Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[C:13]1([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20]C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClC1C=CC=CC=1Cl>[C:13]1([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([P:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:20])=[N:4][N:3]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: COP(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1nnc(P(=O)(c2ccccc2)c2ccccc2)c2ccccc12
Reaction time: 312 h

Procedure:
To a stirred, refluxing mixture of 5.00 g of 1,4-dichlorophthalazine in 50 ml of o-dichlorobenzene under nitrogen was added dropwise 15.00 of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 6 hours and then allowed to stand at room temperature for 13 days. The resulting solid was separated by filtration, washed with benzene and with hexane, recrystallized from 125 ml of toluene with decolorizing charcoal treatment, and dried at 100° C./0.1 mm (13 Pa) to give 6.41 g of 1,4-bis(diphenylphosphinyl)phthalazine (shown by formula in Claim 13) as a light-yellow solid, mp 225°-228.5° C. Anal. Calcd C32H24N2O2P2 : C, 72.45; H, 4.56; N, 5.28; P, 11.68. Found: C, 72.49; H, 4.62; N, 5.36; P, 11.95.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(Cn2cncn2)cc1

Procedure:
U.S. Pat. No. 4,978,672 (referred to herein as '672, Indian Reference not available) provides 4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile and the process of its preparation. The patent discloses reacting 4-bromomethylbenzonitrile with 1,2,4-triazole to yield 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile. 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile is then reacted with 4-fluorobenzonitrile to give 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile. This patent does not disclose the purity of 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, compound of formula 1. When we followed the patented process we also get the unwanted isomer 4-[1-(1,2,4-triazol-4-yl)methyl]benzonitrile, a compound of formula 4 (20 to 40%) in step 1. When the reaction mixture of step 1 is treated with 4-fluorobenzonitrile it yields 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)-methyl]-benzonitrile, a compound of formula 1, and its isomer, a compound of formula 5. Thus the impurity of formula 4 has to be separated before treating it with 4-fluorobenzonitrile, which involves an additional step of column purification, which is reported in '672 and makes the process tedious and commercially unviable.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH2:28][NH:27][N:26]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:33])=[O:32])[C:25]=3[CH2:24]2)[CH2:11][O:10]1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH2:28][NH:27][N:26]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:32])=[O:33])[C:25]=3[CH2:24]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (52 mg, 0.099 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (1 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated and purified on reverse phase HPLC using H2O/acetonitrile containing 0.05 TFAv/v, to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.21-1.27 (m, 2H); 1.38-1.43 (m, 2H); 2.06 (q, 1H, J=14 Hz); 2.73-2.79 (m, 1H); 2.29-3.06 (m, 1H); 3.57-3.64 (m, 1H); 3.74 (t, 1H, J=12 Hz); 3.81-3.90 (m, 1H); 4.44-4.54 (m, 3H); 4.69 (d, 1H, J=12 Hz); 4.71-4.81 (m, 2H); 7.18-7.26 (m, 2H); 7.27-7.32 (m, 1H); 7.74 (s, 1H). LC-MS: 425.21 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N[C:16](N)=[O:17]>O>[CH2:13]([N:12]1[C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[C:2]=2[N:1]=[C:16]1[OH:17])[CH3:14]
Reactant: CCNc1ccc2cccnc2c1N
Reactant: NC(N)=O
Solvent: O
Product: CCn1c(O)nc2c3ncccc3ccc21
Temperature: 140 °C

Procedure:
22.4 g (0.12 mol) of 8-amino-7-ethylaminoquinoline and 9 g (0.15 mol) of urea are heated at 160° C. for 2 h, stirring vigorously. The mixture is allowed to cool to 140° C., and 50 ml of water are slowly added dropwise. After further cooling to 100° C., another 100 ml of water are added. The precipitate is filtered off with suction, washed again with hot water and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.C(N(CC)S(C1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(S(=O)(=O)N(CC)CC)=CC=3)=CC=2C(O)=O)=CC=1)(=O)=O)C>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: CCN(CC)S(=O)(=O)c1ccc(Nc2cc(C(=O)O)c(Nc3ccc(S(=O)(=O)N(CC)CC)cc3)cc2C(=O)O)cc1
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 0.08 h
Yield: 102.2 %

Procedure:
To 720 g of polyphosphoric acid (116.5%) heated at 90° C. were added 12.0 g of 2,5-di[4-(N,N-diethylsulfamoyl)anilino]terephthalic acid. The mixture was stirred for five minutes, after which 120 g of 2,5-di(4-chloroanilino)terephthalic acid were added over a period of approximately 45 minutes, the temperature being maintained below 110° C. by adjustment of the addition rate. The reaction mixture was held at 113° C. for five hours and then cooled to 95° C. To this mixture was added 89.4 g of phosphoric acid (75%) dropwise over a period of 20 minutes. The resultant melt was allowed to stir for 15 minutes at 92° C. and then poured slowly into 1240 g of methanol, the temperature being maintained below reflux by adjustment of the addition rate. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 112 g of 2,9-dichloroquinacridone as a magenta pigment.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7](=[CH:10][N:11]([CH3:13])C)[CH:8]=[O:9])=[CH:4][CH:3]=1.NC[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[CH:10][NH:11][CH2:13][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=[O:9])=[CH:14][CH:15]=1
Reactant: CN(C)C=C(C=O)Oc1ccc(Cl)cc1
Reactant: CCOC(=O)CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CNC=C(C=O)Oc1ccc(Cl)cc1

Procedure:
2-(4-Chlorophenoxy)-3-dimethylaminoacrylaldehyde (11.3 g., 50 mmoles) was dissolved in 200 ml. of ethanol, mixed with a solution of ethyl glycinate (14 g., 100 mmoles) in 90 ml. of 1 N sodium hydroxide and refluxed for 15 hours. Ethanol was evaporated in vacuo, the aqueous residue diluted with 150 ml. of water and product extracted into 200 ml. of ethyl acetate. The ethyl acetate was back-washed with water and concentrated to an oil. Trituration of the oil with 100 ml. of ether gave crystalline 2-(4-chlorophenoxy)-3-carbethoxymethylaminoacrylaldehyde in two crops (7.3 g., Rf 0.55 on silica gel thin layer chromatography with ethyl acetate-1/hexane-1/5% acetic acid as eluant).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CN([C:13]([O:17][N:18]1N=NC2C=CC=N[C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.COCN>C(Cl)Cl.O>[CH3:13][O:17][N:18]([CH3:19])[C:1](=[O:9])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccncc1
Agent: COCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.7 %

Procedure:
To a stirred solution of isonicotinic acid (20.0 g, 162 mmol) in DCM (400 mL) were added HATU (92.6 g, 243 mmol), N-methoxy methylamine (17.24 g, 178 mmol) and TEA (68.7 mL, 487 mmol) at RT under nitrogen atmosphere. The reaction mixture was then stirred at RT for 12 h. The reaction mixture was diluted with water and the aqueous layer was extracted with DCM (3×500 mL). The combined organic extracts were washed with water (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 30-40% EtOAc in Hexane to afford to afford N-methoxy-N-methylisonicotinamide (15.0 g, 55%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6]2.[Br:15]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>ClCCl>[Br:15][C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:10]([O:12][CH3:13])=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:14]
Reactant: COc1cc2c(c(OC)c1)C(=O)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1Br)CCC2=O
Yield: 86.4 %

Procedure:
845 mg of 5,7-dimethoxyindan-1-one was dissolved in 40 ml of dichloromethane. Thereafter, 822 mg of N-bromosuccinimide was added to the reaction solution. After completion of the reaction, chloroform was added to the reaction solution. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was suspended in acetone, and the suspension was filtered, so as to obtain 1.03 g of 4-bromo-5,7-dimethoxyindan-1-one. The obtained product was suspended in a mixed solution consisting of 30 ml of methanol, 10 ml of tetrahydrofuran, and 20 ml of chloroform. Thereafter, 952 mg of methoxylamine hydrochloride and 935 mg of sodium acetate were added to the reaction solution, and the obtained mixture was stirred at room temperature. Approximately 4 hours later, 952 mg of methoxylamine hydrochloride and 935 mg of sodium acetate were further added to the reaction solution. After completion of the reaction, the reaction solution was concentrated. A saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the resultant product, so as to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was suspended in t-butyl methyl ether, and the suspension was filtered, so as to obtain 896 mg of the subject compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(Br)c1N
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To 2-amino-3-bromobenzoic acid (0.5 g, 2.3 mmol) in DMF (5 mL) at rt were added hydroxybenzatriazole (0.46 g, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.53 g, 2.8 mmol), ammonium chloride (0.5 g, 9.7 mmol), and diisopropylethylamine (1.7 ml, 9.7 mmol). The mixture was purged with N2 and stirred for 6 h. The mixture was poured into water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (10 mL) resulting in a precipitate which was collected by filtration and dried to afford 2-amino-3-bromobenzamide as a pale pink solid (0.42 g, 84%). LCMS (ESI) m/z 215/217 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17](I)[CH:18]=1)[CH3:11].[CH3:21][O:22][C:23](=[O:41])[C:24]([CH3:40])([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[CH3:25].[F-].[Cs+]>COCCOC.O>[CH3:21][O:22][C:23](=[O:41])[C:24]([N:26]1[CH:30]=[C:29]([C:17]2[CH:16]=[N:15][C:14]([NH2:20])=[C:13]([O:12][CH:10]([C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[Cl:1])[CH3:11])[CH:18]=2)[CH:28]=[N:27]1)([CH3:40])[CH3:25]
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: COC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(C)(C)n1cc(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)cn1
Temperature: 120 °C

Procedure:
To a solution of 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (6.363 g, 14.901 mmol) and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]propionic acid methyl ester (4.6 g, 15.64 mmol) in DME (27 mL) was added a solution of CsF (6.79 g, 44.7 mmol) in water (9.3 mL). The reaction mixture was degassed 3 times with N2. Pd(dppf)CH2Cl2 was added and the reaction mixture was degassed 3 times with N2. The reaction was heated to 120° C. in the microwave (subsequent Pd was added in intervals of 30 minutes until the reaction was complete). Water was added and the reaction was extracted with EtOAc, dried over Na2SO4, and concentrated to give 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester. The crude product was purified by a silica gel column chromatography with a gradient of 25%-50% EtOAc/hexanes to provide 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester (1.46 g, 21% yield) with a Rf 0.11 (50% EtOAc/hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:20](=[O:22])[CH3:21]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-4-chloroquinoline (20.0 g, 112 mmol) in dichloromethane (125 mL) was cooled to 0° C. Triethylamine (47.0 mL, 0.336 mol) was added followed by a solution of acetyl chloride (16.0 mL, 0.224 mol) in dichloromethane (45 mL), which was added dropwise. The reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional acetyl chloride (4 mL, 56 mmol) was added. The reaction was stirred for four hours at room temperature. Saturated aqueous sodium bicarbonate (100 mL) was added, and the mixture was stirred for three days. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide N-(4-chloroquinolin-3-yl)acetamide as a dark red solid.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[K]>>[C:22]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Agent: [K]
Product: CCOC(=O)C(C(=O)OCC)c1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with potassium diethyl malonate to obtain 4-(bis(carboethoxy)methyl)-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole; this intermediate is deesterified and decarboxylated to yield 4-methyl-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole, m.w., 313.2. In like procedures, the following are prepared:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1.C(#N)C.Cl>ClCCl>[O:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1
Reactant: COC(CCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)OC
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: O=CCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a 500 mL round-bottomed flask with a magnetic stirrer was added biphenyl-2-ylcarbamic acid 1-(9,9-dimethoxynonyl)piperidin-4-yl ester (7.7 g, 15.9 mmol) and then acetonitrile (70 mL) and aqueous 1M hydrochloric acid (70 mL). The resulting mixture was stirred at room temperature for 1 h and then dichloromethane (200 mL) was added. This mixture was stirred for 15 min. and then the layers were separated. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (6.8 g), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[C:17]2([O:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[O:11])=[O:7].Cl.O1CCOCC1>>[O:21]1[C:17]2([C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][CH:31]=[C:3]([C:2]([F:32])([F:33])[F:1])[CH:4]=3)[CH2:14][NH:15][CH2:16]2)[CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C2(CCCO2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CNCC12CCCO2
Reaction time: 2 h

Procedure:
The intermediate of step G (0.18 g) was mixed with 5 mL of 4 N HCl/dioxane. The solution was stirred for 2 h and concentrated under vacuum. MS (M+H)+372.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH2:9]([O:16][NH:17][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CCCCCCBr
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCCBr)NOCc1ccccc1
Reaction time: 18 h
Yield: 29 %

Procedure:
In an ice bath, 2.4 ml triethylamine was added to a suspension of 2.7 g (17 mmol) O-benzylhydroxylamine hydrochloride in 100 ml dichloromethane. 3.6 g (17 mmol)7-bromo heptanoic acid was added, followed by 5.3 g (21 mmol) bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride Stirring was continued at ambient temperature for 18 h. The solution was extracted twice with 150 ml each of 1M aqueous hydrochloric acid and twice with 150 ml each of 1M aqueous sodium bicarbonate. The organic solvent was removed i. vac. and the residue was purified by column chromatography (silica gel; ethyl acetate: heptane 1:1) to give 1.55 g (30%) of 7-bromo-heptanoic acid benzyloxy-amide as a colorless oil. MS: 314 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:29])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26](O)=[O:27])[CH2:22][CH2:23][CH:24]=4)[C:4](=[C:5]23)[CH:3]=1.[NH:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:30]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:29])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26]([N:31]5[CH2:34][CH:33]([OH:35])[CH2:32]5)=[O:27])[CH2:22][CH2:23][CH:24]=4)[C:4](=[C:5]23)[CH:3]=1
Reactant: CN1C=C2C(=C(C3=CCCN(CC(=O)O)CC3)C1)NN=C1C=Cc3cc(F)cc2c31
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C=C2C(=C(C3=CCCN(CC(=O)N4CC(O)C4)CC3)C1)NN=C1C=Cc3cc(F)cc2c31

Procedure:
A mixture of Example 90B (60 mg, 0.125 mmol), azetidin-3-ol, hydrochloric acid (20.57 mg, 0.188 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (57.1 mg, 0.150 mmol) and triethylamine (87 μL, 0.626 mmol) in 2 mL N,N-dimethylformamide was stirred at room temperature overnight. The mixture was extracted with dichloromethane and purified by flash chromatography on silica using an Analogix system (0-10% methanol/dichloromethane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.46-2.90 (m, 10H), 3.17 (d, J=5.1 Hz, 2H), 3.62 (dd, J=10.3, 4.4 Hz, 1H), 3.89-4.14 (m, 5H), 4.33-4.61 (m, 2H), 5.72 (d, J=5.9 Hz, 1H), 5.92 (t, J=6.3 Hz, 1H), 7.18-7.35 (m, 3H), 7.69 (dd, J=10.4, 3.0 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 11.51 (s, 1H). MS (ESI+) m/z 462 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:21]>CC(C)=O.C(Cl)Cl>[CH2:3]([C:10]1[N:11]([CH3:21])[C:12]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=2[N:14]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Brc1ccc2[nH]c(Cc3ccccc3)nc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cn1c(Cc2ccccc2)nc2ccc(Br)cc21
Reaction time: 1 h

Procedure:
Powdered KOH (5.25 g, 93.50 mmol) was added to a stirred solution of 2-benzyl-5-bromo-1H-benzimidazole (5.37 g, 8.70 mmol) in acetone (100 mL), after 10 min, iodomethane (1.28 mL, 20.57 mmol) was added and the mixture was stirred for 1 h and diluted with DCM. The mixture was washed with water and brine, then dried over Na2SO4 and concentrated. The residue was taken up in DCM and hexanes and the resulting suspension filtered. The filtrate was concentrated and the oily residue taken up in hexanes and stirred for about 1 h. The resulting solid was filtered and the filter cake washed with hexanes and dried (2.0 g, 34%). LC-MS [M+H]+=302.1, RT=2.47 min.