Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C@H:9]2[C@@H:13]([CH2:14][OH:15])[O:12][C:11]([CH3:17])([CH3:16])[N:10]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:25][O-:26].[Na+]>CO.O>[OH:15][CH2:14][C@H:13]1[O:12][C:11]([CH3:17])([CH3:16])[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:9]1[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:26][CH3:25])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO)OC1(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1

Procedure:
(4S,5S)-Tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (0.200 g, 0.560 mmol) was dissolved in a 25% solution of SODIUM METHOXIDE (12.8 ml, 56.0 mmol) in methanol and refluxed for 12 hrs and cooled. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give (4S,5S)-tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate, MS m/z: 353.3 (100%, M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])(=O)=O.C[NH2:17]>C1COCC1.CCOCC>[C:10]1([C@H:8]([OH:9])[CH2:7][CH2:6][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN
Reactant: CS(=O)(=O)OCC[C@@H](O)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCC[C@@H](O)c1ccccc1

Procedure:
A solution of (R)-3-phenyl-3-(hydroxy)-propyl methanesulfonate (3 mmol) and methylamine (10 mL, 40% in water) in THF (10 mL) is heated at 65° C. for 3 h. After cooling, the solution is diluted with ether, washed with saturated aqueous sodium bicarbonate and brine, and dried with anhydrous potassium carbonate. Concentration of extract provides (R)-3-phenyl-3-(hydroxy)-propyl amine.
Reaction SMILES: CN([CH2:4][CH:5]1[CH2:12][N:11]2[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]1=[O:13])C.[C-:14]#[N:15].[K+]>>[C:14]([CH2:4][CH:5]1[CH2:12][N:11]2[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]1=[O:13])#[N:15]
Reactant: [C-]#N
Reactant: CN(C)CC1Cn2cccc2C1=O
Agent: [K+]
Product: N#CCC1Cn2cccc2C1=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To 100 ml H2O0 were added 8.6% of compound 2 and 5.2 g KCN. The solution was gently heated to 100° C. and kept stirring for 10 minutes. After cooling to r.t., the reaction mixture was extracted with CH2CI2 (60×3). Evaporated the solvent, 6 g oil was obtained. Purified by column chromatography on silica gel, 4 g of compound 8 was obtained as white powder, mp 68° C., yield 68%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].[I-].[Na+]>CC(=O)CC>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:10]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(CN(c2ccc([N+](=O)[O-])cc2)n2cnnc2)cc1
Yield: 45.6 %

Procedure:
To a suspension of 0.37 g of 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole obtained in Referential Example 3 in 20 ml of 2-butanone were successively added 0.83 g of potassium carbonate anhydride, 1.30 g of p-nitrobenzyl bromide and a catalytic amount of sodium iodide, at room temperature, and the reaction mixture was then heated under reflux for about 2 hours. After cooled, the solvent was removed by distillation under reduced pressure, and a proper amount of water was added to the residue, which was then extracted several times each with ethyl acetate. The ethyl acetate layer separated was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue formed was purified by silica gel column chromatography to give crude crystals from the chloroform/methanol (100/1) eluate. The crude crystals thus obtained were recrystallized from ethanol to give 0.28 g of 4-[N-(4-nitrobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([CH:9]=[N:10][OH:11])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]Cl.[Na+].[C:23]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)#[CH:24]>C(Cl)Cl>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:24]=[C:23]([C:25]3[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=3)[O:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ON=Cc1ccc(-c2ccccc2)c(C(F)(F)F)c1
Reactant: C#Cc1ccc(N)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Nc1ccc(-c2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)no2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-trifluoromethyl-biphenyl-4-carbaldehyde oxime (1 eq) in CH2Cl2 a 10% aqueous solution of NaOCl is added at 0° C. Thereafter a solution of 4-ethynylaniline (1.1 eq) is added and then the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with CH2Cl2 and 3 times extracted with water. The combined organic layers are dried over Na2SO4, filtered and concentrated. Purification is achieved, after drying over Na2SO4, over silica gel using c-hexane/ethyl acetate 9/1→7/3 as mobile phase.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.II.[B:21](OC)([O:24]C)[O:22]C.Cl>C1COCC1>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:21]([OH:24])[OH:22])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COB(OC)OC
Reactant: CCCCCc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Yield: 78 %

Procedure:
4-Bromo-4′-pentylbiphenyl (3 g, 9.9 mmol) was added in one portion to Mg (0.27 g, 11.1 mmol), treated with I2, in THF (40 mL). The mixture was heated at reflux for 3 h, cooled to −78° C. and trimethyl borate (2.06 g, 19.8 mmol) was added dropwise. The mixture was warmed to room temperature over 1 h, acidified with HCl (2 M, 50 mL), extracted with Et2O (3×50 mL). The combined ethereal washes were extracted with NaOH (100 mL, 1 M). The aqueous phase was acidified with concentrated HCl, extracted with Et2O (3×50 mL), dried (MgSO4) and the solvent removed under reduced to give the title compound (2.07 g, 78%) as an off white powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C@@H:23]([CH3:37])[C@@H:24]([CH3:36])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].[N+:44]([C:47]1[N:48]=[CH:49][NH:50][CH:51]=1)([O-:46])=[O:45]>>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH2:25][C@H:24]([CH3:36])[C@H:23]([CH3:37])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:50]3[CH:51]=[C:47]([N+:44]([O-:46])=[O:45])[N:48]=[CH:49]3)[CH:15]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCOCCOCCOCCBr)c2)cc1OC
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCOCCOCCOCCn3cnc([N+](=O)[O-])c3)c2)cc1OC
Yield: 88 %

Procedure:
The Standard Procedure 2 was followed by use of 5b (130.8 mg, 0.2241 mmol, 1.0 equiv), potassium carbonate (63.6 mg, 0.460 mmol, 2.1 equiv), and 4-nitroimidazole (6a, 50.2 mg, 0.444 mmol, 2.0 equiv). After workup and purification with column chromatography (100% EtOAc as eluant), 7c (121.3 mg, 0.1971 mmol) was obtained in 88% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.80 (d, J=6.0 Hz, 6H, 2×CH3), 1.71-1.72 (m, 2H, 2×CH), 2.22-2.28 (m, 2H, 2×ArCH), 2.69-2.73 (m, 2H, 2×ArCH), 3.61-3.85 (m, 21H, 3×OCH3+6×OCH2), 4.08-4.12 (m, 4H, CH2N+CH2O), 6.61 (s, 1H, ArH), 6.65-6.68 (m, 3H, 3×ArH), 6.74-6.77 (m, 2H, 2×ArH), 7.46 (d, J=1.0 Hz, 1H, nitroimidazole C5-H), 7.87 (d, J=1.0 Hz, 1H, nitroimidazole C2-H); 13C NMR (CDCl3, 100 MHz) δ 15.97, 16.00, 38.54, 38.59, 39.01, 39.04, 48.02, 55.59, 55.69, 55.77, 68.26, 69.30, 69.49, 70.32, 70.37, 70.40, 70.49, 110.87, 111.58, 112.07, 114.57, 120.17, 120.77, 121.47, 134.30, 134.40, 136.45, 146.80, 147.33, 147.69, 147.76, 148.48; IR (neat) 2924 (s), 2868 (s), 1607 (w), 1589 (w), 1516 (s), 1456 (m), 1335 (s), 1260 (s), 1236 (s), 1028 (s) cm−1; HRMS (FAB) m/z calcd for C32H46N3O9 (M+H)+: 616.3234. found: 616.3239.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[NH2:1][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1c2ccc(OCCCBr)cc2C1CN1CCCCC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1c2ccc(OCCCN)cc2C1CN1CCCCC1

Procedure:
Sodium azide (1.49 g) is added to a stirred solution of 5-(3-bromopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene (7.3 g) dissolved in a mixture of ethanol/water (7.3 ml/73 ml). The reaction mixture is refluxed overnight, poured into water and extracted with ether. The organic extract is washed with sat'd aqueous NaCl, dried, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]1[CH2:18][CH2:17][CH2:16][C:15]=1[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=[C:9]([C:23]([OH:25])=[O:24])[CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:28]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:23]([OH:25])=[O:24])[CH:8]=2)[C:13]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]([O:21][CH3:22])=[O:20])=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCc1[nH]c2cc(C(=O)O)ccc2c1C1=C(C(=O)OC)CCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1c(C2=C(C(=O)OC)CCC2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-butyl-3-(2-methoxycarbonyl-cyclopent-1-enyl)-1H-indole-6-carboxylic acid on Wang resin (100 mg; compound 7-1, prepared according to the procedure outlined in Example 7) in dimethylformamide (1.5 mL) was added sodium hydride (60% in mineral oil; 20 mg) and the mixture was stirred at room temperature for 30 min. Benzyl bromide (0.1 mL) was added and the mixture was stirred for 3 h. The mixture was filtered, washed with water (1×1.5 mL), tetrahydrofuran (2×1.5 mL), dichloromethane (2×1.5 mL), and dried. The product was cleaved from the resin by treatment with 1:1 trifluoroacetic acid/dichloromethane for 1 h; 1H NMR (DMSO-d6) δ 0.76 (t, 3 H), 1.20 (m, 2 H), 1.98 (m, 2 H), 2.00 (m, 2 H), 2.68 (t, 2 H), 2.82 (m, 4 H), 3.43 (s, 3 H), 5.56 (s, 2 H), 6.96 (d, 2 H), 7.30 (m, 4 H), 7.60 (d, 1 H), 7.90 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1OC
Temperature: 0 °C

Procedure:
3,4-dimethoxybenzyl alcohol (20 g, 119 mmol) was dissolved in toluene (60 ml) and cooled to 0° C. Thionyl chloride (7.48 g, 61.4 mmol) was added dropwise to the cooled solution of the alcohol over a period of 30 minutes, and the reaction was maintained at 0° C. for an additional 30 minutes. The reaction was quenched by pouring onto an ice/water mix (100 ml), and the organic phase was separated. The aqueous phase was then extracted into toluene (2×20 ml) and the combined toluene solution was dried over anhydrous sodium sulfate. The toluene was removed at reduced pressure to afford an oil which solidified upon standing, with a yield of 21 g. The material was characterized as a single spot by thin layer chromatography (TLC).
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH2:9][C:8]([CH3:13])([CH:11]=[O:12])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:14][Mg+].[Br-]>C(OCC)C>[CH2:1]([C:5]1[CH2:10][CH2:9][C:8]([CH:11]([OH:12])[CH3:14])([CH3:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1=CCC(C)(C=O)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)CC1=CCC(C)(C(C)O)CC1
Yield: 89.9 %

Procedure:
4-Isobutyl-1-methylcyclohex-3-enecarbaldehyde 3a (20 g, 111 mmol) was dissolved in diethyl ether (120 ml) and the solution stirred under nitrogen. An ice-bath was used to keep the temperature below 20° C. while MeMgBr (3M, 48 ml, 144 mmol) was added over 30 min. The ice-bath was removed and the reaction stirred for a further 30 min before being poured slowly, and under nitrogen, onto 2M HCl (50 ml). The phases were separated and the upper organic phase washed twice with brine (2×100 ml), dried (MgSO4) and concentrated in vacuo to give 19.6 g of a colorless oil. The product was purified by distillation (0.1 mbar, 90° C.) to give 4c as a 4:5 mixture of diastereomers containing 6.5% of a third isomer (14 g, 52% yield, colourless oil, 95% pure).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:14][C:15](=[O:34])[CH:16]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH:11]([CH3:13])[CH3:12].[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:14][C:15](=[O:34])[CH:16]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:21][CH:20]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C(NC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C(NC(=O)C(COC1=CCC(c2ccccc2)C=C1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.6 %

Procedure:
A solution of 2 M Na2CO3 (4 mL) was added at room temperature under an atmosphere of Argon to a mixture of the compound obtained in Example 22, step f (401 mg, 0.848 mmol), Pd(PPh3)2Cl2 (154 mg, 0.22 mmol) and phenylboronic acid (145 mg, 1.1872 mmol) in toluene (10 mL) and the reaction was heated to reflux. After 5 h, the reaction was cooled to room temperature. The mixture was diluted with EtOAc, and washed with brine. The combined organic layers were dried over anhydrous NaSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography which gave the title compound as a white solid (255 mg, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:17])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(Cl)Cl.C(O)(=O)C>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=3)[C:7](=[O:17])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(c2ccccc2)c2cc(O)ccc21
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccc(O)cc2N1c1ccccc1
Temperature: 140 °C
Yield: 17 %

Procedure:
A mixture of 6-hydroxy-1-phenyl-1H-indole-2,3-dione (13 mg, 0.054 mmol) and 3-(trifluoromethyl)aniline (160 mg, 1 mmol) in CH2Cl2 (1 mL) and acetic acid (1 drop) was heated at 140° C. The crude product was purified preparative TLC [Eluent: EtOAc/hexane (2:3)], giving the desired product (3.5 mg, 17%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][C:14](=[O:16])[CH3:15])=[CH:6][C:5]=1[O:17][CH3:18].[CH3:20]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([N:13]([C:14](=[O:16])[CH3:15])[CH3:20])=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: COS(C)(=O)=O
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])c(N(C)C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-acetylamino-2-methoxy-5-nitro-benzoic acid methyl ester (4.0 g, 14.9 mmol), methanesulfonic acid methyl ester (1.3 mL, 15.4 mmol) and K2CO3 (4.0 g, 28.9 mmol) in 40 mL DMF was stirred overnight at ambient temperature. The mixture was poured onto ice water and diluted with dichloromethane. The organic phase was separated, dried and concentrated i.vac.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[O:26][C:27]([F:30])([F:29])[F:28])[C:19]([O:21][CH3:22])=[O:20].[CH:31]1(O)[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:31]1([O:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[O:26][C:27]([F:28])([F:29])[F:30])[C:19]([O:21][CH3:22])=[O:20])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(OC(F)(F)F)c(O)c1
Reactant: OC1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(F)(F)F)c(OC2CCCC2)c1

Procedure:
Diisopropyl azodicarboxylate (0.61 mL) is added to a solution of methyl 3-hydroxy-4-trifluoromethoxybenzoate (0.74 g), cyclopentanol (0.19 g) and triphenylphosphine (0.81 g) in tetrahydrofuran (10 mL) and the mixture is heated overnight at reflux. Solvent is evaporated off under reduced pressure and the resulting yellow oil is triturated with diethyl ether. The white solid thus formed is filtered off, and the filtrate is evaporated under reduced pressure and subjected to mplc, to give methyl 3-cyclopentyloxy-4-trifluoromethoxy-benzoate in the form of a pale yellow oil (0.6 g).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[C:17](=[O:18])[NH:16][C:15]2[C:19]([CH2:23][O:24][Si](C(C)(C)C)(C)C)=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[N:12]1)C1C=CC=CC=1.CC(O)=O.CCOCC>Br>[NH2:10][CH:11]1[C:17](=[O:18])[NH:16][C:15]2[C:19]([CH2:23][OH:24])=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[N:12]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc2c1NC(=O)C(NC(=O)OCc1ccccc1)N=C2c1cccc(F)c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC1N=C(c2cccc(F)c2)c2cccc(CO)c2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A mixture of Intermediate 37G (255 mg, 0.466 mmol) in 33% HBr in HOAc (1149 μl, 6.98 mmol) was stirred at room temperature for 1 h. Ether was added and the resulting solid precipitate was collected by filtration and rinsed with ether. The solid was dissolved in MeOH (10 mL) and K2CO3 (1.3 g) was added. The mixture was stirred for 40 min. and then filtered and concentrated to dryness to afford Intermediate 37H (133 mg). HPLC: RT=1.102 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=300.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:10]=[C:11]([CH2:20][OH:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:7]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[CH2:20][O:21][S:29]([CH3:28])(=[O:31])=[O:30])=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(Br)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)n1c(-c2cc(COS(C)(=O)=O)ccc2-n2cncn2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a round bottom flask is added [3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]methanol (583 mg, 1.4 mmol) in CH2Cl2 (5 mL), followed by the addition of methansulfonyl chloride (0.15 mL, 1.9 mmol) and triethylamine (0.4 mL, 2.9 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with saturated NaHCO3 (10 mL), extracted with EtOAc (3×10 mL). The organic layer is separated, washed with brine, dried under anhydrous Na2SO4 (500 mg), filtered and concentrated to afford methanesulfonic acid 3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]-triazol-1-yl-benzyl ester (690 mg, 100%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][S:15]([O-:17])=[O:16].[Na+]>CS(C)=O.O>[CH3:14][S:15]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11])(=[O:17])=[O:16]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C#N)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 22 h

Procedure:
4-Fluoro-3-(trifluoromethyl)benzonitrile (400 mg, 2.12 mmol) was suspended together with sodium methanesulfinate (216 mg, 2.12 mmol) in DMSO (2 ml) and stirred at 80° C. for 22 hours. The reaction was then cooled, diluted with 25 ml H2O and filtered. Filtered solids were evaporated from toluene to give 536 mg of the title substance (quant).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[CH:19]=[CH:18][O:17][CH:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[O:17]1[CH:18]=[CH:19][C:15]([CH2:14][N:11]2[CH:4]=[C:3]([CH2:2][C:5]3[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=3)[N:13]=[N:12]2)=[CH:16]1
Reactant: [N-]=[N+]=NCc1ccoc1
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccoc3)nn2)c[nH]1
Yield: 42.9 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.101 g, 0.639 mmol) was reacted with 3-azidomethyl-furan (0.094 g, 0.767 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol-2-ylamine hydrochloride (0.077 g, 43%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), δ 7.60 (s, 1H), δ 7.38 (s, 1H), δ 6.53 (s, 1H), δ 6.37 (s, 1H), δ 5.46 (s, 2H), δ 3.95 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.1, 145.3, 144.1, 141.0, 123.3, 123.1, 110.3, 110.2, 109.9, 51.3, 19.9 ppm; HRMS (ESI) calcd for C11H12N6O (M+) 244.1145. Found 244.1145.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[CH3:16][CH:15]([NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:17]
Reactant: [H][H]
Reactant: CC(C)NCC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)NCC1CCNC1
Yield: 76.4 %

Procedure:
A mixture of 13.4 g (58.0 mmol) of 1-phenylmethyl-N-(2-propyl)-3-pyrrolidinemethanamine, 1.0 g of 20% palladium on carbon and 130 ml of methanol was shaken in an atmosphere of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst was removed by filtration through Celite; the filtrate concentrated and distilled in vacuo to give 6.3 g of N-(2-propyl)-3-pyrrolidinemethanamine, bp 58°-60° C./3.5 mm.