Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11]O)C[CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)C1)[CH2:8]2.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:43](C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:20]1[C:21]2[C:16](=[CH:15][C:14]([O:13][C:5]3[CH:6]=[C:7]4[C:9](=[CH:3][CH:4]=3)[N:43]=[CH:11][CH:1]=[CH:8]4)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc2ncccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cnc2ccc(Oc3ccc4ncccc4c3)cc2c1
Reaction time: 0.25 h
Yield: 19.6 %

Procedure:
A mixture of 1-adamantanemethanol (5.00 g, 30.0 mmol) and 6-hydroxyquinoline (13.1 g, 90.2 mmol) in tetrahydrofuran (75 mL) was stirred for 15 min. Then, triphenylphosphine (10.2 g, 39.0 mmol) was added, followed by diethyl azodicarboxylate (6.14 mL, 39.0 mmol). The reaction mixture was refluxed for 18 h. The solvent was then removed by rotary evaporation. The resulting gel was filtered through paper with diethyl ether (3×25 mL). The filtrate was rotary evaporated, and the resulting gel was filtered through paper with hexanes (3×25 mL). Again the filtrate was rotary evaporated, the resulting gel was filtered through paper with hexanes (3×25 mL), and the filtrate was rotary evaporated. This provided 3.8 g (43%) of crude product as a red oil. This oil was chromatographed (2:1 hexanes/ethyl acetate) to provide 1.6 g (18%) of (94):
Reaction SMILES: O[C:2]1([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:17](=[O:19])[NH:18][C:12]=3[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:2]1([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:17](=[O:19])[NH:18][C:12]=3[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4(O)CCCCC4)cc3NC(=O)C2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCCCC4)cc3NC(=O)C2)c1
Yield: 46.3 %

Procedure:
Prepared from 3-[7-(1-hydroxy-cyclohexylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 135) (50 mg, 0.13 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (22 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[C:25]([C:26](O)=[O:27])[C:24]=1[C:32](O)=[O:33])([O-:22])=[O:21].C(N(C(C)C)CC)(C)C.C(N=C=NC(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:32](=[O:33])[C:24]4[C:25](=[CH:29][CH:30]=[CH:31][C:23]=4[N+:20]([O-:22])=[O:21])[C:26]3=[O:27])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3cccc([N+](=O)[O-])c3C1=O)OC2
Reaction time: 0 h

Procedure:
In a 4-ml scintillating vial, a solution of the above 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (63 mg, 0.2 mmol) in tetrahydrofuran (2.0 ml) was treated with 3-nitro-phthalic acid (66 mg, 0.3 mmol), diisopropylethylamine (190 μl, 1.1 mmol), and 1,3-diisopropyl-carbodiimide (120 μl, 0.77 mmol). The reaction mixture was shaken vigorously for 10 seconds before being stirred at 50° C. for 43 hours and at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with 0.5N aqueous hydrochloric acid (25 ml), saturated sodium bicarbonate (25 ml), and brine (25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo affording crude 2-amino-5-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) 4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.Cl.[C:37]1([CH3:46])[CH:42]=[CH:41][C:40]([C:43]([NH2:45])=[NH:44])=[CH:39][CH:38]=1.C(O)(=O)C>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])=[C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:45][C:43]([C:40]3[CH:41]=[CH:42][C:37]([CH3:46])=[CH:38][CH:39]=3)=[N:44]2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccc(C2=NC(c3ccc(Cl)c(Cl)c3)C(C(=O)OCCCc3ccccc3)=C(COCCN3CCCCC3)N2)cc1
Temperature: 60 °C
Yield: 0.3 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (7.9 g, 22.7 mmol), 3,4-dichlorobenzaldehyde (4.0 g, 22.7 mmol), p-toluamidine hydrochloride (3.87 g, 22.7 mmol) and glacial acetic acid (1.3 mL, 22.7 mmol) was stirred in N,N-dimethylformamide (40 ml) for 2 days at room temperature and then heated to 60° C. for 7 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (45 mg) as an oil. Electrospray MS m/z 620/622 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[O:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH2:33]([Mg]Br)[CH:34]=[CH2:35].CCOCC>C1COCC1>[CH2:35]([C@:29]1([OH:32])[C@H:26]2[O:27][CH2:28][C@@H:24]([O:23][C:21]3[NH:22][C:4]4[C:5]([N:20]=3)=[N:6][C:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)=[CH:10][CH:9]=3)=[C:2]([Cl:1])[CH:3]=4)[C@H:25]2[O:31][CH2:30]1)[CH:34]=[CH2:33]
Reactant: C=CC[Mg]Br
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred suspension of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (314.3 mg, 0.702 mmol) in THF (7.0 ml) was degassed (3×) and placed under nitrogen after being cooled to 0° C. in an ice bath. Allylmagnesium bromide 1.0 M in ether (1.4 ml, 1.400 mmol) was added to the reaction mixture dropwise over 6 minutes. After 1 hour, the reaction mixture was removed from the ice bath and allowed to warm to room temperature. The reaction mixture was transferred via pipette into saturated aqueous NaHCO3 (50 ml) before being partitioned between EtOAc (100 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a pale yellow residue. The residue was purified by flash chromatography utilizing a 40 g silica RediSep Rf® column and employing a 0-80% EtOAc/hexane gradient. The product fractions were combined and evaporated under reduced pressure to give the title compound as a colorless residue. LC-MS: calculated for C27H24ClN3O4 489.15 observed m/e: 490.19 (M+H)+ (Rt 1.23/2 min); 1H NMR δ (ppm) (CD3OD): 7.81 (s, 1H), 7.70-7-75 (m, 4H), 7.69 (d, J=7.9 Hz, 2H), 7.47 (t, J=7.7 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 5.90-5.99 (m, 1H), 5.53 (qt, J=5.5 Hz, J=10.8 Hz, 1H), 5.14 (broad d, J=12.9 Hz, 2H), 4.96 (t, J=5.3 Hz, 1H), 4.10-4.18 (m, 3H), 3.67 (abqt, J=8.5 Hz, J=24.6 Hz, 2H), 2.30-2.38 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:12][N:11]3[CH:24]=2)=[CH:4][CH:3]=1.[I:25]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)=[N:12][N:11]3[C:24]=2[I:25])=[CH:6][CH:7]=1
Reactant: Cc1c(N2CCNCC2)nn2cc(-c3ccc(F)cc3)nc2c1C
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(N2CCNCC2)nn2c(I)c(-c3ccc(F)cc3)nc2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution, cooled to 0° C., of 1.15 g (3.53 mmol) of 2-(4-fluorophenyl)-7,8-dimethyl-6-piperazin-1-ylimidazo[1,2-b]pyridazine in 20 mL of dichloromethane, is added dropwise a solution of 2.29 g (14.1 mmol) of iodine monochloride in 5 mL of methanol and the medium is stirred for 30 minutes at room temperature. 5% sodium thiosulfate solution is then added and the medium is basified by addition of sodium hydrogen carbonate.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:17]([NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:8])([F:19])[F:20])[CH:11]=1)=[O:18]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: CN1CCCC1=NC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Conversion of the hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) to the free base (4.9 g. assuming 100% conversion) is carried out in the usual manner. After drying over K2CO3, the benzene layer is stirred at room temperature and 9.36 g. (0.05 mole) of m-trifluoromethylphenylisocyanate is added (some solid precipitates). The reaction mixture is stirred overnight. The resulting solid is collected, m.p. = 155°-156° C. The benzene filtrate, upon removal of the solvent, affords an additional crop of solid material, m.p. 131°-137° C. Recrystallizations of the combined solids from acetone-pet. ether gives the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea, m.p. = 155°-156.5° C.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].C(N(CC)CC)C.[C:14]([O:18][C:19]([O:21]N=C(C1C=CC=CC=1)C#N)=O)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.O>[CH3:17][C:14]([CH3:15])([O:18][C:19]([N:1]([CH3:2])[CH2:3][C:4]([OH:6])=[O:5])=[O:21])[CH3:16]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CNCC(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CN(CC(=O)O)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A mixture of sarcosine (1.5 g., 16.7 mmole), triethylamine (3.5 ml., 1 eq.), and water (10 ml.) is treated with 2-(t-butyoxycarbonyloxyimino)-2-phenylacetonitrile (4.5 g., 1.1 eq.) in dioxane (10 ml.) at 25°. After 3 hours, the reaction mixture is diluted with water and then washed twice with ethyl acetate. The aqueous phase is acidified to pH 3.0 with 10% citric acid and the resulting oil is extracted with ethyl acetate (twice). The combined extracts are washed with brine, dried (MgSO4), and evaporated to give 3.0 g. of N-[(1,1-dimethylethoxy)carbonyl]-N-methylglycine as a viscous oil which crystallizes on standing; m.p. 84°-85.5°. Tlc (dichloromethane/methanol/acetic acid; 100:5:5) shows a single spot at Rf 0.6.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:6][CH2:5]1.[C:7]([CH2:10][N:11]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([CH2:23][C:24]([OH:26])=[O:25])[CH2:16][CH2:15][N:14]([CH2:27][C:28]([OH:30])=[O:29])[CH2:13][CH2:12]1)([OH:9])=[O:8].[OH-].[K+]>O1CCOCC1.O>[OH:6][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][N:20]1[CH2:21][CH2:22][N:11]([CH2:10][C:7]([OH:9])=[O:8])[CH2:12][CH2:13][N:14]([CH2:27][C:28]([OH:30])=[O:29])[CH2:15][CH2:16][N:17]([CH2:23][C:24]([OH:26])=[O:25])[CH2:18][CH2:19]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: COCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
7.63 g (86.58 mmol) of glycidyl methyl ether and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6 N potassium hydroxide solution. It is stirred for 24 hours at 50° C. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5 N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent =gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.38 g (77% of theory) of a greatly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]3[CH:33]=[CH:32][N:31](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:14]=2)[CH2:5][CH2:4]1.[OH-].[K+]>CO>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]3[CH:33]=[CH:32][NH:31][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:20][CH:21]=3)[N:14]=2)[CH2:5][CH2:4]1.[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]3[CH:33]=[CH:32][NH:31][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]4)=[CH:20][CH:21]=3)[N:14]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCC(CN)CC4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCC(CN)CC4)c4cc[nH]c4n3)cc2)CC1
Product: NCC1CCN(c2nc(Nc3ccc(N4CCNCC4)cc3)nc3[nH]ccc23)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (60 mg, 0.10 mmol) in MeOH (3 mL), aq. 1N KOH (1 mL) was added. It was stirred at 60° C. for 3 h. After being concentrated in vacuo, the residue was acidified with HOAc (1 mL). The mixture was then purified by HPLC to give 4-(4-(aminomethyl)piperidin-1-yl)-N-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (3 mg) (MS 407.5 (M+H); UV 202.6, 269.9 nm) and 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (15 mg) (MS 449.5 (M+H); UV 202.6, 273.4 nm).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=O.O.[NH2:16][NH2:17]>CO>[CH3:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([NH:16][NH2:17])=[O:2])[CH:13]=2)[CH:9]=[CH:10]1
Reactant: NN
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Solvent: O
Solvent: CO
Product: Cn1ccc2ccc(C(=O)NN)cc21

Procedure:
A mixture of 1-methyl-1H-indole-6-carboxylic acid methyl ester (3.2 g, 16.1 mmol), hydrazine monohydrate (8.5 g, 169 mmol) and methanol (50 ml) was stirred reflux for 15 h. The mixture was evaporated, water was added and the product was isolated by extraction with chloroform, followed by evaporation.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C=O.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH2:22])=[O:21].[C:28](=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:28][NH:22][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([C:16]([F:26])([F:27])[F:15])[CH:18]=2)[CH2:11][CH2:12]1
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(N2CCNCC2)nc1
Agent: C=O
Agent: [K+]
Solvent: CCO
Product: O=C(NCN1CCN(c2ccccn2)CC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), 3-trifluoromethylbenzamide (95 mg, 0.5 mmol), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 30 mg (55%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (t, J=4 Hz, 4H), 3.52 (t, J=4 Hz, 4H), 4.22 (d, J=5 hz, 1H), 6.62 (t, J=5 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.51 (t, J=6 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.92 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.10 (m, 2H), 9.05 (t, J=5 Hz, 1H); MS (ESI/APCI−) m/e 363 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]1=[O:25].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:9]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Cl)C(=O)OC1)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCC(N2CCC3(CCNCC3)C2=O)=C1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (2.26 g, 6.09 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (9.39 mL, 122 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles, the residue was partitioned between methylene chloride (100 mL) and 1N sodium hydroxide (100 mL). The alkaline phase was extracted with methylene chloride (2×100 mL). The combined organic phase was dried over sodium sulfate and concentrated to give 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LC/MS: (M+1)+: 271.07, 272.96.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:13][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
m-Nitrobenzoic acid (11.2 g, 67.0 mmol) was taken up in sulfuric acid (30 mL) and heated to 60° C. To this solution was added N-bromosuccinimide (14.3 g, 80.4 mmol) in three portions each over a 15 minute period. After stirring for 2 h, the mixture was poured into crushed ice (100 g) to precipitate a solid. The solid was filtered, washed with water followed by hexanes to give the desired product (16 g, 97%). LCMS for C7H3BrNO4 (M−H)+: m/z=244.0, 246.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:8]=[C:9](Br)[C:10]=1[OH:11])=[O:4].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([OH:11])=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:6]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccccc2)c1O
Temperature: 80 °C
Reaction time: 10 h
Yield: 70.5 %

Procedure:
To a solution of 5-Bromo-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methylester (0.3 g, 0.8 mmol) in toluene (5 mL) was added phenylboronic acid (0.19 g, 1.6 mmol), tetrakistriphenylphosphine (0.0.09 g, 0.08 mmol), Na2CO3(2.4 ml, 1N solution) and stirred the reaction mixture at 80° C. for 10 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silicagel column chromatography (20:80 EtOAc:hexane) gave pure 4′-Hydroxy-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (0.21 g).
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=[O:2].[O:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][NH2:34].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.C(OCC)(=O)C>[OH:2][CH:1]1[C:3]2[C:4](=[CH:9][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]=[N:24][N:25]([CH3:27])[CH:26]=4)=[CH:18][CH:17]=3)=[C:11]([CH3:14])[C:12]=2[CH3:13])[C:5](=[O:6])[N:34]1[CH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][O:28]1
Reactant: NC[C@@H]1CCCO1
Reactant: COC(=O)c1cc(Cc2ccc(-c3cn(C)nn3)cc2)c(C)c(C)c1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccc(-c3cn(C)nn3)cc2)cc2c(c1C)C(O)N(C[C@@H]1CCCO1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)benzoate (0.13 g) in THF (3.00 mL) were added 1-((2S)-tetrahydrofuran-2-yl)methanamine (0.04 mL) and anhydrous magnesium sulfate (0.04 g), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:14]1[O:16][CH2:15]1.[CH2:17]([C:21](C)=[O:22])C(C)C>>[OH:22][CH2:21][CH2:17][O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:13][CH2:15][CH2:14][OH:16])=[O:12]
Reactant: CC(=O)CC(C)C
Reactant: C1CO1
Reactant: O=C(O)CCCCCCCC(=O)O
Product: O=C(CCCCCCCC(=O)OCCO)OCCO

Procedure:
The reaction of 0.25 moles azelaic acid with 0.55 moles ethylene oxide under pressure using methyl isobutyl ketone in the presence of the catalyst of Example II (0.15% by wt. of total system) at 153° C gave bis(2-hydroxyethyl)azelate in quantitative crude yield. The material was isolated as a grey-white solid melting at 46°-47° C from a n-butyl chloride-acetone mixture in 88.5% yield.