Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]#[C:15][Si](C)(C)C)[CH:13]=1>CO>[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]#[CH:15])[CH:13]=1
Reactant: C[Si](C)(C)C#Cc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cncc(Cl)c1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
Add potassium carbonate (4.35 g, 31.5 mmol) to a solution of 3-chloro-5-trimethylsilanylethynyl-pyridine (5.51 g, 26.3 mmol), (prepared as described in PREPARATION 26), in methanol (120 mL) and stir for 2 h. Concentrate, add water (150 mL), and extract with diethyl ether (2×100 mL). Wash the organic phase with an aqueous saturated solution of sodium chloride (100 mL), dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes to give the title compound as a pale yellow solid (1.9 g, 52%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=3)[C:24]([CH3:38])([CH3:37])[C:23]2=[O:39])[CH2:17][CH2:16]1)=O)(C)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[NH4+:52].[OH-]>ClCCl>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH:25]2[CH2:26][N:22]([CH:18]3[CH2:19][CH2:20][CH2:21][N:15]([C:13]([NH2:52])=[O:12])[CH2:16][CH2:17]3)[C:23](=[O:39])[C:24]2([CH3:38])[CH3:37])=[N:30][CH:31]=1)#[N:36]
Reactant: CC(C)(C)OC(=O)N1CCCC(N2CC(COc3ccc(C#N)cn3)C(C)(C)C2=O)CC1
Reactant: [NH4+]
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2CCCN(C(N)=O)CC2)CC1COc1ccc(C#N)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (0.75 mL) was added to a solution of Example 2F (0.108 g, 0.24 mmoles) in dichloromethane (0.75 mL) and stirred for one hour. The solvent was evaporated in vacuo. The residue was taken in dichloromethane (1.5 mL) and cooled to −78° C. Triphosgene (24 mg, 0.08 mmoles) was added and stirred for one hour. To the reaction, NH4OH (1 mL) was added and stirred at room temperature for one hour. The product was extracted with dichloromethane, dried with MgSO4, filtered, and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% trifluoroacetic acid) over eighteen minutes at a flow rate of 40 mL/minute to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.48 (dd, J=2.33, 0.64 Hz, 1H), 7.80 (dd, J=8.66, 2.33 Hz, 1H), 6.82 (dd, J=8.66, 0.78 Hz, 1H), 5.81 (b,r, 2H), 4.50 (dd, J=10.87, 6.04 Hz, 1H), 4.36 (dd, J=10.86, 8.24 Hz, 1H), 4.03-4.19 (m, 1H), 3.16 (m, 4H), 3.46 (dd, J=9.85, 7.64 Hz, 1H), 3.08 (dd, J=9.87, 7.94 Hz, 1H), 2.45 (qd, J=7.94, 6.01 Hz, 1H), 1.43-1.82 (m, 6H), 1.24 (s, 3H), 1.06 (s, 3H). MS (APCI+) m/z 386.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N+:30]([O-:32])=[O:31])[CH:25]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:5][C:3]#[N:4])[CH:27]=[CH:28][C:29]=1[N+:30]([O-:32])=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (2) (4.18 g, 25 mmol) was dissolved in anhydrous DMF (100 mL). To this solution was added benzyl bromide (3.27 mL, 27.5 mmol) and potassium carbonate (3.8 g, 27.5 mmol). The reaction mixture was stirred at room temperature for 18 h, filtered and evaporated. The residue was taken up into ethyl acetate (250 mL) and water (250 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and evaporated leaving 3-benzyloxy-4-nitro-benzaldehyde (3) as an orange solid (6.31 g, 98% yield): 1HNMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.45 (m, 5H), 5.40 (s, 2H); 13CNMR (400 MHz, DMSO-d6) δ 192.4, 151.2, 143.5, 139.9, 135.9, 128.9, 128.6, 127.9, 125.9, 122.7, 115.5, 71.1. To a suspension of sodium hydride (0.29 g, 12 mmol) in anhydrous THF (25 mL) at 0° C. was added via dropping funnel diethyl cyanomethylphosphonate (4) (1.94 mL, 12 mmol) in anhydrous THF (5 mL) followed by 3-benzyloxy-4-nitro-benzaldehyde (3) (2.6 g, 10 mmol) in anhydrous THF (30 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solvent was evaporated and the residue was taken up into ethyl acetate (50 mL) and water (25 mL). The organic phase was washed with brine (25 mL), dried over MgSO4, filtered and evaporated leaving 3-(3-benzyloxy-4-nitro-phenyl)-acrylonitrile (5) as an orange-red solid (0.28 g, 100% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.04 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J=16.6 Hz, 1H), 7.45 (m, 6H), 6.72 (d, J=16.6 Hz, 1H), 5.33 (s, 2H); 13CNMR (400 MHz, DMSO-d6) δ 151.4, 148.9, 140.8, 139.5, 136.0, 128.9, 128.6, 128.0, 126.0, 120.7, 118.5, 114.5, 101.3, 71.1; MS calculated for C16H12N2O3 (M)+: 280. found 280. 3-(3-Benzyloxy-4-nitro-phenyl)-(5) (0.28 g, 1.0 mmol) was dissolved in anhydrous methanol (20 mL). To this solution was added 10% palladium on carbon (56 mg, 20% wt) under a blanket of carbon dioxide. The hydrogenation was carried out under 60 psi of hydrogen at room temperature for 4 h, filtered through a pad of Celite and evaporated to yield an orange oil. This oil was stirred in hexane, decanted and vacuum dried leaving 3-(4-amino-3-hydroxy-phenyl)-propionitrile (1) as an orange solid (0.58 g, 100% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.81 (bs, 1H), 6.31 (m, 3H), 4.30 (bs 2H), 3.18 (s, 2H), 2.35 (s, 2H); 13CNMR (400 MHz, DMSO-d6) δ 144.3, 135.5, 127.1, 120.8, 119.6, 114.9, 30.5, 19.2; MS calculated for C9H10N2O (M)+: 162. found 162.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.[Br:18]Br>CC(O)=O>[Br:18][C:7]1[C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:2]=1[F:1]
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]ccc(OCc2ccc(F)cc2F)c1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 102.1 %

Procedure:
To an ice-cold solution of 4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one (0.75 g, 3.1 mmol) in AcOH (12 mL) was added a solution of bromine (0.2 mL, 3.5 mmol) in AcOH (6 mL), and the reaction mixture was stirred 10 min. The solvent was removed under reduced pressure to afford 3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as a white solid (1.0 g, 100%): ESI MS m/z 299 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[C:14](=O)[NH:13][C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:11][C:5]=1[NH:6]2.O=P(Cl)(Cl)[Cl:25].C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl.CO>[Cl:25][C:14]1[C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][C:5]=2[N:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=1
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1cccc(Cl)c12
Temperature: 115 °C
Yield: 70 %

Procedure:
To 9 (2 g, 6.274 mmol) was added 30 mL of POCl3 in a 250 mL round bottom flask. The reaction mixture was refluxed at 110-120° C. for 4 hours. After this the POCl3 was evaporated and the mixture was neutralized using NH4OH. The aqueous mixture was filtered (the precipitate being the compound). The filtrate also contained some compound. Therefore, it was extracted using chloroform and ethyl acetate. The precipitate obtained was dissolved in chloroform and methanol. Both the dissolved precipitate and extracted filtrate were dried using sodium sulfate overnight. To the solution was added silica, and solvent was removed under reduced pressure to provide a silica gel plug. The plug was transferred on top of a column packed with silica gel, twenty times the weight of plug, eluted with chloroform, 1% methanol in chloroform and 5% methanol in chloroform. Fractions containing the product 10 (TLC) were pooled and evaporated to give a solid. The overall yield was 70%. TLC Rf 0.86 (chloroform-methanol 5:1), m.p. 245.6-246.1° C., 1H NMR: δ 1.24 (s, 9H, pivaloyl); 7.37-7.63 (m, 3H, phenyl); 10.32 (s, 1H, 9-NH, exch); 12.96 (s, 1H, 2-NH, exch).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: O=C(CCl)Nc1ccccc1Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: ClCc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
A solution of 2-chloro-N-(2-anilinophenyl)acetamide (10 g) and p-toluenesulfonic acid monohydrate (4.5 g) in benzene (250 ml) was refluxed for 1.5 hours under an azeotropic dehydration. After being cooled to ambient temperature, the reaction mixture was diluted with an aqueous sodium bicarbonate solution and extracted with ethyl acetate three times. The combined organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel (100 g) with dichloromethane as an eluent to afford 2-chloromethyl-1-phenyl-1H-benzimidazole (3.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[C:13]([O:20][CH3:21])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH:15]=[O:16])[C:13]=2[O:20][CH3:21])[CH:3]=1
Reactant: COc1c(O)cccc1C=O
Reactant: N#Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1Oc1cc(Br)ccc1C#N
Yield: 82.8 %

Procedure:
4-Bromo-2-fluorobenzonitrile (0.41 g, 2.0 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.31 g, 2.0 mmol) and cesium carbonate (0.66 g, 2.0 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 18 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-bromo-2-(3-formyl-2-methoxyphenoxy)-benzonitrile (0.55 g, 81%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl.O>CS(C)=O>[C:10]([C:9]1([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:11]
Reactant: N#CCc1cc(F)cc(F)c1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2cc(F)cc(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
To a solution of 3,5-difluorophenylacetonitrile (24.2 g, 0.158 mol) in DMSO (240 ml) was added sodium hydride (60% w/w dispersion in mineral oil, 13.3 g, 0.332 mol) portionwise over 10 min. The reaction mixture was stirred for 40 min at room temperature and then bis-(2-chloroethyl)ether (24.9 g, 0.174 mol) was added slowly and stirring continued for an additional 1 h. The reaction mixture was poured into water (500 ml) and the mixture was extracted with an ethyl acetate-toluene mixture (2:1 v/v, 400 ml×3). The combined extracts were washed with 2N aqueous HCl (300 ml), water (300 ml) and brine (300 ml), dried (MgSO4) and concentrated to 100 ml. The precipitated solids were collected and washed with cold Et2O (50 ml) to afford 26.3 g (71%) of the titled compound as off white solids.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6]1([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:7]2=[O:12]>C(O)(=O)C.Br>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6]1([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:7]2=[O:12]
Reactant: COc1cccc2c1CC1(CCCCC1)C2=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2cccc(O)c2CC12CCCCC2

Procedure:
5.6 g of 4'-methoxy-spiro(cyclohexane-1,2'-indan)-1'-one in 80 ml acetic acid and 20 ml 48% (w/w) aqueous hydrogen bromide are refluxed for 20 hours. The mixture is evaporated, diluted with water and extracted with ether. Evaporation of the solvent yields 4'-hydroxy-spiro(cyclohexane-1,2'-indan)-1'-one; M.Pt. 162°-164° (from ethanol).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][O:7][CH:8]([CH:11]=[CH2:12])[CH2:9]O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:9][CH:8]([O:7][CH3:6])[CH:11]=[CH2:12])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C=CC(CO)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C=CC(COC(C)=O)OC
Temperature: 60 °C

Procedure:
In a 3-liter, 3-necked round bottom flask equipped with a mechanical stirrer, nitrogen inlet, temperature probe and vigoreux column was placed 1200 mL toluene, sodium acetate (88.59 g, 1.08 mol) and 2-methoxy-3-buten-1-ol (250.0 g, 2.45 mol). Mixture heated to 60° C. with stirring. Once temperature had stabilized, acetic anhydride (288.83 g, 2.80 mol) added dropwise over 2.5 hours. Maintained temperature for 1.5 hrs then increased temperature to 70° C. for 1 hour. Gas chromatography showed no trace of starting material in reaction. Began cooling reaction to room temperature. When reaction had cooled to 38° C., one liter of a 5% sodium bicarbonate solution was added at high speed to decompose any excess acetic anhydride remaining in the reaction. Extracted reaction twice with water, layers separated, the aqueous layer extracted twice with toluene and added to the organic layer. Organic layer dried with anhydrous magnesium sulfate, filtered and concentrated by rotovap. Yield 222.43 g (63.0%) of a clear, colorless material. 1H NMR consistent with 1-acetoxy-2-methoxy butene.
Reaction SMILES: C([O-])C.[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([CH3:9])=O.[F:14][C:15]([F:41])([F:40])[C:16]1[CH:17]=[C:18]([NH:22][N:23]=[C:24](OS(C2C=CC(C)=CC=2)(=O)=O)[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:20][CH:21]=1>C(O)C.CCOC(C)=O>[CH2:12]([O:11][C:5]([C:6]1[C:24]([C:25]([F:26])([F:27])[F:28])=[N:23][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:40])([F:41])[F:14])[CH:17]=2)[C:7]=1[CH3:9])=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)OC(=NNc2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nn(-c2cccc(C(F)(F)F)c2)c1C
Reaction time: 1 h

Procedure:
A solution of sodium ethanolate 21% (in ethanol, 0.75 ml, 2 mmol) was added to ethyl acetoacetate (0.25 ml, 1.97 mmol) in 3 ml ethanol at 0° C. After 1 h at 0° C., a solution of (2Z or E)-1-[3-(trifluoromethyl)phenyl]-2-(2,2,2-trifluoro-1-{[(4-methylphenyl)sulfonyl]-oxy}ethylidene)hydrazine (254 mg, 0.60 mmol) in 5 ml ethanol was added. Stirring was continued for 18 h at room temperature and then the yellow solution was diluted with EtOAc washed with water and brine. The combined organic layers were dried over magnesium sulfate and evaporated. Column chromatography (EtOAc:n-heptane 1:3) delivered the title compound as light yellow solid (107 mg, 48%). MS: 367.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[Na].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OC)=O)=[CH:25][CH:24]=1>C(O)C>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)Cc1ccc(C)cc1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(Cc2nc3c(nnn3C(C)CCCc3ccccc3)c(=O)[nH]2)cc1
Yield: 57.9 %

Procedure:
1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide are dissolved in a solution of 439 mg of sodium (19 mmol) in 38 ml of ethanol. 2.22 g (14.6 mmol) of methyl 4-methylphenylacetate are added, and the mixture is then refluxed overnight. The solvent is removed under reduced pressure, the residue is taken up with CH2Cl2, the organic phase is extracted twice with 1N HCl and dried over Na2SO4 and the solvent is removed under reduced pressure. Two chromatographic purifications (cyclohexane/ethyl acetate=3:1) give 853 mg (57%) of a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.Br.[CH:11](O)(C)[CH3:12]>>[Cl:9][C:4]1[N:3]2[CH:11]=[CH:12][N:1]=[C:2]2[C:7]([I:8])=[CH:6][CH:5]=1
Reactant: Nc1nc(Cl)ccc1I
Reactant: CC(C)O
Agent: Br
Product: Clc1ccc(I)c2nccn12
Temperature: 25 °C

Procedure:
2-amino-3-iodo-6-chloropyridine (2 g, 7.874 mmol) is taken up in isopropanol (30 mL) under N2. Diethoxy-2-bromoacetal (2.5 mL, 15.748 mmol, 2 equiv.) is added to the suspension followed by HBr 48% (2 mL). The resulting mixture is then refluxed for 12 h and cooled down to room temperature. The mixture is partly concentrated under vacuum and the resulting slurry is taken up in diethyl ether which causes the precipitation of a solid that is separated by filtration and washed with little amounts of diethyl ether to afford the desired material as a powder.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][C:9]([NH2:11])=[NH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[O-].[Na+].[Cl-].[Na+]>O>[Cl:1][NH:10][C:9](=[NH:11])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: N=C(Cc1ccccc1)NCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
The crude 2-phenyl-acetamidine hydrochloride (1.32 g, 7.74 mmol) was dissolved in water (10 mL) and cooled to 0° C. A ˜1.7 M solution of sodium hypochlorite in water (3.68 mL, 6.26 mmol) was added dropwise. The reaction mixture was stirred 1 h, then solid sodium chloride was added to saturate the aqueous phase, which was extracted with ethyl acetate (2×25 mL). The combined organic phases were filtered through sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 33% ethyl acetate/hexanes) to afford N-chloro-2-phenyl-acetamidine (155 mg, 9% over two steps) as an off-white semi-solid: H1-NMR (400 MHz, CDCl3) δ=3.67 (2H, s), 5.13 (2H, br), 7.31 (5H, m).
Reaction SMILES: C(O[C:4]([N:6]1[CH:14]2[CH:9]([C:10]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([OH:15])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2([OH:15])[CH2:11][CH2:12][CH2:13][CH:14]3[CH:9]2[CH2:8][CH2:7][N:6]3[CH3:4])=[CH:21][CH:20]=1
Reactant: CCOC(=O)N1CCC2C1CCCC2(O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC2C1CCCC2(O)c1ccc(Cl)cc1

Procedure:
15 g of (3aRS, 4SR, 7aRS)-4-p-chlorophenyl-hexahydro-4-hydroxy-1-indoline carboxylic acid ethyl ester and 4 g of lithium aluminum hydride in 100 ml of tetrahydrofuran were heated at reflux for 15 hours. Any remaining lithium aluminum hydride was destroyed by the addition of water. Partition between water and diethyl ether afforded after separation and working up of the organic phase the title compound as an oil (M.P. of the face base from diethyl ether/petroleum ether 98°-101°).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([Br:26])[CH:17]=3)[C:11]=1[C:12]([NH:14][OH:15])=[NH:13])=[CH:8][CH:7]=[C:6]1[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=21.[O:31]1CCC[CH2:32]1>O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([Br:26])[CH:17]=3)[C:11]=1[C:12]1[NH:13][C:32](=[O:31])[O:15][N:14]=1)=[CH:8][CH:7]=[C:6]1[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=21
Reactant: COc1cc(C2C(C(=N)NO)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Reactant: C1CCOC1
Solvent: O
Product: COc1cc(C2C(c3noc(=O)[nH]3)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-hydroxy-4H-benzo[h]chromene-3-carboxamidine (21), (118 mg, 0.25 mmol) and diimidazole carbonyl (40.5 mg, 0.25 mmol) are suspended in 10 ml tetrahydrofuran at room temperature and then is stirred under LC-MS control under heating. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10](=[O:43])[N:11]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([NH2:30])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:31])[CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6].Cl[C:45]([O:47][CH3:48])=[O:46]>C(N(CC)CC)C>[CH3:48][O:47][C:45](=[O:46])[NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[CH:22][C:21](=[O:31])[N:20]2[CH2:19][CH2:18][N:15]1[CH2:14][CH2:13][CH:12]([N:11]([C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:43])[CH2:32][C:33]2[CH:42]=[CH:41][C:36]3[O:37][CH2:38][CH2:39][O:40][C:35]=3[CH:34]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.1 %

Procedure:
To 2 mL of a chloroform solution containing 80 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 45 mg of triethylamine and 42 mg of methyl chloroformate were added, and stirred at room temperature for 3 days. To the reaction mixture, 225 mg of triethylamine and 210 mg of methyl chloroformate were added, and stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; hexane:ethyl acetate=1:4], to give 40 mg of N-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yl)carbamic acid methyl ester as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)[CH3:33]>COCCOC>[CH2:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:33]
Reactant: CCc1ccccc1B(O)O
Reactant: Cc1ccc(OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(C)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 72.4 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-methyl-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.247 mmol) in DME (3 ml)/2M Na2CO3 (0.435 ml, 0.8645 mmol) was treated with 2-ethylphenylboronic acid (74 mg, 0.493 mmol), Pd[PPh3]4 (29 mg, 0.0247 mmol in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white solid (77 mg, 72%). MS m/e 431.34 (M+H+)