Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[Cl:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: COc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
o-Anisidine (0.69 ml, 6.0 mmol) was dissolved in methylene chloride (10 ml) and, with cooling in an ice bath, mixed with 20% sodium hydroxide (5 ml) and 4-chloromethylbenzoyl chloride (1.17 g, 6.0 mmol). After 30 minutes of stirring at the same temperature, the reaction mixture was extracted with methylene chloride and then washed with 1N hydrochloric acid, water and saturated brine in that order. After drying on anhydrous magnesium sulfate, the solvent was removed by evaporation, and the resulting light beige solid was purified by recrystallization (ether-hexane) to obtain 1.56 g (94.2%) of the title compound in the form of colorless needle crystals.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16][CH2:15]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCC1COc2ccccc2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
46.14 g (242 mmol) of p-toluenesulphonyl chloride are added while stirring at room temperature to a solution of 36.12 g (220 mmol) of 3-hydroxymethylchroman in 100 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room temperature and then poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. 65.84 g (94%) of 3-(p-toluenesulphonyloxymethyl)chroman having a melting point of 86°-87° are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:20]>CO>[NH2:20][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Solvent: CO
Product: CC(C)(O)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
A mixture of 1.1 g (0.004 mole) of 4-chloro-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline and 30 ml of 15 to 20% ammonia in methanol was heated at 150° to 160° C. for five hours in a bomb reactor. The mixture was filtered and the solid washed sequentially with methanol, ethyl acetate, water, and methanol then dried. Recrystallization from a mixture of ethyl acetate and methanol gave white solid 4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline, m.p. 270°-272° C., Analysis: Calculated for C14H16N4O: % C, 65.6; % H, 6.3; % N, 21.9; Found: % C, 65.6; %H, 6.3; % N, 21.9.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[NH+:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[CH2:15](Br)[C:16]#[CH:17]>>[CH3:8][C:7]1[CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]=[N:3][C:2]=1[NH:1][CH2:17][C:16]#[CH:15]
Reactant: Cc1cc(-c2ccccc2)[nH+]nc1N
Reactant: C#CCBr
Product: C#CCNc1nnc(-c2ccccc2)cc1C

Procedure:
4-Methyl-6-phenyl-3-(prop-2-ynylamino)-pyridazine is prepared by heating 7 g of 3-amino-4-methyl-6-phenyl-pyridazinium and 9 ml of propargyl bromide at 60° C. for 2 hours. After evaporation of the excess propargyl bromide, the residue is taken up in 300 ml of anhydrous benzene, and 1.77 g of sodium are added. The mixture is heated under reflux for 15 hours and the solution is then poured into excess solid carbon dioxide and left in contact therewith for several hours.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:5][CH:4]=1.[Li+].CC([N-]C(C)C)C.[C:25](C#N)(=[O:29])[O:26][CH2:27][CH3:28]>>[O:14]=[C:10]1[CH:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:4][CH:5]=2)[CH2:13][CH2:12][CH:11]1[C:25]([O:26][CH2:27][CH3:28])=[O:29]
Reactant: CCOC(=O)C#N
Reactant: O=C1CCCC1c1ccc(C(F)(F)F)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)C1CCC(c2ccc(C(F)(F)F)nc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
2-(6-(trifluoromethyl)pyridin-3-yl)cyclopentanone (700 mg, 3.05 mmol) was added to a solution of LDA (2.291 mL, 4.58 mmol) at −78° C. After stirring for 30 min at −78° C., ethyl carbonocyanidate (0.329 mL, 3.36 mmol) was added to the reaction mixture. The resulting solution was warmed to room temperature with stirring over 3 h. The reaction mixture was quenched with 1 mL of water, washed with brine, dried over MgSO4, and purified by Biotage (Hexanes/EtOAc 2:1) to afford ethyl 2-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentanecarboxylate (764 mg, 2.54 mmol, 83% yield). LC-MS (M+H)+=302.2.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][NH:14][CH3:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC#N>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:14]([CH3:15])[CH3:13])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.2 %

Procedure:
A mixture of 4-acetylbenzoic acid (10.0 g, 60.9 mmol), 40% aqueous solution of dimethylamine (8.24 g, 73.1 mmol), EDC (14.0 g, 73.1 mmol), HOBT (11.2 g, 73.1 mmol) and DIEA (21.3 mL, 122 mmol) in CH3CN (150 mL) was stirred at room temperature for 15 h and concentrated. The residue was dissolved in ethyl acetate (600 mL), washed with water (2×80 mL), brine (80 mL), dried (MgSO4) and concentrated to provide 4-acetyl-N,N-dimethylbenzamide (9.80 g, 84%). MS (E+) m/z: 191 (M+H); HPLC retention time: 0.88 min (Analytical HPLC Method F).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:23][C:24]([F:42])([F:41])[C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)=[CH:27][CH:26]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][C:28]2[CH:39]=[CH:40][C:25]([C:24]([F:23])([F:41])[F:42])=[CH:26][CH:27]=2)=[CH:31][CH:32]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]([F:19])[F:20])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)F)cc1
Reactant: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)F)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(difluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-[4-(trifluoromethyl)phenoxy]benzoic acid used in Example 41 (41a) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:32])=[C:11]([C:28]([F:31])=[CH:29][CH:30]=1)[CH2:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:35]([Si:38](Cl)([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])([CH3:37])[CH3:36].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([F:32])=[C:11]([C:28]([F:31])=[CH:29][CH:30]=1)[CH2:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[N:15]([Si:38]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:35]([CH3:37])[CH3:36])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1Cc1c[nH]c2ncc(-c3cccnc3)cc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2c(F)ccc(OCc3ccccc3)c2F)c2cc(-c3cccnc3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To 3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (P-1455, 700.0 mg, 1.64 mmol, prepared as described in Example 24, Scheme 43a) in tetrahydrofuran (40.0 mL) was added sodium hydride (60% in mineral oil, 100.0 mg, 2.5 mmol). After 10 minutes, triisopropylsilyl chloride (0.60 mL, 0.0028 mol) was added to the reaction. The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (548, 0.85 g, 89%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:17][CH:16]=1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([N:24]([CH3:25])[CH3:26])=[O:27])=[CH:17][CH:16]=1
Reactant: CN(C)C(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)COc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a degassed solution of [4-(4-dimethylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester (28) (0.26 g, 0.68 mmol) in ethanol (10 mL) was added 10% palladium on activated carbon (0.1 g, 50% wet). The mixture was stirred at room temperature overnight under atmospheric hydrogen. The catalyst was filtered through a pad of diatomaceous earth and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide, 100:5:1, v/v) to provide 2-[4-(4-aminobutyl)phenoxy]-N,N-dimethylacetamide 29 (100 mg, 60% yield) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.55 (m, 4H), 2.55 (m, 2H), 2.66 (m, 2H), 2.90 (s, 3H), 3.05 (s, 3H), 4.70 (s, 2H), 6.80 (d, 2H), 7.05 (d, 2H). m/z (ESI): 251 [C14H22N2O2+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26](=[S:28])[NH2:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:30][C:31](=O)[CH3:32]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26]1[S:28][CH:30]=[C:31]([CH3:32])[N:27]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(N)=S)C1
Solvent: c1ccccc1
Product: Cc1csc([C@@H]2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Temperature: 75 °C
Yield: 44.9 %

Procedure:
To a solution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamothioylcyclohexylcarbamate (0.5 g, 0.0012 mol) in dry benzene (20 mL) under nitrogen was added chloroacetone (0.34 g, 0.0036 mol) and the reaction mixture was heated at 75° C. over night. Benzene was removed under vacuum and the crude was extracted with ethyl acetate. The organic layer was washed with brine, concentrated and purified by recrystallisation from ether to give 0.24 g (44%) of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-(4-methylthiazol-2-yl)cyclohexylcarbamate as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.65 (m, 3H), 1.78 (m, 2H), 2.19 (m, 2H), 2.42 (s, 3H), 3.49 (m, 1H), 3.70 (m, 1H), 4.05 (m, 1H), 5.04 (s, 2H), 5.29 (bs, 1H), 6.75 (s, 1H), 7.34 (m, 5H); 13H NMR (400 MHz, CDCl3) δ 16.4, 27.4, 27.8, 32.7, 41.9, 46.5, 49.7, 66.0, 78.5, 112.3, 127.3, 127.4, 127.8, 135.9, 151.8, 154.6, 155.2, 169.2. MS found: (M+H)+=446.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[NH:10][N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[C:19]([CH:35]=[O:36])=[C:20]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]#[N:34])=[CH:25]2)[CH:21]=[CH:22][CH:23]=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O.ClCCl.[Cu](I)I>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:18]1[C:19]([CH:35]=[O:36])=[C:20]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([C:33]#[N:34])=[CH:25]3)[CH:21]=[CH:22][CH:23]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cn(-c2cccc(Br)c2C=O)c2ccccc12
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccccc54)c3C=O)ncc2c1
Temperature: 110 °C
Yield: 77 %

Procedure:
To a solution of 6-tert-butyl-8-fluorophthlazine-1(2H)-one (prepared according to US2010/0222325) 36 mg, 0.16 mmol) and 1-(3-bromo-2-formylphenyl)-1H-indole-3-carbonitrile (59 mg, 0.18 mmol) in dry dimethylsulfoxide (1.8 mL) was added sodium bicarbonate (31 mg, 0.36 mmol) under an argon atmosphere. Next copper iodide (35 mg, 0.18 mmol) was added and the mixture was heated to 110° C. for 2 hours. The reaction was cooled to ambient and taken up in water (40 ml) and dichloromethane (40 ml). The material was filtered through a plug of celite, rinsing well with dichloromethane. The filtrate was transferred to a reparatory funnel and the dichloromethane phase was collected. This was washed with a 50% solution of diluted brine (40 ml). The organic phase was collected and the aqueous phases back extracted with dichloromethane (2×35 ml). The dichloromethane phases were combined, dried (MgSO4), filtered and stripped. Then the identical reaction was repeated on a larger scale using 1-(3-bromo-2-formylphenyl)-1H-indole-3-carbonitrile (290 mg, 0.89 mmol) and similar scaled amounts of the reagents described above and under identical procedure and work up. The crude from the two reactions was combined and purified by HPLC (silica gel, eluting with 100% CH2Cl2 to 1% MeOH/CH2Cl2) to provide a semi-pure product. The material was further purified by preparative thin layer chromatography (3 plates, eluting with 0.5% MeOH/CH2Cl2 and then re-eluting with 0.75% and then 1% MeOH/CH2Cl2). The product band was collected to provide 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3 carbonitrile as a yellow foamy solid. (384 mg, 77% yield). LC/MS calcd for C28H21FN4O2 (m/e) 464.49, obsd 465.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9H) 7.24-7.32 (m, 1H) 7.34-7.41 (m, 2H) 7.46-7.60 (m, 3H) 7.75 (d, J=7.55 Hz, 1H) 7.81 (s, 1H) 7.83-7.87 (m, 1H) 7.90 (t, J=7.96 Hz, 1H) 8.25 (d, J=2.64 Hz, 1H) 9.56 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[NH:3]1.Cl.Cl.[CH3:30][C:31]1([CH3:40])[CH2:36][NH:35][CH2:34][C:33]2[CH:37]=[N:38][NH:39][C:32]1=2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CO>[CH3:30][C:31]1([CH3:40])[CH2:36][N:35]([C:18]([C:17]2[CH:16]=[C:15]([N:12]3[CH2:13][CH2:14][CH:9]([N:8]4[CH2:7][CH2:6][C:5]5[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=5[NH:3][C:2]4=[O:1])[CH2:10][CH2:11]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:34][C:33]2[CH:37]=[N:38][NH:39][C:32]1=2
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: O=C(O)c1cccc(N2CCC(N3CCc4ccccc4NC3=O)CC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2cccc(N3CCC(N4CCc5ccccc5NC4=O)CC3)c2)Cc2cn[nH]c21
Temperature: 0 °C

Procedure:
70.0 mg (0.19 mmol) 3-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-benzoic acid, 60 mg (0.27 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-dihydrochloride, 100 μL (0.71 mmol) triethylamine and 70.0 mg (0.22 mmol) TBTU in 1 mL DMF were stirred overnight at RT. The reaction mixture was combined with 1 mL methanol and 10 mL ice water. The precipitated product was suction filtered, washed with water and diethyl ether and purified by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[C:24]2[C:29]([CH:30]=[C:31]3[C:36]=1[CH:35]=[CH:34][CH:33]=[CH:32]3)=[CH:28][CH:27]=[CH:26][CH:25]=2>>[CH:25]1[C:24]2[C:29](=[CH:30][C:31]3[C:36]([C:23]=2[CH2:22][N:8]2[C:9]([O:10][C:11]4[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1c2ccccc2cc2ccccc12
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2c3ccccc3cc3ccccc23)c1
Yield: 44.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (205 mg, yield: 44.1%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH-].[Na+]>Cl>[N:1]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: C1CNCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CCCNCC1

Procedure:
To a solution of homopiperazine (50.0 g, 0.5 mol) in aqueous HCl adjusted to pH 4 using approximately 400 mL of 2N HCl was added ethyl chloroformate (50 mL, 0.53 mol) dropwise maintaining the pH at 4 by the addition of 25% aqueous NaOH. The reaction mixture was brought to pH 14 with 25% aqueous NaOH and extracted with 3×250 mL of Et2O. These extracts were discarded and the aqueous was brought to pH 10 with 2N HCl and Na2CO3. After extracting the aqueous with 3×150 mL of Et2O, these combined extracts were dried over Na2SO4, and stripped of all solvent under reduced pressure. The residue was vacuum distilled at 0.1 mm of Hg and the title compound was obtained as the fraction (25.0 g) distilling at 103° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[C:12]([C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=3)=[N:13][O:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[O-]CC.[Na+].Cl>CN(C=O)C.O.CCOC(C)=O>[C:15]1([C:12]2[C:9]3[CH:10]=[N:11][C:6]([C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5])=[C:7]([OH:21])[C:8]=3[O:14][N:13]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: CCOC(=O)c1ncc2c(C3=CCCCC3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ncc2c(C3=CCCCC3)noc2c1O
Temperature: 25 °C
Yield: 75.9 %

Procedure:
3-Cyclohex-1-enyl-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (77 mg, 0.27 mmol) was dissolved in 10 mL of DMF. Glycine (0.40 g, 5.35 mmol) and sodium ethoxide (0.27 g, 4.01 mmol) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and diluted with 60 mL of water. EtOAc (50 mL) was added and the resulting biphasic mixture was stirred vigorously as 4M hydrochloric acid was added dropwise until pH was 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. The solvent was evaporated and the solid residue was taken up in 50 mL of saturated sodium bicarbonate solution. The aqueous phase was washed with hexanes and EtOAc. The aqueous layer was then acidified to pH 2 by addition of concentrated hydrochloric acid and the resulting precipitate was isolated by filtration to give 65 mg of the title compound. MS: (+) m/z 318.26 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[N:8]=[C:7]([NH:9][C:10](OCC)=[O:11])[N+:6]([O-:15])=[C:5]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:4]=1>CN(C)C=O>[CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:6]2[O:15][C:10](=[O:11])[N:9]=[C:7]2[N:8]=1
Reactant: CCOC(=O)Nc1cc(N(C)C)nc(NC(=O)OCC)[n+]1[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cc(N(C)C)nc2nc(=O)on12

Procedure:
1 G. of diethyl 6-dimethylamino-2,4-pyrimidine-dicarbamate-3-oxide is heated to 140° C. for 30 minutes in 10 ml. of N,N-dimethylformamide under an argon atmosphere. The solution is cooled and the solvent is evaporated under reduced pressure. The crystalline residue is recrystallized from methylene chloride/ethanol, there being obtained pure ethyl 5-dimethylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 230°-240° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[I:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[I:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cncn1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1

Procedure:
A solution of ethyl 1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (14) (5 g, 21.4 mmol), N-iodosuccinimide (12 g, 53.4 mmol), and THF (100 mL) was refluxed overnight. A solution of saturated sodium thiosulfate was added and the reaction was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to give ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: Cc1cc(O)cc(Br)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 110 °C
Yield: 85.2 %

Procedure:
To a solution of 3-bromo-5-methylphenol (2.0 g, 0.0106 mol) in DMF (15 mL) was added K2CO3 (2.93 g, 0.02 mol) at RT. 2-Chloro-5-(trifluoromethyl)pyridine (1.94 g, 0.0106 mol) was added and the reaction was refluxed at 110° C. for 12 h. The reaction mixture was quenched with water and extracted with EtOAc three times. The total organic extract was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3 g, 84.5%). 1H NMR (500 MHz, CDCl3): δ 8.45 (s, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.26 (d, J=14.95 Hz, 1H), 7.13 (s, 1H), 7.03 (d, J=10 Hz, 1H), 6.90 (s, 1H), 2.36 (s, 3H).
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2S(C)(=O)=O)[O:11][CH3:12])=[O:9])[C:4](=[O:25])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:25])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[O:11][CH3:12]
Reactant: CON(Cc1ccc(F)cc1S(C)(=O)=O)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OC
Yield: 100 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methoxy-acetamide was reacted with methanol using the procedure described for the synthesis of compound 90-C to yield 3-[(4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester as a white sticky solid (0.102 g, 100% yield). This was reacted with paraformaldehyde and 4-amino-butyric acid using the procedure described for Compound 810 to give the title compound as an orange solid (0.018 g, 14% yield). 1HNMR (300 MHz, CDCl3) δ: 7.78 (1H, dd, J=8.05, 2.56 Hz), 7.59–7.54 (1H, m), 7.36–7.29 (1H, m), 5.35 (2H, s), 4.25 (2H, s), 3.83 (3H, s), 3.60 (2H, t, J=6.95 Hz), 3.22 (3H, s), 2.43 (2H, t, J=6.95 Hz), 2.00–1.96 (2H, m).