Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:23][CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(NC1CCCc2ccccc21)c1ccc([N+](=O)[O-])cc1
Yield: 90 %

Procedure:
A solution of 18.9 g of 4-nitrobenzoyl chloride in 100 ml of tetrahydrofuran was added rapidly to a solution of 10.0 g of 1,2,3,4-tetrahydro-1-naphthylamine in 200 ml of tetrahydrofuran and 180 ml of 20% aqueous potassium carbonate. The reaction mixture was stirred vigorously and heated at reflux for 2 hours. After cooling, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water, 1N hydrochloric acid, water, and a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resulting solid was recrystallized from benzene to afford the title intermediate in 90% yield as a colorless solid, m.p. 156°-157° C.
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:5]([OH:11])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1.[H][H].C([Li])(C)(C)C.CN([CH:22]=[O:23])C>C1COCC1>[Cl:10][C:8]1[CH:9]=[C:4]([CH:22]=[O:23])[C:5]([OH:11])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: [H][H]
Reactant: Oc1ncc(Cl)cc1Br
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)cnc1O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 38.1 %

Procedure:
To a suspension of NaH (0.22 g, 60% dispersion in oil, 5.5 mmol) in anhydrous THF (20 mL) under argon atmosphere was added 3-bromo-5-chloro-pyridin-2-ol (1.03 g, 5 mmol) in a portionwise manner. After hydrogen evolution had ceased the mixture was cooled to −78° C. and tert-butyl lithium (10 mmol) was added at such a rate that the temperature did not rise above −65° C. The mixture was stirred for 5 mins then DMF (15 mmol) was added keeping the temperature below −50° C. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (300 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>CN1CCCC1=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])=[O:14])[N:3]=2)=[CH:24][CH:23]=1
Reactant: C[C@H](NC(=O)c1nc(Br)c2ccccc2c1O)C(=O)O
Reactant: Sc1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: C[C@H](NC(=O)c1nc(Sc2ccc(Cl)cc2)c2ccccc2c1O)C(=O)O
Temperature: 210 °C
Yield: 6.1 %

Procedure:
To a solution of 250 mg of (S)-2-{[1-bromo-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid in 0.7 ml of 1-methyl-2-pyrrolidinone was added 433 mg of 4-chlorobenzenethiol. The solution was heated at 210° C. for 30 min. using a CEM Discover microwave reactor. The solution was concentrated under vacuum. The resultant residue was crystallized from methanol to yield 18 mg of a tan solid; MS (−): m/z 401.10 (M−1)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:19]1[CH2:27][CH2:26][CH2:25][CH:21]([C:22]([OH:24])=[O:23])[CH2:20]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([N:19]3[CH2:27][CH2:26][CH2:25][CH:21]([C:22]([OH:24])=[O:23])[CH2:20]3)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)C1CCCNC1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCCC(C(=O)O)C3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (106.5 mg; 0.35 mmol; 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). Nipecotic acid (Emkachem)(42.8 mg; 0.33 mmol; 1 eq.) and triethylamine (97 μl; 0.70 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, filtrated, affording Compound (21) as a brown solid (31 mg; 23%). M− (ESI): 393; M+ (ESI): 395. HPLC (method A), Rt: 2.60 min (purity: 95.4%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:12]([N:34]3[CH2:35][CH2:36][N:31]([C:28]4[S:29][CH:30]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:27]=4)[CH2:32][CH2:33]3)=[O:19])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: Cc1nc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2o1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(NC(=O)N3CCN(c4nc(-c5ccccc5)cs4)CC3)cc2o1

Procedure:
A solution of 2,2,2-trichloroethyl (2-methyl-1,3-benzoxazol-6-yl)carbamate (200 mg, 0.618 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (152 mg, 0.618 mmol), diisopropylethylamine (0.215 ml, 1.24 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The solid was recrystallized from ethyl acetate to give 100 mg (38.6%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>CS(C)=O.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CNC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)C(=O)c1ccc(Br)nc1
Reaction time: 24 h
Yield: 46 %

Procedure:
N,N′-Carbonyldiimidazole (1 g, 6.17 mmol) was added to a solution of 6-bromonicotinic acid (1 g, 4.95 mmol) in dimethylsulfoxide (4.16 mL) and the mixture was stirred for 24 hours. Dimethylamine (40% in water, 8.3 mL, 37 mmol) was then added and the mixture was stirred for a further 18 hours. The reaction mixture was then diluted with dichloromethane (20 mL) and washed with water (10 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to afford the title compound in 46% yield, 520 mg.
Reaction SMILES: Cl(O)(=O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:21]=[CH:20][C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][C:13]([CH2:22][NH2:23])=[N:12]3)[N:9]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[OH2:35]>N1C=CC=CC=1>[S:30]([NH:23][CH2:22][C:13]1[CH:14]=[CH:15][C:16]2[C:11](=[C:10]3[C:19](=[CH:18][CH:17]=2)[CH:20]=[CH:21][C:8]([CH2:7][NH:6][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:31])=[O:35])=[N:9]3)[N:12]=1)([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: O
Reactant: NCc1ccc2ccc3ccc(CN)nc3c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCc2ccc3ccc4ccc(CNS(=O)(=O)c5ccc(C)cc5)nc4c3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,9-Bis(aminomethyl)-1,10-phenanthroline perchlorate (a) (1.76 g, 4 mmol) synthesized in Example 1(1) was dissolved in pyridine (20 ml). p-Toluenesulfonyl chloride (1.6 g, 8 mmol) was added to the solution with cooling using an ice bath, then the reaction mixture was stirred at room temperature for 3 hours. The resulting solution was poured into water (200 ml) and extracted with chloroform (200 ml). The chloroform layer was chromatographed on a silica gel column using chloroform/methanol as eluent to give the desired 2,9-bis(tosylaminomethyl)-1,10-phenanthroline (b) (yield=1.87 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29].C([O-])(=O)C.[Na+].[CH:36]([NH2:38])=O.C(OC(=O)C)(=O)C>[Cu](Cl)Cl.C(OCCCC)(=O)C>[C:36]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29])#[N:38]
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: NC=O
Agent: Cl[Cu]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
2-Bromo-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene (2.4 parts), copper (II) chloride (0.67 parts), anhydrous sodium acetate (1.2 parts), formamide (1.8 parts), acetic anhydride (2.0 parts) and n-butyl acetate (44 parts) are mixed together and heated, with stirring, to 110° C. during 15 minutes. The temperature is maintained for 5 hours after which time the reaction is complete. The mixture is cooled to room temperature and poured into petroleum-ether (boiling range 60-80°) (400 parts). The precipitate is collected, washed with petroleum-ether (100 parts) and dried. 2-Cyano-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene is obtained in 96% yield.
Reaction SMILES: [Cl-].[Cl:2]C1C=CC(C[N+]2C=CN3C=CC=C3C=2)=CC=1.[Br-].[Cl:20]C1C=CC(C[N+]2N3C=CC=CC3=CC=2)=CC=1.[Br-].[Cl:38][C:39]1[CH:58]=[CH:57][C:42]([CH2:43][N+:44]2[CH:56]=[C:47]3[C:48]4[C:53]([CH:54]=[CH:55][N:46]3[CH:45]=2)=[CH:52][CH:51]=[CH:50][CH:49]=4)=[CH:41][CH:40]=1>>[Cl-:2].[Cl:20][C:41]1[CH:40]=[C:39]([Cl:38])[CH:58]=[CH:57][C:42]=1[CH2:43][N+:44]1[C:54]2[C:55](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:46]2[CH:45]=[CH:49][CH:48]=[C:47]2[CH:56]=1
Reactant: Clc1ccc(C[n+]2cc3c4ccccc4ccn3c2)cc1
Reactant: Clc1ccc(C[n+]2ccn3cccc3c2)cc1
Reactant: Clc1ccc(C[n+]2ccc3ccccn32)cc1
Agent: [Br-]
Agent: [Cl-]
Product: Clc1ccc(C[n+]2cc3cccn3c3ccccc32)c(Cl)c1

Procedure:
2-(4-chlorobenzyl)pyrrolo[1,2-a]pyrazinium chloride; 1-(4-chlorobenzyl)pyrazolo[1,5-a]pyridinium bromide; 1-(2,4-dichlorobenzyl)-1H-imidazo[2,1-a]isoquinolinium chloride; 1-(4-chlorobenzyl)-1H-imidazo[2,1-a]isoquinolinium bromide; and 2-(4-chlorobenzyl)imidazo[5,1-a]isoquinolinium bromide.
Reaction SMILES: [Br:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12]Br)([CH2:5]3)[CH2:3]1)[CH2:9]2.[I:14][C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][N:17]4[CH:16]=[C:15]([I:14])[CH:19]=[N:18]4)([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: Ic1cn[nH]c1
Reactant: BrCC12CC3CC(CC(Br)(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: BrC12CC3CC(C1)CC(Cn1cc(I)cn1)(C3)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-adamantane (1.0 g) and 4-iodopyrazole (0.63 g) in N,N-dimethylformamide (10 mL) was cooled to 0° C. To this solution was added 60% sodium hydride (0.20 g). The solution was stirred at 65° C. overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed three times with water, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C>[S:5]1[CH:6]=[CH:2][C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]1=2.[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[S:5][CH:6]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Brc1csc2ccccc12
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: c1ccc(COc2ccc(Oc3csc4ccccc34)cc2)cc1
Product: c1ccc2sccc2c1
Yield: 35 %

Procedure:
To a solution of 3-bromo-benzo[b]thiophene (69.62 g, 0.325 mol) in 55 mL of anhydrous collidine under N2 was added 4-benzyloxyphenol (97.6 g, 0.488 mol) and cuprous oxide (23.3 g, 0.163 mol). The mixture was heated to reflux for 24 hours. Upon cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and the crude mixture filtered through a pad of CELITE® (Aldrich, Milwaukee, Wis.) to remove inorganic salts. The filtrate was washed with 1 N hydrochloric acid (3×150 mL). The organic was dried with sodium sulfate and concentrated in vacuc to a liquid. Thianaphthene was removed by distillation (10 mm Hg, 115-120° C.). The remainder of the material was chromatographed (silicon dioxide, hexanes: ethyl acetate 85:15) to provide 12.2 g of benzo[b]thiophene and 12.95 g (35% based on recovered starting material) of 3-(4-benzyloxyphenoxy)benzo[b]thiophene as an off-white solid. mp 84-86° C. 1H NMR (CDCl3) d 7.91-7.83 (m, 2H), 7.47-7.34 (m, 7H), 7.04 (q, JAB =9.0 Hz, 4H), 6.47 (s, 1H), 5.07 (s, 2H).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].CN(C)C=O.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[CH2:20]C(O)=O>C1(C)C=CC=CC=1>[Cl:6][CH2:1][C:2](=[O:3])[CH2:20][C:14]1[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:19]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(CCl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
50 ml of oxalyl chloride and 0.5 ml of dimethylformamide were added to a stirred suspension of 5.12 g of (2,6-dichlorophenyl)acetic acid in 120 ml of toluene. The mixture was stirred at room temperature for 2.5 hours and then evaporated to dryness. The residue was suspended in 40 ml of diethyl ether and the suspension was added gradually to 250 ml of a 0.25M solution of diazomethane in diethyl ether. The mixture was stirred at room temperature for 2 hours and then cooled to 0° C. Hydrogen chloride was then bubbled through the mixture for 10 minutes. 300 ml of water were added to the mixture and the phases were separated. The organic phase was washed with 200 ml of saturated sodium hydrogen carbonate solution and 300 ml of water, dried over anhydrous sodium sulphate and evaporated to give 6.04 g of 1-chloro-3-(2,6-dichlorophenyl)-2-propanone in form of a white solid. This solid was taken up in 21 ml of chloroform, 7.19 g of triphenylphosphine were added and the solution was stirred and heated under reflux for 6 hours. The mixture was cooled and poured into 200 ml of diethyl ether. The resulting precipitate was collected, washed with diethyl ether and dried to give 8.605 g of [3-(2,6-dichlorophenyl)-2-oxopropyl]triphenylphosphonium chloride in the form of a white solid. This solid was taken up in 1.5 l of warm water and the mixture was filtered. The filtrate was stirred while 12.5 ml of 5% sodium hydroxide solution were added. The mixture was extracted twice with 600 ml of diethyl ether each time and the combined extracts were washed with 1 l of water, dried over anhydrous sodium sulphate and evaporated. The residue was recrystallized from 150 ml of diethyl ether and yielded 4.286 g of [3-(2,6-dichlorophenyl)-2-oxopropylidene]triphenylphorphorane of melting point 98°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([O:27]C)=[O:26])[S:24][C:17]=12)=[O:11].[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([OH:27])=[O:26])[S:24][C:17]=12)=[O:11]
Reactant: COC(=O)c1cc2nccc(Oc3cccc(C(=O)Nc4cc(C)ccc4F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc4cc(C(=O)O)sc34)c2)c1
Reaction time: 2.5 h

Procedure:
To a stirred solution of methyl 7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate (170 mg, 0.39 mmol) in 15 ml of MeOH was added 1 ml of 1M NaOH. Reaction was complete within 2.5 hours. The mixture was poured into 100 ml of water and acidified with 2M HCl to pH=5 with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid as white solid. Yield: 150 mg, 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH:20]=[C:19]([C:21]([NH2:23])=[O:22])[C:18]([C:24]([F:27])([F:26])[F:25])=[N:17]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:23][C:21]([C:19]2[C:18]([C:24]([F:25])([F:27])[F:26])=[N:17][N:16]([CH3:15])[CH:20]=2)=[O:22])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(N)=O)c(C(F)(F)F)n1
Reactant: O=C1CCCCC1c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)NC2=C(c3ccc(Cl)cc3)CCCC2)c(C(F)(F)F)n1
Yield: 57.4 %

Procedure:
0.521 g 2-(4-chlorophenyl)-cyclohexanone (prepared as described in J. Org. Chem. 70, 2005, page 2967) and 0.482 g 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid amide were suspended with 5 mg p-toluenesulfonic acid in 20 ml toluene and heated to reflux temperature of the solvent for 24 hours under continuos removal of water. The reaction mixture was washed with 5% sodium bicarbonate and water, dried and the solvent was removed under vacuum. The reaction product was purified by chromatography on a silica gel column (eluent: ethylacetate:hexane 1:1). 0.55 g 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(4-chlorophenyl)-cyclohex-1-enyl]-amide was obtained in the form of crystals (m.p. 145-148° C.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.[CH:18]([C:21]1([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:23][O:22]1)([CH3:20])[CH3:19]>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:23][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([OH:22])[CH:18]([CH3:20])[CH3:19])[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(C)C1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of sodium hydride (0.261 g, 50-60%) in dry DMF (5 mL) at 0° C. was added 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (0.3 g). The reaction mixture was stirred at RT for 30 min. To the reaction mixture was added 4-(2-isopropyloxiran-2-yl)pyridine (0.288 g in 2 mL DMF) at RT. After 12 h stirring, the reaction mixture was diluted with ice-water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was triturated with diethyl ether to obtain pure product, 90 mg). 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.30 (d, 2H), 7.30 (m, 3H), 7.10 (d, 1H), 6.82 (d, 1H), 4.50 (m, 2H), 4.22 (m, 2H), 3.42 (m, 1H), 3.30 (m, 2H), 2.80 (s, 3H), 2.62 (m, 1H), 1.78 (m, 1H), 1.15 (d, 3H), 0.6 (d, 3H).
Reaction SMILES: [NH:1]=[C:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11])[CH2:3][O:4][CH3:5].Cl.Cl[O-].[Na+]>CO>[CH3:18][O:17][C:16]1[C:7]2[N:6]=[C:2]([CH2:3][O:4][CH3:5])[NH:1][C:8]=2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COCC(=N)Nc1cc(C(=O)OC)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: COCc1nc2c(OC)ccc(C(=O)OC)c2[nH]1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution of methyl 3-(1-imino-2-methoxy-ethylamino)-4-methoxybenzoate [15.7 g, Reference Example 4(a)] in methanol (150 ml) was treated with 1M hydrochloric acid (62.6 ml) then with sodium hypochlorite solution (32.3 ml, 13%). Further aliquots of sodium hypochlorite solution were added until all the starting material was consumed. The solution containing methyl 3-(1-chloroimino-2-methoxy-ethylamino)-4-methoxybenzoate was treated with a saturated solution of sodium carbonate (8.62 g) in water. The mixture was then refluxed for 1 hour, then cooled to room temperature, then diluted with water and then extracted with chloroform. The chloroform extract was washed with brine, dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) then with a mixture of ethyl acetate and hexane (6:1, v/v) to give the title compound (13.0 g) as a solid. M+250. NMR (CDCl3): δ 3.48(s, 3H), 3.98(s, 3H), 4.10(s, 3H), 4.78(s, 2H), 6.70(d, J=8 Hz, 1H), 7.87(d, J=8 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=[N:3]1.[F:9][C:10]1[CH:38]=[CH:37][CH:36]=[CH:35][C:11]=1[CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C:15]([C:22]2[N:23]=[C:24](I)[C:25]3[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[NH:28][C:26]=3[N:27]=2)=[N:14]1>CN1CCCC1=O>[F:9][C:10]1[CH:38]=[CH:37][CH:36]=[CH:35][C:11]=1[CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C:15]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[C:25]3[C:30]([CH3:31])([CH3:32])[C:29](=[O:33])[NH:28][C:26]=3[N:27]=2)=[N:14]1
Reactant: Cn1nccc1CN
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: CN1CCCC1=O
Product: Cn1nccc1CNc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C(C)(C)C(=O)N2

Procedure:
111.1 mg (1.0 mmol) of 1-(1-methyl-1H-pyrazol-5-yl)methanamine was put in a vial of a microwave reactor block and a solution of 51.4 mg (100 μmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) in 0.6 ml of 1-methyl-2-pyrrolidinone was added. Then the reactor block was sealed and was irradiated for 6 h with microwaves, in order to reach and maintain a temperature of the mixture of 170° C. After cooling, it was purified by preparative LC-MS (method 6). The product-containing fractions were concentrated by evaporation by means of a centrifugal dryer under vacuum. The residue of the individual fractions was in each case dissolved in 0.6 ml DMSO and combined. Then the solvent was evaporated completely in the centrifugal dryer. 32.7 mg (61% of theor.) of the target product was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH3:13])([CH3:12])[C@@H:5]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[NH2:6].C(N(CC)CC)C.S=[C:22]1[CH2:26][S:25][C:24](=[O:27])[NH:23]1>C(O)C>[CH3:2][O:3][C:4]([CH3:13])([CH3:12])[C@@H:5]([C:7]([N:9]([CH3:10])[CH3:11])=[O:8])[NH:6][C:22]1[CH2:26][S:25][C:24](=[O:27])[N:23]=1
Reactant: O=C1NC(=S)CS1
Reactant: COC(C)(C)[C@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(C)(C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing 3-methoxy-N,N-dimethyl-L-valinamide hydrochloride obtained in B) (697 mg) and triethylamine (810 mg) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (533 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (560 mg).