Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])C.C(O[C:15]([C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=1)=[O:16])C>>[CH2:15]([O:16][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([C:4](=[O:5])[CH2:20][C:21](=[O:23])[CH2:22][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=2)=[O:16])[CH:11]=1)[CH3:17]
Reactant: CCOC(=O)c1ccccn1
Reactant: CCOC(=O)c1cc(OCC)ccn1
Product: CCOc1ccnc(C(=O)CC(=O)CC(=O)c2cc(OCC)ccn2)c1

Procedure:
This compound is prepared in a manner analogous to that described in Example 1, Step 1, for pyridine-2-carboxylic acid ethyl ester, but instead 4-ethoxy-pyridine-2-carboxylic acid ethyl ester from Example 17 is used. The yellowish crude product is used for further syntheses without special purification steps. IR (cm−1): 1557 (vs); 1469 (w); 1436 (w); 1300 (m); 1207 (m); 1186 (m); 1035 (m); 818 (m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].C([Li])(C)(C)C.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([B:20]([OH:25])[OH:21])[CH:3]=2)[NH:7][CH:6]=1)([OH:14])=[O:13]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(O)Cc1c[nH]c2ccc(B(O)O)cc12
Temperature: -30 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a solution of (5-bromo-1H-indol-3-yl)-acetic acid (1 g, 3.94 mmol) in THF (66 mL) at −78° C. is added tert-butyl lithium (1.7 M in pentane, 11.6 mL, 19.7 mmol) dropwise and stirred at −78° C. for 30 minutes at −30° C. for 1 hour. Cooled down to −78° C. again and treated dropwise with triisopropyl borate (4.53 mL, 19.7 mmol). The reaction mixture is allowed to warm to room temperature during 1 hour quenched with 2N hydrochloric acid. This mixture is extracted with ether. The extract is dried over sodium sulfate and concentrate to obtain an oil which is subjected to silica gel chromatography affording 3-carboxymethyl-1H-indol-5-yl boronic acid (185 mg, 20%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#N)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.CO.[OH:21]S(O)(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:21])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc2nc(-c3ccc(C#N)cc3)cn2c1
Reactant: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: CO
Product: Cc1ccc2nc(-c3ccc(C=O)cc3)cn2c1
Reaction time: 2.5 h

Procedure:
1.0 g of 6-methyl-2-(4'-cyanophenyl)imidazo[1,2-a]-pyridine in 20 ml dry benzene was treated with Dibal (5.5 ml of 1M solution). After stirring for 2-3 hrs, methanol 15 ml was added, followed by 10 ml of 10% H2SO4. The precipitate was filtered, dissolved in water and basified with 15% NaOH. The collected precipitate was recrystallized from ethanol. Yield 0.68 g (68%); mp 210°-211° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.C([N:34](C(C)C)[CH:35]([CH3:37])[CH3:36])C.CC(N)C>CN(C=O)C>[CH:35]([NH:34][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)([CH3:37])[CH3:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and propan-2-amine (11.5 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 64.8 mg (65%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.84 (s, 1H), 9.93 (br. s., 1H), 8.64 (d, J=2.0 Hz, 1H), 8.02-8.11 (m, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H), 4.43-4.63 (m, 3H), 4.25 (s, 2H), 4.07 (dd, J=14.1, 6.6 Hz, 1H), 3.93-4.02 (m, 1H), 3.37-3.55 (m, 1H), 2.96-3.25 (m, 4H), 2.68 (td, J=12.9, 2.5 Hz, 1H), 2.02-2.11 (m, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.33-1.72 (m, 4H), 1.14 (d, J=6.8 Hz, 6H). [M+H] calc'd for C25H33N7O2, 464; found, 464.
Reaction SMILES: [ClH:1].C([N:9]([C:14]1[CH:19]=[C:18]([CH:20]([OH:39])[CH2:21][NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:36]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]=3[CH:27]=2)[C:17]([OH:40])=[CH:16][CH:15]=1)[S:10]([CH3:13])(=[O:12])=[O:11])C1C=CC=CC=1>CO.C(Cl)(Cl)Cl>[ClH:1].[CH:27]1[C:28]2[NH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]=2[CH:37]=[CH:38][C:26]=1[O:25][CH2:24][CH2:23][NH:22][CH2:21][CH:20]([C:18]1[C:17]([OH:40])=[CH:16][CH:15]=[C:14]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:19]=1)[OH:39]
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1ccc(O)c(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(O)c(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)c1

Procedure:
According to the procedures described in Example 2, Intermediate 78 and the recovered product from the filtration (total sum of 30 mg) were treated by subjecting them to a hydrogenolysis for 13 hours using 10% palladium/carbon black (30 mg) with subsequent trituration of the resulting crude product from methanol/ethyl acetate, whereby the above-identified compound (9 mg) was obtained. Rf=0.34 (methanol/chloroform of 1/9).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH2:8][CH:7]([N:18]2C(=O)C3C(=CC=CC=3)C2=O)[C:6]1=[O:29].O.NN>CO.CCOCC>[NH2:18][C@@H:7]1[CH2:8][CH:9]=[CH:10][C@@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]1=[O:29].[NH2:18][C@H:7]1[CH2:8][CH:9]=[CH:10][C@@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]1=[O:29]
Reactant: COCCN1C(=O)C(N2C(=O)c3ccccc3C2=O)CC=C[C@H]1c1ccccc1
Agent: NN
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COCCN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Product: COCCN1C(=O)[C@H](N)CC=C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To 2-[(7S)-1-(2-methoxyethyl)-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-1H-isoindole-1,3(2H)-dione (6c) (420 mg) dissolved in MeOH (10 mL) was added hydrazine hydrate (0.1 mL) and the mixture was stirred overnight at RT. A white precipitate formed in solution. The reaction mixture was diluted with ether and the precipitate was filtered and washed with ether. The etheral filtrate was concentrated and the resulting residue dissolved in DCM. The DCM solution was washed with H2O and brine, dried (Na2SO4) and concentrated. The diastereomeric mixture was separated via preparative plate chromatography (eluent 10% MeOH in 1:1 ether/DCM) to give (3R,7S)-3-amino-1-(2-methoxyethyl)-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (6e) and (3S,7S)-3-amino-1-(2-methoxyethyl)-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (6d) (combined yield of 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([CH2:6][O:5][C:4]1[CH:3]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:11]=[CH:10][CH:9]=1)#[N:8]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCOc1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
(3-Aminophenoxy)-acetonitrile (3.0 g) was dissolved in 12 ml of pyridine, cooled in an ice bath, treated with 3.47 g of methanesulfonyl chloride, and stirred at room temperature for 3 hours. The mixture was poured into ethyl acetate, washed with hydrochloric acid, then with water, dried, and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (3:7) giving 3.0 g of N-(3-cyanomethoxyphenyl )-methanesulfonamide. An aliquot of this product was crystallized from ethyl acetate:hexane (3:7) to give a solid, mp 91-92° C. ##STR56##
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:6]=1[N:16]1[CH:20]=C(C#N)[C:18]([C:23]([F:26])([F:25])[F:24])=[N:17]1.Cl.C([O:30][CH2:31][CH3:32])C>>[C:31]([C:32]1[C:18]([C:23]([F:26])([F:24])[F:25])=[N:17][N:16]([C:6]2[C:7]([Cl:15])=[CH:8][C:9]([C:11]([F:13])([F:14])[F:12])=[CH:10][C:5]=2[Cl:4])[CH:20]=1)(=[O:30])[CH3:1]
Reactant: CCOCC
Reactant: C[Mg]I
Reactant: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Agent: Cl
Product: CC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesium iodide (prepared from magnesium (0.26 g) and methyl iodide (1.5 g) in diethyl ether (25 ml)), was treated with a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-cyano-3-trifluoromethylpyrazole (2 g) in diethyl ether (20 ml), dropwise. The resulting pale yellow solution was refluxed for 24 hours, cooled, and treated with hydrochloric acid (2N, 10 ml). After stirring for 0.5 hour at room temperature, the reaction mixture was diluted with ether (50 ml). The ethereal extract was washed with water (50 ml), dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a yellow gum. This was purified by chromatography on silica (Merck, 230-400 mesh, 0.7 kg cm−2) eluting with a mixture of dichloromethane and petroleum ether (4:1) to give 4-acetyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole as a white solid, m.p. 134° C.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]3[C:6]=2[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[CH:3]=1.FC(F)(F)[C:32](O)=[O:33]>CCOC(C)=O.C[O-].[Na+].CO.C(Cl)Cl.[Cu]Br>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:4]1[CH:3]=[C:2]([O:33][CH3:32])[C:7]2[O:8][CH:9]3[CH:10]([CH2:11][NH:12][CH2:13][CH2:14]3)[C:6]=2[CH:5]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3c(Br)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCNCC21
Temperature: 85 °C
Reaction time: 4.5 h

Procedure:
In a 7 mL vial, copper (I) bromide (0.15 mmol, 22 mg) was diluted with 0.1 mL EtOAc and 0.6 mL of sodium methoxide in methanol (25 wt %). tert-Butyl 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.5 mmol, 250 mg) was added to the thick slurry and heated to 85° C. on the orbit shaker. An additional 0.1 mL of EtOAc was added. After 4.5 hr, the solvent was removed in vacuo. The resulting material was diluted with water and extracted three times with EtOAc. The combined organics were washed with brine, dried over NaSO4, decanted and concentrated to give crude yellow-brown oil. This material was diluted with 4 mL CH2Cl2 and cooled to 0° C. with an ice bath. After 15 min, 4 ml trifluoroacetic acid was added and the reaction was stirred at rt. After 2 hr the solvent was removed in vacuo to give crude oil after a NaOH workup. The crude material was purified by column chromatography (0.5/3.5/96 NH4OH/CH3OH/CH2Cl2) to give 105 mg colorless oil (60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[C:20]#[N:21]>CN(C)C=O.N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][C:18]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=2[C:20]#[N:21])=[CH:5][CH:4]=1
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(OCc2cccc([N+](=O)[O-])c2C#N)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.4 %

Procedure:
4-Methoxyphenol (0.1 g, 0.83 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.2 g, 0.83 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried. Purification by silica gel chromatography (50% hexanes in dichloromethane) yielded 100 mg of 2-(4-methoxyphenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19])=[O:8].[CH2:20](Cl)[CH:21]=[CH2:22]>CN(C)C=O>[CH2:22]([N:9]([CH:7]=[O:8])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19])[CH:21]=[CH2:20]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC=O
Reactant: C=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN(C=O)c1ccc([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
155 g of potassium carbonate were introduced into 500 ml of dimethylformamide. 50 g (0.28 mol) of N-formyl-2-methyl-4-nitroaniline were added to this mixture to give an orange solution, which became blood-red after 128.6 g (136.8 ml, 1.68 mol) of allyl chloride were added. The resultant reaction mixture was stirred overnight and subsequently poured into 1.5 1 of ice water. The crude product which deposited was extracted twice from the aqueous phase with 400 ml of dichloromethane in each case. The two combined dichloromethane phases were washed three times with 500 ml of water in each case, subsequently dried over sodium sulfate and then evaporated, to give 58.3 g of N-allyl-N-formyl-2-methyl-4-nitroaniline (yield: 95%) as an orange oil which crystallized in the refrigerator. The product had a melting point of 56° C. and the following physical/chemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=O)=[N:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[NH2:29][C:30]1[C:35]([NH2:36])=[CH:34][C:33]([CH:37]2[CH2:41][CH2:40][CH2:39][N:38]2C(OC(C)(C)C)=O)=[C:32]([O:49][C:50]2[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][CH:51]=2)[CH:31]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:36][C:35]3[CH:34]=[C:33]([CH:37]4[CH2:41][CH2:40][CH2:39][NH:38]4)[C:32]([O:49][C:50]4[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][CH:51]=4)=[CH:31][C:30]=3[N:29]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(N)c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccc(Br)cn4)[nH]c3cc2C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
220 mg of 5-bromopyridine-2-carboxylic acid and 260 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added in order to a pyridine (10 ml) solution of 500 mg of t-butyl 2-(4,5-diamino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidine-1-carboxylate, and the reaction liquid was stirred at room temperature for 12 hours. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, the resulting residue was dissolved in 10 ml of trifluoroacetic acid, and the reaction liquid was heated under reflux for 3 hours. After cooled, the reaction liquid was distilled under reduced pressure, and the resulting residue was diluted with chloroform, and then made basic with aqueous saturated sodium bicarbonate added thereto. Then, the organic layer was washed with saturated saline and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol/aqueous ammonia=50/1/0.1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5](N)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.S(=O)(=O)(O)[OH:12].[OH-].[Na+]>>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:12])[C:4]=2[CH:3]=[N:2]1
Reactant: Nc1cccc2[nH]ncc12
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc2[nH]ncc12

Procedure:
500 mg (375 mmol) of 1H-indazol-4-ylamine (prepared according to J. Chem. Soc. 1955, 2412, 2419) are stirred in 10% strength sulfuric acid at 180° C. in an autoclave at intrinsic pressure overnight. The reaction solution is cooled to room temperature and neutralized with 1N sodium hydroxide solution, and the salts are filtered off. The filtrate is concentrated to dryness.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].[OH-:37].[K+]>C(#N)C.CCOC(C)=O>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: OCCCCCCCCCCCCCC#CCOC1CCCCO1
Reactant: [OH-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)CCCCCCCCCCCCC#CCOC1CCCCO1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
RuCl3 (10 mg) and potassium persulphate (2.8 g, 10.2 mmol) were added to a solution of 16-(tetrahydro-2H-pyran-2-yloxy)hexadec-14-yn-1-ol (1.2 g, 3.55 mmol) in acetonitrile (20 mL). After 10 min, KOH (30 mL of a 2 M soln) was added. After an additional 3 h, the reaction mixture was neutralized to pH 7, diluted with EtOAc (100 mL), and washed with water (3×75 mL). The combined aqueous extracts were back-extracted with EtOAc (3×75 mL). All of the organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by SiO2 column chromotography using 20% EtOAc/hexanes as eluent to give 16-(tetrahydro-2H-pyran-2-yloxy)hexadec-14-ynoic acid (1.05 g, 91%) as a colorless oil that was used without further purification. TLC: 50% EtOAc/hexanes, Rf≈0.35. Lit. ref.: R. S. Varma; M. Hogan Tetrahedron Lett. 1992: 33, 719.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:26][O:25][C:24]3[CH:27]=[C:28]4[C:32](=[CH:33][C:23]1=3)[CH2:31][CH2:30][O:29]4)[C:5](=[O:22])[N:6]2[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=[O:13].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:61]1[CH:66]=[C:65](B(O)O)[CH:64]=[N:63][CH:62]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:12](=[O:13])[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([C:65]3[CH:66]=[N:61][CH:62]=[N:63][CH:64]=3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:26][O:25][C:24]3[CH:27]=[C:28]4[C:32](=[CH:33][C:23]2=3)[CH2:31][CH2:30][O:29]4)[C:5]1=[O:22]
Reactant: O=C(CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Br)cccc21)Nc1ccccc1F
Reactant: OB(O)c1cncnc1
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: O=C(CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(-c3cncnc3)cccc21)Nc1ccccc1F

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 2-(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidine-5-boronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (53%) as a colorless solid: mp 229-230° C.; 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.26-8.15 (m, 3H), 7.98 (s, 1H), 7.41 (t, 1H), 7.15-7.05 (m, 4H), 6.89 (d, 1H), 6.68 (s, 1H), 6.06 (s, 1H), 4.81-4.76 (m, 2H), 4.59-4.42 (m, 4H), 3.00 (t, 2H); 13C NMR (75 MHz, CDCl3) δ 178.2, 164.4, 162.5, 161.0, 157.0, 155.8, 141.8, 132.6, 131.1, 129.4, 125.8, 125.5, 125.4, 125.2, 125.1, 124.7, 121.9, 120.6, 119.9, 118.7, 115.1, 114.8, 109.5, 93.4, 79.0, 72.4, 57.8, 44.9, 28.9; MS (ES+) m/z 509.5 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]2[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:33]=2[N:34]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]2[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([NH:39][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=3)[CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5cccc(OC(F)(F)F)c5)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)-benzothiazol-6-yl]-3-trifluoromethoxybenzamide was prepared from 3-trifluoromethoxybenzoyl chloride (19 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 48 mg, 88 μmol, 78%). LC/ESI-MS: m/z=542 [M+H]+; m/z=540 [M−H]−; Rt=3.72 min.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]([CH3:19])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1)(C(C)(C)C)(C)C.O1CCCC1.C(O)(=O)C>O>[OH:8][CH2:9][C:10]1[N:11]([CH3:19])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1
Reactant: Cn1c(CO[Si](C)(C)C(C)(C)C)nc2cnccc21
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(CO)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
A solution of 3.00 g of 2-t-butyldimethylsilyloxymethyl-1-methyl-1H-imidazo[4,5-c]pyridine (prepared as described in Preparation 72) in 60 ml of a 1:1:1 by volume mixture of tetrahydrofuran, acetic acid and water was stirred at room temperature for 1 hour and then at 60° C. for 5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate and then concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.97 g of the title compound, melting at 285-290° C.