Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([C:12]1[C:13]([NH:19][CH2:20][CH3:21])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:11].[Cl:25][CH2:26][C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([C:12]1[C:13]([N:19]([CH2:20][CH3:21])[C:27](=[O:28])[CH2:26][Cl:25])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:11]
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCN(C(=O)CCl)c1nc(C)ccc1C(=O)c1cccc(Cl)c1

Procedure:
To a DMF solution of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine were added chloroacetyl chloride and pyridine, followed by reaction at room temperature. Thereafter, the whole was worked up and purified in a usual manner to obtain N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]—N-ethylchloroacetamide. To an acetonitrile solution of the compound were added N-tert-butoxycarbonylpiperazine and potassium carbonate, followed by reaction under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 2-[4-tert-butoxycarbonylpiperazin-1-yl]—N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]-N-ethylacetamide. The resulting compound was reacted with sodium methoxide in methanol under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 3-(1 -tert-butoxycarbonylpiperazin-4-yl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one. NMR1: 4.73 (2H, q, J=7.3 Hz), 3.15-3.35 (2H, m), 1.38 (9H, s).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[BH4-].[Na+].C(OCC)(=O)C>CO>[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 178.4 %

Procedure:
The monosilylated material (2) (90 g, 0.20 mol) was dissolved in 1 L of distilled methanol and the solution cooled to 0° C. under an inert atmosphere. Sodium borohydride (36 g, 0.98 mol) was added portionwise over 1.5 hour at 0–5° C. The mixture was allowed to warm to room temperature with stirring over 16 hours. The majority of the methanol (approx. 700 mL) was removed under reduced pressure and the resulting grey suspension was diluted with water (250 mL). Hydrochloric acid (1 M; 190 mL) was added dropwise at room temperature to provide a white suspension. Ethyl acetate (500 mL) was added and the suspension stirred for 30 minutes to provide homogeneous aqueous and organic phases. The aqueous layer was separated and further extracted with 2×500 mL of ethyl acetate. The organic layers were combined and washed with saturated, aqueous sodium bicarbonate (300 mL) and saturated, aqueous sodium chloride (300 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford the crude product as a colourless foam (79 g). The foam was subjected to dry-flash chromatography to provide (3) (65 g, 72%) as a colourless foam. Rf 0.51 (methanol/ethyl acetate, 0.5:9.5). 1H NMR (300 MHz, DMSO-d6) δ: 7.76 (1H, d, J=7.9 Hz), 7.69–7.66 (4H, m), 7.45–7.39 (6H, m), 4.63–4.57 (2H, m), 4.39 (1H, d, J=5.2), 4.27 (1H, d, J=7.6), 3.85–3.58 (7H, m), 3.43–3.38 (1H, m), 1.85 (3H, s), 0.99 (9H, s). 13C NMR (300 MHz, DMSO-d6) δ: 171.2, 135.6, 135.5, 133.9, 133.8, 130.0, 128.1, 70.9, 69.5, 68.6, 66.7, 61.1, 53.4, 27.0, 22.9, 19.3.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][C@H:4]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[NH:5]C(OC(C)(C)C)=O.[ClH:33]>C(O)(=O)C.C(O)C>[ClH:33].[ClH:33].[CH3:32][N:2]([CH3:1])[CH2:3][C@H:4]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[NH2:5]
Reactant: CC(C)CCNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CN(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)CCNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](N)CN(C)C

Procedure:
A solution of [3-dimethylamino-N2 -(t-butoxycarbonyl)-D-alanyl]-N-(3-methylbutyl)-L-phenylalaninamide (1.84 g.) in acetic acid saturated with hydrogen chloride (50 ml.) was stirred for one and one half hours at room temperature, then stripped of volatiles under vacuum. A solution of the residue (1.87 g.) in ethyl acetate was washed with saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride, and filtered. Hydrogen chloride (8.2 millimoles) in ethanol was added and the solution was stripped of volatiles, affording (3-dimethylamino-D-alanyl)-N-(3-methylbutyl)-L-phenylalaninamide dihydrochloride as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=3)=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:11]3[C:12](=[N:14][N:15]([CH3:17])[CH:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[CH:35]1([CH2:38][NH2:39])[CH2:37][CH2:36]1>>[CH:35]1([CH2:38][NH:39][C:27]2[N:26]=[C:25]([C:9]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:13][C:12]4=[N:14][N:15]([CH3:17])[CH:16]=[C:11]4[C:10]=3[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:30]=[CH:29][N:28]=2)[CH2:37][CH2:36]1
Reactant: NCC1CC1
Reactant: Cn1cc2c(-c3ccc(O)cc3)c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc2n1
Product: Cn1cc2c(-c3ccc(O)cc3)c(-c3ccnc(NCC4CC4)n3)c(-c3ccc(F)cc3)nc2n1

Procedure:
Following a similar procedure to that described in example 128, but starting from 4-[6-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-2-methylpyrazolo[3,4-b]pyridin-4-yl]phenol (obtained in section b) and (cyclopropylmethyl)amine, the title compound was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([CH:10]([CH3:12])[CH3:11])[N:4]=1.[CH2:13](Br)[CH:14]=[CH2:15]>>[Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:15][CH:14]=[CH2:13])[N:6]=[C:5]([CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: C=CCBr
Reactant: CC(C)c1nc(O)cc(CCl)n1
Product: C=CCOc1cc(CCl)nc(C(C)C)n1

Procedure:
4-Chloromethyl-6-hydroxy-2-isopropyl-pyrimidine is reacted with allylbromide analogously to the process described in Example 86 in order to produce 4-chloromethyl-2-isopropyl-6-(2-propenyloxy)-pyrimidine which is required as the starting material in Example 24. This product is obtained in the form of an oil, 1H-NMR (CDCl3): 1.30 (d, 2×CH3), 3.15 (m, CH), 4.55 (s, CH2), 4.93 (m, CH2), 5.37 (m, CH2), 6.12 (m, CH), 6.75 (s, CH).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][O:13][CH3:14])[C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[CH:7][CH:8]=2)[N:3]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)[CH3:17]>CN1C(=O)CCC1>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH2:12][O:13][CH3:14])=[CH:11][C:2]([NH:29][CH:26]3[CH2:27][CH2:28][N:23]([CH2:22][C:21]4[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:19]([O:18][CH2:16][CH3:17])[CH:20]=4)[CH2:24][CH2:25]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: COCc1cc(Cl)nc2cc(Cl)ccc12
Solvent: CN1CCCC1=O
Product: CCOc1cc(CN2CCC(Nc3cc(COC)c4ccc(Cl)cc4n3)CC2)ccc1OC
Yield: 13.6 %

Procedure:
A solution of 2,7-dichloro-4-methoxymethyl-quinoline (36.3 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.5 equiv; intermediate A1) in NMP (2 mL) was heated by microwave irradiation to 200° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 9.6 mg (14%) of the title compound. MS (ISP): 470.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:6][C:5]([N:18]2[C:22](=[O:23])[N:21]([CH2:24][CH2:25][CH2:26][F:27])[N:20]=[N:19]2)=[C:4]([F:28])[CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:28])=[C:5]([N:18]3[C:22](=[O:23])[N:21]([CH2:24][CH2:25][CH2:26][F:27])[N:20]=[N:19]3)[CH:6]=2)=[CH:14][CH:13]=1
Reactant: O=c1n(CCCF)nnn1-c1cc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)cc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Oc2cc(-n3nnn(CCCF)c3=O)c(F)cc2Cl)cc1

Procedure:
1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one is etherified with 4-fluoronitrobenzene in the presence of potassium carbonate in N,N-dimethylformamide to form 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one (Compound A). Compound A is then reduced with iron powder in acetic acid and water to produce 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one (Compound B). Acetone is added to a stirring mixture of Compound B in hydrochloric acid. The mixture is cooled to about 5° C., and a solution of an equimolar amount of sodium nitrite in water and a molar excess of methyl acrylate are added in succession. The resultant mixture is stirred for 15-20 minutes, after which copper (I) chloride is slowly added. The mixture is stirred at room temperature for approximately 30 minutes and then poured into ice water. The resulting mixture is then treated with an organic solvent (e.g., ethyl acetate) to extract the product, methyl 2-chloro-3-[4-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5H-5-oxo-tetrazol-1-yl]phenoxy]phenyl]propionate, which may then be purified, as by column chromatography on silica gel.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C.[N+:24]([O-])([OH:26])=[O:25].N([O-])=O.[Na+]>O>[N+:24]([C:2]1[O:3][C:4]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc2c(-c3ccccc3)c(Br)oc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reaction time: 0.75 h

Procedure:
A mixture of 2.2 g (0.007 mole) of 2-bromo-3-phenyl-7-benzofurancarboxylic acid and 50 ml of acetic acid is heated on a steam bath for 45 minutes to facilitate dissolution. To this mixture is added 2 ml of nitric acid, then 0.96 g (0.0139 mole) of sodium nitrite while stirring the mixture rapidly at about 80°-90° C. After stirring for about 45 minutes the mixture is poured into water. The solid is separated by filtration and recrystallized from ethanol to provide 2-nitro-3-phenyl-7-benzofurancarboxylic acid, m.p. 271°-272° C.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([OH:21])=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33]I)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:5]1[N:6]([CH3:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([O:21][CH2:33][CH2:32][CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:10][CH:9]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(O)ccc2c1=O
Reactant: ICCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(OCCCCc3ccccc3)ccc2c1=O

Procedure:
A solution of 3-tert-butyl-6-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one (50 mg), 4-phenyl-1-iodobutane (100 mg) and cesium carbonate (100 mg) in DMF (2.5 mL) was heated at 80 C for 6 h. The reaction was partitioned between water and EtOAc. The organic solution was dried (Na2SO4) and concentrated, then purified by flash chromatography (20% EtOAc in hexanes) to give the titled compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26][C:27]([OH:29])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>O>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7](/[CH:10]=[C:26](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[C:27]([OH:29])=[O:28])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Reactant: O=C(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCCc1ncc(/C=C(/C(=O)O)c2ccccc2)n1Cc1ccccc1Cl
Temperature: 140 °C
Reaction time: 6 h
Yield: 18.1 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (554 mg, 2 mmol), phenylacetic acid (310 mg, 2.3 mmol), potassium carbonate (126 mg, 0.91 mmol), and acetic anhydride (1 mL) was heated gradually to 140° C. and held at this temperature for 6 hours. The cooled reaction was diluted with water and the oily solid was separated, triturated several times with ether, and the solid was crystallized several times from methanol/ethyl acetate to give 143 mg (18%) of the title compound; mp 210°-212° C. The NMR was consistent with the trans olefinic product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:26]=[CH:27][C:21]=2[N:20]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:25]2[CH:26]=[CH:27][C:21]3[N:20]=[C:19]([C:7]4[C:6]5[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=5)[N:9]([CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)[N:8]=4)[NH:23][C:22]=3[CH:24]=2)[CH2:30][CH2:31]1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Yield: 80.7 %

Procedure:
4-((2-(5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-benzo[d]imidazol-6-yl)methyl)morpholine (20 mg, 0.043 mmol) was added to the 10% Pd/C (5 mg) in ethanol (10 mL) and then hydrogen gas (60 psi) was applied for 6 h at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (15 mg) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21](F)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13].N1C=CC=CC=1>CCOCC>[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([CH2:5][O:4][CH:2]([CH3:1])[CH3:3])[CH2:11]3)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CC(C)OCC1CNCCN1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC(C)C)C3)cc21
Temperature: 80 °C
Yield: 107 %

Procedure:
A mixture of 2 g of 2-[(1-methylethoxy)methyl]piperazine, 1.27 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine was heated at 80° C. for 3 hours, then evaporated in vacuo. The residue was reevaporated three times from toluene, giving a gum. Ether was added to the gum which solidified. The solid was triturated with ether containing methanol and then dried giving 2.1 g of solid. A 1 g portion was purified by chromatography, giving 650 mg of the desired product, mp 144°-146° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A solution of 2-(4-methyl-1H-imidazol-1-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.3 g, 4.37 mmol) in MeOH (20 mL)/THF (20 mL) was treated sequentially with NH4Cl (7.02 g, 131 mmol) and zinc dust (2.86 g, 43.7 mmol) and stirred at RT for 2 h. The mixture was diluted with THF, the solids removed via filtration through diatomaceous earth, washed with THF and the filtrate concentrated to dryness. The material was treated with THF, the solids removed via filtration and the filtrate concentrated to dryness, treated with DCM and sonicated. The resulting solid was collected via filtration and dried to afford 5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine (800 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J=1.4 Hz, 1 H), 8.28 (d, J=5.8 Hz, 1 H), 7.83 (d, J=2.9 Hz, 1 H), 7.63 (s, 1 H), 7.31-7.30 (m, 2 H), 6.70 (dd, J=5.8, 2.2 Hz, 1 H), 6.51 (d, J=8.9 Hz, 1 H), 6.05 (s, 2 H), 2.14 (d, J=1.0 Hz, 3 H); MS (ESI) m/z: 268.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH:38]([Sn](CCCC)(CCCC)CCCC)=[CH2:39]>>[CH2:38]([C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:22])([CH3:23])[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1)[CH3:39]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Product: CCc1ccc(N(CCc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and vinyltributyltin. 1H NMR (CDCl3) δ 8.02 (d, 1H, J=2.0), 7.32 (dd, 1H, J=8.8; 2.0), 7.12 (d, 2H, J=8.6), 7.07 (d, 2H, J=8.5), 7.0 (d, 2H, J=8.4), 6.82 (d, 2H, J=8.4), 6.42 (d, 1H, J=8.8), 4.50 (s, 2H), 3.67 (t, 2H, J=7.4), 2.80 (t, 2H, J=7.4), 2.49 (q, 2H, J=7.6), 1.55 (s, 6H), 1.19 (t, 3H, J=7.6). MS: m/z 503 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[CH:37](O)=O>CC1C=CC=CC=1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[NH:15][CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:1]=[CH:37]3)[CH2:10][CH2:11]2)=[CH:23][CH:24]=1
Reactant: Nc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=CO
Solvent: Cc1ccccc1
Product: O=c1c2ccccc2ncn1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 73 %

Procedure:
A mixture of 4.86 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide, 1.4 parts of formic acid and 45 parts of methylbenzene was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in trichloromethane, water and ammonium hydroxide. The organic phase was separated, dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 3.6 parts (73%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4(3H)-quinazolinone; mp. 190.6° C. (compound 137).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH2:26][C@H:27]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]1[O:33][C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:26][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CCCCC[C@H](COS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Reactant: Oc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H](COc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1)OC1CCCCO1
Temperature: 80 °C
Reaction time: 5 h
Yield: 121.5 %

Procedure:
In a 500 ml four-necked flask were charged 12.2 g (43.7 mmol) of 5-hydroxy-2-(4-benzyloxyphenyl)pyrimidine, 24 g (65.5 mmol) of (R)-2-tetrahydropyranyloxyheptyl tosylate, 12 g of potassium carbonate, and 183 ml of DMF, and the mixture was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into 500 ml of ice-water and extracted with ethyl acetate. The extract was washed with water, and the solvent was removed by distillation under reduced pressure to obtain 28.6 g of a crude product, which was purified by silica gel column chromatography to obtain 25.3 g of the titled compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([NH:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:18])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:26]([NH:36][C:37](=[N:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])SC)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C=O)C>[C:41]([NH:40][C:37](=[N:36][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:14]([NH:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:18])=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]
Reactant: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-N2 -(Boc)-(R)-N-[1-(4-hydroxyphenyl)ethyl]ornithine amide (11.47 g; 0.33 mmol; from step (a) above) in DMF (50 mL) was added N,N'-bis(Cbz)-S-methylisothiourea (11.8 g; 0.33 mmol). The solution was stirred overnight at room temperature followed by removal of the solvent under reduced pressure. The resultant oil was chromatographed on a plug of silica gel (7.5 cm×12.5 cm) eluting first with CH2Cl2 (800 mL) to remove the higher Rf impurities. The eluent was switched to EtOAc (600 mL) to elute the sub-title compound as a white foam (14.67 g).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([OH:16])=[O:15].[Cl-].[Cl-].[Cl-].[Al+3]>>[CH3:8][O:7][C:1]1[CH:6]=[C:5]2[C:4](=[CH:3][CH:2]=1)[C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=[CH:13]2
Reactant: O=C(O)c1ccco1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(C(=O)O)cccc2c1

Procedure:
This starts from anisole; this is reacted with furan-2-carboxylic acid in the presence of a large excess of aluminium trichloride to give 6-methoxy-naphthalene-1-carboxylic acid (see J. Am. Chem. Soc. 69, page 2262 and European Patent No. A1-200,840).