Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[NH:4].S(O)(O)(=O)=O.CNC(N)=N.C[O-].[Na+].[NH2:19][C:20]1[C:21]([C:33](OC)=[O:34])=[N:22][C:23]([Cl:32])=[C:24]([NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[N:25]=1>CO>[CH3:1][NH:2][C:3]([NH:5][C:33]([C:21]1[C:20]([NH2:19])=[N:25][C:24]([NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:23]([Cl:32])[N:22]=1)=[O:34])=[NH:4]
Reactant: CNC(=N)N
Reactant: COC(=O)c1nc(Cl)c(NC2CCCC2)nc1N
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CNC(=N)NC(=O)c1nc(Cl)c(NC2CCCC2)nc1N
Temperature: 0 °C

Procedure:
To a solution of methylguanidine in methanol (150 ml.) prepared from methylguanidine sulfate (108.5 g.) and sodium methoxide (40.4 g.) is added methyl 3-amino-5-cyclopentylamino-6-chloropyrazinoate (32.85 g.). The reaction is refluxed for 1/2 hour then poured into ice water (300 ml.) affording 28.0 g. of N-methylamidino-3-amino-5-cyclopentylamino-6-chloro-2-pyrazinecarboxamide which melts at 184°-187° C. after recrystallization from 2-propanol.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:48])[C@H:6]([CH2:44][CH2:45][S:46][CH3:47])[NH:7][C:8](=[O:43])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](C(OC(C)(C)C)=O)(C(OC(C)(C)C)=O)[CH:17]2[CH2:22][NH:21][CH2:20][CH2:19][NH:18]2)=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl.[Cl-].[Na+]>CO.CCCCC.O1CCOCC1>[NH:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH:17]1[CH2:16][NH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][C@H:6]([C:5]([OH:48])=[O:4])[CH2:44][CH2:45][S:46][CH3:47])=[O:43])=[C:10]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:11]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2CNCCN2)cc1-c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCC
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)c1ccc(NCC2CNCCN2)cc1-c1ccccc1)C(=O)O
Reaction time: 5 h
Yield: 34.2 %

Procedure:
Sodium hydroxide (0.642 mL of a 0.979 M aqueous solution, 0.629 mmol) was added to a solution of the product of Example 286D (0.344 g, 0.524 mmol) in methanol (2 mL). After 5 hours the mixture was lyopholized, and the resulting white foam was treated with HCl (4.7 mL of a 4 M dioxane solution, 18.8 mmol). After 7 hours, pentane was added and the yellow precipitate was isolated by filtration to afford the desired compound (79.3 mg, 24%) as the bis-hydrochloride, mono-sodium chloride salt.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.C([Li])(C)(C)C.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:21]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].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>[CH:29]1([O:28][C:22]2[CH:21]=[C:20]([C:2]3[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:5]=[C:4]([CH3:13])[CH:3]=3)[CH:25]=[CH:24][C:23]=2[O:26][CH3:27])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1cc(Cl)n(-c2ccccc2)n1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(C)nn2-c2ccccc2)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.8 %

Procedure:
A solution of 5-chloro-3-methyl-1-phenyl-1H-pyrazole (61.8 mg, 0.32 mmol) in 5 mL of THF was cooled to −78° C. and t-butyllithium (0.47 mL, 1.7 M in heptane) was slowly added. The mixture was stirred at −78° C. for 1.5 hours and then zinc chloride (1.56 mL, 0.5 M) was added and after stirring at −78° C. for 15 minutes was warmed to room temperature. A solution containing 4-bromo-2-cyclopentyloxy-1-methoxybenzene (148 mg, 0.54 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in 1 ML of THF was added and the reaction was heated to 60° C. for 12 hours. The mixture was diluted with 20 mL of ethyl acetate and the organic layer was washed with 10 mL of a saturated ammonium chloride solution, 20 mL of water and 20 mL of brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography using a gradient elution from 20% to 50% ethyl acetate in hexanes yielded 31 mg of 5-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazole. 1H-NMR (CDCl3, 300 MHz) δ 7.3 (m, 5H), 6.8 (m, 2H), 6.6 (d, 1H), 6.3 (s, 1H), 4.4 (m, 1H), 3.8 (s, 3H). 2.4 (s, 3H), 1.7-1.5 (m, 8H). (M+1)=349.1
Reaction SMILES: C([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:38])[CH:18]([C:24]2[CH:33]=[CH:32][C:31]3[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=3[CH:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd].CCCCC>[CH3:34][C:30]1([CH3:35])[CH2:29][CH2:28][C:27]([CH3:36])([CH3:37])[C:26]2[CH:25]=[C:24]([CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O:16][C:13]3[CH:12]=[CH:11][C:10]([C:9]([OH:39])=[O:8])=[CH:15][CH:14]=3)=[O:38])[CH:33]=[CH:32][C:31]1=2
Reactant: [H][H]
Reactant: CCCCCC(C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: CCCCCC(C(=O)Oc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
403 mg of (RS)-Benzyl-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanoyloxy]-benzoate in 10 ml of ethyl acetate with 80 mg of palladium on carbon (10% w/w) was subjected to an atmospheric pressure of hydrogen for 1 hour. The mixture was filtered over Celite and washed with about 10 ml ethyl acetate. The solution was evaporated, giving a colorless oil. Trituration in pentane gave a white amorphous solid, 303 mg, m.p. 133-135° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[C:11]([OH:17])[CH:10]=2)=[O:5])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[C:11]([OH:17])[C:10]=2[N+:19]([O-:21])=[O:20])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc2cc(Cl)c(O)cc2oc1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2cc(Cl)c(O)c([N+](=O)[O-])c2oc1=O
Yield: 47.5 %

Procedure:
2.75 g (10.2 mmol) of 3-ethoxycarbonyl-6-chloro-7-hydroxycoumarin was added into 10 ml of concentrated sulfuric acid, 1.74 g (20.4 mmol) of concentrated nitric acid was added in portions under the cooling of ice-salt bath, the reaction was monitored through thin-layer chromatography to confirm the completion, and ice was added to seize the reaction. The reaction mixture was then filtered and washed by water, dried to give 1.52 g of the title compound (241).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[C:3](=[N:6]\[OH:7])/[S:4][CH3:5].[CH3:10][N:11]=[C:12]=[O:13]>C(N(CC)CC)C>[F:1][C:2]([F:9])([F:8])/[C:3](=[N:6]\[O:7][C:12](=[O:13])[NH:11][CH3:10])/[S:4][CH3:5]
Reactant: CS/C(=N/O)C(F)(F)F
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)O/N=C(/SC)C(F)(F)F
Yield: 73.9 %

Procedure:
One drop of triethylamine was added to a mixture of 6.37 g (0.04 mol) of S-methyl (E)-2,2,2-trifluoro-N-hydroxythioacetimidate and 2.28 g (0.04 mol) of methyl isocyanate. An exothermic reaction ensued, and the reaction mixture was cooled in an ice-bath. The reaction mixture solidified on cooling. Recrystallization from ether gave 6.39 g (74% yield) of S-methyl (E)-2,2,2-trifluoro-N-(methylcarbamoyloxy)thioacetimidate as colorless crystals., mp. 83°-85°. Analysis of the isomer prepared in a similar procedure follows:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(O)c1ccc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(C(=O)O)s2)cn1

Procedure:
The title compound is prepared as described in EXAMPLE 31, Part I, but with 5-bromothiophene-2-carboxylic acid and 6-methoxypyridin-3-ylboronic acid hydrochloride as starting materials, and 10 molar equivalents of 0.4M aqueous sodium carbonate. 1H NMR (DMSO) δ 13.10 (br s, 1H), 8.55 (d, 1H), 8.03 (dd, 1H), 7.66 (d, 1H), 7.50 (d, 1H), 6.90 (d, 1H). ESI MS (M+1)+: 236.
Reaction SMILES: [CH2:1]1[O:9][C@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>O>[OH:11][CH2:10][CH2:12][NH:13][CH2:1][C@H:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9]
Reactant: NCCO
Reactant: c1ccc([C@H]2CO2)cc1
Solvent: O
Product: OCCNC[C@@H](O)c1ccccc1

Procedure:
5 g of (S)-(+)-styrene oxide and 15.410 mL ethanol amine were stirred at room temperature overnight. The solution is poured into water and the water was extracted with dichloromethane. The combined dichloromethane layers were washed with brine and concentrated in vacuo. The oil was used crude. Assumed quantitative yield carried on to the next step. Theoretical wt: 7.9 g
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].IC.[C:13](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(F)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(F)cc1C=O

Procedure:
20.0 g (0.143 mol) of 5-fluoro-2-hydroxybenzaldehyde are dissolved in 250 ml of acetonitrile. 81.04 g (0.57 mol) of iodomethane and 39.5 g (285 mol) of potassium carbonate are added, and the suspension is heated at reflux for 3 hours. The suspension is filtered and the mother liquor is diluted with ethyl acetate, washed twice with water, dried over magnesium sulphate and filtered, and the solvents are evaporated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][O:29][C:30]2[CH:31]=[C:32](CN)[CH:33]=[CH:34][CH:35]=2)[CH2:24]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH2:28][CH:25]5[CH2:26][CH2:27][N:23]([CH3:22])[CH2:24]5)[CH:35]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: CN1CCC(COc2cccc(CN)c2)C1
Solvent: CO
Product: CN1CCC(COc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)C1

Procedure:
The title compound was synthesized according to Example 13c from methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (0.352 g, 1.09 mmol) and 1-{3-[(1-methylpyrrolidin-3-yl)methoxy]phenyl}methanamine (0.200 g, 0.91 mmol) in MeOH (2 mL) to give the title compound. Yield: 0.225 g (44%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.59-7.62 (m, 2H), 7.45 (s, 1H), 7.39-7.42 (m, 2H), 7.22-7.26 (m, 1H), 6.81-6.91 (m, 3H), 5.17 (s, 2H), 3.83 (d, 2H, J=6.9 Hz), 2.60-2.66 (m, 2H), 2.38-2.57 (m, 3H), 2.32 (s, 3H), 1.97-2.08 (m, 1H), 1.51-1.60 (m, 1H). MS (ESI+) 465.99 (M+1H+)
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:8][CH2:18][C:17]1[C:10]([F:9])=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C#N)c1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Product: N#Cc1cccc(CBr)c1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
NBS (1.729 g, 9.71 mmol) was added to a solution of 2-fluoro-3-methylbenzonitrile (1.25 g, 9.25 mmol) in acetonitrile (25 mL). The obtained mixture was refluxed, and then benzoic peroxyanhydride (0.045 g, 0.18 mmol) was added. The reaction mixture was refluxed overnight, then cooled to r.t. and water was added. The aqueous phase was discarded and the organic phase was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using a gradient of EtOAc in heptane as eluent to give the title compound (1.39 g, 70% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 4.75 (s, 2 H) 7.43 (t, 1 H) 7.93 (t, 2 H); MS (EI) m/z 213 M.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:18])([Cl:17])[C:13](=[NH:16])OC>>[Cl:11][C:12]([Cl:18])([Cl:17])[C:13]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[NH:16]
Reactant: NNC(=O)c1ccccc1
Reactant: COC(=N)C(Cl)(Cl)Cl
Product: N=C(NNC(=O)c1ccccc1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
A mixture of 9.1 g (0.07 mole) benzoylhydrazine and 20 ml (28.5 g, 0.16 mole) methyl 2,2,2-trichloroacetimidate was stirred 16 hours at room temperature. The solid that was left was washed with petroleum ether and dried to give 18.6 g (100% yield) of product (mp 170°-172° C.). A sample recrystallized from ethanol had mp 178°-181° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [CH2:1]([C:8]1[O:12][CH:11]=[C:10]([CH2:13][OH:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([CH:17]1[CH2:19][C:18]1([C:24](OC)=[O:25])[C:20]([O:22][CH3:23])=[O:21])=[CH2:16].C1(C=CC(O)=CC=1)O>C([O-])(=O)C.[Ca+2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.CO>[CH:15]([CH:17]1[CH2:19][C:18]1([C:24]([O:14][CH2:13][C:10]1[CH:9]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:12][CH:11]=1)=[O:25])[C:20]([O:22][CH3:23])=[O:21])=[CH2:16]
Reactant: OCc1coc(Cc2ccccc2)c1
Reactant: C=CC1CC1(C(=O)OC)C(=O)OC
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: Oc1ccc(O)cc1
Solvent: CO
Product: C=CC1CC1(C(=O)OC)C(=O)OCc1coc(Cc2ccccc2)c1
Yield: 34.9 %

Procedure:
Twenty grams (0.106 mol) (5-benzyl-3-furyl)carbinol was charged to a stirred glass reactor with 39 g (0.212 mol) dimethyl 2-vinylcyclopropane-1,1-dicarboxylate, 0.5 g hydroquinone, 0.5 g calcium acetate and 0.38 g dibutyltin diacetate and heated. After the temperature reached about 165° C., methanol began to distill from the reaction mixture and was collected by means of a suitable condenser-trap arrangement. When the transalcoholysis was essentially complete (3.2 g methanol collected; reaction temperature 182° C.) heating was terminated. Excess dimethyl 2-vinylcyclopropane-1,1-dicarboxylate was removed by distillation and the resulting crude light brown oil worked up to recover 12.6 g (35% yield) methyl (5-benzyl-3-furyl)methyl 2-vinylcyclopropane-1,1-dicarboxylate. B.p. 160°-162° C. at 0.018 mm Hg; nD21 1.5335. Infrared and nuclear magnetic resonance spectra were consistent with the desired structure.
Reaction SMILES: N1C=CC=CC=1C1N=NN(C2C=CC(NC3C4N(C=CN=4)C(C4C=CC(C(N)=O)=CC=4)=CN=3)=CC=2)C=1.[N+:37]([C:40]1[N:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1)([O-])=O.O.O.[Sn](Cl)Cl>CO.Cl>[N:46]1([C:43]2[CH:42]=[CH:41][C:40]([NH2:37])=[N:45][CH:44]=2)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cn1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: NC(=O)c1ccc(-c2cnc(Nc3ccc(-n4cc(-c5ccccn5)nn4)cc3)c3nccn23)cc1
Solvent: CO
Solvent: O
Product: Nc1ccc(N2CCOCC2)cn1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
In the same way as described in for Compound 154, step 2 using 4-(6-nitro-pyridin-3-yl)-morpholine (2.39 g, 11.43 mmol), tin(II) chloride dihydrate (12.9 g, 57.17 mmol) in MeOH (40 mL) and conc. HCl (12.4 mL). The reaction mixture is concentrated in vacuo cooled to 0° C. and dissolved in water. The aqueous solution is basified using conc. NaOH and extracted with ethyl acetate (3×). The organic layers are combined, dried over MgSO4, filtered and concentrated to afford the title compound (1.77 g, 87%) which is used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[CH3:2][N:3]([CH2:4][CH2:5][CH2:6][CH2:7][Cl:8])[P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: CNCCCCCl
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCCCl)P(=O)(Cl)Cl
Temperature: -40 °C
Reaction time: 6 h
Yield: 84.7 %

Procedure:
N-methyl-N-(4-chlorobutyl)amine hydrochloride (2.0 g, 12.73 mmol) was dissolved in 20 mL of anhydrous CH2Cl2 and cooled to −40° C. Phosphorous oxycloride (1.2 mL, 12.73 mmol) was added neat followed by the drop wise addition of triethyl amine (3.6 mL, 25.46 mmol) in 5 mL of CH2Cl2. Warmed reaction to 0° C. and slowly to room temperature. Allowed reaction to stir at room temperature for 6 hours. The reaction mixture was poured over ice, added saturated ammonium chloride and separated layers. Extracted water layer 3× with CH2Cl2, combined organic layers, dried over anhydrous sodium sulfate and concentrated under reduce pressure. Purified by silica gel flash chromatography (3:1 Hex/EtOAc) to yield a clear oil (2.57 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:10]=1)[C:7]([NH:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH3:20])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)COCc1ccc(Cl)cc1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COCC(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-(isobutoxymethyl)benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].CC1(C)C(C)(C)OB([C:34]2[CH2:35][CH2:36][CH2:37][N:38]([C:40](=[O:42])[CH3:41])[CH:39]=2)O1.C([O-])(=O)C.[K+].O1CCOCC1>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:36]3[CH2:35][CH2:34][CH2:39][N:38]([C:40](=[O:42])[CH3:41])[CH:37]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Reactant: CC(=O)N1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1C=C(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.2 %

Procedure:
To a degassed solution of (1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (706 mg, 1.791 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridin-1(2H)-yl)ethanone (0.5 g, 1.991 mmol), potassium acetate (1.5 g, 15.28 mmol), and dioxane (10 mL) was added A-Phos (140 mg, 0.198 mmol). The solution was stirred at 80° C. After 16 hours, the reaction was allowed to cool to room temperature, diluted with H2O (10 mL), and the aqueous layer extracted with DCM (5 mL). The combined organic layers were concentrated in vacuo and purified by Prep TLC (1:1 hexanes/EtOAc) to give 1-(5-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-3,4-dihydropyridin-1(2H)-yl)ethanone (1.6 mg, 3.65 μmol) as a light yellow film. MS (ESI, pos. ion) m/z: 439.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:21]1[C:22](O)=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=1)([CH2:19][OH:20])[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:19][O:20][C:22]3[CH:23]=[C:24]4[C:25](=[CH:29][C:21]1=3)[CH2:26][CH2:27][O:28]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A mixture of 4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (1.81 g, 3.88 mmol), triphenylphosphine (2.04 g, 7.77 mmol) and diisopropyl azodicarboxylate (1.57 g, 7.77 mmol) in anhydrous dioxane (60 mL) was heated at reflux for 16 h. After cooling down to ambient temperature, the solvent was removed in vacuo. The gummy residue was diluted with ethyl acetate (50.0 mL), washed with water (3×25.0 mL), brine (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (80%) to give the title compound (0.64 g, 37%) as colorless solid: mp>200° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (d, 1H), 7.77 (dt, 1H), 7.37 (d, 1H), 7.27 (dt, 1H), 7.19-7.13 (m, 2H), 6.94 (dd, 1H), 6.61 (s, 1H), 6.33 (s, 1H), 5.08 (d, 1H), 5.03 (d, 1H), 4.93 (d, 1H), 4.74 (d, 1H), 4.48 (t, J=8.6 Hz, 2H), 2.96 (t, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 162.2, 161.8, 155.3, 149.8, 145.3, 137.6, 131.0, 130.5, 126.8, 123.3, 122.2, 119.9, 119.5, 119.0, 118.1, 109.3, 92.4, 77.5, 72.5, 58.8, 45.3, 28.8; MS (ES+) m/z 451.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[C:11]#[CH:12])=[CH:5][CH:4]=1.ClC(Cl)=N[C:30]1[CH:37]=[CH:36][C:33]([O:34][CH3:35])=[CH:32][CH:31]=1.CC1C=CC(CN2CCNCC2)=CC=1.C([Li])CCC.COC1C=CC=CC=1C=C(Br)Br>C(OCC)C.O1CCCC1.CCCCCC>[CH3:35][O:34][C:33]1[CH:36]=[CH:37][CH:30]=[CH:31][C:32]=1[C:12]#[C:11][C:10](=[N:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc(N=C(Cl)Cl)cc1
Reactant: C#CC(=Nc1ccc(OC)cc1)N1CCN(Cc2ccc(C)cc2)CC1
Agent: COc1ccccc1C=C(Br)Br
Agent: Cc1ccc(CN2CCNCC2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(N=C(C#Cc2ccccc2OC)N2CCN(Cc3ccc(C)cc3)CC2)cc1

Procedure:
1-(2-Methoxyphenyl)-3-(4-methoxyphenylimino-3-[4-(4-methylbenzyl)-1-piperazinyl]propyne can be prepared by working as in Example 11 but starting with a solution of N-dichloromethylene-p-anisidine (20.6 g) in ethyl ether (200 cc) to which a solution of 4-(4-methylbenzyl)piperazine (38.4 g) in tetrahydrofuran (150 cc) is added. The solution obtained after filtration is added in the course of 30 minutes at a temperature of about -70° C. to a solution of 2-(2-methoxyphenyl)ethynyllithium obtained by adding, in the course of 20 minutes, at a temperature of about -70° C., a 1.6M solution (126 cc) of butyllithium in hexane to a solution of 2-methoxy-β,β-dibromostyrene (29.5 g) in tetrahydrofuran (300 cc). 1-(2-Methoxyphenyl)-3-(4-methoxyphenylimino)-3-[4-(4-methylbenzyl)-1-piperazinyl]propyne (30.6 g), m.p. 83° C., is thereby obtained.