Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CN(C=O)C>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[O:1][CH2:17][CH2:16]1
Reactant: Oc1cccnc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
2,3-Dihydroxypyridine (2.22 g, 20.0 mmol) was dissolved in N,N′-dimethylformamide (100 mL), and added potassium carbonate (5.52 g, 40.0 mmol) at room temperature. 5 minutes after, 1,2-dibromoethane (2.6 mL, 30.0 mmol) was added at the same temperature, and stirred at 90° C. overnight. The reaction solution was reverted to room temperature, filtered, and the obtained filtrate was concentrated in vacuo. Then, the obtained residue was added ethyl acetate. The suspension was filtered, washed ethyl acetate, and concentrated in vacuo. The title compound (157 mg (yield 5.7%)) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:31])=[C:17]([C@:19]2([CH3:30])[CH2:24][S:23](=[O:26])(=[O:25])[C:22]([CH3:28])([CH3:27])[C:21]([NH2:29])=[N:20]2)[CH:18]=1>>[NH2:29][C:21]1[C:22]([CH3:27])([CH3:28])[S:23](=[O:25])(=[O:26])[CH2:24][C@:19]([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:31])([CH3:30])[N:20]=1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc(N)ccc2F)CS1(=O)=O
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(C)CS(=O)(=O)C(C)(C)C(N)=N3)c2)cn1
Yield: 65.8 %

Procedure:
Prepared from commercially available 5-methoxypyrazine-2-carboxylic acid (CAS-no. 40155-42-8) (43.2 mg, 281 μmol, Eq: 1.2) and (R)-5-(5-amino-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (70 mg, 234 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (67 mg, 154 μmol, 65.8% yield) as a white foam. MS (ISP): m/z=436.5 [(M+H)+].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2[CH3:21])(=[O:10])=[O:9])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>O1CCOCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:12]=2[CH3:21])(=[O:9])=[O:10])[CH2:7]1
Reactant: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-dimethylethyl(2S)-2-methyl-4-{[2-methyl-5-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 20) (2.1 g, 4.97 mmol) in 1,4-Dioxane (50 mL) was treated by HCl 4M in dioxane (6.21 mL, 24.85 mmol). The reaction mixture was stirred overnight at room temperature. LCMS showed a 1:1 ratio between starting material and expected product. HCl 4M in dioxane (6.21 mL, 24.85 mmol) is added and the reaction mixture stirred for 4 h. LCMS showed about 10% of remaining starting material. HCl 4M in dioxane (6.21 mL, 24.85 mmol) is added and the reaction mixture stirred for 1 h.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[C:5]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:6]([C:8]([N+:18]([O-])=O)=[CH:9][C:10]=1[O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[NH2:7]>CO.O.[Fe]>[Cl:3][C:4]1[C:5]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:6]([NH2:7])[C:8]([NH2:18])=[CH:9][C:10]=1[O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1c([N+](=O)[O-])cc(Oc2cccnc2)c(Cl)c1Oc1cccnc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cc(Oc2cccnc2)c(Cl)c(Oc2cccnc2)c1N

Procedure:
128 mg of ammonium chloride and 67 mg of iron powder were added to a suspension of 143 mg of 3-chloro-2,4-bis(pyridin-3-yloxy)-6-nitroaniline in 8 ml of methanol and 4 ml of water, and the reaction liquid was heated under reflux for 2 hours. The reaction liquid was filtered, and the solvent was evaporated away under reduced pressure. The residue was diluted with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away to obtain the entitled compound as a pale brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCCC(=O)O)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A 500 ml single-neck flask was charged with 7-(4-methoxyphenyl)heptanoic acid (A3) (20.0 g, 90 mmole), freshly distilled 48% hydrobromic acid (80 ml), and glacial acetic acid (40 ml). The mixture was heated to reflux by immersing the flask in an oil bath regulated at 140° C. for 3.5 hours. At the end of this time, water (80 ml) was added, the flask was cooled to room temperature, and placed in the refrigerator overnight. The resulting solid, 7-(4-hydroxyphenyl)heptanoic acid, was collected by suction filtration, washed with water (2×80 ml), and dried in vacuo. The product was of sufficient purity to be used in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]([OH:7])/[CH:4]=[CH:5]/[I:6].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]([CH3:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]([O:7][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)/[CH:4]=[CH:5]/[I:6]
Reactant: CCCCC(C)(C)C(O)/C=C/I
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCCC(C)(C)C(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 11.2 g. (0.0396 mole) of 4,4-dimethyl-1-iodo-trans-1-octen-3-ol (Example 996) with 12.8 g. of triphenylmethyl bromide in 50 ml. of pyridine and purification of Florisil®, all as described in Example 728 gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1Cl

Procedure:
A solution of 2,3-dichloro-4,5-difluorobenzoic acid (9.3 g) and dimethylformamide (0.013 ml) in thionyl chloride (40 ml) was refluxed for 2.5 hours, and then concentrated. The resulting residue was purified by distillation in nitrogen atmosphere to give the title compound (8.7 g) as pale yellow oil, bp 123°-126° C./40 mmHg.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([CH2:36]OS(C)(=O)=O)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>CN(C)C=O>[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)=[O:24])[C@H:20]([CH2:36][S:3][C:4]2[N:8]([CH3:9])[N:7]=[N:6][N:5]=2)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: Cn1nnnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnnc1SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of sodium hydride (62.8% suspension in oil) (0.38 g) in N,N-dimethylformamide (12 ml) was added 5-mercapto-1-methyl-1H-tetrazole (1.14 g) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. This solution was added dropwise to a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-methanesulfonyloxymethyl-1-(4nitrobenzyloxycarbonyl)pyrrolidine (3.0 g) in N,N-dimethylformamide (60 ml) under ice-cooling. The mixture was stirred at 60°-70° C. for 2 hours. The reaction mixture was poured into ice-water (200 ml) and extracted 3 times with ethyl acetate (100 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (40:1, V/V). The fractions containing the desired compound were collected and concentrated under reduced pressure to give (2S,4R)-4-t-butyldimethylsilyloxy-2-(1-methyl-1H-tetrazol- 5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.68 g).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([C@@H:15]1[O:17][CH2:16]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CO>[CH2:13]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:15]1[O:17][CH2:16]1
Reactant: ClC[C@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: CO
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Temperature: 20 °C
Reaction time: 15 h
Yield: 68.2 %

Procedure:
Into a reaction vessel were put potassium phthalimide (5.00 g, 27.0 mmol), benzyltrimethylammonium chloride (0.50 g, 2.70 mmol) and methanol (50 ml) and then thereto was added (R)-epichlorohydrin (9.99 g, 81.0 mmol). The mixture was stirred at 20° C. for 15 hours and the solvent was removed. To the residue was added ethyl acetate (30 ml), the mixture was washed with water (20 ml) and ethyl acetate was removed to give crude (R)-glycidylphthalimide (3.74 g, yield: 68%, optical purity: 99% e.e.) as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][C:12]1[N:13]=[CH:14][C:15]([C:18](O)=O)=[N:16][CH:17]=1.N>>[CH3:11][C:12]1[N:13]=[CH:14][C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[N:16][CH:17]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Cc1cnc(-c2nc(-c3cccnc3)no2)cn1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 5-methylpyrazine-2-carboxylic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 2.71 (s, 3H), 7.66 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 8.59 (dt, J=7.9, 1.8 Hz, 1H), 8.74-8.78 (m, 2H), 9.33 (dd, J=2.0, 0.8 Hz, 1H), 9.40 (d, J=1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z 240 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].[Cl:27][CH2:28][C:29](Cl)=[O:30]>CN(C)C(=O)C>[Cl:27][CH2:28][C:29]([O:25][CH:22]([CH2:23][O:24][C:29](=[O:30])[CH2:28][Cl:27])[CH2:21][NH:20][C:18](=[O:19])[C:4]1[C:3]([I:26])=[C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])[C:15]([I:16])=[C:6]([C:7]([NH:9][CH2:10][CH:11]([O:14][C:29](=[O:30])[CH2:28][Cl:27])[CH2:12][O:13][C:29](=[O:30])[CH2:28][Cl:27])=[O:8])[C:5]=1[I:17])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Solvent: CC(=O)N(C)C
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c1I

Procedure:
reacting 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with chloroacetyl chloride in N,N-dimethylacetamide to produce N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:31][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CC(C)(C)CN
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and neopentylamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)(=[O:12])[CH3:11].C(O)(=O)C>CO.[C].[Pd]>[C:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCN2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCC(N2CCc3ccccc32)CC1
Yield: 82.2 %

Procedure:
Indoline (25 ml), 1-acetyl-4-piperidone (25 g) and glacial acetic acid (20 ml) were dissolved in methanol (300 ml). After adding 10% palladium carbon (1.0 g) thereto, catalytic reduction was carried out under atmospheric pressure. After the completion of the reaction, the reaction solution was filtered through celite, washed with methanol and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and basified with a 5 N aqueous solution of sodium hydroxide followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound (35.6 g) as a pale yellow wax (yield: 82.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:37]>>[CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[C:7](=[O:37])[C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=[Se]=O
Reactant: COc1ccc(SCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Product: COc1ccc(SCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[3-(3,4-dimethoxy-phenylthio)-propyl]-methylamine and selenium dioxide analogously to Example 55.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[Li]C(C)(C)C.[Sn:19](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:28]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[C:5]1[N:1]([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)[N:2]=[N:3][CH:4]=1)[CH2:29][CH2:30][CH3:31]
Reactant: N#Cc1ccc(-n2ccnn2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnnn1-c1ccc(C#N)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
4-[1,2,3]Triazol-1-yl-benzonitrile (0.105 g, 0.6 mmol) and dry THF (6 ml) and a magnetic stirrer were placed in a flask. The flask was flushed with argon and kept under an inert atmosphere and cooled to −78° C. At this temperature, tert-BuLi (0.36 ml, 1.7M, 0.6 mmol) was added dropwise during 1-2 minutes. The mixture was stirred at this temperature for 15 minutes and Bu3SnCl (0.19 g, 0.6 mmol) was added during 1 minute, and the mixture was then allowed to slowly reach RT. The crude mixture was directly purified on silica (heptane:EtOAc 4:1) giving 0.12 g (43%) of the title stannane.
Reaction SMILES: C([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(O)=O.[Br:29]Br>C(Cl)(Cl)(Cl)Cl>[Br:29][CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: BrBr
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)O)OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(CCCC(Br)CCCCCCC(=O)OCC)OC(C)=O

Procedure:
A mixture of ethyl 8-carboxy-12-acetoxyheptadecanoate (31.5 g., 0.079 mole), red mercuric oxide (12.8 g., 0.059 mole), and carbon tetrachloride (200 ml.) is stirred at room temperature while bromine (12.6 g., 0.079 mole) is added dropwise during one hour. The resulting mixture is heated at reflux for one hour. The mixture is then cooled, filtered, washed with dilute hydrochloric acid, water and brine and dried over sodium sulfate. The solution is evaporated in vacuo to leave the product as a yellow residual weighing 24.5 g. The product is purified by chromatography on a column containing 250 g. of silica gel using chloroform as eluting solvent. There is obtained 14.4 g. of purified ethyl 8-bromo-12-acetoxyheptadecanoate, a yellow oil with Rf 0.49 on silica gel thin layer chromatography with chloroform elution. pmr (CDCl3) δ 0.90 (3H,t); 2.03 (3H, s CH3CO); 4.07 (1H, m HCBr); 4.13 (2H, q); 4.92 (1H, m HCO).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]([F:26])[CH:16]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]([F:26])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCO)c(F)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCO)c(F)c3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 37.1 %

Procedure:
To a mixture of methyl 6-chloro-5-[3-fluoro-4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylate (85 mg, 0.23 mmol) in methanol (5 mL) and water (2 mL) was added sodium hydroxide (90 mg, 2.3 mmol). The reaction mixture was heated at 70° C. and stirred for 24 hours. The mixture was acidified by 1N HCl to pH 4 and extracted with ethyl acetate (10 mL×3). The combined organic layers was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. It was purified by preparative HPLC to give the title compound (31 mg, 52% yield) as a white solid. MS (AP−) 386.1 (M+Na)−. 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.98 (s, 1H), 8.08 (s, 1H), 7.925 (s, 1H), 7.62 (s, 1H), 7.25-7.15 (m, 3H), 4.59 (t, 1H), 4.16 (t, 2H), 3.58 (q, 2H), 1.90 (m, 2H).
Reaction SMILES: [I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1.[OH-].[Li+]>C(#N)C.O>[I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccccn3)n(C)c2I)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)O)cc2)c1I

Procedure:
A solution of methyl 4-(5-iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate (Intermediate 7, Step 3, 1.5 g, 3.58 mmol) and lithium hydroxide (0.257 g, 10.73 mmol) in acetonitrile (6 mL) and water (6 mL) was heated to 50° C. for 2 h. The mixture was concentrated and extracted with EtOAc. The organics were dried (MgSO4) and concentrated to afford 4-(5-iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoic acid. LCMS: m/z 406.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH:31]([CH3:33])[CH3:32])[C:23]2=[O:34])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.CO>[CH3:33][CH:31]([N:24]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:21][CH:20]=2)[C:23]1=[O:34])[CH3:32]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CC(C)n1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc21
Temperature: 180 °C
Yield: 30.6 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (270 mg) was added to a solution of 3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (330 mg) and NaH (53.9 mg) in DMF (5 mL) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].Cl>C(Cl)Cl.CN(C)C=O>[CH2:20]([N:22]([CH2:23][CH3:24])[C:9]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=1)=[O:11])[CH3:21]
Reactant: CCNCC
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 120 ml of methylene chloride was suspended 6.0 g of 4-(methoxycarbonyl)-benzoic acid, to which were added 3.5 ml of oxalyl chloride and 0.05 ml of N,N-dimethylformamide at 0-5° C. After a reaction at the same temperature as above for 3 hours, the mixture was stirred at ambient temperature for 24 hours. Then, a 90.7 g portion of the reaction mixture was taken out, and 6.9 ml of diethylamine was added thereto. The mixture was stirred at ambient temperature for 3 hours, and then poured into ice water. pH was adjusted to 1.0 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 5.89 g of methyl 4-[(diethylamino)carbonyl]-benzoate was obtained as a red oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>>[Cl:20][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:13]#[N:14]
Reactant: COc1cc2[nH]cc(C#N)c(=O)c2cc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Temperature: 165 °C

Procedure:
A mixture of 5.3 g (21.6 mmol) of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-quinoline-3-carbonitrile and 9 g (43.2 mmol) of phosphorous pentachloride was heated at 165° C. for 2 hours. The mixture was diluted with hexanes and the solid was collected. The solid was dissolved in 700 ml ethyl acetate and washed with cold dilute sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel giving 5.2 g of 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile as a tan solid.