Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([Cl:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([Cl:18])[C:12]([C:13]#[N:14])=[C:15]([Cl:17])[CH:16]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(Cl)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(Cl)c(C#N)c(Cl)c3)n2)[nH]n1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-dichlorobenzonitrile (0.121 g, 0.41 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.063 g, 0.41 mmol), HOBt (0.083 g, 0.615 mmol), DIPEA (0.214 mL, 1.23 mmol) and EDCI (0.118 g, 0.615 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). Yield 6.3 mg. 1H NMR (400 MHz; CDCl3): δ 1.29 (d, 3H), 2.55 (s, 3H), 4.36 (m, 2H), 4.57 (m, 1H), 6.64 (d, 1H), 7.40 (s, 1H), 7.58 (d, 1H), 7.83 (s, 2H).
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH:17]2[S:27][C:26]3[C:28]4[C:19]([CH:20]=[N:21][C:22]=4[N:23]=[CH:24][CH:25]=3)=[CH:18]2)=[O:16])[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(O)C.C(=O)([O-])O.[Na+]>[CH2:29]([N:7]1[CH2:8][CH2:9][CH2:10][N:4]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]2[S:27][C:24]3[N:23]4[C:19](=[CH:20][N:21]=[C:22]4[CH:28]=[CH:26][CH:25]=3)[CH:18]=2)=[O:16])[CH2:5][CH2:6]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NCCCN1CCCNCC1)C1C=C2C=Nc3nccc(c32)S1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCCN1CCCN(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Yield: 55 %

Procedure:
In 10 ml of ethanol were suspended 606.9 mg (1.3 mM) of N-[3-(hexahydro-1,4-diazepin-1-yl)propan-1-yl]-5-thia-1,8-diazaacenaphthylene-4-carboxamide trihydrochloride and 342.1 mg (2.0 mM) of benzyl bromide, followed by addition of 0.91 ml (6.5 mM) of triethylamine, and the mixture was refluxed overnight. This reaction mixture was diluted with 5% aqueous solution of sodium hydrogen carbonate and and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over Na2SO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=2/3) to provide the title compound as deep-red liquid (320.0 mg, 55.0%).
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([O:6][CH3:7])[O:4][CH3:5].[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18]>C(O)C>[C:14]([O-:21])(=[O:20])/[CH:15]=[CH:16]\[C:17]([O-:19])=[O:18].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][NH+:11]([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][NH+:11]([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CO[Si](CCCN(C)C)(OC)OC
Solvent: CCO
Product: CO[Si](CCC[NH+](C)C)(OC)OC
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
5.0 g of trimethoxysilylpropyldimethylamine and 24 g of ethanol were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 3.0 g of maleic acid was dissolved in 26 g of ethanol was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was stirred for half a day and therefrom, ethanol was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, trimethoxysilylpropyldimethylamine and maleic acid as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in ethanol to obtain a 62.6% ethanol solution of trimethoxysilylpropyldimethylammonium maleate.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].[CH3:18][CH2:19][OH:20]>>[CH2:19]([O:20][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1)[CH3:18]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: O=C([O-])[O-]
Reactant: CCO
Agent: [K+]
Product: CCOC(=O)c1cnc(OCC)cn1
Yield: 39 %

Procedure:
To a slurry of methyl 5-chloropyrazine-2-carboxylate (250 mg, 1.45 mmol) in EtOH (5 mL) was added potassium carbonate (300 mg, 2.18 mmol). The resultant solution was stirred at RT for 2 hours. The mixture was concentrated. The residue was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford ethyl 5-ethoxypyrazine-2-carboxylate (110 mg, 39%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:23][CH:22]2[CH:18]([CH2:19][NH:20][CH2:21]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C>C(#N)C.[NH4+].[Cl-]>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:20]2[CH2:19][CH:18]3[CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:23][CH:22]3[CH2:21]2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CN(c3ncnc(Cl)n3)CC2C1
Yield: 44.1 %

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (150 mg, 0.953 mmol) in ACN (5 mL) was added a solution of Intermediate 15 (202 mg, 0.953 mmol) and DIPEA (0.33 mL, 1.91 mmol) in ACN (5 mL) at 0° C. dropwise. After 10 min the mixture was diluted with saturated aqueous NH4Cl solution. The aqueous layer was then extracted with DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hexanes to 80% EtOAc/Hexanes) afforded the desired product as a white solid (137 mg, 44%). MS (ESI) mass calculated for C14H20ClN5O2, 325.13; m/z found, 326.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([CH:9]1[CH2:13][C:12]([O:14]CC)=[CH:11][C:10]1=O)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(O)=O>C(O)C>[C:1]([O:5][C:6]([C:7]1[C:9]2[CH2:13][C:12](=[O:14])[CH2:11][C:10]=2[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1)=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: NNCc1ccccc1
Reactant: CCOC1=CC(=O)C(C(=O)C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1nn(Cc2ccccc2)c2c1CC(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of the intermediate from step A (2.15 g, 8.45 mmol) in ethanol (100 mL) was added benzyl hydrazine hydrochloride (1.8 g, 9.22 mmol) and HOAc (10 mL). The reaction mixture was stirred at room temperature for 16 hours and then refluxed at 70° C. for 30 minutes. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, saturated NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) using 30% ethyl acetate-hexanes to give the desired product (1.64 g) a brown oil.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].S(Cl)(Cl)=O.[C:11]([O:15][C:16](=[O:20])CC#N)([CH3:14])([CH3:13])[CH3:12].[H-].[Na+]>C1COCC1.C(O)(=O)C>[C:11]([O:15][C:16](=[O:20])[CH:3]([C:4]#[N:5])[C:2](=[O:1])[CH3:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)CC#N
Reactant: CC(C)(C)OC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)C(C#N)C(=O)OC(C)(C)C

Procedure:
Scheme 2 below shows an alternative procedure for the preparation of 3-oxo-butyronitrile ii. This alternative procedure involves conversion of acetic acid vi to the corresponding acid chloride by reaction with a chlorinating agent such as thionyl chloride (SOCl2) followed by reaction of the anion of tert-butylcyanoacetate prepared by reaction of tert-butylcyanoacetate with a base such as sodium hydride (NaH) in a solvent such as THF to give 2-cyano-3-oxo-butanoic acid tert-butyl ester vii, which undergoes deprotection of the ester and decarboxylation to give 3-oxo-butyronitrile ii by reaction with an acid such as trifluoroacetic acid (TFA).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9]N1C(=O)CCC1=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][Cl:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1ccc(S)cc1
Product: Fc1ccc(SCl)cc1
Yield: 75.7 %

Procedure:
Employing the procedure of Example 13, p-fluorothiophenol (5.0 g., 39 mmoles) and N-chlorosuccinimide (5.2 g., 39 mmoles) were reacted to form p-fluorobenzenesulfenyl chloride (4.8 g., oil).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13][CH2:14][C:15]1[N:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-:24].[K+].[K+].OO>CS(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH2:13][CH2:14][C:15]1[N:20]=[C:19]([C:21]([NH2:22])=[O:24])[CH:18]=[CH:17][CH:16]=1
Reactant: Cn1cc(-c2ccccc2)nc1CCc1cccc(C#N)n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1cc(-c2ccccc2)nc1CCc1cccc(C(N)=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-picolinonitrile (10 mg, 0.035 mmol) in dimethyl sulfoxide (2 mL) at 0° C. was added potassium carbonate (24 mg, 0.175 mmol) and hydrogen peroxide (12 mg, 0.350 mmol). After stirring at room temperature for 1 h, the mixture was quenched with sat. NaHSO4 (aq.), and extracted with EtOAc (30 mL×2). The organic phase was dried and concentrated under reduced pressure. The residue was purified by prep-HPLC to give a white solid (3 mg). MS (ESI): m/z 307 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1.C([N:28](C(C)C)CC)(C)C>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH:28][O:19][CH3:18])=[O:6]
Reactant: COc1cccc(N)c1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CONC(=O)c1c(N)cccc1OC
Temperature: 21 °C
Reaction time: 72 h
Yield: 16.9 %

Procedure:
A mixture of 2-amino-6-methoxybenzoic acid (4.6 g, 27.52 mmol) and carbonyl-1,1′-dimidazole (5.35 g, 33.02 mmol) in THF (70 ml) was stirred at 21° C. under nitrogen for 3 days. N,N-diisopropyl-N-ethyl-amine (1.667 ml, 9.57 mmol) and O-methylhydroxylaminehydrochloride (0.545 ml, 7.18 mmol) were added. The solution was heated to 50° C. for 3 hours. After cooling and concentration under vacuum, the reaction mixture was diluted with EtOAc, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine, dried over magnesium sulfate, concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 10 to 20% EtOAc in DCM to afford 2-amino-N,6-dimethoxybenzamide (318 mg, 33.9%) as a white solid. Mass spectrum: MH+ 197; NMR Spectrum: (DMSOd6) 3.67 (s, 3H), 3.71 (s, 3H), 5.57 (bs, 2H), 6.19 (d, 1H), 6.31 (d, 1H), 7.02 (dd, 1H)
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:47][CH2:48][CH3:49])[C:13]([C:15]1=[CH:16][C:17]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[O:41])=[CH:36][CH:35]=3)=[CH:30][C:18]=2[N:19]=[C:20]([NH:22]C(=O)OC(C)(C)C)[CH2:21]1)=[O:14])(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.N.CO>C(Cl)Cl>[NH2:22][C:20]1[CH2:21][C:15]([C:13]([N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH2:47][CH2:48][CH3:49])=[O:14])=[CH:16][C:17]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[O:41])=[CH:38][CH:39]=3)=[CH:30][C:18]=2[N:19]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a mixture of tert-butyl (1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate (459 mg, 0.37 mmol) in CH2Cl2 (4 mL) at 0° C. was added TFA (1.00 mL). The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude material that was azeotroped with toluene-EtOH (3 mL/1 mL) twice. The crude material was dried under reduced pressure for 30 min. The crude material was dissolved into CH2Cl2 (˜3 mL) again and treated with NH3 in MeOH (0.30 mL, 2.1 mmol, 7 N solution in MeOH) at room temperature. The resulting mixture was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (3 to 7% MeOH in CH2Cl2, gradient) to afford 105 mg (59%) of (1E,4E)-2-amino-N-(3-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide. MS APCI (+) m/z 475 detected; 1H-NMR (400 MHz, CDCl3) δ 7.67 (d, 2H), 7.60 (d, 2H), 7.51 (br s, 1H), 7.30-7.37 (m, 2H), 6.88 (s, 1H), 3.60-3.69 (m, 6H), 3.48-3.52 (m, 4H), 2.83 (s, 2H), 1.82-2.00 (m, 6H), 1.68-1.74 (m, 2H), 0.93 (t, 3H).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH3:29])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[CH:18]=3)=[CH:11][CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:24]([C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[CH:20][CH:21]=2)[N:16]([CH2:28][CH3:29])[C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:30])=[O:5])=[CH:10][CH:11]=1)#[N:25]
Reactant: CCn1c(-c2ccc(OCC(=O)OC(C)(C)C)cc2)c(C#N)c2ccc(OC)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(-c2ccc(OCC(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Yield: 98.9 %

Procedure:
[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (745 mg, 1.83 mmol) is stirred in 20% TFA in CH2Cl2 at room temperature for 3 hours. This is concentrated and the residue is partitioned between H2O and EtOAc. The organic layer is dried and concentrated. The residue is triturated with CH2Cl2 to yield [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (634 mg, 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:7]2.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:7]2
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N)c2NC1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1Cc2cccc(N)c2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate produced in Example 6 (10 g) was added to N,N-dimethylformamide (100 mL), and sodium hydride (1.65 g) was added thereto under cooling on ice. The mixture was stirred at room temperature for one hour. Subsequently, under cooling on ice, benzyl bromide (6.48 g) was added to the mixture, and stirring was performed at room temperature for one hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, to thereby recover a residue. The residue was purified through silica gel column chromatography (ethyl acetate: n-hexane=1:2), whereby the title compound (10.8 g) was yielded.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: COc1ccc(N)c(F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)c(F)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
With vigorous stirring, 9.15 g (0.065 mole) of 2-fluoro-4-methoxyaniline was added to 60 mL of concentrated hydrochloric acid that had been cooled to -10° C. A solution of 4.83 g (0.070 mole) of sodium nitrite in 30 mL of water was slowly added dropwise, while the temperature was kept at or below -10° C. Upon completion of addition, the reaction mixture was stirred at -10° C. for one hour, after which 33.85 (0.150 mole) of tin(II) chloride dihydrate in 50 mL of concentrated hydrochloric acid was added slowly, dropwise, while the temperature was kept below -5° C. After the reaction mixture had stirred for one hour as it warmed to ambient temperature, the crude product was filtered from the mixture and dissolved in 250 mL of water. This solution was made basic with 4N sodium hydroxide and extracted with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was placed on a silica gel column and eluted with methylene chloride to remove colored impurities and then with ethyl acetate to obtain the desired product. The solvent was evaporated under reduced pressure to yield 6.30 g of 2-fluoro-4-methoxyphenylhydrazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:32]([CH3:34])=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
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: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)c(C)n1
Yield: 64.3 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (88 mg, 0.24 mmol) in 1,2-dimethoxyethane (2.5 mL) was added 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (144 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium (0) (28 mg, 0.024 mmol), and 2 M Na2CO3 (361.2 μL, 0.72 mmol). The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes. The reaction mixture was evaporated to dryness and purified by silica gel chromatography eluting with (0-20% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (70 mg, 61%). ESI-MS m/z calc. 453.44. found 454.3 (M+1)+. Retention time 1.89 minutes.
Reaction SMILES: [CH3:1][NH2:2].[O:3]1[CH2:29][CH:4]1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([CH3:18])([CH3:17])[O:14]2)=[CH:9][CH:8]=1>C(O)C>[C:19]1([C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH:4]([OH:3])[CH2:29][NH:2][CH3:1])=[CH:8][CH:9]=3)[O:14][C:13]([CH3:18])([CH3:17])[CH:12]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Reactant: CN
Solvent: CCO
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)C=C2c1cccc2ccccc12
Reaction time: 48 h
Yield: 63 %

Procedure:
Methylamine (9.5 ml) was added to 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)-2H chromene (4.5g., 0.013 moles) in ethanol (9.5ml) and the solution left to stand at room temperature for 48 hours. Removal of solvent gave the title compound as an orange oil (3.2g., 63%). N.M.R. (τCDCl3) 8.54(s, 3H, CH3 --), 8.48(s, 3H, CH3 --), 7.06(s, 3H, N--CH3), 6.72(d, 2H, --CHCH2 --), 6.05(d, 2H, --CH2CH--), 4.51(s, 1H, vinylic CH), 3.40-3.80 (m, 3H, aromatic H's), 2.10-2.75(m, 7H, aromatic H's).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34]Cl)([O-:24])=[O:23]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([S:34][C:26]3[CH:27]=[CH:28][C:29]([N+:31]([O-:33])=[O:32])=[CH:30][C:25]=3[N+:22]([O-:24])=[O:23])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(SCl)c([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc(Sc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])sc2-c2ccc(OC)cc2)cc1
Yield: 85.2 %

Procedure:
A suspension of 2,3-bis(4-methoxyphenyl)thiophene (6.6 g, 22.3 mmoles) and 2,4-dinitrobenzenesulfenyl chloride (5.5 g, 22.3 mmoles) in 55 ml of trifluoroacetic acid was heated at reflux for 15 minutes. The reaction mixture was cooled in ice; the lustrous crystals were collected and washed with cold ether to give the title compound (9.4 g), m.p. 143°-145°
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17]([CH2:20][CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:22][CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Amine preparation: Toluene-4-sulfonic acid 3-methylsulfanyl-propyl ester was prepared from 3-(methylthio)-1-propanol using standard conditions. Treatment with mCPBA in DCM yielded toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester. A mixture of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester and toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester was heated in MeCN in the prescence of potassium carbonate to yield 4-[(3-methanesulfonyl-propyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.