][CH:24]=[CH2:25])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][CH2:24][CH3:25]
Reactant: C=CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Yield: 92.3 %

Procedure:
The same operation as in Example (90d) was performed using tert-butyl cis(±)-4-(benzylamino)-3-allyloxypiperidine-1-carboxylate obtained in Example (113c) (4.96 g, 14.3 mmol), 10% Pd/C (wet, 1.5 g), ammonium formate (5.42 g, 86 mmol) and methanol (30 mL), to obtain 3.41 g of the title compound as a colorless oily substance (93%).
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:2]1([CH2:1][CH2:8][CH:9]([OH:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](=[CH:19][C:20](=[O:22])[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)CCc1ccccc1
Agent: CC(=O)C=Cc1ccccc1
Product: CC(O)CCc1ccccc1

Procedure:
Next, the reaction product was analyzed by NMR using proton (nuclear magnetic resonance apparatus, hereinafter to be called 1H-NMR). FIG. 5 is a view illustrating the reaction products from hydrogenation reaction of benzalacetone of Example 1. As is obvious from the figure, 4-phenyl-2-butanone and 4-phenyl-2-butanol were obtained by hydrogenation of benzalacetone within five minutes as reaction time at the yield of 97% and 3%, respectively.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:16][F:17])([CH3:15])[CH:3]=1.Cl.[CH3:19][N:20](C)C=O>>[C:19]([C:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:16][F:17])([CH3:15])[CH:3]=1)#[N:20]
Reactant: CN(C)C=O
Reactant: CC1(CF)C=C(Br)c2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Product: CC1(CF)C=C(C#N)c2cc([N+](=O)[O-])ccc2O1

Procedure:
A mixture of 5.6 g of 4-bromo-2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran, 1.84 g of cuprous cyanide and 50 ml of N,N-dimethylformamide was refluxed with heating for 5 hours under a nitrogen atmosphere. When aqueous HCl solution was added to the mixture under ice-cooling, crystals were separated out. The crystals were collected by filtration, washed with water and dissolved in methylene chloride. After it washed with water and dried, the solvent was evaporated off. The resultant residue was purified with silica gel column chromatography (developing solution: CH2Cl2) to obtain 3.27 g of 4-cyano-2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran with a melting point of 169°-171° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-])=O)[CH:6]=[C:5]1[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.O1CCCC1.O.NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.CO>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:13])[CH:6]=[C:5]1[C:16]1[S:17][CH:18]=[CH:19][N:20]=1
Reactant: COCn1c(-c2nccs2)cc2cccc([N+](=O)[O-])c21
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCn1c(-c2nccs2)cc2cccc(N)c21
Yield: 97.5 %

Procedure:
A mixture of 1-(methoxymethyl)-7-nitro-2-(1,3-thiazol-2-yl)-1H-indole (2.14 g), iron(III) chloride hexahydrate (0.12 g), activated carbon (1.20 g), tetrahydrofuran (10 mL) and methanol (10 mL) was heated under reflux for 20 min. To the reaction mixture was added hydrazine monohydrate (2.20 g) over 15 min while heating under reflux. The reaction mixture was heated under reflux for 2 hr, filtrated, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (1.87 g, yield 97%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24](O)=O>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: Clc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)c(Cl)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(2,4-dichlorophenyl)propionic acid (220 mg; 1 mmol) as described in method 2;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1)[NH2:8]
Reactant: Cc1ncn(-c2c(F)cc([N+](=O)[O-])cc2F)n1
Agent: [Pd]
Solvent: CO
Product: Cc1ncn(-c2c(F)cc(N)cc2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Step R (2): 10% Palladium on carbon (0.890 g, 0.830 mmol) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (2.00 g, 8.33 mmol dissolved in methanol (200 mL). The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 18 h under the hydrogen atmosphere. The vessel was subsequently purged with nitrogen gas. The crude reaction mixture was filtered through a short plug of diatomaceous earth (Celite®). The reaction vessel and Celite® were rinsed with fresh methanol. The combined filtrates were concentrated in vacuo. The residue was dried under high vacuum to afford 3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (1.76 g, 8.37 mmol, quantitative yield) as a blackish/gray solid. LC-MS (M+H)+ 211.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.10 (1 H, s), 6.25-6.36 (2 H, m), 4.17 (2 H, br. s.), 2.49 (3 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([C:20]([CH3:30])([C:26]([O:28]C)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:31]#[N:32])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O.CO>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([C:20]([CH3:30])([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:31]#[N:32])=[CH:33][CH:34]=2)=[O:10])=[CH:35][CH:36]=1
Reactant: COC(=O)C1(C)CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C(=O)O)CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Reaction time: 3 h
Yield: 34.2 %

Procedure:
Methyl 7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyano-4-methylchroman-4-carboxylate (12 mg, 0.0238 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (0.0475 mL, 0.238 mmol) and 200 μL of water and methanol. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using the Horizon with a 25 cartridge and running a gradient 0.5% methanol/0.5% acetic acid/CH2Cl2 to 10% methanol/0.5% acetic acid/CH2Cl2 to yield the title compound (4.0 mg, 34.3% yield) as a white solid. MS (ESI)=490.9 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:19])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1.Cl>CO.C1COCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH2:6][C:5]([OH:19])=[O:4])=[CH:9][C:10]=1[C:15]([F:16])([F:17])[F:18]
Reactant: COC(=O)CNc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 2 N aqueous NaOH solution (15.0 ml, 30.0 mmol) was added to a solution of (4-bromo-3-trifluoromethyl-phenylamino)-acetic acid methyl ester (4.30 g, 13.8 mmol) in methanol-THF (6:1, 35.0 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was made acidic with hydrochloric acid and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over MgSO4 and concentrated under reduced pressure to give (4-bromo-3-trifluoromethyl-phenylamino)-acetic acid (4.03 g, 98%).
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29](S(C)=O)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29]([O:7][CH2:6][CH:2]4[CH2:1][O:5][CH2:4][O:3]4)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1
Reactant: OCC1COCO1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCC2COCO2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To a solution of glycerol formal (0.729 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a white precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a white solid (0.195 g, 51%). Mass (m/z): 384.1 (M++1), 382.1 (M+−1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=O)[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:39]1[C:43]2[CH:44]=CC=C[C:42]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N)(C)C>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH3:42][CH:43]([NH:39][C:34](=[O:36])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[N:32][CH2:31]1)[CH3:44]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.2 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and isopropylamine (34 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) and crystallized from acetonitrile to give the title compound (128 mg, yield 79%) as white crystals.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14]1.C(Cl)Cl.O.NN>C(O)C>[NH2:3][O:12][CH:13]1[CH2:14][N:15]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(ON2C(=O)c3ccccc3C2=O)CN1C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(ON)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of di-tert-butyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]pyrazolidine-1,2-dicarboxylate 142 (1.81 g, 4.18 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.240 mL, 4.18 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 143 (1.04 g, 83%) as a white foam.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23](Cl)[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+:2]=[N-:3].[NH3:25]>CO>[N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH2:25])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: N
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Solvent: CO
Product: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(N)ncnc43)[C@@H]2O1
Yield: 56 %

Procedure:
A solution of 7-[(3aS,4R,6R,6aR)-6-(Azidomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 2.87 mmol) in 7M NH3 in MeOH (0.41 ml) was heated to 100° C. in a sealed bomb for 48 hrs. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by silica flash column chromatography, eluting with 100% DCM to 16% MeOH in DCM afford the title compound (527.5 mg, 56%) as a brown gum: MS (ESI+) for C15H19N7O2 m/z 330.5 [M+H]+, 352.0 [M+Na]+; LC purity 99% (UV), 100% (ELS) (ret. time, 1.34 min); 1H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.03 (d, J=3.6 Hz, 1H), 6.37 (d, J=3.6 Hz, 1H), 5.08 (s, 2H), 4.98-5.03 (m, 1H), 4.98-5.03 (m, 1H), 4.91-4.98 (m, 1H), 4.61 (dd, J=7.1, 5.5 Hz, 1H), 4.61 (dd, J=7.1, 5.6 Hz, 1H), 3.57 (dd, J=5.9, 2.8 Hz, 2H), 2.15-2.36 (m, 1H), 2.36-2.61 (m, 2H), 1.58 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)=[CH:11][CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:14]=2)=[CH:5][CH:4]=1.BrB(Br)Br>ClCCl.C([O-])(=O)C.[Na+]>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)=[CH:11][CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)c1
Agent: BrB(Br)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(O)cc2)c(-c2ccc(O)cc2)c1
Reaction time: 16 h
Yield: 32.8 %

Procedure:
2.7 g of methyl 4,4″-dimethoxy-(1,1′:2′,1″-terphenyl)-5′-carboxylate (product prepared according to J. Med. Chem. (1989) 32 1814-1820) in 30 ml of dichloromethane is cooled down to −30° C., under an inert atmosphere, 2.7 ml of tribromoborane is added and agitation is carried out at −30° C. for 16 hours. The reaction medium is diluted with a saturated solution of sodium acetate, the aqueous phase is extracted with ethyl acetate, the organic phase is dried then evaporated. The crude reaction product is chromatographed on silica eluting with a cyclohexane/ethyl acetate mixture 70/30. In this way 814 mg of expected product is obtained.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-:29])=[O:28])=[CH:25][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:6]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:1][CH:3]2[O:5][CH2:4]2)=[O:28])=[CH:30][CH:31]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: ClCC1CO1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC2CO2)cc1
Temperature: 105 °C
Reaction time: 5 h

Procedure:
A mixture of 89.0 g of epichlorohydrin, 92.0 g of sodium 4-(n-hexadecylamino)benzoate, and 350 ml of hexamethylphosphoramide is stirred at 105° C for 5 hours, allowed to cool, and poured into 1.0 liter of water. The white solid is collected by filtration, recrystallized from acetonitrile and then from hexane-methylene chloride to yield 2,3-epoxypropyl 4-(n-hexadecylamino)benzoate, mp 86°-89° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5](Br)[N:6]=1.C([Li])CCC.[Cl-].[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24](=[O:29])[CH2:25]2)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>C(OCC)C>[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24]([OH:29])([C:5]1[N:6]=[CH:2][S:3][CH:4]=1)[CH2:25]2)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Brc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cscn1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
2,4-dibromothiazole (1.1 g, 4.52 mmol) in diethyl ether (5 mL) was added to a solution of n-butyl lithium (2.5 M, 2 mL, 5 mmol) in diethyl ether (10 mL) at −78° C. and stirred for 0.5 hours. Trimethylsiliyl chloride (0.57 mL, 4.52 mmol) was added and the reaction mixture stirred for a further 0.5 hours before more n-butyl lithium (2.5M, 2 mL, 5 mmol) was added and stirred for 0.5 hours. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.9 g, 4 mmol) in diethyl ether (5 mL) was added and stirred for 0.5 hours before the reaction mixture was warmed to room temperature. Saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20-30% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.22 g). LCMS m/z 311.3 [M+H]+. R.T.=3.05 min. (Analytical Method 3).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=O)[N:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:17]([C:13]1[N:12]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:16]=[CH:15][CH:14]=1)=[O:19])[CH2:21][CH2:22][CH3:23]
Reactant: CCc1cc(-c2cccc(C(=O)O)n2)c(C)[nH]c1=O
Reactant: CCCCN
Product: CCCCNC(=O)c1cccc(-c2cc(CC)c(=O)[nH]c2C)n1

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carboxylic acid and n-butyl amine to afford the title compound. MS: m/e=314 (M+H).