Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]1[N:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[N:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN1Cc2cc(-c3ccc(C(F)(F)F)nn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 102.2 %

Procedure:
A mixture of (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (350 mg, 0.80 mmol, prepared in Step F in Example 26), 3-chloro-6-(trifluoromethyl)pyridazine (176 mg, 0.96 mmol) and cesium carbonate (786 mg, 2.41 mmol), in water (0.8 mL) and N,N-dimethylformamide (4 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (33 mg, 0.04 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to give (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (373 mg, 28%) as a brown oil: ESI MS m/z 456 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.FC(F)(F)S(O[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH2:18][C@H:19]([N:26]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][O:21]2)(=O)=O>>[CH2:34]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:19]1[CH2:18][C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[O:21][CH2:20]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: OB(O)c1cncnc1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4cncnc4)c3C2)cc1
Yield: 78 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 78% yield, starting from 5-pyrimidinylboronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro -2H-chromen-5-yl trifluoromethanesulfonate; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1 H), 8.86 (s, 2 H), 7.24-7.34 (m, 8 H), 7.15-7.23 (m, 3 H), 6.86 (d, 2 H), 4.32-4.38 (m, 1 H), 4.00-4.08 (m, 1 H), 3.61-3.75 (m, 4 H), 3.05-3.14 (m, 1 H), 2.93-3.03 (m, 1 H), 2.46-2.54 (m, 1 H, obscured by DSMO); MS (ESI) m/z 408[M+H+].
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:10](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:8][C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CC(C#N)=Cc1ccccc1
Reactant: N=C(N)c1ccncc1
Product: NCc1c(N)nc(-c2ccncc2)nc1-c1ccccc1

Procedure:
The title compound, MS: m/e=278.0 (M+H+), was prepared from isonicotinamidine and 2-benzylidene-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[S:17][C:18]([NH2:20])=[N:19][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21]I>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[S:17][C:18]([NH:20][CH3:21])=[N:19][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C

Procedure:
104 mg 60% sodium hydrid was added to 700 mg 2-amino-4,5,7,8-tetrahydro-thiazolo (4,5-d) azepine-6-carboxylic acid tert-butyl ester in 1.5 mL THF at 0° C. Then, 162 μL methyliodide was dropped to the mixture. The reaction was stirred over night at RT. The solvent was removed and the residue was purified by HPLC and 121 mg of the desired product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]([O:27][C:28](=[O:35])[C@@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH2:30])[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[CH2:25]([O:27][C:28](=[O:35])[C@@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH:30][C:21](=[O:22])[C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH3:26]
Reactant: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: CCOC(=O)[C@H](N)CCSC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCSC)NC(=O)[C@@H](Cc1cn(C)c2ccccc12)NC(=O)OC(C)(C)C
Yield: 101.2 %

Procedure:
To a suspension of N-tert-butoxycarbonyl-1-methyl-D-tryptophan (1.60 g) and hydrochloric acid salt of D-methionine ethyl ester (1.06 g) in dry methylene chloride (30 ml) which was cooled on an ice bath and stirred was added a solution of triethylamine (0.50 g) in dry methylene chloride (10 ml). The mixture was stirred for 30 minutes, and to the mixture was added a solution of N,N'-dicyclohexylcarbodiimide (1.04 g) in dry methylene chloride (10 ml). The resulting mixture was stirred overnight. After removal of the solvent, crude residue was taken up with a mixture of ethyl acetate and water, filtered, and organic layer was washed with 10% hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to give crystalline N-tert-butoxycarbonyl-1-methyl-D-tryptophyl-D-methionine ethyl ester (2.43 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](N1C=CN=C1)([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)(=[O:10])=[O:9].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[N:11]1([S:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:10])=[O:9])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=S(=O)(Oc1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a solution of phenol (400 mg, 4.3 mmol) in THF (25 mL) was added 1,1′-sulfonyldiimidazole (1.0 g, 5.1 mmol) and Cs2CO3 (2.8 g, 8.5 mmol). The mixture was stirred at ambient temperature for 16 h. The solvent was removed and the residue was purified by silica gel chromatography to yield the title compound (580 mg, 60%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:10](=O)[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]1)C>O.C(OCC)C>[CH:18]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][CH3:10])[CH2:17][CH2:16]1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)NC1CCN(C(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CNC1CCN(C(C)C)CC1
Temperature: 25 °C

Procedure:
100 ml absolute diethyl ether were placed in a dry three-necked flask equipped with a condenser. 4.35 g LiAlH4 (6 equiv.) were added and the mixture was stirred at room temperature under an argon atmosphere. Carefully, 4.10 g (19.13 mmol) (1-isopropyl-piperidin-4-yl)-carbamic acid ethyl ester were added portionwise and the resulting mixture was refluxed for 7 h. Since the conversion was not complete, 1.00 g (≈1.4 equiv.) LiAlH4 was added and the mixture was refluxed for further 2 h. The reaction mixture was cooled and, carefully, 14 ml water were added dropwise over a 20-minute period. The mixture was diluted with 40 ml water and 50 ml diethyl ether. The phases were separated. The aqueous phase (suspension) was treated with a 10% NaOH-solution and washed twice with 100 ml diethyl ether. The organic phases were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was obtained as a colorless oil. Yield: 2.91 g MS (ES+): m/e=157.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][C:15]3([CH3:20])[CH3:19])[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH3:33][O:32][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][C:15]3([CH3:20])[CH3:19])[C:6]=2[N:21]=1)[C:27]([OH:29])=[O:28]
Reactant: CN1C(=O)CCN(C2CCCC2(C)C)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1(C)C)CCC(=O)N2C
Yield: 66 %

Procedure:
A mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-5-methyl-9-(2,2-dimethyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-59), 0.06 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.087 g of (rac)-3-methoxy-4-[5-methyl-9-(2,2-dimethyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-59a) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:30][CH2:29]1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCC2CC(c3cccc([N+](=O)[O-])c3)=NO2)CC1
Yield: 84.5 %

Procedure:
3-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl] propanal (23.8 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine. (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 31.2 mg (78.6%) of the target compound was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[H][H]>[Pd].CO>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: c1ccc(CN2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: c1cc(C2=NCCO2)ccc1OCCCN1CCNCC1
Yield: 100 %

Procedure:
A mixture of 56 parts of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]-4-(phenylmethyl)piperazine and 480 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 46.9 parts (100%) of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]piperazine as a residue (int. 16).
Reaction SMILES: CN([CH2:4][CH:5]=[N:6][C:7](=O)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.O.[NH2:18][NH2:19]>C(O)(=O)C>[CH3:4][C:5]1[N:6]=[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:19][N:18]=1
Reactant: CN(C)CC=NC(=O)C=Cc1ccccc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c(/C=C/c2ccccc2)n1
Temperature: 90 °C
Yield: 96 %

Procedure:
N-[(Dimethylamino)ethylidene]-cinnamamide (2.0 g, 9.0 mmol) was added to a solution of hydrazine hydrate (0.59 mL, 10 mmol) and acetic acid (25 mL). The mixture was heated to 90° C. for 3 h, cooled, and concentrated in vacuo. The resulting material was basified (pH 8) with solid K2CO3, and partitioned between ethyl acetate and water. The organics were dried over Na2SO4 and concentrated in vacuo. The resultant material was purified by flash column chromatography on silica eluting with 1:2 hexane-ethyl acetate to afford 3-methyl-5-[(E)-2-phenylethenyl]-1H-1,2,4-triazole (1.6 g, 96% yield) as a white powder. M.p. 131–134° C. 1H NMR (CDCl3,300 MHz) δ 7.68 (d, J=16 Hz, 0.3H), 7.59 (d, J=16 Hz, 0.7H), 7.49 (m, 2H), 7.32 (m, 3H), 7.05 (d, J=16 Hz, 1H), 6.49 (d, J=16 Hz, 0.4H), 6.21 (br s, 0.3H), 5.88 (br s, 0.3H), 2.53 (s, 3H). MS (EI ionization) 184 (M+−H).
Reaction SMILES: C(C1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=3[S:8](=[O:21])(=[O:20])[C:7]=2[CH:22]=1)#N.S(=O)(=O)(O)O.[C:28]([OH:31])(=[O:30])[CH3:29]>>[N+:17]([C:14]1[CH:15]=[CH:16][C:9]2[S:8](=[O:21])(=[O:20])[C:7]3[CH:22]=[C:29]([C:28]([OH:31])=[O:30])[CH:4]=[CH:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=1)([O-:19])=[O:18]
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C=C2
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C=C2

Procedure:
400 Mg. 3-cyano-8-nitrodibenzo[b,f]thiepin-5,5-dioxide is refluxed in 5 cc. acetic acid and 5 cc. 50% aqueous sulfuric acid for 24 hours. The mixture is cooled down, the crystallized material is filtered, washed with water, dried at 135° C. in vacuum to yield 345 mg. (81.2%) acid, m.p. 310°-312° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([OH:14])=O)[CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:26]1([S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[O:40][CH3:41])=[CH:34][C:33]=2[C@H:43]2[CH2:47][CH2:46][CH2:45][NH:44]2)(=[O:31])=[O:30])[CH2:28][CH2:27]1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][C@H:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([N:44]2[CH2:45][CH2:46][CH2:47][C@@H:43]2[C:33]2[CH:34]=[C:35]([NH:38][C:39](=[O:42])[O:40][CH3:41])[CH:36]=[CH:37][C:32]=2[S:29]([CH:26]2[CH2:27][CH2:28]2)(=[O:31])=[O:30])=[O:14])[CH:9]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)Nc1ccc(S(=O)(=O)C2CC2)c([C@H]2CCCN2)c1
Reactant: COc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Agent: Cl
Product: COC(=O)Nc1ccc(S(=O)(=O)C2CC2)c([C@H]2CCCN2C(=O)[C@H](Nc2cc(C(N)=O)ccc2F)c2ccc(F)c(OC)c2)c1

Procedure:
Example 87 was prepared according to the general coupling condition using 27A and 85J. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.00-1.08 (m, 2H) 1.13 (m, 1H) 1.36-1.43 (m, 1H) 1.73 (m, 1H) 2.02-2.14 (m, 2H) 2.52 (m, 1H) 3.22-3.29 (m, 1H) 3.71 (s, 6H) 4.16 (ddd, J=10.22, 6.81, 6.70 Hz, 1H) 5.46 (s, 1H) 5.88 (dd, J=7.91, 5.27 Hz, 1H) 6.98-7.06 (m, 4H) 7.08-7.15 (m, 3H) 7.32 (dd, J=8.35, 1.76 Hz, 1H) 7.68 (d, J=9.23 Hz, 1H) 9.44 (s, 1H), LC-MS 643 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)([CH3:20])[CH3:19].O>CN(C=O)C>[CH:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(C(C)C)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a suspension of sodium hydride (a 60% liquid paraffin dispersion, 5.92 g, 148 mmol) in DMF (150 mL) was added triethyl 2-phosphonopropionate (35.0 g, 148 mmol) at 0° C., and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added 4-isopropylbenzaldehyde (20.0 g, 135 mmol), and the mixture was stirred at room temperature 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 30.1 g (yield 96%) of the oily title compound.
Reaction SMILES: F[C:2]1[N:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:15]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+]>CN1C(=O)CCC1>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[N:11][C:2]([O:35][CH2:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=[CH:17][CH:16]=4)[CH2:26][CH2:27]3)=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[CH2:7]1
Reactant: OCCCCN1CCN(c2cccc3ccccc23)CC1
Reactant: CC1(C)CC(=O)Nc2nc(F)ccc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC1(C)CC(=O)Nc2nc(OCCCCN3CCN(c4cccc5ccccc45)CC3)ccc21
Temperature: 70 °C
Yield: 48 %

Procedure:
7-Fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (247 mg, 1.272 mmol), 4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (365 mg, 1.285 mmol) and sodium t-butoxide (367 mg, 3.82 mmol) were combined in a dried flask 3 necked flask under N2. NMP was added and the solution was heated in an oil bath to 70° C. for 4 hours. The reaction was cooled to room temperature and poured into ice water. The solid that was collected was slurried in CH2Cl2 and ethyl acetate and purified by liquid chromatography (MPLC, gradient of 100% CH2Cl2 to 100% ethyl acetate) to give the title compound as a foam (280 mg, 0.610 mmol, 48%). MS: APCI: M+1: 459.2 (Exact Mass: 458.27).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[S:12])[C:6]=2[CH:5]=[CH:4]1.CI.[C:15]([O-])(O)=O.[Na+].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[CH3:15][S:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][NH:3]2
Reactant: S=C1CCCc2[nH]ccc21
Reactant: O=C([O-])O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1cccc2[nH]ccc12
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
NaH (637 mg, 15.87 mmol, 60% dispersion) was added in portions to a solution of 1,5,6,7-tetrahydro-indole-4-thione (2 g, 13.23 mmol) in THF (100 mL) at −20° C. under N2 and stirred for 20 min. MeI (1.3 mL, 19.84 mmol) was added in dry THF (10 mL), and the reaction mixture stirred at −20° C. for 1 h. The reaction mixture was then poured into NaHCO3 (sat'd aq), and the crude product extracted into benzene (˜250 mL). The organic layer was washed with brine, and dried over Na2SO4. To this was added DDQ (3 g, 13.23 mmol), and the mixture stirred at RT for 1 h. The solvent was removed under vacuum, the residue taken up in CHCl3, and the insoluble solid filtered off. The solvent was removed by evaporation to dryness and the solid immobilized on silica gel. The product was purified by column chromatography (0 to 25% EtOAc/hexane) to provide 4-methylsulfanyl-1H-indole (1.2568 g, 58.2% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]([CH2:26][CH3:27])[C:22]([O:24]C)=[O:23])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:12][C:7]=2[CH:6]=1)=[O:4]>[OH-].[K+]>[C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]([CH2:26][CH3:27])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:12][C:7]=2[CH:6]=1)([OH:4])=[O:2]
Reactant: CCC(C(=O)OC)c1cccc(C(=O)c2cc3cc(C(=O)OC)sc3s2)c1
Agent: [K+]
Agent: [OH-]
Product: CCC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Temperature: 20 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
Methyl 2-{3-(5-methoxycarbonyl-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}butyrate (19.1 g), suspended in a mixture of potassium hydroxide pellets (16.6 g), distilled water (75 cc) and ethanol (200 cc), is stirred for 48 hours at a temperature of about 20° C. The resulting solution is diluted with distilled water (300 cc), washed three times with diethyl ether (total 600 cc), decolourizing charcoal (3 g) is added, and the solution is filtered and added dropwise to a 5 N aqueous solution of hydrogen chloride (100 cc) cooled in an ice bath, the rate of addition being regulated in such a way that the temperature of the mixture remains below 10° C. The resulting crystals are filtered off, washed three times with distilled water (total 150 cc) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. 2-{3-(5-Carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}butyric acid (15.8 g), melting at 240° C., is obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C@H:11]1[CH2:16][NH:15][C:14]2[CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[CH:20][C:13]=2[N:12]1[C:31](=[O:33])[CH3:32].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>ClCCl>[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39]([N:15]1[CH2:16][C@H:11]([CH3:10])[N:12]([C:31](=[O:33])[CH3:32])[C:13]2[CH:20]=[N:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:17][C:14]1=2)=[O:40]
Reactant: CC(=O)N1c2cnc(-c3ccc(S(C)(=O)=O)cc3)cc2NC[C@@H]1C
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2cnc(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)c2ccco2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
N,N-Diisopropylethylamine (0.3 mL, 1.718 mmol) was added to a solution of (S)-1-(3-methyl-7-(4-(methylsulfonyl)phenyl)-2,3-dihydropyrido[4,3-b]pyrazin-4(1H)-yl)ethanone (0.004 g, 0.012 mmol) and furan-2-carbonyl chloride (0.2 mL, 2.029 mmol) in dichloromethane (1.0 mL), and the mixture stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-1-(1-(furan-2-carbonyl)-3-methyl-7-(4-(methylsulfonyl)phenyl)-2,3-dihydropyrido[3,4-b]pyrazin-4(1H)-yl)ethanone (0.0038 g, 75%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.13-1.22 (m, 3 H), 2.25 (br s, 1 H), 2.31 (s, 3 H), 3.02 (s, 3 H), 3.88 (br s, 1 H), 4.05-4.18 (m, 1 H), 5.03 (br s, 1 H), 6.55 (dd, J=3.52, 1.76 Hz, 1 H), 7.20-7.26 (m, 1 H), 7.45 (dd, J=1.76, 0.88 Hz, 1 H), 7.78 (s, 1 H), 7.89-8.02 (m, 4 H). MS (ESI, pos. ion) m/z 440.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][Sn](C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([CH3:20])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nc(C)c2snc(C)c2c1O
Temperature: 120 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a solution of 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester (0.338 mmol) in DMF (2.05 mL) was added tetramethyltin (0.67 mmol) and PdCl2(PPh3)2 (0.0338 mmol). The reaction mixture was stirred at 120° C. for 1 h. After cooling to r.t., the mixture was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was washed with brine and water, then dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2, gave the title compound (38.1 mg) as a white solid: MS (m/z) 281.2 (M+1).