Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CO>[C:1]1([S:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CO
Product: O=S(=O)(c1ccccc1)N1CCNCC1

Procedure:
A solution of benzenesulfonyl chloride, piperazine and methanol allows us to obtain benzenesulfonyl piperazine. This product is dissolved into methanol and replaced with compound A (N-7-bromoethyl 3-isobutyl-1-methylxanthine) to obtain compound 21. By replacing the ethyl bromide with propyl bromide, compounds 22 and 23 can be produced. By replacing p-toluene-sulfonyl chloride or o-toluenesulfonyl chloride with benzenesulfonyl chloride, compounds 24, 25, or 26 may be produced.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[O:8][C:7]([CH2:12]Cl)=[N:6]2.[I-:14].[Na+].O.[Cl-].[Na+].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[O:8][C:7]([CH2:12][I:14])=[N:6]2
Reactant: O=c1oc(CCl)nn2ccc(Cl)c12
Reactant: [I-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=c1oc(CI)nn2ccc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of 5-chloro-2-(chloromethyl)-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-4-one (2.87 g, 13.1 mmol) in 57 mL of dry acetone under inert atmosphere was added 3.93 g (26.2 mmol) of sodium iodide and this mixture was stirred at room temperature overnight. Next day, the reaction mixture was poured into a 1/1 mixture of water/brine (100 mL) and extracted with diethyl ether (2×75 mL). The organic layers were washed with water and brine, dried (MgSO4) and concentrated in vacuum to afford 3.95 g of the title compound (95% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([Cl:30])[CH:24]=[CH:23]2.C1COCC1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([Cl:30])[CH:24]=[CH:23]3)[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: Clc1ccc2cc(CBr)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc2nc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid benzyl ester (4.65 g, 19.8 mmol) and 6-bromomethyl-2-chloroquinoline (5.40 g, 21.0 mmol) in 80 mL of a 3:1 mixture of THF:DMF at 0° C. is added sodium hydride (0.81 g, 20.2 mmol, 60% mineral oil dispersion). The resulting mixture is stirred for 1 hour at 0° C. then at room temperature for 18 hours. The reaction mixture is quenched with saturated NH4Cl solution, then diluted with EtOAc. The organic layer is washed sequentially with 1N HCl, water, saturated NaHCO3 and saturated NaCl, then dried over MgSO4, filtered and concentrated. The crude product is triturated in Et2O/hexanes/EtOAc and filtered to afford the title compound (6.96 g, 17.0 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ8.08 (d, 1H), 8.00 (d, 1H), 7.69 (s, 1H), 7,63 (dd, 1H), 7.41 (d, 1H), 7.35 (s, 5H), 5.15 (s, 2H), 4.78 (s, 2H), 4.28 (s, 2H), 3.70 (m, 2H), 3.32 (bs, 2H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>>[CH3:11][N:12]([C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:13][CH2:14][OH:15]
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CNCCO
Product: CN(CCO)c1c([N+](=O)[O-])cnn1C
Yield: 81 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 2-(methylamino)ethanol gave 2-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)ethanol as a yellow oil (0.2 g, 81%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.79 (s, 3H), 3.72 (q, J=5.4 Hz, 2H), 3.33 (t, J=5.4 Hz, 2H), 2.93 (s, 3H), 1.91 (t, J=5.4 Hz, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][C:3]=1[CH3:27].[OH:28]O.O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:4][C:3]=1[CH3:27]
Reactant: OO
Reactant: Cc1cc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An amount of 9.2 gm (0.02 mol) of 6-[4-(4-bromo-3-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one is dissolved in 100 ml of glacial acetic acid, and 2 ml (0.02 mol) of 30% hydrogen peroxide are added. The mixture is stirred for three hours at ambient temperature, poured onto 400 ml of water, and extracted three times with ethyl acetate. The organic phase is washed with water and dried with sodium sulfate, and the ethyl acetate is distilled off. The solid residue is recrystallized from ethyl acetate/diisopropyl ether.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([NH:28][C:29](=O)[O:30]C2C=CC([N+]([O-])=O)=CC=2)=[CH:24][CH:23]=1.CS(C)=O>C1(C)C=CC=CC=1>[Cl:21][C:22]1[N:27]=[CH:26][C:25]([NH:28][C:29]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(Nc1ccc(Cl)nc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)nc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (50 mg, 180 μmol, example 87, Step 3) and 4-nitrophenyl 6-chloropyridin-3-yl-carbamate (119 mg, 406 μmol) in toluene (1.0 mL) was subjected to a microwave irradiation at 180° C. for 30 min. Then, DMSO (1.0 mL) was added and the solution mixture was filtered. The filtrate was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound, which was dissolved in MeOH (1.0 mL). Then, the solution was washed through PL-HCO3 MP-Resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.3 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 432 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][CH3:10])=[CH:6][C:5]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH2:16][O:17][CH3:18].[Li]CCCC.CN([CH:27]=[O:28])C>CCOCC>[CH3:18][O:17][CH2:16][O:15][C:3]1[CH:4]=[C:5]([O:11][CH2:12][O:13][CH3:14])[CH:6]=[C:7]([CH2:8][O:9][CH3:10])[C:2]=1[CH:27]=[O:28]
Reactant: COCOc1cc(COC)c(Br)c(OCOC)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1cc(COC)c(C=O)c(OCOC)c1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution of 2-bromo-1,5-bis-methoxymethoxy-3-methoxymethyl-benzene (10.5 g, 32.8 mmol) in Et2O (100 mL) was treated with n-BuLi (28.7 mL, 71.9 mmol) at −78° C. for 1 h. Then, DMF (27.7 mL, 359 mmol) was added to the reaction and the resulting mixture was warmed to room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=2:1) affording the title compound (7.21 g). 1H NMR (300 MHz, CD3OD) δ 10.49 (s, 1H), 7.46 (s, 1H), 6.45 (s, 1H), 5.27 (s, 2H), 5.24 (s, 2H), 4.83 (s, 2H), 3.51 (s, 3H). 3.50 (s, 3H), 3.49 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33]Br>O>[C:12]1([CH3:19])[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:10]1[C:5]2[C:4](=[O:21])[N:3]([CH3:22])[C:2]([NH:1][CH2:33][CH2:32][O:31][CH3:30])=[N:7][C:6]=2[N:8]([CH3:20])[CH:9]=1
Reactant: COCCBr
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCNc1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a solution of 2-amino-5-mesityl-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (55 mg, 0.18 mmol) and N,N-dimethylformamide (2 ml) was added sodium hydride (60% in oil, 24 mg, 0.60 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of 2-methoxyethylbromide (232 mg, 0.60 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 2 hours and heating under reflux for 2 hours, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (9:1) to give 15 mg (23%) of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[CH:8]=1.[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31](O)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([O:1][CH2:2][CH2:3][C:4]4[O:5][C:6]5[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=5[CH:8]=4)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc2oc(CCO)cc2c1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3o2)ccc2c(-c3ccccc3)coc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)benzo furan-5-acetate and 3-phenyl-6-hydroxy-7-propylbenzofuran as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH3:15])=[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:27]>O1CCCC1>[CH3:15][C:5]1[C:4]([CH2:3][CH:1]=[O:27])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CO
Reactant: Cc1c(CC#N)cccc1NS(C)(=O)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(CC=O)cccc1NS(C)(=O)=O
Temperature: 5 °C
Reaction time: 1.25 h

Procedure:
N-(3-cyanomethyl-2-methyl-phenyl)-methanesulfonamide (3.75 g) was dissolved in 50 ml of dry tetrahydrofuran and cooled in an ice bath under an atmosphere of nitrogen. To this mixture was added 67 ml of 1M diisobutylaluminum hydride (DIBAL) in tetrahydrofuran. The mixture was stirred at 5° C. for 75 minutes. Excess reagent was decomposed with methanol and the solvent was evaporated. The residue was treated with EtOAc, washed with cold 1M hydrochloric acid, washed with brine and dried, and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with methanol:dichloromethane (5:95), giving 1.1 g of N-[2-methyl-3(2-oxo-ethyl)-phenyl]-methanesulfonamide as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cncc(Br)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cncc(Br)c1)C(=O)OCC
Temperature: 25 °C

Procedure:
To a 500 mL RBF containing 5-bromopyridin-3-amine (60.0 g, 347 mmol) was added diethyl 2-(ethoxymethylene)malonate (71.0 mL, 354 mmol) and 121 mL of toluene. The reaction mixture was heated to reflux for 3 h. The reaction mixture was allowed to cool RT overnight, and the resulting precipitate was collected by filtration and dried to give the desired product as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].C(=O)([O-])[O-:18].[K+].[K+].OO>CS(C)=O>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:16])=[O:18]
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile in DMSO (40 mL), added potassium carbonate (0.50 eq, 2.59 g), then added hydrogen peroxide solution (3.5 mL of 30% solution in deionized water) dropwise over ice bath over the course of 10 minutes. After the final addition, kept on ice bath for 2 h, then heated to room temperature and stirred until complete by TLC. After 24 h, reaction had not come to completion, so the amount of hydrogen peroxide was doubled (additional 3.5 mL). Still incomplete, though progressing, the reaction was stirred at room temperature over the weekend. Reaction was complete by TLC after 3 days of stirring and was poured into 350 mL of ice water. After precipitate formed, solution was filtered and washed with water to obtain 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide as gray powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[CH2:16][CH3:17])(C)(C)C>C(Cl)Cl>[F:33][C:30]1[CH:31]=[CH:32][C:20]2[N:19]=[C:18]([C@@H:15]([NH2:14])[CH2:16][CH3:17])[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:21]=2[CH:29]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
TFA (0.50 mL, 6.73 mmol) was added to a solution of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tert-butyl ester (92 mg, 0.25 mmol) in DCM (2 mL) and the reaction stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo and passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give the title compound (57 mg, 85%) as a red oil. LCMS (Method J): RT=2.08 min, [M+H]+=270.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>CS(C)=O>[F:14][C:15]1[N:16]=[C:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH3:11])[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(F)n1
Reactant: COc1cc(C#N)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C#N)ccc1Oc1cccc(F)n1
Temperature: 100 °C
Yield: 61.2 %

Procedure:
To 4-hydroxy-3-methoxybenzonitrile (2.6 g, 17 mmol) in DMSO (15 mL) was added sodium hydride (0.44 g, 18 mmol) and 2,6-difluoropyridine (1.0 g, 8.7 mmol). After heating at 100° C. for 18 hours the reaction was partitioned with ethyl acetate and water. The organic layer was separated, washed with water, dried (Na2SO4), and the solvent was removed in vacuo to give 4-(6-fluoropyridin-2-yl)oxy-3-methoxybenzonitrile (1.3 g); NMR (CDCl3) 7.8 (q, 1), 7.35 (m, 1), 1.75 (m, 2), 6.85 (d, 1), 6.65 (m, 1), 3.85 (s, 3) ppm.
Reaction SMILES: [C:1]1([C:7]([CH:9](Br)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[N:26]/[NH:27][C:28](=[NH:30])[NH2:29])=[CH:21][CH:20]=1>C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[N:26]/[N:27]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:29]=[C:28]2[NH2:30])=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Reactant: COc1ccc(/C=N/NC(=N)N)cc1
Solvent: CCO
Product: COc1ccc(/C=N/n2c(N)nc(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of desyl bromide (1.72 g, 6.26 mmol), and 2-[(E)-1-(4-methoxyphenyl) methylidene]-1-hydrazinecarboximidamide (2.4 g, 12.5 mmol) was heated at reflux in ethanol (10 mL) for 2 h. The mixture was cooled at room temperature for additional 10 h, and a yellow precipitate formed. The yellow precipitate was filtered, washed with hot water and recrystallized from ethanol to give N1-[(E)-1-(4-methoxyphenyl)methylidene]-4,5-diphenyl -1H-1,2-imidazolediamine 3 (1.57 g, 68%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH2:16]([CH2:31][C:32](Cl)=[O:33])[CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19].[OH-].[Na+]>C1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([O:9][C:32](=[O:33])[CH2:31][CH2:16][CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)Cl
Reactant: CCN1CCC(O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCN1CCC(OC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C)CC1
Yield: 17.2 %

Procedure:
In a 200-ml three-necked flask equipped with dropping funnel, thermometer and reflux condenser, there were placed 4.80 g of N-ethyl-4-hydroxypiperidine, 3.23 g of pyridine and 50 ml of benzene, and 11.60 g of farnesylacetyl chloride was added dropwise under reflux. After completion of the dropping, the mixture was refluxed for a subsequent 2 hour period and then cooled. Addition of 30 ml of 20% aqueous solution of sodium hydroxide, stirring, phase separation and silica gel column chromatography of the upper layer yielded 2.4 g of N-ethyl-4-farnesylacetoxy-piperidine as a pale-yellow liquid. The product was identified by proton NMR and mass spectrometry. The proton NMR data are shown in the following.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]3[C:19]([O:25][CH3:26])=[N:20][CH:21]=[CH:22][C:23]=3[I:24])[NH:15]2)=[CH:11][CH:10]=1)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[I:24][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([O:25][CH3:26])[C:18]=1[C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH:7][CH3:6])[CH:17]=2
Reactant: COc1nccc(I)c1-c1cc2ccc(N(C)C(=O)OC(C)(C)C)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc2cc(-c3c(I)ccnc3OC)[nH]c2c1
Yield: 92.8 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (520 mg, 1.08 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (1 mL) at 25° C. The solution was heated to reflux for 3 h. The solution was concentrated in vacuo and poured into water. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-methyl-amine (380 mg, 92%) as a white product. MH+ 379.9.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH2:23]([NH2:26])[CH2:24][NH2:25]>C1C=CC=CC=1>[NH2:25][CH2:24][CH2:23][N:26]1[CH2:2][C:3]2[C:4](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccccc1C(O)c1ccccc1
Reactant: NCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: NCCN1Cc2ccccc2C1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 127 g. (0.59 mole) of 2-hydroxymethylbenzhydrol was dissolved in 900 ml. of benzene, 80 g. of anhydrous magnesium sulfate was added and the mixture was cooled in an ice bath. Hydrogen bromide was bubbled into the stirred solution until saturation which took about 30 minutes. During this time the temperature of the solution was kept at 15°-18°. The ice bath was removed and the temperature was allowed to rise to 35° in the course of 1 hour. The mixture was heated for another hour at 40°-45° on a steam bath. During the whole time hydrogen bromide was passed into the solution to keep it saturated. The mixture was filtered and the solution was concentrated in vacuo to give a red oil which was dissolved in 200 ml. of benzene and added to 342 g. (5.7 moles) of ethylenediamine in the course of 15 minutes. During the addition the mixture was stirred and cooled to maintain a temperature of ca. 40°. The mixture was stirred at 25° for 70 minutes. Two layers were obtained and separated. The benzene layer was washed with water and concentrated in vacuo. The residual oil was dissolved in 250 ml. of ether. This solution was extracted twice with 300 ml. of cold 1N hydrochloric acid. The acidic aqueous phase was made alkaline with aqueous sodium hydroxide and extracted with 350 ml. of ether. The ethereal solution was washed with 250 ml. of water, dried and concentrated. The residue was an amber oil which crystallized on scratching. This material melted up to ca. 45°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:25])=[O:24]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl 5-aminoisophthalate (2.09 g, 10 mmol) in dichloromethane (30 mL), pyridine (2.43 mL, 30 mmol) was added at room temperature. At 0° C., methanesulfonyl chloride (0.86 mL, 11 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and ethyl acetate (50 mL) was added. The resulting white precipitate was filtered and washed with hexanes to give dimethyl 5-(methylsulfonamido)isophthalate in 95% (2.715 g) yield as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5].[Br:18][CH2:19][C:20](Br)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:21]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1

Procedure:
A solution of 41 g (0.165 mole) 2-amino-5-chloro-4'-hydroxybenzophenone in 800 ml of ether and 200 ml of water was cooled to 5°. The mixture was stirred while 20 ml (0.277 mole) of bromoacetyl bromide and a 20% solution of sodium carbonate were added alternately keeping the solution slightly basic. After 20 min. the reaction mixture was filtered to collect 60 g (about 100%) of product mp 201°-202°. Recrystallization from ethanol gave colorless prisms, mp 201°-203°.