Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A 2 L flask was charged the solution of 4-chloro-1-methyl-2-nitrobenzene (60 g, 0.35 mol) in MeOH (1 L), Raney Ni was added, the air in flask was replaced three times with H2, the mixture was stirred for 3 h at rt. The solution was filtered and concentrated. The residue was dissolved in CH2Cl2 (500 mL), and the solution was washed with brine, dried over Na2SO4. Solvent removal gave 5-chloro-2-methylbenzenamine (50 g, 0.35 mol). 1H NMR (CDCl3, 400 MHz) δ 7.02-6.93 (d, 2H), 6.70-6.60 (d, 2H), 3.67 (s, 2H), 2.14 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[N:15]=[C:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[NH:13][C:12]=3[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[N:15]=[C:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:13]([CH3:26])[C:12]=3[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(CC(C)(C)O)[nH]c2c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(CC(C)(C)O)n(C)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30.7 %

Procedure:
To a solution of methyl 4-(4-fluorophenyl)-2-(2-hydroxy-2-methylpropyl)-1H-benzimidazole-6-carboxylate (125 mg, 0.365 mmol) and cesium carbonate (297 mg, 0.913 mmol) in N,N-dimethylformamide (0.730 mL) was added methyl iodide (0.025 mL, 0.402 mmol). Stirred at ambient temperature for 2.5 h. Filtered and purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (40 mg): LC-MS [M+1]=357.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH:16]=1)[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[CH:28]1([C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[CH:16]=2)[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:30][CH2:29]1
Reactant: OB(O)C1CC1
Reactant: CCOP(=O)(Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1cc(Oc2ccc(C(F)(F)F)cn2)cc(C2CC2)c1)OCC
Temperature: 50 °C
Yield: 93.6 %

Procedure:
To a solution of diethyl 3-bromo-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylphosphonate (0.93 g, 1.99 mmol) and cyclopropylboronic acid (0.204 g, 2.38 mmol) in THF (5.6 mL) was added potassium phosphate (1.27 g, 5.99 mmol). The mixture was degassed by purging with argon. PdCl2(dppf2 (162.2 mg, 0.198 mmol) and water (0.11 mL) were added to the reaction mixture and the mixture was degassed again. The reaction was heated at 50° C. for 1 h. The reaction mixture was concentrated and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (20% ethyl acetate in hexane) to give the title compound (0.8 g, 94%). 1H NMR (500 MHz, CDCl3): δ 8.42 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 6.96 (d, J=9 Hz, 1H), 6.90 (s, 1H), 6.86 (s, 1H), 6.73 (s, 1H),), 4.02 (m, 4H), 3.14 (s, 1H), 3.10 (s, 1H), 1.87 (m, 1H), 1.24 (m, 6H), 0.96 (d, J=8.5 Hz, 2H), 0.69 (d, J=5 Hz, 2H); m/z (430.0, M+ H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:18][CH2:17]3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([N:16]3[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:21]3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A mixture containing ethyl 3-[1-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]piperidin-4-yl]propanoate (50 mg), concentrated hydrochloric acid (1 ml) and dioxan (4 ml) was stirred at 50°-60° C. for 1 hour, then concentrated to give a foam which was triturated with hot isopropanol. Filtration gave the title compound (48 mg) as pale cream prisms, m.p. 188°-190° C. NMR (d6DMSO+d4AcOH): δ 1.0-1.3(2H,m); 1.5-1.6(3H,m); 1.8(2H,d); 2.3(2H,t); 2.6-2.8(1H,m); 2.95-3.15(1H,m); 3.5(4H,br.s); 3.6-3.7(1H,m); 4.0-4.2(4H,br.s); 4.3-4.5(3H,m); 7.25(2H,d); 8.35(2H,d); m/e 361(M+H)+ ; calculated for C19H28N4O3. 2HCl. H2O: C, 50.6; H, 7.2; N, 12.4; H2O, 4.0; found: C, 50.3; H, 7.2; N, 12.2; H2O, 4.0%.
Reaction SMILES: [C:1]([P:5](=[O:20])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C(OCC)OCC)([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([PH:5](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)P(=O)(Cc1ccccc1)C(C)(C)C
Agent: Cl
Product: CC(C)(C)[PH](=O)Cc1ccccc1

Procedure:
Following a procedure analogous to that to Example 13, but using tert.butyl(benzyl)(diethoxymethyl)phosphine oxide (1.7 g) and 15 ml of concentrated hydrochloric acid, tert.butyl(benzyl)phosphine oxide is obtained as a white solid, m.p. 80°-2° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:43])[CH3:42].[Cl-].[NH4+]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:43])[CH3:42]
Reactant: Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
1.15 gram (2.54 mmol) of (−)-2-amino-2′-diphenylphosphino-1,1′-binaphthyl (the formula (1-1a)) was dissolved in 51 ml of methylene chloride, followed by the addition of 0.25 ml (3.04 mmol) of pyridine and 0.20 ml (2.78 mmol) of acetyl chloride under 0° C. The reaction mixture was stirred at room temperature for 3 hours. To the reaction solution, 30 ml of saturated aqueous solution of ammonium chloride was added and extracted with 100 ml of methylene chloride. The extract was washed with 70 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:3 mixture of ethyl acetate and hexane) to obtain 1.11 gram of the titled compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15]O)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O>ClCCl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][Cl:23])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(OCc2ccc(C(F)(F)F)cc2)ccn1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(COc2ccnc(CCl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.2 g (7.8 mmol) of the title compound from Example 3 are dissolved in 50 ml of anhydrous dichloromethane and a solution of 2 ml of thionyl chloride in 6 ml of dichloromethane is added dropwise at -10° C. The mixture is warmed to room temperature, stirred for 30 minutes more, and concentrated. The crystalline residue is brought to crystallization using diisopropyl ether and dried using an oilpump, m.p. 133°-135° C.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:20][N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32]C(N)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>>[C:15]([C:7]1[S:6][C:5]2[C:3](=[O:4])[N:12]([C:14]3[CH:32]=[CH:33][C:28]([N:24]4[CH2:25][CH2:26][CH2:27][N:21]([CH3:20])[CH2:22][CH2:23]4)=[CH:29][CH:30]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1)(=[O:19])[CH:16]([CH3:17])[CH3:18]
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: COC(=O)c1sc(C(=O)C(C)C)cc1N=CN(C)C
Product: CC(C)C(=O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1

Procedure:
3-(Dimethylaminomethyleneamino)-5-isobutyrylthiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 410.54 (C22H26N4O2S) was obtained in this way; MS (ESI): 411 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][C:14]=2[Cl:24])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[Cl:24])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OCC)cc2Cl)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Cl)ccc(C(C)=O)c1O
Yield: 89.8 %

Procedure:
A mixture of ethyl 4-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3-chlorobenzoate (1.0 g), ethanol (10 ml) and 1N sodium hydroxide (10 ml) was refluxed for 0.5 hour, then concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and concentrated, and the crystals were collected by filtration. There was obtained 4-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3-chlorobenzoic acid as needles (840 mg). Melting point 171°-172° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][C:13](=[O:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:12][C:13]([C:26]([F:28])([F:27])[F:25])([OH:15])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (25 mg, 0.056 mmol), prepared using procedures described in Example 6, was taken into DMF (0.5 mL) followed by addition of (trifluoromethyl)trimethylsilane (40 μL, 0.28 mmol) and cesium carbonate (22 mg, 0.067 mmol) and the mixture was stirred for one hour at room temperature. The mixture was partitioned with ethyl ether and water and the organic phase washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:2 as eluent afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol (19.8 mg, 69% yield) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 8.31-8.26 (br, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.13-7.10 (m, 1H), 6.86-6.80 (m, 1H), 6.65-6.60 (m, 1H), 4.42 (br s, 2H), 4.18 (br s, 2H). MS (EI) for C17H11F61N2O2: 517 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([OH:6])[C:4]#[CH:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>[CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([O:6][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[C:4]#[CH:5]
Reactant: C#CC(O)C(C)(C)CCCC
Reactant: C1=COCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: C#CC(OC1CCCCO1)C(C)(C)CCCC
Temperature: 25 °C

Procedure:
To a solution of 23.1 g. (0.150 mole) of 4,4-dimethyl-1-octyn-3-o1 (Example 994) in 126 g. of freshly distilled dihydropyran is added 1 drop of phosphorus oxychloride and the solution is maintained at ambient temperature in a tightly stoppered flask for 20 hours. Five drops of triethylamine are then added and the mixture is evaporated in vacuo to an oil. The oil is chromatographed on 600 g. of silica gel and the product is eluted with 5% ethyl acetate in benzene yielding a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][S-:15].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:14][S:15][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(SC)nc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 40.2 %

Procedure:
To a solution of ethyl (6-chloropyridin-3-yl)acetate (10.7 g) in N,N-dimethylformamide (100 mL) was added sodium methanethiolate (11.3 g), and the mixture was stirred at room temperature for 23 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-50:50, volume ratio) to give the title compound (4.55 g, yield 40%) as a colorless oil. MS: 212 (MH+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[CH2:25][C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:24][CH2:25][C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CCCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 37.5 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.35 g) and 4-(but-3-yn-1-ylamino)-1,3-thiazol-2(5H)-one (1 g) in 2-propanol (20 mL) was added piperidinium acetate (0.58 g). The reaction mixture was stirred at 80° C. for 6 hr and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (0.73 g).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:14])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cn1ccnn1
Agent: Cl
Product: O=C(Cn1ccnn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 174, (S)-2-(2-(1H-1,2,3-triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (17.6 mg, 7%). 1H-NMR (400 MHz, CDCl3): σ 8.37 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.38-7.29 (m, 6H), 7.02 (t, 2H), 6.96-6.91 (m, 4H), 6.85 (d, 1H), 5.19-5.11 (m, 2H), 4.70-4.65 (m, 1H), 4.64 (d, 1H), 4.55 (d, 1H), 3.98 (dd, 1H), 3.58 (t, 1H). MS (EI) for C26H24FN5O4. found 490.2 (MH+).
Reaction SMILES: I.CS[C:4](=[NH:16])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24][NH2:25])=O)=[CH:20][CH:19]=1>N1C=CC=CC=1>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]([NH:5][C:4]2[NH:16][C:22]([C:21]3[CH:26]=[CH:27][C:18]([OH:17])=[CH:19][CH:20]=3)=[N:24][N:25]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CSC(=N)Nc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1ccc(O)cc1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Temperature: 25 °C
Yield: 47.6 %

Procedure:
S-methyl N-[3-(trifluoromethyl)phenyl]isothiourea hydroiodide (9.09 g, 25.11 mmol) and 4-hydroxybenzoic acid hydrazide (3.82 g, 25.11 mmol) were suspended in ca. 50 mL of anhydrous pyridine under Ar. The mixture was brought to reflux and refluxed under Ar for 12 hrs. Then the dark-yellow solution was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting reddish-yellow solid was re-dissolved in ca. 50 mL of 4:1 mixture of EtOAc/MeOH, ca. 20 g of silica gel was added and solvent was removed in vacuo. The impregnated silica gel was loaded into 25 g ISCO sample cartridge and the product was purified using ISCO system (solid method, 80 g column, 45 min, 0% to 50% EtOAc gradient in hexane). Solvent was removed in vacuo to give the title product as a white solid (3.83 g). Yield 47.6%.
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[NH:31]1[CH2:34][CH2:33][CH2:32]1.N>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([N:31]3[CH2:34][CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: C1CNC1
Agent: N
Solvent: CCO
Product: OCC1CC(n2c(N3CCC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Reaction time: 18 h
Yield: 40.9 %

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in ethanol (7 mL). Azetidine (Aldrich, 250 mg, 4.4 mmol as 98%) was added and the solution was refluxed under nitrogen for 48 hours. Methanolic ammonia (saturated at 0° C., 20 mL) was added to the cooled solution and this solution was stirred for an additional 18 hours. Volatiles were evaporated, the residue was redissolved in ethanol (10 mL) and 1N sodium hydroxide (0.96 mL) was added. Volatiles were evaporated and the residual solids were triturated with water (3 mL) and filtered. Resolidification of the solid from acetonitrile-methanol gave title compound as white powder (146 mg, 41%), m.p. 221°-222° C.; 1H-NMR(DMSO-d6)δ: 7.78 and 7.53 (both s, 1 each, 2 aromatic CH), 5.05 (t, J=4.3 Hz, 1, OH), 4.91 (d, J=5.3 Hz, 1, OH), 4.59 (d, J=3.7 Hz, 1, OH), 4.45-4.40 (m, 2, OCH and NCH), 4.25-4.15 (m, 4, 2 CH2N), 3.82-3.79 (m, 1, OCH), 3.66-3.43 (both m, 1 each, OCH2), 2.40-2.32 (m, 2, CH2), 2.03-1.95 (m, 3, CH2 and NCH); mass spectrum (CI): 372(M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH:5]=[C:6]4[CH:19]=[N:18][CH:17]=[CH:16][C:7]4=[N:8][C:9]=3[O:10][C:11]=2[C:12]([NH2:15])=[CH:13][CH:14]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[C:4]3[CH:5]=[C:6]4[CH:19]=[N:18][CH:17]=[CH:16][C:7]4=[N:8][C:9]=3[O:10][C:11]=2[C:12]([NH:15][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)c2c1oc1nc3ccncc3cc12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c2c1oc1nc3ccncc3cc12)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-chloro-11-oxa-7,10-diaza-benzo[b]fluoren-1-ylamine (35 mg, 0.13 mmol) in the dichloromethane (2.0 mL) is added 3-(trifluoromethyl)benzoyl chloride (54.2 mg, 0.26 mmol). After the mixture is stirred for 24 hours at room temperature, it is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (98/2) to give the product as a solid: 1H NMR 400 MHz (DMSO) δ 10.85 (s, 1H), 9.53 (s, 1H), 9.37 (s, 1H), 8.63 (d, 1H), 8.24 (s, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.67 (t, 1H), 7.48 (d, 1H); MS m/z 442.85 (M+1).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)([CH3:4])[CH3:3].C(N1C=C(B2OC(C)(C)C(C)(C)O2)[C:32]([C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-])=O)=[CH:46][CH:45]=2)=[N:31]1)C>>[CH3:4][C:2]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[C:8]([C:45]2[CH:46]=[CH:47][N:50]=[C:32]3[NH:31][CH:48]=[CH:49][C:44]=23)[CH:7]=[N:6]1)([CH3:3])[CH3:1]
Reactant: CC(C)(C)n1ncc(B2OC(C)(C)C(C)(C)O2)c1-c1ccc([N+](=O)[O-])cc1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CC(C)(C)n1ncc(-c2ccnc3[nH]ccc23)c1-c1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure described for Intermediate 6 with 1-(1,1-dimethylethyl)-5-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, provided the title compound. ESMS [M+H]+: 362.2
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]\[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.O.[NH2:15]N>C(O)C>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:15]1
Reactant: NN
Reactant: CN(C)/C=C\C(=O)c1ccccn1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc[nH]n2)nc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
Compound 16a (1 g, 6.2 mmol) obtained from the aforesaid process and hydrazine hydrate (2 mL) were dissolved in ethanol (3.3 mL), and reacted at 60° C. for 0.5 hour. Then, the mixture was cooled to room temperature, and then the solvent was removed in vacuum to afford the product 17a (874.7 mg) as a faint yellow solid, with a yield of 97.3%.
Reaction SMILES: C1(COC2C(C3N(CC4C=C[C:21]([CH2:24][CH2:25][C:26]([OH:28])=O)=[CH:20][CH:19]=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46](CC3CCCCC3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.BrCC1CCCCO1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:19][CH:20]3[CH2:21][CH2:24][CH2:25][CH2:26][O:28]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH3:61])[CH:37]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCO1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCO1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 2-bromomethyl-tetrahydro-pyran (CAS Reg. No. 34723-82-5). Brown powder (39%). MS (Turbo Spray): m/z=393.2 (M+H).