Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:11]=[C:12](/[CH:19]=[CH:20]/[C:21]([OH:23])=O)[N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12.[C:24]([O:28][C:29](=[O:38])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37])([CH3:27])([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[N:10]1[CH:11]=[C:12](/[CH:19]=[CH:20]/[C:21]([NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30][C:29](=[O:38])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:23])[N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)/C=C/c1cnc2ccccn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
Diisopropylethylamine (DIPEA, 0.34 g, 2.63 mmol) was added to a solution of (E)-3-(imidazo[1,2-a]pyridin-3-yl)acrylic acid (0.17 g, 0.88 mmol) in 20 mL of dichloromethane (DCM). After addition of tert-butyl-2-aminophenylcarbamate (0.22 g, 1.65 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.43 g, 1.14 mmol) the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the reaction mixture was washed with saturated sodium bicarbonate (NaHCO3) and brine. It was dried over Na2SO4, filtered and evaporated to give crude (E)-tert-butyl (2-(3-(imidazo[1,2-a]pyridin-3-yl)acrylamido)phenyl)carbamate. The solid was washed with ethyl acetate (50 mL) and saturated NaHCO3 gave pure product as a light colored solid (0.11 g). ES+(M+H)+379.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:18])=O>CN(C)C=O>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:18])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Temperature: 50 °C

Procedure:
A mixture of 150.0 g (0.725 mol) of 4-(2,2-dimethyl-1-oxopropyl)-benzoic acid and 0.3 ml of dimethylformamide are added with stirring at 22° C. to 30° C. to 180 ml (2.47 mol) of thionyl chloride over a period of 60 minutes. The resulting solution is heated to an internal temperature of 85° to 90° C., and maintained at this temperature for 15 minutes. The solution is allowed to cool to 50° C. to remove as much thionyl chloride as possible by vacuum distillation (20-30 torr) at an internal temperature of 45° to 55° C. Distillation is discontinued when the internal temperature reaches 55° C and 95 ml of dry toluene are added. The distillation is continued under vacuum at an internal temperature of 45° to 55° C. and again discontinued when the internal temperature reaches 55° C. at 20-30 torr. After allowing the residue to cool to 25° C. and diluting it with 950 ml of dry toluene, the solution is set aside for use below.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([OH:16])[C:9]3[S:15][CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:31])([F:30])[S:26]([O:16][C:8]1[C:9]2[S:15][CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:7]=1)(=[O:28])=[O:27]
Reactant: Oc1nc(C2CCCC2)nc2c1SCCC2
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1nc(C2CCCC2)nc2c1SCCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a suspension of 2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (2.9 g, 12.3 mmol) in methylene chloride (100 mL) at 0° C. was added N,N-dimethylaminopyridine (0.020 g, cat.), triethylamine (3.5 mL, 24.6 mmol) and trifluoromethanesulfonic acid (2.3 mL, 13.5 mmol). The suspension was warmed to rt and stirred for 3 h. The mixture was cooled to 0° C. and the reaction was quenched with a saturated solution of NaHCO3. The organic layer was washed a saturated solution of NaHCO3 and brine. The organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (3.40 g, 75%) as, a yellow solid. MW=368.40. 1H NMR (CDCl3, 500 MHz) δ 3.28-3.20 (m, 1H), 3.10-3.05 (m, 1H), 2.98 (t, J=6.5 Hz, 2H), 2.31-2.24 (m, 2H), 2.09-1.99 (m, 2H), 1.89-1.76 (m, 4H), 1.70-1.62 (m, 2H); APCI MS m/z 369 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][CH2:4][C@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H]1CN
Yield: 100 %

Procedure:
A mixture of (R)-tert-butyl 2-(azidomethyl)azetidine-1-carboxylate (17 g, 80 mmol), 10% Pd/C (2 g) and MeOH (150 mL) was stirred under 45 psi hydrogen for 1 hour. The catalyst was filtered off and the filtrate was concentrated to give (R)-tert-butyl 2-(aminomethyl)azetidine-1-carboxylate (14.9 g, yield 100%). LRMS (M+H+) m/z 187.3.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([F:34])=[C:8]2[C:12]([C:13](=[O:33])[C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[N:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:11][NH:10][C:9]=12)(=O)[CH3:2].Cl.[O:36]([NH2:38])[CH3:37]>CCO>[F:34][C:7]1[CH:6]=[N:5][C:4](/[C:1](=[N:38]/[O:36][CH3:37])/[CH3:2])=[C:9]2[NH:10][CH:11]=[C:12]([C:13](=[O:33])[C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:25]=[N:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[C:8]=12
Reactant: CC(=O)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CO/N=C(\C)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C

Procedure:
To a suspension of 1-(7-acetyl-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.05 g, 0.11 mmol) in EtOH (10 mL) was added methoxylamine hydrochloride (0.05 g, 0.60 mmol). The mixture was heated to reflux for 1 h, and was then cooled to rt, and concentrated in vacuo. The residue was diluted with MeOH, and the solids that formed were collected and washed with water. The title compound was isolated as a light-yellow solid (0.025g). LCMS: m/e 492.4 (M+H)+, ret time 2.068 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.02 (s, 1 H) 8.36 (d, J=2.14 Hz, 1 H) 8.27 (d, J=3.36 Hz, 1 H) 7.56-7.71 (m, 5 H) 4.13-4.16 (m, 3 H) 3.68-3.73 (m, 2 H) 3.43-3.48 (m, 2 H) 3.29-3.36 (m, 2 H) 3.13-3.18 (m, 2 H) 2.36 (s, 3 H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(N4CCOCC4)ncnc32)[C@]1(C)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 30 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.3 g, 0.64 mmol) in ethanol (about 5 ml) was added morpholine (about 0.56 ml, 6.49 mmol) and stirred at room temperature for about 15 hours. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.1 g) as a colorless gummy mass. Yield: 30%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([OH:33])(=[O:32])[CH2:28][CH2:29][C:30]#[CH:31].C(N(CC)CC)C>COCCOC.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:31]#[C:30][CH2:29][CH2:28][C:27]([OH:33])=[O:32])=[CH:20][CH:19]=1)=[O:26])[CH3:9]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: C#CCCC(=O)O
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(C#CCCC(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.200 g, 0.46 mmol), 4-pentynoic acid (0.054 g, 0.55 mmol), copper iodide (spatula tip), triethylamine (0.12 mL, 0.84 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.053 g, 0.05 mmol) were combined in DME (5 mL), and the reaction was purged with N2 for 15 minutes and then stirred at 80° C. overnight. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound. Mass spec. data (M+H)=453.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 4.00 g of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate and 5 ml of aniline was stirred at 110° C. for 24 hours. The reaction mixture was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 3.94 g of the desired compound as a syrup.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH:6]1[CH3:20])=[O:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:29]([O:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[OH:45])=[O:37])[CH3:30]>CC(=O)CC>[CH2:29]([O:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[O:45][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4])=[O:37])[CH3:30]
Reactant: CCOC(=O)CCCC(=O)c1cc(Cl)ccc1O
Reactant: CC1CN(C(=O)CCl)C(C)CN1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 60 °C
Reaction time: 12 h
Yield: 47.7 %

Procedure:
To a solution of (2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.10 g, 0.35 mmol) in 2-butanone (1 mL) was added potassium carbonate (0.13 g, 0.90 mmol), potassium iodide (0.065 g, 0.39 mmol) and 5-(5-chloro-2-hydroxy-phenyl)-5-oxo-pentanoic acid ethyl ester (0.11 g, 0.39 mmol). The reaction was stirred at 60° C. for 12 hours, then cooled and concentrated. Chromatography on silica gel gave the title compound (0.089 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=O)=[O:12].[Na+].S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:25])=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([Cl:25])(=[O:14])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 104 g of commercially available sodium 2-chloro-5-nitrobenzenesulfonate, 200 ml of acetonitrile and 200 ml of sulfolane stirred at 25° C., was added 153 ml of phosphorus oxychloride over a period of 30 minutes. The temperature was not allowed to exceed 40° C. After completion of the addition, the reaction mixture was heated to 70° C. for 1.5 hours. On cooling to 0° C., the reaction mixture was poured over ice. The resulting solid product was washed with cold water, filtered and air-dried to give 77.6 g of the title compound with a melting point of 87°-89° C.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9](Cl)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=[O:15])C>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9](=[O:15])[NH:10][N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)O
Reactant: Clc1ccc(-n2ccnc2)nn1
Product: O=c1ccc(-n2ccnc2)n[nH]1
Yield: 55 %

Procedure:
9.93 g (0.055 mole) of 6-(1-imidazolyl)-3-chloropyridazine [prepared according to J. Med. Chem. 24, 59 (1981)] are boiled with 7.7 g (0.0781 mole) of fused potassium acetate in 114 ml of acetic acid under reflux for 10 hours and then evaporated to dryness under reduced pressure. The residue is taken up in 200 ml of chloroform, the precipitate is filtered off, washed 4 times with water, then with ether and diisopropyl ether and dried to give 4.9 g (55% yield) of the aimed product, m. p. 239°-240° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1.Cl.[CH2:18](O)[CH3:19]>>[NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:18][CH3:19])=[O:14])=[CH:8][CH:9]=1
Reactant: NCCc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCC(=O)c1ccc(CCN)cc1

Procedure:
On to a mixture of 127.2 g. (0.49 mole) of the acid obtained according to (b) and 800 ml. ethanol is passed, while stirring, gaseous hydrogen chloride and the reaction mixture is heated to reflux temperature for 2 hours, whereafter it is then strongly cooled. The precipitated crystals are filtered off with suction, washed with cold ethanol and dried over anhydrous calcium chloride. Yield 137.1 g. (97% of theory) of hydrochloride; m.p. 162°-165° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH3:25])[C:21]([NH2:23])=[O:22])=[CH:16][CH:15]=1)C(OCC)=O)C>C(O)C>[N:32]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:24]([CH:20]([C:21]([NH2:23])=[O:22])[C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:7][C:6]([OH:38])=[O:5])=[CH:19][CH:18]=2)[CH3:25])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CCOC(=O)C(Cc1ccc(C(C(N)=O)C(C)c2ccccc2N2CCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(CCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Five milliliters of 1N sodium hydroxide solution were added to a solution of 0.85 gm (1.7 m mol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzyl malonic acid diethyl ester in 18 ml of ethanol. After stirring for two hours at 50° C., the mixture was evaporated in vacuo, and water and 5 ml of 1N hydrochloric acid were added. The precipitate formed was filtered off, dried in vacuo, and heated for 30 minutes up to 120° C., whereby carbon dioxide was split off. The product obtained was purified by column chromatography on silica gel (chloroform/methanol=20:1).
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([CH3:38])([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:9]([CH2:28][CH2:29][CH3:30])[CH:8]=1)C.[OH-].[Na+].Cl>CCO>[CH3:38][C:5]([O:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[C:9]([CH2:28][CH2:29][CH3:30])[CH:8]=1)[C:4]([OH:39])=[O:3]
Reactant: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A solution of 3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-3-propyl-phenyl}-2-methyl-2-phenoxy-propionic acid ethyl ester in EtOH (1.5 mL) was treated with 5 N NaOH (140 μL) and then warmed to 65° C. After 18 h, the mixture was acidified to pH=1 with 5 N HCl. The mixture was extracted with EtOAc and then the combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure to yield the title product. MS (EI) 500.2 (M+H)+; LC RT=3.22 min (>99% pure).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[NH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=1
Reactant: CC(C)(C)CCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCC(C)(C)C)cc1

Procedure:
A solution of 10 g. of 13,13-dimethyltetradecyl bromide and 10.8 g. of ethyl 4-aminobenzoate in 75 ml. hexamethylphosphoramide is heated at 110° C. for 17 hours. The cooled solution is diluted with 100 ml. water, filtered, and the residue is washed in portions with 100 ml. 50% ethanol-water. After drying, the product is crystallized from ethanol to yield ethyl 4-(13,13-dimethyltetradecyl)aminobenzoate as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[CH:19][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(O)C>[C].[Pd].O1CCCC1>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[C:5]3[CH:19]=[C:20]([CH3:21])[C:2]([CH3:1])=[CH:3][C:4]=3[N:8]=[CH:7]2)=[CH:11][CH:12]=1
Reactant: Cc1cc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2cc1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2ncn(Cc3ccc(N)cc3)c2cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
A mixture of 5,6-dimethyl-1-(4-nitrobenzyl)-1H-benzimidazole (2.5 g), 10% palladium carbon (300 mg), ethanol (150 ml) and tetrahydrofuran (150 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-methanol gave 1-(4-aminobenzyl)-5,6-dimethyl-1H-benzimidazole (1.88 g, 84%) as colorless prism crystals. melting point: 238-239° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)=[CH:11][C:10]=1[O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32].C1(O)C=CC=CC=1.N(C)(C)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[C:31]#[N:32])[C:17](=[O:20])[CH2:16]2)=[CH:11][C:10]=1[O:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(OCc3ccccc3)c(OC3CCCC3)c2)CN1
Reactant: N#Cc1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)C
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: N#Cc1cccc(N2CC(c3ccc(OCc4ccccc4)c(OC4CCCC4)c3)CC2=O)c1
Reaction time: 24 h
Yield: 74 %

Procedure:
A mixture of 4-(4-benzyloxy-3-cyclopentyloxyphenyl)pyrrolidin-2-one, 3-bromobenzonitrile, phenol (0.1 mmol), copper acetate (0.15 mmol), arylboronic acid (0.12 mmol), 4 Å Molecular Sieves (“MS”) (p100 mg) and CH2Cl2 (1 mL) was created in a dry round bottom flask. (CH3)3N (0.22 mmol) was added, the flask was sealed, and the mixture was stirred for 24 h. The reaction mixture was then diluted with 10 mL of CH2Cl2 and filtered. The filtrate was washed with saturated NH4Cl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel or preparative liquid chromatography-mass spectrometry LC-MS to give pure product. Yield: 74%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1([OH:18])[CH2:17][NH:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:16]2[CH2:17][C:14]([OH:18])([CH3:13])[CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1(O)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(O)CN(C2CN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.21 g, 1.23 mmol), 3-methylazetidin-3-ol (0.13 g, 1.48 mmol) and 4 Å molecular sieves (1.2 g) in DCE (5 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.52 g, 2.47 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the solution was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, 0:100 to 100:0) to give 3-Hydroxy-3-methyl-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester as a colourless oil (0.09 g, 30%). 1H NMR (300 MHz, CDCl3): δ 3.93 (dd, J=9.2, 7.2 Hz, 2H), 3.82-3.70 (m, 2H), 3.50-3.40 (m, 1H), 3.32 (d, J=8.1 Hz, 2H), 3.21 (d, J=8.1 Hz, 2H), 1.51 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][C:11](O)=O.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15].B(F)(F)F>>[CH3:11][C:10]1[O:17][C:14](=[O:16])[CH:15]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=12
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1cc2ccccc2[nH]1
Agent: FB(F)F
Product: Cc1oc(=O)cc2c1[nH]c1ccccc12

Procedure:
Indoleacetic acid was reacted with acetic anhydride in the presence of boron trifluoride to obtain 1-methylpyrano[3,4-b]indol-3-one. The product was reacted with dimethyl acetylenedicarboxylate to obtain dimethyl 1-methylcarbazole-2,3-dicarboxylate.