Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]([C:19]([OH:28])([CH2:24][C:25]([CH3:27])=[CH2:26])[C:20]([F:23])([F:22])[F:21])[NH:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[N:11][C:12]([CH3:18])=[N:13]3)=[C:4]([O:31][CH3:32])[CH:3]=1.C(OCC)(=O)C.C(N(CC)CC)C>CO.[Pd].[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]([C:19]([OH:28])([CH2:24][CH:25]([CH3:26])[CH3:27])[C:20]([F:22])([F:21])[F:23])[NH:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[N:11][C:12]([CH3:18])=[N:13]3)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: C=C(C)CC(O)(C(Nc1cccc2nc(C)ncc12)c1ccc(F)cc1OC)C(F)(F)F
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1C(Nc1cccc2nc(C)ncc12)C(O)(CC(C)C)C(F)(F)F
Yield: 16.6 %

Procedure:
17 mg (0.04 mmol) of (rac.) 2-{4-fluoro-alpha-[(2-methylquinazolin-5-yl)amino]-2-methoxybenzyl}-1,1,1-trifluoro-4-methylpent-4-en-2-ol is shaken in 2 ml of methanol, 2 ml of ethyl acetate and 0.05 ml of triethylamine with 20 mg of palladium on carbon (10%) for 5 hours under hydrogen atmosphere. The reaction mixture is mixed with 200 mg of activated manganese dioxide and filtered through Celite after 10 minutes. It is concentrated by evaporation, and 3 mg of the desired product is obtained after preparative thin-layer chromatography on silica gel (cyclohexane/ethyl acetate 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(NC(C)C)(C)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][S:39]([C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CN(C)c1ccncc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)c2cccs2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.7 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (5 mL) were added N,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) and thiophenesulfonyl chloride (126 mg, 0.69 mmol) and the reaction mixture was stirred at ambient temperature for 4 d. The resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=50:30:20 to 20:60:20) afforded the title compound (95 mg, 33%) as an orange solid. MS: m/e=495.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.C[O:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)=[O:11].[NH2:21][C:22]1[CH:23]=[C:24]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1)=[O:26]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:21][C:22]2[CH:23]=[C:24]([CH:37]=[CH:38][C:39]=2[CH3:40])[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=2)=[O:26])=[O:17])=[CH:14][CH:13]=1)([OH:9])=[O:11]
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(C(=O)O)cc1

Procedure:
Triethylamine (0.26 ml) was added to a stirred mixture of 4-methoxycarbonylbenzoyl chloride (0.221 g), 4-dimethylaminopyridine (0.01 g), 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.2 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with methylene chloride and washed with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution. The organic solution was dried over magnesium sulphate and evaporated. The residue was triturated under isohexane. The resultant solid was isolated and dried under vacuum at 55° C. to give the required starting material as a solid (0.286 g); NMR Spectrum: (CDCl3) 2.4 (s, 3H), 2.98 (s, 6H), 3.98 (s, 3H), 6.54 (m, 1H), 6.92 (d, 1H), 7.2 (m, 3H), 7.35 (d, 1H), 7.71 (d, 1H), 7.92 (s, 1H), 7.98 (d, 2H), 8.18 (d, 2H), 8.35 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[CH:16][CH:15]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCOc1ccc(C(=O)C(CCOCc2ccccc2)c2ccc(Cl)cc2)cc1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C(O)(c2ccccc2)C(CCOCc2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]butan-1-one (9.4 g, 0.021 mol) is added to Grignard reagent prepared from bromobenzene (13.1 g, 0.083 mol) and Mg turnings (2.0 g, 0.083 mol) in dry tetrahydrofuran. The mixture is refluxed for 3 h. Saturated ammonium chloride solution is added to the cooled reaction mixture, the THF layer is separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with water and the solvents are evaporated. The residual product (10.7 g) is used in the next reaction step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:20](=[O:23])[CH2:21]Br)[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[C:14]1([CH:12]([CH3:13])[CH2:11][N:10]2[CH2:9][CH2:8][NH:7][CH2:21][C:20]2=[O:23])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(CN(CCNC(=O)OC(C)(C)C)C(=O)CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC(CN1CCNCC1=O)c1ccccc1
Yield: 74.5 %

Procedure:
In the same way as that described in Example 2, Step 3, using 2-[(bromoacetyl)(2-phenylpropyl)amino]ethyl carbamic acid tert-butyl ester (1.64 g, 4.11 mmol), trifluoroacetic acid (4 mL) and CH2Cl2 (40 mL), followed by K2CO3 (1.1 g, 8.2 mmol) and EtOH (100 mL). The piperazinone (668 mg, 75%) was isolated as a colourless oil. 1H NMR (250 MHz, CDCl3) δ1.28 (3H, d, J=6.8 Hz), 2.72-2.93 (3H, m), 3.04-3.26 (3H, m), 3.28 (1H, d, J=17.3 Hz), 3.52 (1H, d, J=17.3 Hz), 3.85-3.93 (1H, m), 7.19-7.35 (5H, m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:24])=[C:19]([CH2:21][CH2:22][OH:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OCC)=O)=[N-])=O)C>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:24])=[C:19]([CH2:21][CH2:22][O:23][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=3)[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CCO
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CCOc1ccc(C=O)cc1
Temperature: -5 °C
Yield: 74.1 %

Procedure:
The compound of Step C 3.61 g (10.9 mmole), 1.53 g (12.5 mmole) 4-hydroxybenzaldehyde, and 3.29 g (12.5 mmole) triphenylphosphine were dissolved in 30 ml tetrahydrofuran with stirring, under nitrogen. The solution was chilled to -5° C. and a solution of 1.97 ml (12.5 mmole) diethyldiazodicarboxylate in 10 ml. tetrahydrofuran was added over 10 minutes, with stirring. The reaction exothermed to +3° C. The bath was removed and the reaction stirred under nitrogen for 3 days. The reaction was stripped, dissolved in methylene chloride and placed in the freezer. The diethoxycarbonylhydrazine was then filtered off and the filtrate was chromatographed on 400 ml silica, eluting with a 5% isopropyl alcohol/hexane. The appropriate fractions were bulked and stripped to give 3.52 g (74%) product which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:24](Br)[CH2:25][OH:26]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:24][CH2:25][OH:26])[CH2:11][CH2:12]1
Reactant: OCCBr
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCN(c2ccccn2)CC1

Procedure:
To a mixture of 1-(2-pyridyl)piperazine (5 g), potassium carbonate powder (9 g) and N,N-dimethylformamide (30 ml) was added dropwise ethylene bromohydrin (5.74 g) under stirring. The mixture was stirred at room temperature for 6 hours, diluted with water (100 ml) and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel chromatography [eluent: dichloromethane-methanol (95:5)] to give 4-(2-pyridyl)-1-piperazineethanol as crystals, m.p. 82.5°-84° C. Yield 4.68 g (73.7%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:31][C@@H:32]([C@@H:34]4[CH2:38][C:37](=[O:39])[NH:36][CH2:35]4)[CH3:33])=[CH:10][C:11]([C:13]4[CH:22]=[C:21]5[C:16]([N:17]([CH3:30])[CH2:18][CH2:19][N:20]5C(OC(C)(C)C)=O)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([O:31][C@@H:32]([C@H:34]4[CH2:35][NH:36][C:37](=[O:39])[CH2:38]4)[CH3:33])=[CH:10][C:11]([C:13]4[CH:22]=[C:21]5[C:16](=[CH:15][CH:14]=4)[N:17]([CH3:30])[CH2:18][CH2:19][NH:20]5)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1cc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCN3C)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)NCCN3C)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
tert-butyl 7-(1-cyclopropyl-7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)-4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (40 mg, 0.075 mmol) was dissolved in DCM (2 mL), TFA (0.29 mL, 3.76 mmol) was added. The reaction was stirred at rt for 16 h. The mixture was quenched with saturated NaHCO3, extracted with EtOAc (3×30 ml). The combined organic layers were washed with water (2×5 mL), concentrated and purified by flash chromatography eluted with 5% to 20% MeOH/EtOAc to give 23.8 mg, (73.3%) of (R)-4-((R)-1-((1-cyclopropyl-5-(1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-1H-benzo[d]imidazol-7yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.57 (s, 1H), 7.19 (s, 1H), 6.88 (s, 1H), 6.74 (dd, J=2.4, 2.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.48 (d, J=8.1 Hz, 1H), 5.54 (s, 1H), 4.76-4.73 (m, 1H), 3.67-3.63 (m, 1H), 3.40-3.30 (m, 3H), 3.20-3.11 (m, 3H), 2.77 (s, 4H), 2.38-2.23 (m, 2H), 1.29 (d, J=6 Hz, 3H), 1.06-0.96 (m, 4H), LCMS-ESI+ (m/z): [M+H]+ calcd for C25H29N5O2:431.23; found 432.22.
Reaction SMILES: N[C@H](C(O)=[O:8])CC(C)C.CC1(C)S[C@@H]2[C@H](N[C:20]([C@H:22](N)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=O)C(=O)N2[C@H]1C(O)=O.O=C[C@H]([C@@H]([C@@H](CO)O)O)O>>[C:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:8])[CH3:20]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(=O)c1ccccc1
Reaction time: 7.5 h

Procedure:
A gene encoding leucine dehydrogenase from B. stearothermophilus is subjected to mutagenesis by error-prone PCR according to the method of May, et al. The error-prone PCR is performed in a 100 CL reaction mixture containing 0.25 ng of plasmid DNA as template dissolved in PCR buffer containing 0.2 mM of each dNTP, 50 pmol of each primer and 2.5 units of Taq polymerase. Conditions for carrying out the PCR are as follows: 2 minutes at 94 CC; 30 cycles of 30 sec 94 CC, 30 sec 55 CC; 2 minutes at 72 CC. The PCR product is double digested with Nco I and Bgl II and subcloned into pBAD/HisA vector which has been digested with the same restriction enzymes. The resulting leucine dehydrogenase mutant library is transformed into an E. coli host strain LMG194 and plated on LB agar supplied with 100 μg/mL ampicillin. Individual transformants are inoculated into master plates containing 0.2 mL LB Broth with 100 μg/mL ampicillin, and growth is allowed to take place for 8-16 hours at 37 CC with shaking at 200 rpm. Each well in each master plate is then re-inoculated by a replica plating technique into a new second stage 96-well plate pre-loaded with the same growth media plus 2 g/L of arabinose, and growth is allowed to continue for 5-10 hours at 37 CC with shaking at 200 rpm. The second stage plates are then centrifuged at 14,000 rpm for 20 minutes, and the supernatant is decanted. The cell pellet in each well is washed with 200 CL of water. The washed cell pellet is suspended in 30 CL of B-Per. After mixing, the suspension of cells in B-Per reagent is allowed to stand for 10 minutes at room temperature, and a solution having the following composition is then added to each well in the plate:
Reaction SMILES: [OH:1][CH:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)[CH2:3][CH3:4].Cl.N1C=CC=CC=1.Cl[O-].[Ca+2].Cl[O-]>ClCCl>[C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)(=[O:1])[CH2:3][CH3:4]
Reactant: CCC(O)c1cc(-c2ccccc2)no1
Agent: Cl
Agent: [Ca+2]
Agent: [O-]Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)c1cc(-c2ccccc2)no1

Procedure:
In 10 ml of dichloromethane, 1.0 g (5.0 mmol) of 5-(1-hydroxypropyl)-3-phenylisoxazole was dissolved. To the solution were added 100 mg (0.9 mmol) of pyridine hydrochloride, followed by the further addition of 1.4 g (9.9 mmol) of calcium hypochlorite. They were reacted at room temperature for 5 hours. After completion of the reaction, insoluble matter was filtered off and the organic layer wa washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was then recrystallized from ethanol, whereby the target compound, namely, 5-propiony-3-phenylisoxazole was obtained as crystals.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:3]=1.[OH-:22].[Na+]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:4]2[NH:3][C:2](=[O:22])[C:11]3[C:6](=[N:7][CH:8]=[CH:9][N:10]=3)[N:5]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(OCc2nc(N)c3nccnc3n2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: COc1ccc(OCc2nc3nccnc3c(=O)[nH]2)cc1

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 5.5 g (0.0194 mole) of 4-amino-2-[(4-methoxyphenoxy)methyl]pteridine in 150 ml of 5% aqueous sodium hydroxide. The solid obtained is taken up in dilute sodium hydroxide for purification. The insoluble portion is removed by filtration. The filtrate is acidified with acetic acid to pH 5.5. The precipitate formed is isolated by filtration; it is finally recrystallized from a mixture of ethanol and N,N-dimethylformamide. Yld: 1.7 g (31%), m.p. 233°-234° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]=[C:19]1[S:23][C:22](=[O:24])[NH:21][C:20]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:33]([C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH:13]=[C:12]2[CH:18]=[C:19]1[S:23][C:22](=[O:24])[NH:21][C:20]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: O=C1NC(=O)C(=Cc2c[nH]c3ccc(OCc4ccccc4)cc23)S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(=Cc2cn(S(=O)(=O)c3cccs3)c3ccc(OCc4ccccc4)cc23)S1
Reaction time: 18 h

Procedure:
The product from step A (50 mg) was treated with 1.2 equivalents of NaH in DMF solution with cooling for 1 hr. 2-Thienylsulfonyl chloride (34 mg, 1.3 equivaltents) was added cautiously. After 18 hrs. at ambient temperature and finally at 70° C., the mixture was poured onto ice and the precipitate was filtered. The title compound was filtered and washed with ether. HPLC ‘System 1’ (Ex. 1) showed 80% purity; structure confirmed by mass spec [m\e 497 (M+1)].
Reaction SMILES: [BH4-].[Na+].Br[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([F:21])[CH:8]=1)=[O:6].[OH-].[Na+]>O1CCOCC1.CO.O>[F:21][C:9]1[CH:8]=[C:7]([CH:5]2[CH2:4][O:6]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Fc1cc(C2CO2)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Sodium borohydride (1.25 g) was added in portions to a stirred solution of 2-bromo-1-[3-fluoro-4-(phenylmethoxy)phenyl]ethanone (16.6 g) in dioxan (100 ml) and methanol (100 ml) at 0°. After 0.5 h a solution of sodium hydroxide (4.0 g) in water (20 ml) was added and the mixture stirred for a further 1 h at 0°. Water was added and the mixture extracted with EA. The extracts were dried and evaporated to give the title compound as a colourless oil (12.6 g) which partially solidified on standing, t.l.c. (PE-EA 6:4) Rf 0.40.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.[Pd]>[CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1

Procedure:
To a 500 ml, 3-necked round bottom flask were added 92 g (500 mmole) p-aminodiphenylamine, 61 ml (600 mmole) cyclohexanone, 82 ml (800 mmole) nitrobenzene, 120 ml xylene solvent and 1.0 g of 5% palladium on carbon catalyst (0.05 g Pd). Using essentially the procedure of Example 1 the reaction was (A) carried out without acid and then again (B) in the presence of 3 millimoles of sulfuric acid. Reaction (B) provided about 40% (mole) more yield of DPPD over reaction (A) after 7 hours at reflux.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=S)[CH:26]=[CH:27][CH:28]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[O:19][C:18]([C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([C:3]5[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[NH:10][C:11]=4[CH:17]=3)=[N:20][N:21]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C=Nc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 4 °C
Reaction time: 1.75 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add 3-chloro phenyl isothiocyanate (69 uL, 0.512 mmol) and stir for 1.75 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 30 min. Allow to stir at room temp overnight. Dilute the reaction with EtOAc (50 mL) and extract with water (10 mL) and 1 N NaOH (10 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Combine the aqueous phases, chill to 4° C., and filter. Combine the solids and suspend them in boiling toluene/EtOAc. Cool the suspension to 4° C. and filter. Wash the solid with Et2O. Dry to afford the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 7.07 (ddd, J=7.96, 2.02, 0.76 Hz, 1 H) 7.40 (t, J=8.15 Hz, 1 H) 7.50-7.55 (m, 1 H) 7.62-7.67 (m, 1 H) 7.70 (s, 1 H) 7.72 (d, J=2.02 Hz, 1 H) 7.75-7.91 (m, 3 H) 8.11 (br. s., 1 H) 10.99 (br. s., 1 H) 13.28 (br. s., 1 H); MS m/z=457.9 (M+1).
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:33]([CH3:37])[C:34](Cl)=[O:35])[CH3:32]>C(O)CO>[I-:1].[CH2:31]([N:33]([CH3:37])[C:34]([O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:35])[CH3:32]
Reactant: CCN(C)C(=O)Cl
Reactant: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: OCCO
Solvent: CC#N
Product: CCN(C)C(=O)Oc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Temperature: 60 °C

Procedure:
Mix 7.9 g (0.02 mol) (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VIII) with 180 ml of acetonitrile, 4.1 g (0.03 mol) of potassium carbonate, 3.6 g (0.03 mol) ethyl(methyl)carbamic chloride and 0.1 g of macrogol 400 at room temperature, heat the mixture to 60° C. and let it react for 12 hours. After cooling to room temperature, filter it and reduce the pressure to recover the solvent and receive 10.3 g of red-brown liquid to be directly used in the next reaction.
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:24]([O:23][C:21]([CH2:20][N:8]1[C:4]2[CH:3]=[C:2]([I:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(I)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21

Procedure:
A mixture of 1.90 g (5.27 mmol) of tert-butyl 5-iodo-2-oxo-2,3-dihydro-benzimidazole-1-carboxylate (VI b), 1.13 g (5.80 mmol) of tert-butyl bromoacetate and 2.23 g (6.86 mmol) of cesium carbonate in acetonitrile (60 ml) was heated under reflux for 3 h. The solvent was removed in vacuo, water was added to the residue, and the aqueous mixture was extracted four times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 15-40% ethyl acetate in heptane). Yield: 2.26 g (90%) of white solid.