Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:26][C:27]1[CH:31]=[CH:30][O:29][CH:28]=1>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: BrCc1ccoc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 1.14 g (3.76 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 30 ml of anhydrous DMF and, at room temperature, carefully added to a suspension containing 0.24 g (6.05 mmol) of 60% sodium hydride. This mixture was stirred for 30 minutes and 8.2 ml (4.92 mmol) of a freshly prepared 0.6 M solution of 3-bromomethylfuran in ethyl ether were dropwise added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude mixture was extracted between ethyl acetate and water. The organic phase was washed with water and brine, dried with magnesium sulphate, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel affording 1.4 g (97% of yield) of the expected product.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN([CH:9]=[O:10])C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=O)=[CH:14][CH:13]=1>ClC(Cl)C>[Cl:3][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])=[C:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)[CH:9]=[O:10]
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=CC(=C(Cl)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: -5 °C

Procedure:
7 ml of POCl3 are added dropwise to a solution of 6.6 ml of DMF in 4 ml of dichloroethane, cooled to −5° C., under nitrogen, and then the temperature is allowed to rise and 7 g of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone are added. The reaction medium is heated at 50° C. for 16 hours and then the mixture is poured into 100 ml of ice-cold water. The medium is extracted with DCM and then the organic phase is washed with a saturated NaHCO3 solution, water, and then an NaCl solution. 1.45 g of the expected compound are obtained, which compound crystallizes from isopropyl ether, m.p.=128° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8].[Cl-].[OH:10][NH3+:11].C(N(CC)CC)C>>[OH:10][N:11]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[NH2:8]
Reactant: N#Cc1ccccn1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: NC(=NO)c1ccccn1

Procedure:
1.0 g (9.6 mmol) of pyridine-2-carbonitrile, 1.0 g (14.4 mmol) of hydroxylammonium chloride and 1.6 ml (11.5 mmol) of triethylamine were reacted according to the General Method 5A. Yield: 1.06 g (80% of theory)
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.Br[CH:16]1[C:22](=O)[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1.[OH-].[NH4+:32].C([O-])(=O)C.[NH4+:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:10][C:8]([C:7]1[C:6]([CH3:13])=[CH:5][C:4]([CH3:14])=[C:3]([C:1]2[NH:37][C:16]3[CH2:17][CH2:18][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][C:22]=3[N:32]=2)[CH:12]=1)=[O:9]
Reactant: COC(=O)c1cc(C=O)c(C)cc1C
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCN(C(=O)OC(C)(C)C)CC3)c(C)cc1C
Temperature: 130 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Into a 10-mL sealed tube, was placed methyl 5-formyl-2,4-dimethylbenzoate (compound 83.2, 500 mg, 2.60 mmol), tert-butyl 4-bromo-5-oxoazepane-1-carboxylate (compound 82.3, 1.1 g, 3.8 mmol), ammonium hydroxide (25%) (1.2 mL, 7.8 mmol), ammonium acetate (900 mg, 11.7 mmol) in N,N-dimethylformamide (6 mL). The resulting mixture was stirred for 3 h at 130° C. behind a blast shield, then cooled to room temperature and diluted with ethyl acetate (150 mL). The mixture was washed with brine (5×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane/methanol (10:1) as the eluent to yield 0.80 g (46%) of the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:24])([CH3:23])[C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:24])([CH3:23])[C:9]2=[S:35])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
To a suspension of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound of Example 9, 182 mg) in dioxane (10 mL) was added Lawesson's reagent (202 mg), and the mixture was stirred at room temperature for 2 hours and then stirred at 40° C. for 24 hours. The reaction mixture was diluted with chloroform and the mixture was filtered through a NH-silica gel pad and washed with ethyl acetate. The filtrate and the washings were combined and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=19/1→3/2) to give N-[4-(4-fluorophenyl)-2,2-dimethyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (25 mg) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>C(#N)C>[Cl:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: ClCCCBr
Reactant: Oc1cnc2c(n1)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCCOc1cnc2c(n1)CCCC2
Yield: 64.8 %

Procedure:
1.5 g (10 mmol) of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline was dissolved in 40 ml of acetonitrile. To the resultant solution were added 2.76 g (20 mmol) of potassium carbonate and 1.19 ml (12 mmol) of 1-bromo-3-chloropropane. The resultant mixture was heated under reflux for 2 hours and then, subjected to filtration to thereby filter off insoluble substances. The solvent of the filtrate was distilled off in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was charged in a column of 42 g of silica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) and eluted with chloroform, to thereby obtain 1.47 g of 2-(3-chloropropoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 67%).
Reaction SMILES: [I-].[Na+].[N-:3]=[N+:4]=[N-:5].[Na+].Cl[CH2:8][CH2:9][CH2:10]/[C:11](/[C:27]1[O:28][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[N:30][N:31]=1)=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:3]([CH2:8][CH2:9][CH2:10]/[C:11](/[C:27]1[O:28][C:29]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[N:30][N:31]=1)=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1)=[N+:4]=[N-:5]
Reactant: COc1cc(/C=C(\CCCCl)c2nnc(Cc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C(\CCCN=[N+]=[N-])c2nnc(Cc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.5 %

Procedure:
Sodium iodide (35 mg) and sodium azide (20 mg) were added to a solution of 2-{4-chloro-1-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}butyl}-5-(4-fluorobenzyl)[1,3,4]oxadiazole (72 mg) in DMF (2 mL), and the reaction solution was stirred at 80° C. for five hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=3:1->ethyl acetate) to obtain 50 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5](Br)[CH3:6])[CH3:2].[N:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]=[CH:10][CH:11]=[CH:12]2)[CH3:6])[CH3:2]
Reactant: Oc1ccc2ncccc2c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc2ncccc2c1
Temperature: 90 °C
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-propionic acid ethyl ester (14.6 mL, 0.112 mol), quinolin-6-ol (16.3 g, 0.112 mol) and Cs2CO3 (44 g, 0.135 mol) in 500 mL of DMF was heated to 90° C. for overnight. The mixture was filtered and diluted with Et2O (500 mL). Organic layer was washed with water and brine. The combined aqueous layer was then extracted with EtOAc. Combined organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. Crude material was purified by chromotography (Rf=0.3 in hexanes/acetone=1:1) to give 22 g of title compound as light yellow oil. 1H NMR (400 MHz, CDCl3) δδ 8.78 (dd, 1H, J=4.0, 0.8 Hz), 8.02 (d, 1H, J=8.8 Hz), 8.01 (d, 1H, J=8.0 Hz), 7.42 (dd, 1H, J=9.4, 3.0 Hz), 7.35 (dd, 1H, J=8.6, 4.2 Hz), 7.26 (d, 1H, J=1.2 Hz), 6.99 (d, 1H, J=2.8 Hz), 4.89 (q, 1H, J=6.8 Hz), 4.27-4.20 (m, 2H), 1.69 (d, 3H, J=6.8 Hz), 1.24 (t, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[Sn](Cl)(Cl)Cl.[CH2:21]=[O:22]>C1(C)C=CC=CC=1>[OH:22][C:21]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: Cc1ccccc1O
Reactant: C=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(C=O)c1O

Procedure:
To a stirred solution of o-cresol (4.0 g, 37 mmol) in triethylamine (3.8 ml, 26.6 mmol) and toluene (100 ml) is added dropwise SnCl4 (0.95 g, 36.5 mmol) under an atmosphere of nitrogen. After the addition of paraformaldehyde the mixture is heated at reflux for 18 h. The reaction mixture is quenched by pouring onto crushed ice and the pH is adjusted to 2 by addition of aqueous HCl. The product is extracted with ether and the resulting organic phase is washed with brine and dried over sodium sulfate. Evaporation of the solvent and purification by chromatography yields the title compound. (CDCl3, 400 MHz): 11.26 (s, 1H); 9.86 (s, 1H); 7.37 (m, 2H); 6.91 (t, 1H); 2.23 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH:14]=[CH:13][CH2:12][N:11]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][N:11]1[CH2:12][CH:13]=[CH:14][CH2:15][CH:10]1[CH2:9][CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCC1CC=CCN1Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC1CC=CCN1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-[1-(3,4-dichlorobenzyl)-1,2,3,6-tetrahydropyridin-2-yl]ethylcarbamic acid tert-butyl ester (1.0 g, 2.9 mmol) dissolved in dichloromethane at 5° C. was added trifluoroacetic acid (10 mL). After stirring at room temperature for 2.5 h the solvent was evapaorated, partitioned between dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic layer was separated, dried and evaporated to yield the title compound as a colourless gum. δH (CDCl3+D2O) 1.46-1.63 (1H, m), 1.71-1.95 (2H, m), 2.18-2.47 (1H, m), 2.68-3.07 (4H, m), 3.60 (2H, s), 5.30 (1H, s), 5.57 (1H, d, J=10.1 Hz), 5.74 (1H, d, J=10.2 Hz), 7.10-7.50 (3H, m); MS (ES+) 285 (100%) MH+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][N:40]([C:13]([C:12]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][O:10][C:11]=3[CH3:16])=[O:15])[CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 77.7 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (619 mg, 1.43 mmol, 78%) was obtained.
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([CH:11](C(C)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[C:20](Cl)(=[O:25])[CH2:21]CCC.C(OC(=O)C)(=O)C>O.C(O)(=O)C.[Zn]>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:1][C:20](=[O:25])[CH3:21])[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:16]
Reactant: O=N[O-]
Reactant: CCCCC(=O)C(C(C)=O)C(=O)OCC
Reactant: CCCCC(=O)Cl
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of sodium nitrite (41.3g) in water was added slowly to a cooled solution of ethyl 2-valerylacetoacetate (118.7g) in acetic acid (100 ml.), and the temperature was kept below 10°. Ice (100g) was added, followed by acetic anhydride (105.0g). Zinc dust (total 65.4g) was added portionwise, keeping the temperature below 20° with stirring, until the reaction was complete. The mixture was allowed to stand overnight at room temperature, and it was then filtered. The solid was washed wih chloroform, and the filtrate was extracted with chloroform. The chloroform extracts were washed with sodium carbonate solution and dried. The solvent was removed under vacuum, and the residue was purified by column chromatography (silica gel) eluting with petroleum ether (b.p. 60-80°)/ethyl acetate, to yield ethyl-2-acetamido-3-oxoheptanoate, 13.5g, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=2[N:9]=[CH:8]1.[NH:32]([C:34]([CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1)=[O:35])[NH2:33].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([NH:33][NH:32][C:34]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[O:35])=[O:17])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(C(=O)O)ccc43)cc2OC)cn1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C(=O)NNC(=O)C5CCN(C(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carboxylic acid (0.30 g, 0.72 mmol) in dichloromethane was added tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (0.24 g, 0.98 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.34 g, 0.89 mmol), diisopropylamine (0.19 g, 1.47 mmol). The resulting mixture was allowed to stir at room temperature. After 16 h, the mixture was concentrated and the residue was purified by silica gel chromatography (2% methanol/dichloromethane elute) to afford 0.30 g (65%) tert-butyl 4-(2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1>CO>[OH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O-:16])=[O:15])=[CH:12][CH:11]=1.[CH2:1]([NH3+:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CO
Product: O=C([O-])c1ccc(O)cc1
Product: [NH3+]Cc1ccccc1

Procedure:
Benzylamine (1.07 g; 10 mmol) was added dropwise to a solution of 4-hydroxybenzoic acid (1.38 g; 10 mmol) in methanol (10 cm3). A white solid formed immediately. The product was collected by filtration and recrystallized from water to produce white needle-like crystals. Found: C, 68.6%; H, 6.2%; N, 5.6%. Calculated for C14H15NO3 : C, 68.57%; H, 6.12%; N, 5.71%. M.pt. 229°-230° C.
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])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:28][C:27]([O:26][CH3:25])=[O:30])=[CH:18][CH:17]=1
Reactant: COC(=O)CBr
Reactant: COc1cc2ncnc(Oc3ccc(O)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenol (100 mg) was dissolved in dimethylformamide (2 ml) to prepare a solution. Sodium hydride (15 mg) was added to the solution, and the mixture was stirred at 0° C. for 10 min. Methylbromoacetate (0.037 ml) was added thereto, and the mixture was further stirred at 0° C. for 30 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Diethyl ether was added to the residue, and the precipitated crystal was collected by filtration and was washed to give the title compound (88 mg, yield 71%).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=3[F:24])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12](Cl)[N:11]=[CH:10][CH:9]=3.Cl.C([O-])(O)=[O:29].[Na+]>C1COCC1>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=3[F:24])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:29])[C:13]=3[C:4]=2[CH:3]=1
Reactant: O=C([O-])O
Reactant: Fc1cc(F)c(Nc2nc3ccc(Br)cc3c3c(Cl)nccc23)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]ccc2c(Nc3c(F)cc(F)cc3F)nc3ccc(Br)cc3c12
Temperature: 25 °C

Procedure:
To a solution of 9-bromo-1,5-dichlorobenzo[c]-2,6-naphthyridine (800 mg, 2.4 mmol) in THF (10 mL) were added 2,4,6 trifluoroaniline (359 mg, 2.4 mmol) and sodium tert-butoxide (703 mg, 7.32 mmol) and the reaction mixture was heated to 85° C. for 45 min. The solution was cooled to room temperature, quenched with methanol and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% hexane to 100% EtOAc, gradient elution) to afford 9-bromo-1-chloro-N-(2,4,6-trifluorophenyl)benzo[c]-2,6-naphthyridin-5-amine. 9-Bromo-1-chloro-N-(2,4,6-trifluorophenyl)benzo[c]-2,6-naphthyridin-5-amine was taken up in THF (10 mL) and 6 N HCl (10 mL) and heated to 85° C. for 2 hr. The reaction was cooled to room temperature, neutralized with saturated NaHCO3 and extracted with EtOAc. The organic layers were dried over Mg2SO4, filtered, and concentrated. Column chromatography on silica gel (100% hexane to 100% EtOAc) provided the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([NH:8][CH3:9])[C@H:5]([OH:10])[CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.O>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:8]([C@H:6]2[C@H:5]([OH:10])[CH2:4][N:3]([CH2:1][CH3:2])[CH2:7]2)[CH3:9])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCN1C[C@@H](O)[C@H](NC)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc(Cl)cc2)C1
Temperature: -5 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
A solution of 17.0 g (118 mmoles) of trans-1-ethyl-4-methylamino-3-pyrrolidinol in 180 ml of methylene chloride was mixed with 15 g of powdered anhydrous potassium carbonate and cooled to -5° C. The mixture was kept at or below 0° C. while a solution of 20.6 g (118 mmoles) of p-chlorobenzoyl chloride in 100 ml of methylene chloride was added dropwise. After the mixture was stirred at ambient temperature for 18 hr, it was poured into 100 ml of water. The organic layer was separated, dried and concentrated. The residue was crystallized from cyclohexane to give 25 g (75%) of white crystals, m.p. 91°-93° C.
Reaction SMILES: O.Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[O:13])=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([O-:29])=[O:28].[F-].[Cs+]>O1CCOCC1.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>[CH3:26][C:11]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)=[CH:4][CH:5]=1)[C:12]([NH:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)=[O:13]
Reactant: CC(CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: CC(CCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 90 °C
Yield: 182.2 %

Procedure:
Water (1.0 mL) was added to a solution of (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.35 g, 0.806 mmol), which may be prepared as in Preparation 2, Step 4, in 1,4-dioxane (5.0 mL). (4-nitrophenyl)boronic acid (209 mg, 1.01 mmol), cesium fluoride (0.49 mg, 3.22 mmol) and tetrakis(triphenylphosphine)palladium (0.094 g, 0.810 mmol) were added and the solution was heated to 90° C. After 4 hours the reaction was concentrated in vacuo and the resulting residue was triturated with ethyl acetate. The suspension was filtered through celite. The filtrate was washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification on Biotage flash 40S (hexanes/ethyl 6:4-1:1) afforded the title compound as a yellow solid (700 mg, 50%). LCMS m/z 475.2 (M−1).