Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:12]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:17])=[CH:16][CH:15]=2)=[O:14])[CH2:30][CH2:31]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
4-(1,1-Dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoic acid (268 mg) described in Preparation Example 18, 1-(2,4-dimethylphenyl)piperazine (199 mg), 1-hydroxybenzotriazole 1 hydrate (142 mg) were dissolved in N,N-dimethylformamide (5 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (202 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (256 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)cc1
Yield: 14 %

Procedure:
Using 1.00 g of (4-chlorobenzyl)malononitrile, 10 ml of N,N-di-methylformamide, 1.0 g of sodium hydride (60% in oil), and 0.93 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.21 g of 2-(4-chlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (15)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1Oc1ccc(OC)cc1
Yield: 96.5 %

Procedure:
The compound of step 1 (2.3 g) in methanol (150 ml) containing 10% Pd/C (0.5 g) was hydrogenated under one atmosphere of hydrogen for 18 h. The mixture was filtered (kieselguhr) and solvent removed from the filtrate under reduced pressure to give the title compound (2.0 g) as a yellow oil. 1H NMR (CDCl3) δ: 3.69 (2H, brs), 3.77 (6H, s), 6.76-6.87 (6H, m), 7.19 (1H, d, J=2.5 Hz).
Reaction SMILES: [Cl-].[Cl:2]C=[N+](C)C.[C:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)(O)=[O:8]>C(Cl)Cl>[CH:14]([C:13]1[CH:16]=[CH:17][C:10]([C:7]([Cl:2])=[O:8])=[CH:11][CH:12]=1)=[O:15]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of (chloromethylene)dimethylammonium chloride (Vilsmeier Reagent; 37.7 g, 0.280 mol) in CH2Cl2 (300 mL) at 0° C. was treated with 4-carboxybenzaldehyde (40.0 g, 267 mmol) in one portion. The reaction mixture was stirred at 0° C. for 30 min, then at room temperature for 2 h. HPLC analysis of an aliquot of the reaction mixture quenched into MeOH indicated consumption of 4-carboxybenzaldehyde. The reaction mixture was filtered through a medium porosity glass frit. The filtrate, containing the title compound, was stored at 0° C., and used in the next step without further manipulation.
Reaction SMILES: [K].[C:2]([OH:10])(=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][CH2:12]SC#N>CO>[Cl:11][CH2:12][O:10][C:2](=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CSCCl
Reactant: OC(=S)c1ccccc1
Agent: [K]
Solvent: CO
Product: S=C(OCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28 g (0.16 mol) of the potassium salt of thiobenzoic acid were dissolved in 550 ml of methanol, and 17 g (0.16 mol) of chloromethyl thiocyanate were added dropwise at -5°. After slowly warming the reaction mixture to room temperature, it was subsequently stirred at 40° for a further 30 minutes and concentrated, the residue was extracted by shaking with water/ethylene chloride, the organic phase was concentrated and the oily residue was freed from chloromethyl thiocyanate residues by heating to 80°-100°/0.5 to 2 mm Hg for several hours; yield 30 g (this corresponds to a yield of 90% of the theretical conversion).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]#N)=[CH:13][C:8]=2[NH:7][C:6]1=[O:16].C(O)=[O:18]>O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:18])=[CH:13][C:8]=2[NH:7][C:6]1=[O:16]
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Solvent: O
Product: O=Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 96 %

Procedure:
A mixture of 930 mg (4.28 mmol) of 1-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (Intermediate 13) and 949 mg of Ni—Al alloy 1:1 in 7.3 ml of 75% formic acid in water is stirred at 90° C. for 6.5 hr. After filtration, the residue is again dissolved in 7.3 ml of 75% formic acid, 949 mg of Ni—Al alloy are added and the system is stirred at 90° C. for 1 hr. After filtration, 5 ml of 2N NaOH and 5 ml of EtOH are added and the system is stirred at rt overnight. The pH is made 6-7 by addition of 2N HCl and the solution is concentrated. The residue is chromatographically purified over silicagel eluting with hexane/EtOH (100/0 to 0/100). 0.91 g of pure title compound are obtained (96% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:23][C:24]([F:31])([F:30])[C:25](OCC)=[O:26]>C(#N)C>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25](=[O:26])[C:24]([F:31])([F:30])[F:23])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a solution of 5.07 g (23.7 mM) of tert-butyl 4-aminomethylpiperidine-1-carboxylate and 5.0 ml (35.9 mM) of triethylamine in acetonitrile (40 ml) was added 5.6 ml (47.1 mM) of ethyl trifluoroacetate at room temperature and the mixture was stirred at room temperature for 1.5 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. The solvent was then distilled off under reduced pressure to provide the title compound as light-yellow solid (6.40 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:17]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Cl:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
To a solution of 5.00 g (26.8 mmol) of methyl 3-chloro-4-hydroxybenzoate dissolved in 40 mL of CH2Cl2 was added 6.55 g (53.6 mmol) of 4-dimethylaminopyridine, 4.85 g (32.2 mmol) of tert-butyldimethylchlorosilane and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was filtered, diluted with ethyl acetate, washed with 0.1 N HCl, saturated NaHCO3, and brine. The product layer was then dried (MgSO4), filtered and evaporated in vacuo to afford 8.05 g (100%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.I[CH2:8][CH2:9][OH:10].C(N(CC)CC)C>C(O)C>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:8][CH2:9][OH:10])=[N:2]1
Reactant: OCCI
Reactant: Sc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OCCSc1nc[nH]n1
Yield: 34.7 %

Procedure:
A solution of 1H-1,2,4-triazole-3-thiol (14.7 g, 145 mmol), 2-iodoethanol (25.0 g, 145 mmol) and triethylamine (14.7 g, 145 mmol) in ethanol (400 mL) was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was acidified with water and 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (10%-100% ethyl acetate/hexane) to give the title compound as a colorless oil (7.30 g, 35%).
Reaction SMILES: O.[OH:2][C:3]1([CH2:16][CH:17]([OH:20])CO)[CH2:15][CH2:14][C:6]2([O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][O:7]2)[CH2:5][CH2:4]1>ClCCl>[OH:2][C:3]1([CH2:16][CH:17]=[O:20])[CH2:15][CH2:14][C:6]2([O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11]2)[CH2:5][CH2:4]1
Reactant: CC1(C)COC2(CCC(O)(CC(O)CO)CC2)OC1
Solvent: O
Solvent: ClCCl
Product: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (7 mL) and NalO4 (5.41 g) are added to a solution of 3-(9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-propane-1,2-diol (4.63 g) in dichloromethane (70 mL) chilled in an ice bath. The cooling bath is removed and the resulting mixture is vigorously stirred at room temperature overnight. The mixture is then filtered and the filtrate is dried (Na2SO4) and concentrated to give the crude title compound that is directly subjected to the next reaction step. Yield: 4.28 g (crude); Mass spectrum (ESI+): m/z=243 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])([O:11][CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH3:10])=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(O)c1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(OCOCC[Si](C)(C)C)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To compound 31 (532 mg, 2.46 mmol) in anhydrous DMF (5 mL) at 0° C. is added sodium hydride (60% in mineral oil, 138 mg, 3.45 mmol). The mixture is stirred at rt for 1 h and then cooled to 0° C., to which is added SEMCl (0.564 uL, 3.2 mmol). The mixture is stirred at rt for 16 h, 50° C. for 1 h, cooled to rt and quenched with water, extracted with ethyl acetate. The organic phase is washed with brine, dried and rotavaped. The oily residue is purified by silica gel chromatography (10-15% ethyl acetate in heptane) to afford the title compound as clear oil (474 mg, 56%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24](I)=[N:25][C:26]=3[C:17]=2[N:16]([CH3:28])[N:15]=1)=[O:13])[CH3:2].[CH3:29][C:30]#[N:31]>>[NH2:31][C@H:30]1[CH2:1][CH2:3][C@H:4]([NH:11][C:24]2[N:23]=[CH:22][C:21]3[CH2:20][CH2:19][C:18]4[C:14]([C:12]([NH:11][C:4]5[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=5[CH2:9][CH3:10])=[O:13])=[N:15][N:16]([CH3:28])[C:17]=4[C:26]=3[N:25]=2)[CH2:5][CH2:29]1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(I)nc1-2
Reactant: CC#N
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(N[C@H]3CC[C@H](N)CC3)nc1-2
Temperature: 110 °C

Procedure:
N-(2,6-diethylphenyl)-8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (500 mg, 1.01 mmol) was dissolved in CH3CN (3 ml) and treated with trans-1,4-diaminecyclohexane (346 mg, 303 mmol). The mixture was heated at 110° C. for 10 minutes under microwave irradiation. The solvent was removed under reduced pressure and the crude was purified by column chromatography to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH2:18]>N1CCOCC1>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:9]3[CH2:8][CH2:7][O:18][CH2:1][CH2:5]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Solvent: C1COCCN1
Product: CC(C)(C)c1nc2cc(N3CCOCC3)c([N+](=O)[O-])cc2s1

Procedure:
A solution of 170 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole described in Example 5, in 200 ml of morpholine is refluxed for 6.5 hours, cooled and poured into water. The solid is filtered, washed with water and cold alcohol to give 2-tert-butyl-5-[morpholin-4-yl]-6-nitrobenzothiazole melting at 119°-121°.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].N1C=CC=CC=1.[CH3:12][O:13][N:14]=[C:15]([CH:17]([NH:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])[CH3:18])[CH3:16]>C1C=CC=CC=1>[CH3:12][O:13][N:14]=[C:15]([CH:17]([N:19]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])[C:3](=[O:4])[CH2:2][Cl:1])[CH3:18])[CH3:16]
Reactant: O=C(Cl)CCl
Reactant: CON=C(C)C(C)Nc1c(C)cccc1C
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CON=C(C)C(C)N(C(=O)CCl)c1c(C)cccc1C
Yield: 782.7 %

Procedure:
A sample of 54.2 g (0.048 mol) chloroacetyl chloride and a sample of 34.8 g (0.44 mol) pyridine was added over a 25-minute period to a solution of 97.0 g (0.44 mol) 3-(2,6-dimethylphenylamino)-2-butanone O-methyloxime maintained at 45° C. in 500 ml benzene. The pyridine was added slightly faster than the chloroacetyl chloride. The reaction temperature rose to about 50°-58° C. during the addition. The reaction mixture was then cooled, washed with water, washed with 5% aqueous sodium bicarbonate solution, stirred with silica gel, filtered and evaporated under reduced pressure to give 111.5 g of 3-(N-chloroacetyl-2,6-dimethylphenylamino)-2-butanone O-methyloxime, as an oil. The infrared spectrum of the product showed carbonyl absorption at 5.9 micron and O--CH3 absorption at 9.5 micron. The product is tabulated in Table I as Compound No. 5-B.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>C(OC(=O)C)(=O)C>[CH2:14]([O:13][CH:12]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH3:15]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)OCC
Temperature: 159 °C
Yield: 95.1 %

Procedure:
160.2 g (1.0 mol) of diethyl malonate, 474.2 g (3.2 mol) of triethyl orthoformate, 4 g of acetic anhydride and 0.5 g of catalyst from Example 1 were initially introduced into the apparatus described in Example 1 and the mixture was heated to boiling. A mixture of 10 g of acetic anhydride and 30 g of triethyl orthoformate were continuously added dropwise in the course of 6 hours. The low-boiling component formed was distilled off at a head temperature of 78° to 79° C. The reaction temperature slowly increased to 159° C. The mixture was kept at this temperature for a further hour. The unreacted orthoester was then distilled off at reduced pressure, the catalyst was filtered off and the crude product was purified by distillation at 0.5 mbar. In this way 205.6 g of diethyl ethoxymethylenemalonate were obtained, which corresponds to a yield of 95.1% of the theoretical yield.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[CH2:21](O)[CH3:22]>O>[N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:21][CH3:22])=[O:10])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])[nH]n1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 5-nitropyrazol-3-carboxylic acid (19.9 g) in ethanol (200 mL) was added dropwise thionyl chloride (9.7 mL) over a period of 5 minutes and the mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and ethanol (50 mL) and to the mixture was neutralized with sodium hydrogencarbonate (54 g). The mixture was filtered and the residue was washed with ethanol. The filtrate and the washings were combined and concentrated in vacuo. The residue was azeotropically distilled with ethanol and the residue was dissolved in ethyl acetate, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and to the residue was added isopropylether. The precipitates were collected by filtration and washed with ethyl acetate/diisopropylether (1/2) to give ethyl 5-nitropyrazol-3-carboxylate (20 g, yield: 85%) as a colorless solid.
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([F:36])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[F:36][C:28]1[CH:27]=[C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)[CH:31]=[CH:30][C:29]=1[C:32]([F:35])([F:34])[F:33]
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Reactant: O=C(CBr)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (45 mg, 0.232 mmol) with 2-bromo-N-{4-[3-fluoro-4-trifluoromethylphenyl]-1,3-thiazol-2-yl}acetamide (107 mg, 0.279 mmol) in the presence of NaH (13 mg, 0.555 mmol) in dry DMF (5.0 mL) to give 35 mg of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.27 (s, 3H), 3.17 (s, 3H), 3.36 (s, 3H), 5.34 (s, 2H), 6.07 (s, 1H), 7.85-7.91 (m, 1H), 7.94-8.05 (m, 3H), 12.82 (br s, 1H); ESI-MS (m/z) 496.23 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:13][NH2:14].[F:15][C:16]([F:20])([F:19])[C:17]#[N:18]>CO.CCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:13][NH:14][C:17](=[NH:18])[C:16]([F:20])([F:19])[F:15]
Reactant: CC(C)Oc1cc(NN)c(Cl)cc1Cl
Reactant: N#CC(F)(F)F
Solvent: CCCCC
Solvent: CO
Product: CC(C)Oc1cc(NNC(=N)C(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Under a dry nitrogen atmosphere a stirred solution of 2.4 g (0.01 mole) of 2,4-dichloro-5-(1-methylethoxy)phenylhydrazine in 140 mL of methanol was cooled to -60° C. in a dry ice-isopropanol bath. Trifluoroacetonitrile (23.2 g, 0.24 mole) was bubbled into the cold solution during a two minute period. After complete addition the cold solution was stirred for 30 minutes, then allowed to warm slowly to room temperature during the next three hours. A stream of nitrogen gas was bubbled into the room temperature solution to aid in the vaporization and removal of trifluoroacetonitrile, leaving a liquid residue. This residue was evaporated further under reduced pressure to leave a resinous material. This material was stirred in cold pentane to produce a solid. The pentane was decanted and the solid triturated in fresh cold pentane. The pentane was decanted and the solid dried under reduced pressure to yield 2.9 g of N-[2,4-dichloro-5-(1-methylethoxy)anilino]trifluoroacetamidine (mp 80.5°-81° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([N+:15]([O-])=O)[C:3]=12.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH2:15])[C:3]=12
Reactant: O=[N+]([O-])c1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
SnCl2 dihydrate (0.85 g, 3.77 mmol) at a temperature of about 0° C. to about 5° C. was added to 4-chloro-3-nitro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (0.20 g, 0.75 mmol) in 6M HCl (5 mL). The mixture was stirred at room temperature for 2 hours, and was then neutralized to a pH of about 8 with a 6N NaOH solution. The mixture was extracted with CHCl3:IPA (3×30 mL; 3:1) and dried over sodium sulfate. After removal of the solvent, 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (0.16 g, 89% yield) was isolated as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[F:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[F:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:3]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccncc2F)c2ccccc21
Product: COc1cccc(-c2cccc(C3(c4ccncc4F)N=C(N)c4ccccc43)c2)c1F
Yield: 69 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine (Scheme #12, I) as described in Example 67 (Scheme #10, D) in 69% yield using 2-fluoro-3-methoxyphenylboronic acid. 1H NMR (DMSO-d6) δ 8.26 (d, J=2.78 Hz, 1 H), 8.14 (d, J=5.05 Hz, 1 H), 7.67-7.61 (m, 1 H), 7.55-7.50 (m, 1 H), 7.34-7.28 (m, 2 H), 7.21-7.10 (m, 4 H), 7.07-6.92 (m, 3 H), 6.77 (br s, 2 H), 6.74-6.68 (m, 1 H), 3.65 (s, 3 H); MS (ESI) m/z 428 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(-c2ncco2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ncco3)cc2)CC1

Procedure:
Prepared in analogy to example 4.4 (a) from 2-(4-Bromo-phenyl)-oxazole and N-BOC -piperazine. MS (m/e): 330.3 (MH+, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:36])[C:7]=2[CH:37]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:36])[C:7]=2[CH:37]=1
Reactant: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)OCC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}phenyl)carbonyl](methyl)amino}propanoate (289 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (153 mg, 56%) as a pale-yellow solid.