Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>N1C=CC=CC=1>[NH2:12][C:11]1[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[N:7]([CH2:14][CH2:15][CH3:16])[C:8](=[O:9])[C:10]=1[NH:13][C:27]([C:17]12[CH2:26][CH:21]3[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]3)[CH2:24]1)[CH2:18]2)=[O:28]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Solvent: c1ccncc1
Product: CCCn1c(N)c(NC(=O)C23CC4CC(CC(C4)C2)C3)c(=O)n(CCC)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
At first, 10 g (44.3 mmol) of 1,3-dipropyl-5,6-diaminouracil was dissolved in 50 ml of pyridine, and 10.6 g (53.1 mmol) of adamantane-1-carbonylchloride was added by portions thereto at 0° C. After stirring for 30 minutes at 0° C., the mixture was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate was added thereto. The residue was extracted with chloroform three times. The organic layers were combined, washed with a saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Then pyridine was removed from the residue by means of azeotropy with toluene to afford 19.5 g (yield: 100%) of 6-amino-5-(adamantane-1-carbonylamino)-1,3-dipropyluracil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:13])[S-:12].C([NH+](CC)CC)C.C([O:24][CH2:25][C:26]([CH2:28]Cl)=O)(=O)C.Cl>C(O)C>[OH:24][CH2:25][C:26]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:12])[S:13][CH:28]=1
Reactant: CC(=O)OCC(=O)CCl
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: CCO
Product: OCc1csc(=S)n1-c1ccc(F)c(F)c1F
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (81.2 g) prepared in the same manner as in Reference Example 1 was added to ethanol (800 ml) and thereto 1-acetoxy-3-chloroacetone (37.7 g) was added dropwise at 5° to 7° C. with stirring over a period of 20 minutes. After stirring the mixture for 50 minutes, 10% solution of hydrogen chloride in ethanol (240 ml) was added and the mixture was refluxed for 3 hours. After the solvent was distilled off under the reduced pressure, cooled water was added to the residue and resultant was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from a mixed solvent of hexane-ethyl acetate to give the title compound (59 g) as pale yellow crystals. The compound had physical properties identical to those of 4-hydroxymethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione prepared in the above Reference Example 18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH:7]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[C:6]=2[CH:18]=1.[H-].[Na+].[CH2:22](I)[CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:22]([N:12]([CH:7]1[C:6]2[CH:18]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:19])[C:5]=2[O:11][CH2:10][CH2:9][CH2:8]1)[S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])[CH2:23][CH2:24][CH3:25]
Reactant: CCS(=O)(=O)NC1CCCOc2c(C)cc(Cl)cc21
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C1CCCOc2c(C)cc(Cl)cc21)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A solution of 0.8 g (2.6 mmol) of 7-chloro-9-methyl-5-(N-ethylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine (Example 10c) in 10 ml of DMF was added dropwise under nitrogen to a suspension of 0.1 g (2.7 mmol) of 80 percent sodium hydride in 8 ml of DMF. After stirring at RT for 30 min, 0.68 g (3.7 mmol) of butyl iodide was added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. After washing the organic phase with dil. hydrochloric acid in water, and drying over magnesium sulfate, it was concentrated in vacuo. 0.9 g of 5-(N-butyl-N-ethylsulfonylamino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 83-87° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[Si]([O:39][CH2:40][CH:41]=O)(C(C)(C)C)(C)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.O>C(Cl)Cl>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:30][CH3:31])=[C:7]([CH:5]4[CH2:6][N:3]([CH2:41][CH2:40][OH:39])[CH2:4]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH:27]([F:29])[F:28])[C:20]=12
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(CCO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.9 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (45 mg, 0.090 mmol), {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (110 mg, 0.63 mmol) and triethylamine (63 μL, 0.45 mmol) in methylene chloride (0.9 mL) was added sodium triacetoxyborohydride resin (0.12 g, 0.27 mmol). The mixture was stirred at room temperature for 2 h, then filtered. The filtrate was treated with 6.0 M hydrogen chloride in water (0.2 mL, 0.9 mmol), and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.5 mg, 5.6%). LCMS calculated for C20H23ClF3N6O2 (M+H)+: m/z=471.1; Found: 471.2. The racemic product was separated on a Phenomenex Lux Cellulose-4 column, eluting with 20% ethanol in hexanes, at flow rate of 18 mL/min, and column loading of ˜4 mg/injection to separate two enantiomers. First peak retention time 13.1 min; second peak retention time 16.3 min.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[P].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)[CH:21]=[CH:22][CH:23]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]2[C:28](=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][C:20]=2[CH:19]=1
Reactant: COc1cccc(CCCCC(=O)O)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [P]
Product: COc1ccc2c(c1)CCCCC2=O
Temperature: 100 °C
Yield: 95 %

Procedure:
To a homogeneous mixture of phosphorus pentoxide and 85% phosphorus acid at 100° C., was added 5-(3-methoxyphenyl)pentanoic acid in small portions over 20 minutes. The vigorously stirred mixture was heated at 100° C. for 6 hours. Then it was poured on ice-water, and extracted with ether (3 times). The organic phase was washed with water and dried over anhydrous sodium sulfate. Evaporation of the combined organic phase afforded a light yellow oil in more than 95% yield; 1H NMR δ 7.77 (d, 1H, J=8.6 Hz), 6.80 (dd, 1H, J=2.5, 8.6 Hz), 6.69 (d, 1H, J=2.5 Hz), 3.84 (s, 3H), 2.90 (t, 2H, J=6.2 Hz), 2.71 (t, 2H, J=5.9 Hz), 1.91-1.76 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:14][NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:31]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)NC(=O)C(N)Cc1ccc(OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
A solution consisting of 1.00 g (4.64 mmol) N-tert-butoxycarbonyl-L-leucinal and 1.52 g (4.64 mmol) 2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Example 2, Step C) in 20 mL methanol containing 1% acetic acid was stirred at 25° C. for 20 minutes, at which time a solution of 0.614 g (9.29 mmol) sodium cyanotrihydridoborate (Aldrich, Milwaukee, Wis.) in 12 mL methanol was added and the resulting mixture stirred for 24 hours. The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling subsided. The mixture was neutralized with saturated NaHCO3 solution then extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulphate, and evaporated at reduced pressure to give a clear, colorless oil which was chromatographed on a silica gel column using 30% to 40% ethyl acetate:hexane to give 735 mg (30%) of [S-(R*,S*)]-(1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester as a clear foam.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C:21]([N:12]1[C@H:8]([CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:6][CH:5]=2)[CH2:9][CH2:10][C:11]1=[O:13])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1

Procedure:
8.6 g (S)-5-Biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (34.22 mmol) is dissolved in 135 ml methylene chloride. 4.2 g DMAP (34.22 mmol) is added. The mixture is further diluted with 10 ml methylene chloride. Then 14.9 g BOC2O (68.44 mmol) is added and further 10 ml methylene chloride is added. This reaction mixture is then stirred at reflux for 7.5 h. Then a further 3.7 g BOC2O is added. After a total reaction time of 24 h at reflux the solvent is evaporated completely. The evaporation residue is then filtered over 460 g of silica gel with an eluent of toluene:ethyl acetate 4:1. The product fractions are concentrated in vacuo to yield the crude product, which is recrystallised from methylene chloride/heptane fraction 1:6, to yield (S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1-a, R1=BOC).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21].C>>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1

Procedure:
1.45 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo[4,3-b]pyridazine was boiled under reflux with 22 ml. acetic anhydride for 1.5 hours at 160° C. bath temperature, the solution obtained was then mixed with charcoal, suction filtered while still hot, washed with a little acetic anhydride and then with ether and dried for 3 hours at 120° C. There was thus obtained 0.79 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-acetamido-s-triazolo[4,3-b]pyridazine in the form of yellow-white crystals which melt at 238° - 239° C. and show a change above 230° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][CH2:17][CH2:18]Br)[CH3:15]>>[C:1]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:15][CH2:14][O:16][CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CCOCCBr
Product: CCOCCC(c1ccccc1)c1ccccc1

Procedure:
According to a second process disclosed by Sperber (loc. cit.) diphenylmethane is reacted with 2-bromoethyl ethyl ether to yield 3,3-diphenyl-1-ethoxypropane. Alkylation of 3,3-diphenyl-1-ethoxypropane with 2-dimethylaminoethyl chloride yielded 5-ethoxy-3,3-diphenyl-N,N-dimethylamine; cleavage of the ethoxy group gave 5-hydroxy-3,3-diphenyl-N,N-dimethylamine hydrobromide, which was reacted with thionyl chloride to give 4,4-diphenyl-1,1-dimethylpiperidinium chloride, from which sublimation in vacuo yielded 1-methyl-4,4-diphenylpiperidine. This synthesis includes 5 reaction steps and provides an overall maximum yield of about 23 percent of theory. The availability of this synthesis for the preparation of homologues of 1-methyl-4,4-diphenylpiperidine, e.g. of 1-ethyl-4,4-diphenylpiperidine or 1-isopropyl-4,4-diphenylpiperidine has to be regarded as doubtful.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH:20]=[CH:21][N:22](C)C)=[CH:15][CH:14]=4)=[C:4]([F:31])[CH:3]=1.O.[NH2:33]N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:33][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=4)=[C:4]([F:31])[CH:3]=1
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3F)c(=O)n(C)c1n2C
Reactant: NN
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2F)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 36 above, with compound C3-(4-chloro-2-fluorophenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido-[2,3-b]indol-2-one and hydrazine monohydrate.
Reaction SMILES: CO[C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1.[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH:37][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:15]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14]=2[CH:30]=1
Reactant: COCCCN
Reactant: COC(=O)CCCCCOc1ccc2nc(N3CCOCC3)n(-c3ccccc3)c2c1
Product: COCCCNC(=O)CCCCCOc1ccc2nc(N3CCOCC3)n(-c3ccccc3)c2c1

Procedure:
135 mg of 6-[[2-(morpholin4-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 94 mg was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([NH:11][C:12]#[C:13][Si](C)(C)C)[CH:10]=1>CCO>[F:3][C:4]([F:19])([F:18])[C:5]1[CH:10]=[C:9]2[C:8]([CH:13]=[CH:12][NH:11]2)=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)C#CNc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1ccc2cc[nH]c2c1
Reaction time: 2 h

Procedure:
Carefully add NaH (10.83 g, 60% in oil, 270.8 mmol, 4 eq.) to EtOH (200 mL). When cool, add a solution of 5-trifluoromethyl-2-trimethylsilanylethynylphenylamine (22.3 g, 67.7 mmol) in EtOH (400 mL) with vigorous stirring. After 2 hours, heat to reflux. After 4 hours, evaporate in vacuo to remove the EtOH and dilute the residue obtained with water and extract with Et2O. Combine the organic layers and wash with brine, dry over MgSO4, filter, and evaporate to give a dark oil. Absorbed the oil onto silica gel and load onto short column of silica gel. Elute with 20% EtOAc in hexanes. Pool fractions containing the product and remove the solvent leaving a dark brown oil. Further purification of the oil by HPLC (silica column) using a gradient 1% Et2O in hexanes to 15% Et2O in hexanes. Pool fractions containing the product and remove the solvent to give the title compound as an orange solid: 1H NMR (300 MHz, d6-DMSO-d6): 6.58 (m, 1H), 7.28 (m, 1H), 7.61 (t, 1H), 7.74 (m, 2H), 11.51 (bs, 1H); MS (EI+): m/z 185 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[CH:12])[CH:6]=1)[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[N:22][OH:23])=[CH:17][CH:16]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[O:23][N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)[CH:12]=2)[CH:6]=1)[CH3:2]
Reactant: C#Cc1cccc(C(=O)OCC)c1
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(-c2cc(-c3ccc(Cl)cc3)no2)c1
Temperature: 25 °C

Procedure:
In a 10 ml round flask, 500 mg (2.9 mmol) of 3-ethynyl-benzoic acid ethyl ester and 652 mg (3.5 mmol, 1.2 eq.) of 4-chloro-N-hydroxy-benzenecarboximidoyl chloride are dissolved in 4 ml of CHCl3. To this solution, 11 mg (0.14 mmol, 0.05 eq.) of pyridine and 290 mg (2.9 mmol) of triethyl amine are added at 0° C. under a nitrogen atmosphere. The orange solution is stirred under warming to room temperature for 20 h. The suspension is filtered and the solution concentrated in vacuo. Chromatographical purification (100 g SiO2; eluent: hexane/ethyl acetate 9:1) yields the title compound as a white solid. Mass spectrum: m/z (M+H)+: 328.2; 330.2
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])([F:28])[F:27]>CN(C=O)C.O.CCOC(C)=O>[F:28][C:26]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])([F:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCBr
Reactant: COc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOc1ccc(C=O)c(OC)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 4-hydroxy-2-methoxybenzaldehyde (1 equiv.) in DMF (0.25 M) was added cesium carbonate (2 equiv.), sodium iodide (0.20 equiv.) and diethyl (3-(2-bromoethoxy)-1,1-difluoropropyl)phosphonate (1.2 equiv.) (described in ref. 88, Ex 7 Step 1). The reaction mixture was stirred at 100° C. for 3 h, after which it was allowed to cool to room temperature. The resulting mixture was then diluted with water and EtOAc. This mixture was transferred to a separatory funnel and washed with water three times. The organic layer was then separated, dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (79%) as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](S)=[N:10][C:9]=2[CH:14]=1.[CH2:15](Cl)/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18]>CN(C)C=O.C(Cl)Cl>[CH3:18]/[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:16]\[CH2:15][N:10]1[C:9]2[CH:14]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=2[N:12]=[CH:11]1
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: COc1ccc2[nH]c(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2ncn(C/C=C(\C)CCC=C(C)C)c2c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a suspension of sodium hydride (0.25 g, 11 mmol) in dimethylformamide (10 mL) at 0° C. under nitrogen was added 6-methoxy-2-mercaptobenzimidazole (1.98 g, 11 mmol) in dimethylformamide (20 mL). The solution was allowed to stir to ambient temperature, then geranyl chloride (1.9 g, 11 mmol) was added and the reaction mixture stirred at 90° C. overnight. Evaporation of the solvent gave a residue which was dissolved in CH2Cl2, washed with H2O and dried over Na2SO4. Evaporation and flash chromatography (Merck Kieselgel, 5% MeOH/CH2Cl2) gave 1-(3,7-dimethyl-2,6(E)-octadienyl)-6-methoxy-1H-1,3-benzimidazole (free base) (2.4 g, 77%) as a 1:1 mixture of 5- and 6-methoxy isomers. Conversion to the oxalate salt in diethyl ether filtration 10 minutes after addition of oxalic acid gave 500 mg of the title compound as a white solid (pure 6-methoxy by 400 MHz NMR with NOE). m.p. 90°-94° C. NMR (DMSO-d6)δ8.3(s,1H), 7.68(d,J=2 Hz,1H), 7.63(d,J=9 Hz,1H), 7.23(m,1H), 5.3 d,J=7 Hz, 1H), 5.0(m,1H), 4.90(d,J=8 Hz,2H), 2.0(m,4H), 1.70(s,3H), 1.58(s,3H), 1.55(s,3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[I-:15].[Na+]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:15][CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[C:12]([OH:14])=[O:13]
Reactant: [I-]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCC(I)C(=O)O

Procedure:
To 11-bromoundecanoic acid dissolved in acetonitrile (50 ml ) were added sodium iodide (2 g) and tetra-n-butylammonium iodide (1 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and distributed into ethyl acetate and water, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give iodoundecanoic acid (0.89 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[BrH:26]>C(O)(=O)C>[BrH:26].[OH:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: COc1cccc(Cn2c(-c3cccc(C)c3)nc3ccccc32)c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc3ccccc3n2Cc2cccc(O)c2)c1
Reaction time: 2 h

Procedure:
This compound was prepared by first synthesizing 1-(3-methoxybenzyl)-2-(3-methylphenyl)benzimidazole as described in Example 65, supra. With an amount of the compound of Example 65 (4.31 g, 13.12 mmol) in glacial acetic acid (50 ml) and hydrobromic acid (300 ml of a 48% w/v in acetic acid solution). This mixture was stirred for 2 hours while warming to reflux. The mixture was then stirred at reflux for about three hours.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Methyl 2-amino-4-chlorobenzoate (1.5 g, 8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH(429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0° C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0° C. with saturated Na2SO4 (50 mL), extracted with Et2O (2×70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69% yield); 1H NMR (400 MHz, MeOD) δppm 4.50 (s, 2H), 6.58 (dd, J=8.06, 2.01 Hz, 1H), 6.70 (d, J=2.01 Hz, 1H), 7.01 (d, J=8.06 Hz, 1H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO 157.03.