Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
Heat a mixture of 4-benzylpiperazine (5.0 mL, 28.8 mmol), 4-flurobenzaldehyde (3.1 mL, 28.8 mmol)) and anhydrous K2CO3 (5.96 g, 43.1 mmol)) in DMF (50 mL) to -150° C. overnight. Cool the mixture to room temperature, partition between water and ether (Et2O), and extract with Et2O. Combine the Et2O extracts, wash with water and brine, dry over anhydrous Na2SO4 and concentrate in vacuo to obtain 7.91 g (98%) of 4-(4-benzylpiperazin-1-yl)benzaldehyde as a yellow solid of sufficient purity to be employed in Example 1 without further purification.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1.[H][H].CO>C(O)C.ClCCl.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12
Reactant: [H][H]
Reactant: CN1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CN1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 64.8 %

Procedure:
To a stirred solution of 9-benzyloxy-2-methyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (444) (60 mg, 0.135 mmol) in ethanol (5 mL), Pd—C (10%, w/w; 10 mg) was added and the reaction mixture was allowed to stir for 1 h in a hydrogen atmosphere at balloon pressure, while silica thin layer chromatography was performed (10% methanol in dichloromethane, Rf=0.3). After completion of the reaction, the reaction mixture was filtered through a celite bed and concentrated. The resulting crude product was triturated with 70% ethyl acetate in hexane to get 9-hydroxy-2-methyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (445) (31 mg, 65%) as a white solid.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Na+].[CH2:14]([O:21][C:22]([NH:24][CH:25]([CH2:29][CH2:30][P:31]([OH:34])([OH:33])=[O:32])[C:26]([O-:28])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:24][CH:25]([CH2:29][CH2:30][P:31]([OH:33])([OH:34])=[O:32])[C:26]([O:28][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NC(CCP(=O)(O)O)C(=O)[O-])OCc1ccccc1
Reactant: OCc1ccccc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: O=C(NC(CCP(=O)(O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Next, 226 mL of benzyl alcohol was cooled to 0° C. and 19.5 g (164 mmol) of thionyl chloride was added dropwise. After stirring for 15 minutes, 21.2 g (62.4 mmol) of 2-(N-benzyloxycarbonylamino)-4-phosphonobutanoic acid monosodium salt was added and stirred at room temperature for 20 hours after the ice bath was removed. Completion of the reaction was confirmed by TLC (BuOH/AcOH/H2O=5:2:2, 254 nm). Benzyl alcohol was removed by vacuum distillation at 70° C. using a vacuum pump. The obtained oily residue was extracted by 300 mL of ethyl acetate and insoluble sodium chloride was removed by filtration. After being washed with 50 mL of water three times, the filtrate was dried over anhydrous sodium sulfate. After the solvent was removed by vacuum distillation, 300 mL of diethyl ether was added, seed crystals were added and the mixture stirred vigorously, and the product was crystallized from product mixture was partially dissolved in the ether, benzyl 2-(N-benzyloxycarbonylamino)-4-phosphonobutanoate (21.2 g, yield 84%) was obtained as white powder-like crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O[CH2:13][NH:14][C:15](=[O:18])[CH2:16][Cl:17]>Cl.CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][Cl:17])=[C:7]([OH:11])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: O=C(CCl)NCO
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1ccc(CNC(=O)CCl)c(O)c1
Yield: 20 %

Procedure:
A solution of 3-acetamidophenol (1.5 g, 10 mmol) and N-(hydroxymethyl)-2-chloroacetamide (1.2 g, 10 mmol) was stirred in 50 ml of 20% HCl in methanol at room temperature for 2 days. After removal of solvent, the desired product was isolated in 20% yield (0.51 g, 2 mmol) by chromatography (silica gel, eluted with ethyl acetate and hexane, 40/60).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1>C(O)(CC)(C)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: ClC1=NN(c2cccnc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCC(C)(C)O
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-4,5-dihydro-1-(3-pyridinyl)-1H-pyrazole (0.182 g, 1.00 mmol) in tert-amyl alcohol (2 mL) was added manganese (IV) oxide (0.870 g, 10 mmol) (Carus black). The mixture was heated at 80° C. for 19 hours. LC analysis indicated complete conversion to product. The reaction was not worked up.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](O)[CH3:25]>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:24][CH3:25])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(O)c1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CCc1cccc(O)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 3-(3-hydroxyphenyl)propionic acid (Lancaster, 66.4 g, 0.4 mol) in ethanol (700 mL) was treated with concentrated sulfuric acid (6 mL), heated to reflux for 2 h, and allowed to cool to RT. The mixture was cooled in ice, neutralized with 10% aqueous sodium carbonate and concentrated in vacuo to about 50 mL. Water (˜200 mL) was added and the mixture was extracted three-times with ethyl acetate. The combined ethyl acetate extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield the title compound as an oil (70 g, 90%).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=O)=[O:4].[SH2:11]>C(O)C.Cl>[CH3:1][N:2]1[S:11][C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:3]1=[O:4]
Reactant: CNC(=O)C1CCCC1=O
Reactant: S
Agent: Cl
Solvent: CCO
Product: Cn1sc2c(c1=O)CCC2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
5 g of 2-(N-methylcarbamoyl)cyclopentanone are dissolved in 100 cc of anhydrous ethanol saturated by anhydrous HCl gas. Into this solution, cooled to 0° C., there is passed for 5 hours a current of H2S and HCl gas. After having de-gassed the reaction mixture, there is added, with agitation, 0.5 molar equivalent of sodium metaperiodate fixed on acidic alumina (Al2O3), the temperature being maintained at 0° C. One-half hour later the reaction mixture is filtered. The filtrate is concentrated under reduced pressure. The residue is taken up in a 1:1 mixture of ethyl acetate and water. The pH of the aqueous solution is then adjusted, with agitation, to about 6 by the addition of sodium bicarbonate. The aqueous phase is decanted, then extracted with chloroform. The chloroform phase is then dried on sodium sulfate, and concentrated. On evaporation, an amorphous white solid, melting at 111° C. is obtained. Mass spectroscopy gives the expected relative peak at m/e: 155 (C7H9NOS)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:19]3[N:26]=[CH:27][C:28]([CH:29]=O)=[C:18]3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].N1CCCCC1.[NH:37]1[CH2:43][C:41](=[O:42])[NH:40][C:38]1=[O:39]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:19]3[N:26]=[CH:27][C:28](/[CH:29]=[C:43]4/[C:41](=[O:42])[NH:40][C:38](=[O:39])[NH:37]/4)=[C:18]3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13]
Reactant: O=C1CNC(=O)N1
Reactant: CN(C)CCCOc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)CCCOc1ccc(Nc2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cc1Cl
Temperature: 85 °C
Reaction time: 6 h
Yield: 65.9 %

Procedure:
To 5-(3-chloro-4-(3-(dimethylamino)propoxy)phenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (79 mg, 0.184 mmol) in EtOH (3 mL) was added piperidine (22 uL 0.221 mmol) followed by hydantoin (21 mg, 0.202 mmol). The reaction mixture was stirred at 85° C. for 6 h. The solvent was removed by rotary evaporation and the residue was diluted with 3 mL of water. The suspension was sonicated and the resulting solid was filtered off and washed with water followed by a 1:1 mixture of EtOH/water. The material was Dried under vacuum to provide 62 mg of (Z)-5-((5-(3-chloro-4-(3-(dimethylamino)propoxy)phenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione LCMS (ES): m/z 511 [M+1]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:25]1([C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:32]3[CH:33]=[CH:34][N:35]=[C:31]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), 2-phenylimidazole (432 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (10 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]-2-(2-phenyl-1-imidazolyl)oxazole was obtained as an oil (512 mg, 39%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[CH3:9][N:10]1[CH2:30][CH2:29][C:14]2=[C:15]([N:22]3[CH2:25][CH:24]([C:26](O)=[O:27])[CH2:23]3)[N:16]3[C:20]([N:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[N:17]3.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:15]2([N:22]3[CH2:25][CH:24]([CH:26]=[O:27])[CH2:23]3)[C:14]3[CH2:29][CH2:30][N:10]([CH3:9])[CH2:11][CH2:12][C:13]=3[N:21]=[C:20]3[N:16]2[N:17]=[CH:18][CH2:19]3)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: CN1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(C2(N3CC(C=O)C3)C3=C(CCN(C)CC3)N=C3CC=NN32)CC1
Reaction time: 2 h

Procedure:
To 11.4 mg (0.10 mmol) N-ethylpiperazine was added a solution of 43 mg (0.10 mmol) 1-(7-Methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid and 0.026 mL (0.15 mmol) DIPEA in 0.5 mL DMF at room temperature. 35.3 mg (0.11 mmol) TBTU was dissolved in 0.5 mL DMF and the solution was added to the reaction mixture. Stirring was continued for 2 h and the reaction mixture was allowed to stand for overnight. The mixture was filtered over basic alumina followed by two washing cycles with 1.5 mL DMF. The solvent was removed and the residue was purified by column chromatography to yield the desired compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16]Br)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.C(O)(=O)C(O)=O.S1C2C=CC=CC=2C(N2CCN(CCCC(C3SC4SCCNC(=O)C=4C=3)=O)CC2)=N1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCc1sc2c(c1CCBr)CCN(C(C)=O)C2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C(CCCN1CCN(c2nsc3ccccc23)CC1)c1cc2c(s1)SCCNC2=O
Agent: O=C(O)C(=O)O
Product: CCc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C(C)=O)C2
Yield: 62 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.5 g of 6-acetyl-3-(2-bromoethyl)-2-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 2.2 g of 6-acetyl-2-ethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 191°-201° C. as oxalate 1/2 hydrate thereof.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH:28]2[CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37](=[O:42])[CH2:36][CH2:35]2.C[Si](Cl)(C)C>C(O)CCC>[CH:28]1([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:31][C:32]3[CH:33]=[C:34]4[C:39](=[CH:40][CH:41]=3)[NH:38][C:37](=[O:42])[CH2:36][CH2:35]4)[N:3]=2)[CH2:30][CH2:29]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: O=C1CCc2cc(Nc3nc(NC4CC4)c4c(-c5ccncc5)c[nH]c4n3)ccc2N1
Temperature: 135 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (85 mg, 0.19 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (70 mg, 0.43 mmol) and TMSCl (0.100 mL, 0.79 mmol) in nBuOH (3 mL) was stirred at 135° C. for 18 h. More TMSCl (0.200 mL) was added. Stirring was continued at 135° C. for another 68 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (5 mg). MS 412.3 (M+H); UV 201.8, 295.8 nm.
Reaction SMILES: [F:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.CO.O.[OH-].[Li+]>O1CCCC1>[C:21]([O:20][C:18]([N:4]1[CH2:5][CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)[CH:2]([F:1])[CH2:3]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)C(F)C1
Reaction time: 3 h
Yield: 90 %

Procedure:
tert-Butyl 3-fluoro-4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate described in Production Example 6-3 (402 mg, 1.19 mmol) was dissolved in tetrahydrofuran (18 mL), methanol (6 mL), and water (4 mL), then a 2 M aqueous lithium hydroxide solution (4.17 mL, 8.34 mmol) was added at room temperature, and then the mixture was stirred for 3 hours. Tetrahydrofuran and methanol were evaporated under vacuum and 1 M hydrochloric acid was added to the residual solution for neutralization. The aqueous layer was extracted with ethyl acetate four times, and the organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:4) to obtain the title compound (347 mg, 90%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([O:10]C)=O)=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:1][N:2]1[C:7]([C:8]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:10])=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: Nc1ccccn1
Reactant: COC(=O)C1=C(O)c2sc3cc(C)ccc3c2S(=O)(=O)N1C
Product: Cc1ccc2c3c(sc2c1)C(O)=C(C(=O)Nc1ccccn1)N(C)S3(=O)=O
Yield: 53 %

Procedure:
Prepared analogous to Example 1 from methyl 2,7-dimethyl-4-hydroxy-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-pyridine with a yield of 53% of theory.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[CH:16])[CH:14]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>C(#N)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.[Cu]I>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH:14]=1
Reactant: C#Cc1cncc(Br)c1
Reactant: Fc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Br)c2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sequentially add triethylamine (161 mL, 1156 mmol), bis(triphenylphosphine)palladium(II) dichloride (2 g, 2.89 mmol) and copper (I) iodide (1.1 g, 5.78 mmol) to a solution of 3-bromo-5-ethynylpyridine (52.7 g, 289 mmol), (prepared essentially as described in PREPARATION 23), and 1-fluoro-4-iodobenzene (58.4 g, 262.7 mmol) in acetonitrile (1000 mL). Purge the system with nitrogen and heat the reaction mixture at 50° C. for 16 h. Concentrate, dissolve the residue in 10:1 hexanes:dichloromethane (1000 mL), filter and concentrate. Stir the residue in 150 mL of hexanes at room temperature for 30 min to produce a slurry. Cool the slurry at 0° C. and filter to give the title compound. From the filtrate, a second crop of the title compound can be isolated (45.5 g, 63%).
Reaction SMILES: [H-].[K+:2].[CH3:3][Si:4]([CH3:15])([CH3:14])[O:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[CH3:15][Si:4]([CH3:3])([CH3:14])[O:5][CH2:6][CH2:7][CH2:8][C-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[K+:2]
Reactant: C[Si](C)(C)OCCCC1=CC=CC1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCC[c-]1cccc1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a suspension of 0.4 g (10 mmol) of potassium hydride in tetrahydrofurane, 1.96 g (10 mmol) of a (3-trimethylsiloxy-propyl)-cyclopentadiene in tetrahydrofurane is added. The reaction is maintained under stirring for 2 hours. Subsequently, the resulting suspension is concentrated to dryness, leaving an oily solid that, when it is washed with hexane, gives a cream-coloured solid. (1.6 g, 7 mmol. Yield:70%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([O:25]CC)=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C)cc3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)cc1
Temperature: 60 °C

Procedure:
A solution of ethyl 1-cyclopropyl-8-(4-methylphenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (90 mg, 0.249 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (43 mg, 1.02 mmol). The reaction was heated to 60° C. for 2 h and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (20 mL) and washed with brine (20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 33 as a yellow solid (65 mg, 78%). ESI-MS m/z: 334 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.31 (d, J=7.2 Hz, 1H), 8.24 (s, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.2 Hz, 2H), 7.38 (d, J=7.2 Hz, 2H), 2.84 (s, 3H), 2.54-2.52 (m, 1H), 2.39 (s, 3H), 1.06-1.03 (m, 2H), 0.77-0.75 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)O1.C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:37]3[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(C#N)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (200 mg, 0.542 mmol), potassium carbonate (150 mg, 1.083 mmol), tetrakis(triphenylphosphine)palladium(0) (6.26 mg, 5.42 μmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (149 mg, 0.650 mmol) then filled with ethanol (2 mL) and toluene (2 mL) and the resulting mixture was stirred under nitrogen at 90° C. for 16 h then cooled to room temperature and partitioned between water (20 mL) and EtOAc (60 mL). The layers were separated and the aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with brine (30 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 10 to 55% AcOEt in hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-6-(4-cyanophenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (176 mg, 0.45 mmol, 83%) as a white solid. LCMS (method G): Retention time 1.03 min, [M+H]+=392.0
Reaction SMILES: C([O:3][C:4]([CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=O)C.[NH3:18]>>[C:4]([CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[NH2:18]
Reactant: N
Reactant: CCOC(=O)C(C)C(=O)N1CCC[C@H]1C(=O)O
Product: CC(C(N)=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-(2-Ethoxycarbonylpropanoyl)-L-proline (2 g.) is dissolved in 10% methanolic ammonia and the mixture stored at room temperature in a pressure flask. When thin layer chromatographic analysis indicates that all the starting material has been converted to the amide, the mixture is concentrated to dryness, and the residual ammonium salt is converted to the free acid with ion exchange resin (Dowex 50 hydrogen form) to obtain 1-(2-carbamoylpropanoyl)-L-proline, yield 1.1 g.