Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[OH:21][CH:22]1[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]1.CC([O-])(C)C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:21][CH:22]2[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: N#CC1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CC(C#N)C3)nc(Cl)nc21
Temperature: 70 °C
Yield: 77 %

Procedure:
2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 3-hydroxycyclobutanecarbonitrile (1.1 equiv), sodium 2-methylpropan-2-olate (1.2 equiv) and 1,4-dioxane (0.14 M) were combined in a sealable vessel with a stir bar. The resulting mixture was put under nitrogen atmosphere, sealed, stirred vigorously, and heated at 70° C. for 16 h. After cooling to room temperature, the reaction mixture was purified using silica gel chromatography (0 to 50% ethyl acetate in hexane) to give the title compound (77% yield). MS (ESI) m/z 505.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19].CCCCCC>CN(C=O)C>[CH2:22]([O:21][C:18]([C:19]1[O:10][C:7]2[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([CH3:11])[C:4]=2[CH:5]=1)=[O:20])[CH3:23]
Reactant: CCOC(C)=O
Reactant: Cc1c(Br)ccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)c(Br)ccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-Bromo-6-hydroxy-2-methyl-benzaldehyde (6.8 g, 0.032 mol)) in anhydrous DMF (50 ml) was added potassium carbonate (13.1 g, 0.095 mol) and cooled to 0° C. Bromo ethyl acetate (7.1 ml, 0.063 mol) was added slowly. The reaction mixture was stirred for one hour at 0° C. The completion of the reaction was confirmed by TLC. The reaction mixture was then heated to 100° C. and maintained for 2 hours. After cooling to room temperature, ice water (250 ml) was added and the mixture was stirred for 20 minutes. The solid separated was filtered, washed with water (100 ml) and dried under vacuum, to get crude product. Column chromatography using 2/5 ethyl acetate/hexane yielded 5-Bromo-4-methyl-benzofuran-2-carboxylic acid ethyl ester (6.2 g, 69.6%)
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.O>O1CCCC1>[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]([OH:11])[CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)c1ccc(F)cc1
Yield: 99 %

Procedure:
1,550 ml (2.0 mol) of a 1.29 M solution of vinylmagnesium chloride in tetrahydrofuran were introduced into a 4 l stirred flask under nitrogen. Subsequently, while stirring under nitrogen at 30°-35° C., a solution of 222.0 g (1,764 mol) of 4-fluorobenzaldehyde in 2,000 ml of tetrahydrofuran was added over the course of 30 min, cooling the reaction mixture with ice. The mixture was then stirred at room temperature under nitrogen for 2.5 h. Subsequently, while stirring and cooling with ice, 180 ml of water were added, the mixture was filtered with suction, and the residue from the filter was washed 3x with 150 ml of tetrahydrofuran. The filtrates were combined, dried with sodium sulfate and concentrated. 265.7 g (99%) of product were obtained in the form of a yellow-brown oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:19])[C@@:11]([O:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:19][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[C@@:11]([O:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: C=CCC[C@@](C)(OC)[C@H](O)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC[C@@](C)(OC)[C@@H](COCc1ccccc1)OC1CCCCO1

Procedure:
A solution of (2R,3R)l-benzyloxy-3-methoxy-3-methyl-6-heptene-2-ol (10) (37.1 mmol, 9.8 g), dihydropyran (55.7 mmol, 5.1 ml) and pyridinium paratoluene sulfonate (3.71 mmol, 0.93 g) in anhydrous dichloromethane (100 ml) is stirred under nitrogen atmosphere for 24 h. Ether (400 ml) is added, and the organic layer is washed with water, brine, saturated aqueous NaHCO3 and brine. After drying over anhydrous magnesium sulfate the solvent is flash evaporated. The product 11b is used as such in the next reaction.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][NH:11][CH3:12].[BH3-]C#N.[Na+]>CO>[CH3:10][N:11]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: O=CCc1ccccc1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of phenylacetaldehyde (5 mM, 0.6 mL) and dimethylamine (5 mM, 3 mL of 2M in MeOH) in MeOH (1 mL), was added NaCNBH3 (5 mM, 360 mg) in a round-bottomed flask. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and H2O was added to the residue before extraction with CH2Cl2. The combined extracts were dried over MgSO4, the solid was filtered off, and the solvent was evaporated under reduced pressure to give a yellow oil. The crude products were purified by column chromatography (silica gel, EtAc:n-hexane, 4:6) to afford pure product in quantitative yield, 0.52 g, 87%, yellow oil. TLC (EtAc:n-hex, 4:6 v/v): RF=0.2. 1H NMR, δ: 7.40-7.20 (m, 5H), 3.20 (m, 4H), 2.20 (S, 6H). 13C NMR, δ: 141.5, 129.1, 128.6, 125.8, 60.9, 45.6, 32.2. Anal. calcd for C10H13N: C, 80.48; H, 10.13; N, 9.39%. Found; C, 90.60; H, 10.20; N, 9.40%.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:21])[CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][C:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:12][CH:13]=2)=[O:19])=[CH:13][CH:12]=1)=[O:7])[CH2:10][CH3:11]
Reactant: CCCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)CCCC(=O)Cl
Product: CCCOC(=O)c1ccc(OC(=O)CCCC(=O)Oc2ccc(C(=O)OCCC)cc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 18 g of propyl p-hydroxybenzoate and 8.5 g of glutaric acid dichloride to yield di(p-propyloxycarbonylphenyl)glutarate, m.p. 74°-75° C., as white crystals.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Br:19])[C:13]=1[NH2:20]>>[Br:19][C:14]1[CH:15]=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:11]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)cc(Br)c1N
Product: O=c1[nH]c2cc(F)cc(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.31 mL, 24.4 mmol) and 1,2-diamino-3-bromo-5-fluorobenzene (500 mg, 2.44 mmol) was heated to reflux under N2 for 5 h. The reaction mixture was dark brown. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH (30 mL). The brown solid was air dried for 1 hr to give 250 mg (39.6% crude yield). A portion of this solid was removed and dissolved in 1N NaOH (10 mL) and a few insoluble particles were removed by gravity filtration. The solution was treated with decolorizing carbon and the mixture was filtered through a pad of celite and the resulting solution acidified with 1N HCl. White crystals formed that were isolated by vacuum filtration and washed with water (20 mL). The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec). 1H NMR (d6 -DMSO) δ6.2 (dd, 1H, JH6-8 =2.7, JH-F =9.3, ArH), 7.35 (dd, 1H, JH6-8 =2.4, JHF =8.4 Hz), 11.1 (br s, 1H, NH), 12.1 (brs, 1H, NH). EIHRMS calc. for C8H4BrFN2O2 : 257.9440, found 257.9455.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]>>[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[O:27])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)CNCC2
Product: COc1cc2c(cc1OC)CN(C(=O)Cc1ccc(OC(C)=O)cc1)CC2

Procedure:
Using the procedure described in Example 12, 15.0 g of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline was reacted with 4-acetoxyphenylacetyl chloride to give 13.0 g of N-(4-acetoxyphenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.
Reaction SMILES: Br[C:2]1[C:3]([C:29]#[N:30])=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:19]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1.[CH:31]([B-](F)(F)F)=[CH2:32].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.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>[C:29]([C:3]1[C:2]([CH:31]=[CH2:32])=[C:6]([C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)[S:5][C:4]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:19]=1)#[N:30]
Reactant: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(Br)c2C#N)ccn1
Reactant: C=C[B-](F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1c(-c2ncn(C3CCCCO3)n2)sc(-c2ccnc(NC(=O)OC)c2)c1C#N
Temperature: 140 °C

Procedure:
A mixture of methyl (4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate (1.14 g, 2.33 mmol), potassium vinyltrifluoroborate (0.624 g, 4.66 mmol), tetrakis(triphenylphosphine)platinum (0) (0.145 g, 0.116 mmol) and potassium carbonate (0.967 g, 7.00 mmol) in N,N-dimethylformamide (14.0 mL) and water (5.0 mL) in a microwave vial was heated under nitrogen atmosphere at 140° C. in a microwave for 15 min. The mixture was cooled to room temperature, quenched with water, extracted with DCM, washed with water then brine, dried over Na2SO4, filtered and rotavaped to give a crude product. Purification on a silica gel column using MeOH/DCM (0/100 to 5/95) afforded the desired product (1.16 g, with PPh3 and O═PPh3 contaminated) with Rf on TLC (MeOH/DCM 5/95) of 0.4, and de-carbamide product (0.627 g, yield 58%). LC/MS: (FA) ES+ 437. 1H NMR (400 MHz, d-chloroform) δ 8.52 (s, 1H), 8.45 (s, 1H), 8.41 (m, 1H), 8.33 (s, 1H), 7.51-7.59 (m, 1H), 7.46-7.49 (m, 1H), 6.28-6.33 (m, 1H), 5.66-5.69 (m, 1H), 5.51-5.54 (m, 1H), 4.09-4.12 (m, 1H), 3.86 (s, 3H), 3.75-3.78 (m, 1H), 2.00-2.20 (m, 3H), 1.68-1.77 (m, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[Cl:19][C:20]1[N:24]=[C:23](Cl)[S:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[Cl:19][C:20]1[N:24]=[C:23]([N:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:18][CH:17]=3)[CH2:16][CH2:15]2)[S:22][N:21]=1
Reactant: COc1ccc(CCN2CCNCC2)cc1
Reactant: Clc1nsc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCN(c3nc(Cl)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-methoxyphenethyl)piperazine dihydrochloride (1.04 g, 3.55 mmol), 3,5-dichloro-1,2,4-thiadiazole (500 mg, 3.23 mmol) and DIPEA (1.33 g, 1.8 ml, 10.3 mmol) in 23 mL EtOH was stirred for 1 h at RT. The reaction solution was concentrated in vacuo and the crude product was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield, after evaporation of the product containing fraction, 1.06 g (97%) of the title compound as white solid. MS (m/e): 339.2 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)[CH3:2].ClN1C(=O)CCC1=O.[F:20][C:21]([F:39])([F:38])[C:22]1[CH:23]=[C:24]([C:32]([C:34]([F:37])([F:36])[F:35])=[CH2:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C(=O)([O-])O.[K+]>CN(C)C=O.O>[F:20][C:21]([F:38])([F:39])[C:22]1[CH:23]=[C:24]([C:32]2([C:34]([F:37])([F:36])[F:35])[O:9][N:8]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:33]2)[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1
Reactant: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: CCc1ccc(C=NO)cc1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Reaction time: 14 h

Procedure:
To a solution of 1.49 g of 4-ethylbenzaldoxime in 10 mL of N,N-dimethylformamide, 1.60 g of N-chlorosuccinimide was added and the resultant mixture was stirred at room temperature for 2 hours. Next, to the reaction mixture, 3.00 g of 3,5-bis(trifluoromethyl)-1-(1-trifluoromethylethenyl)benzene and 3.00 g of potassium hydrogen carbonate were added and the stirring of the resultant reaction mixture was continued at room temperature further for 14 hours. After the completion of the reaction, 10 mL of water was added to the reaction mixture and the resultant reaction mixture was extracted with ethyl acetate (50 mL×1). The organic phase was washed with 20 mL of water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. To the resultant residue, hexane was added and a deposited crystal was filtered off to obtain 3.00 g of the objective substance as a white crystal.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:13]([OH:30])[CH2:14][N:15]1[CH:19]([C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH:17]2[CH2:27][CH2:28][CH2:29][CH:16]12)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C@H:13]([OH:30])[CH2:14][N:15]1[CH:19]([C:20]([NH:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:18][CH:17]2[CH2:27][CH2:28][CH2:29][CH:16]12
Reactant: CC(C)(C)NC(=O)C1CC2CCCC2N1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)C1CC2CCCC2N1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 87.4 %

Procedure:
A solution of 4.6 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-octahydro-cyclopenta[b]pyrrole-2-carboxamide (four diastereomers) in 90 ml of ethanol was hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 72 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 2.958 g of 1-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-octahydro-cyclopenta[b]pyrrole-2-carboxamide (four diastereomers) as a brownish oil; MS: m/e 374 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([CH:34]1[CH2:36][CH2:35]1)[NH2:33]>>[CH:34]1([C:32]2[N:33]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]4)=[O:9])[CH2:11]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)C1CC1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
200 mg (0.480 mmol) of the compound from Example 63A and 96 mg (0.961 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 130 mg (56% of theory).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]1([NH:19][C:20](=O)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20]([CH3:21])=[N:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccccc1
Product: COc1ccc2c(c1)nc(C)n2-c1ccccc1
Yield: 67.1 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 4-Iodo-3-nitroanisole (140 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as a pale yellow solid (80 mg, 67%). mp 88-90° C. 1H NMR (DMSO) δ 2.61 (s, 3 H), 3.88 (s, 3 H), 7.07 (d, J=8.9 Hz, 1 H), 7.25 (d, J=8.9 Hz, 1 H), 7.38 (br s, 1 H), 7.65-7.73 (m, 5 H); 13C NMR δ 12.5, 55.9, 97.7, 112.6, 114.7, 126.9, 127.8, 130.2, 130.3, 132.8, 133.1, 151.2, 157.6, 157.8. HRMS (FAB): cal. for C15H15N2O [M+H]+: 239.1184; found: 239.1180.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[F:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])[O:13][C:14]=2[CH:20]=1
Reactant: CCCNc1ccc(N)cc1-c1nc2ccc(F)cc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2ccc(F)cc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-6-fluorobenzoxazole (71 mg, 0.25 mmol) and 1,2,4-benzenetricarboxylic anhydride (54 mg, 0.28 mmol) the title compound was obtained (84 mg, 73%). 1H NMR (DMSO) δ 8.41(dd, 1H), 8.36(t, 1H), 8.30(s, 1H), 8.07(m, 2H), 7.84(m, 1H), 7.77(dd, 1H), 7.46(dd, 1H), 7.29(m, 1H), 7.03(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS 458.1 m/z (M−H)−.
Reaction SMILES: [NH2:1][C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40](Cl)=[O:41])[CH:33]=2)=[CH:28][CH:27]=1>ClCCl>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40]([NH:1][C:2]3([C:14]([O:16][CH3:17])=[O:15])[CH2:3][CH2:4][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:6][CH2:7]3)=[O:41])[CH:33]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2C)CCC(OC)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.94 g (15.44 mmol) of methyl 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Example 22A) and 1.56 g (15.44 mmol) of triethylamine were dissolved in 56 ml of dichloromethane. 3.92 g (14.03 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetyl chloride (Example 2A), dissolved in 56 ml of dichloromethane, were added dropwise to this solution, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution and with aqueous 1% strength citric acid. After drying over sodium sulphate, the organic phase was concentrated and the product was dried. This gave 6.81 g (97% of theory) of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=O)=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]3=[N:20][O:22][C:32]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[C:16]3[CH:15]=2)=[CH:12][CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Reactant: Cc1ccc(CC#N)cc1
Product: Cc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4F)cc23)cc1

Procedure:
The title compound, light yellow solid (13 mg, 10%), MS (ISP) m/z=388.2 [(M+H)+], mp 147° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: [CH2:1]([N:8]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10](O)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:30])CC>ClCCl>[CH2:1]([N:8]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:30])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To ethyl 3-(benzyl(cyclohexyl)amino)-2-hydroxy-2-methylpropanoate (7 g, 21.9 mmol) in 50 ml of dichlormethane at −78° C., was added DAST (4.3 ml, 32.8 mmol) dropwise. The reaction mixture was gradually warmed up to room temperature and stirred for 2 h. It was then diluted to dichloromethane, washed by NaHCO3, brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=40:1 to 20:1) to give 6.8 g product (97%) as light yellow liquid. [M+H] calc'd for C19H28FNO2, 322. found 322.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+]([O-])=O)=[CH:7][C:5](N)=[C:4]([I:12])[CH:3]=1.S(=O)(=O)(O)O.[N:18]([O-:20])=[O:19].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:12])[CH:5]=[C:7]([N+:18]([O-:20])=[O:19])[CH:8]=1
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1I
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)cc(I)c1
Temperature: 0 °C
Yield: 42.1 %

Procedure:
To a solution of 4-chloro-2-iodo-5-nitroaniline (8.5 g) in ethanol (38 ml) was added concentrated sulphuric acid (4.4 ml) dropwise, then the solution was heated to reflux and solid sodium nitrite (4.9 g) added in small amounts over 30 minutes. The mixture was refluxed a further one hour and poured into ice water, the product extracted into ethyl acetate, washed with water and brine and the organic layer was dried over sodium sulfate. The solution was evaporated and the residue purified by column chromatography to give 5-chloro-3-iodonitrobenzene (3.4 g). δ (360 MHz, DMSO-d6) 8.28 (1H, d, 2-H), 8.35 (1H, d, 6-H) and 8.46 (1H, d, 4-H).