Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]([NH:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44]C)=[O:43])=[CH:40][C:39]=2[Cl:48])=[O:36])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]([NH:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]=2[Cl:48])=[O:36])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=O)N2CCC(c3ccccc3F)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Nc2ccc(C(=O)O)cc2Cl)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a mixture of 330 mg of the crude methyl 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}amino)-3-chlorobenzoate and 10 mL of THF-5.0 mL of methanol was added dropwise 5.0 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. It was neutralized by addition of 5.2 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 274 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}amino)-3-chlorobenzoic acid as a pale yellow amorphous substance. ESI+: 660
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:26](=[O:27])[C:25]2[C@@H:24]3[C:28]([CH3:30])([CH3:29])[C@@:21]([CH3:31])([CH2:22][CH2:23]3)[C:20]=2[NH:19]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:26](=[O:27])[C:25]2[C@@H:24]3[C:28]([CH3:30])([CH3:29])[C@@:21]([CH3:31])([CH2:22][CH2:23]3)[C:20]=2[N:19]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: BrCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A mixture of (2-bromoethyl)benzene (200 μL, 1.46 mmol), (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol) and tetra-n-butylammonium iodide (94 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) was heated in a pressure tube in an oil-bath at 100° C. for 18 h. Additional portions of (2-bromoethyl)benzene (200 μL, 2.2 mmol) and tetra-n-butylammonium iodide (100 mg, 0.27 mmol) were added and the reaction mixture was heated at 100° C. for 3 days, and then allowed to stand overnight at room temperature. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (5×25 mL) and sodium thiosulfate solution (25 mL), dried (magnesium sulfate), filtered, and evaporated and the residue was purified on an Isco 40 g column, eluting with 40-100% ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-phenethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (37 mg, 28%) as a pale yellow oil that solidified on standing. ES(+)-MS (M+H) 409.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:14])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[CH3:1][C:2]1[CH2:3][C:4](=[O:14])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([S:16]([CH3:15])(=[O:18])=[O:17])[S:16]([CH3:15])(=[O:18])=[O:17])=[CH:9][CH:8]=2)[N:6]=1
Reactant: CC1=NN(c2ccc(N)cc2)C(=O)C1
Reactant: CS(=O)(=O)Cl
Product: CC1=NN(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)C(=O)C1

Procedure:
From the reaction of 5-methyl-2-(4-aminophenyl)-2,4-dihydro-pyrazol-3-one and methansulfonylchloride (reaction per Example 11, where methanesulfonylchloride is used in respective molecular amounts), N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)-N-methylsulfonylmethanesulfonamide is obtained. Subsequent reaction with 2-ethyl aniline yields N-(4-(4-(2-Ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)-N-methylsulfonylmethansulfonamide, Mp: 268° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Cl:7][C:8]([Cl:13])([Cl:12])[C:9](Cl)=[O:10].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:7][C:8]([Cl:13])([Cl:12])[C:9]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:10]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cn1cccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Under an ice cooling, N-methylpyrrole (8.10 g, 100 mmol) was dissolved in methylene chloride (100 ml), and trichloroacetyl chloride (20.00 g, 115 mmol) was added thereto. Thereafter, the mixture was stirred at a room temperature for 16 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the mixture. The organic phase was collected by separation, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off. Thus, 2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (16.3 g, 72%) was obtained. The resulting 2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (15.0 g, 66.7 mmol) was dissolved in chloroform (150 ml), and N-bromosuccinimide (12.5 g, 70.2 mmol) was added thereto at a room temperature. The mixture was heated under reflux for 16 hours. After the mixture was allowed to cool, a saturated sodium hydrogen carbonate aqueous solution was added to the mixture. The organic phase was collected by separation, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give the title compound (14.0 g, 69%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28](=[O:47])[NH:29]C(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[C:3]([NH:5][C@@H:6]([C@H:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].C1(OC)C=CC=CC=1.O.C(OCC)(=O)C>FC(F)(F)C(O)=O>[NH2:1][C@@H:2]([CH2:27][C:28](=[O:47])[NH2:29])[C:3]([NH:5][C@@H:6]([C@H:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[CH3:11])[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COc1ccc(C(NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)O)[C@@H](C)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c2ccc(OC)cc2)cc1
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A solution of (2S,3R)-2-[[(2S)-2-amino-3-[N-[bis(4-methoxyphenyl)methyl]carbamoyl]propionyl]amino] 3-[[(1S)-1-carboxy-2-(3 indolyl)ethyl]amino]butyric acid (427 mg) in a mixture of trifluoroacetic acid (3 ml), anisol (0.5 ml) and ethaneditiol (0.1 ml) was stirred overnight at room temperature and the mixture was poured into a mixture of water (10 ml) and ethyl acetate (10 ml). The aqueous phase was separated and subjected to a column of Dowex 50W x 8 (H+, 20 ml). The column was washed with water and the elution was carried out with 2.8% aqueous ammonia. The object fractions were collected and evaporated in vacuo. To the residue was added water and the mixture was lyophilized to give (2S,3R)-2-[[(2S)-2-amino-3-carbamoylpropionyl]amino]3-[[(1S)-1-carboxy-2-(3-indolyl)ethyl]amino]butyric acid (85 mg) as a pale brown powder.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7].CN(C)C=O.Cl[CH2:34][C:35]#[CH:36].[H-].[Na+]>O>[F:27][CH:2]([F:1])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:36][C:35]#[CH:34])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7]
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)ccc1O
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1ccc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)cc1OC
Yield: 13.4 %

Procedure:
477 mg (1.20 mmol) of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(4-chlorophenyl)acrylamide, 5 ml of anhydrous N,N-dimethylformamide, 180 mg (2.40 mmol) of 3-chloropropyne and 72 mg (1.80 mmol) of 60% sodium hydride were stirred at room temperature for 2 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 70 mg of 3-difluoromethoxy-N-[2-{3-methoxy-4-(2-propynyloxy)phenyl}ethyl]-2-(4-chlorophenyl)acrylamide (the present compound 1355).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1.CCN(CC)CC.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Some starting materials may be obtained from Adesis Inc., New Castle, Del.) To a mixture of (2-chloro-5-(4-morpholinoquinolin-6-yl)pyridin-3-yl)methanamine (50 mg, 141 μmol) and Et3N (300 μl, 2152 μmol) in DCM (5 mL) was added pivaloyl chloride (100 μL, 813 μmol). The solution was stirred at rt for 1 h. The mixture was partitioned between DCM (10 mL) and aqueous NaHCO3 (20 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified on silica with 1-5% (2N NH3-MeOH) in DCM to give the product as a yellow solid after concentration (20 mg, 32%). LCMS (ESI, pos. ion): calc'd for C24H27ClN4O2:438.2; found: 439.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.21-1.28 (m, 12 H) 3.19-3.35 (m, 4 H) 3.95-4.08 (m, 4 H) 4.58 (d, J=6.06 Hz, 2 H) 6.37 (br. s., 1 H) 6.93 (d, J=4.89 Hz, 1 H) 7.83 (dd, J=8.90, 1.66 Hz, 1 H) 8.00 (d, J=2.15 Hz, 1 H) 8.10-8.25 (m, 5 H) 8.61 (d, J=2.15 Hz, 2 H) 8.79 (d, J=4.89 Hz, 2 H)
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>C(Cl)Cl>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A suspension of 250 g. of anthraquinone in 200 ml. of methylene chloride is treated under reflux conditions, over the course of about 3 hours, with a nitration acid of 68.4 ml. of 98% strength nitric acid and 85.2 ml. of 100% strength sulphuric acid. The mixture is stirred for a further 4 hours at this temperature and cooled to 20°C. After 700 ml. of methylene chloride have been added, 190 ml. of 98% strength nitric acid are allowed to run in at 20°C. After stirring for about 30 minutes longer, the upper, organic phase is withdrawn and clarified by passing it through a frit, and the filter residue is rinsed with a mixture of 95 ml. of methylene chloride and 5 ml. of 98% strength nitric acid. The clear filtrate is decomposed with 500 ml. of water and the mixture is stirred for a further hour at about 20°C. The lemon-yellow precipitate is then filtered off and is washed successively with 2 × 100 ml. of methylene chloride and 2 × 100 ml. of 1% strength aqueous di-sec.-butylnaphthalene-sulphonate solution and finally with water until neutral. After drying at about 100°C, the yield is 229 g. The product contains 89% of 1-nitroanthraquinone and inter alia contains 0.25% of anthraquinone, <0.25% of 2-nitroanthraquinone and 1.4% of 1,5-dinitroanthraquinone. To remove the remaining subsidiary components, the 1-nitroanthraquinone obtained is stirred with 1,850 ml. of 2.5% strength sodium sulphite solution for 4 hours under reflux conditions, then filtered off hot, washed and dried. 204 g. of 1-nitroanthraquinone are obtained, containing 95% of 1-nitroanthraquinone, 0.25% of anthraquinone, <0.25% of 2-nitroanthraquinone and 0.9% of 1,5-dinitroanthraquinone. A further fraction of 12 g. of 1-nitroanthraquinone and 2 g. of anthraquinone remains in the methylene chloride mother liquor and can, after evaporation of the solvent, be reintroduced into the next nitration batch.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1.N1C=CC=CC=1>C(Cl)Cl>[C:4]([CH:3]([N:2]([CH3:1])[C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: CNC(C#N)c1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)CCC(=O)O)C(C#N)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of the compound obtained in Step A (9 mmol), succinic anhydride (7.5 mmol) and pyridine (1 ml) in methylene chloride (30 ml) is stirred overnight. After conventional treatment, the title compound is obtained in pure form.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)N=1.Cl[C:20]1N=C(C(F)(F)F)C=C[N:21]=1>>[CH3:3][C:8]1[N:21]=[CH:20][C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: Cc1cnc(N2C[C@@H]3CCNC[C@@H]32)cn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 27, substituting 2-bromo-5-methylpyrazine for 2-chloro-4-(trifluoromethyl)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OC[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>CC(C)=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[CH2:49][C:50]([F:53])([F:52])[F:51])[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4)CC3)c21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4CC(F)(F)F)CC3)c21

Procedure:
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone (28 mg, 0.53 mmol; see Example 3) was slurried in acetone (0.4 mL) and treated with diisopropylethylamine (0.032 mL, 0.18 mmol), 4-dimethylaminopyridine (“DMAP”; 0.0006 g, 0.005 mmol) and 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.016 g, 0.066 mmol). The reaction mixture was heated to reflux for 9 hours. Additional 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.016 g, 0.066 mmol) was added and the mixture was heated at reflux for 16 hours. The reaction was concentrated using N2 (g) and chromatographed on SiO2 eluting with 2% MeOH/methylene chloride. After chromatography, the product was dissolved in ethyl acetate and washed 3 times with saturated NH4Cl, once with saturated NaHCO3, once with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The residue was concentrated from dioxane, treated with 4M HCl in dioxane (2 mL) and concentrated in vacuo. The salt was redissolved in MeOH and re-concentrated three times. The salt was dissolved in a minimal amount of MeOH and added dropwise to Et2O. The salt was filtered and washed with Et2O then dried under vacuum (12.8 mg, 39%). MS (ESI+) [M+H] 538.2/540.1. 1H NMR (CD3OD, 400 MHz) δ □8.58 (s, 1H), 7.47-7.36 (m, 4H), 5.31 (t, 1H), 4.48-3.96 (m, 3H), 3.91-3.44 (m, 7H), 2.35-2.27 (m, 1H), 2.23-2.13 (m, 1H), 2.05-1.88 (m, 2H), 1.84-1.71 (m, 1H), 1.68-1.56 (m, 1H), 1.19 (d, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:12])[C:6]=2[S:5][CH:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][C:3]1[C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:12])[C:6]=2[S:5][CH:4]=1)=[N+:20]=[N-:21]
Reactant: CCOC(=O)c1cn(C)c2c(CBr)csc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2c(CN=[N+]=[N-])csc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
A mixture of 1.14 g of ethyl 3-(bromomethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (Preparation 19) and 337 mg of sodium azide in 6 mL of DMF is stirred at room temperature for 3 h, then diluted slowly with water to a volume of 50 ml. The resulting solid is filtered, washed well with water, and dried in vacuo to afford 759 mg of the title compound as a cream colored solid. Recrystallization of a sample from acetonitrile gives tan needles.
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.[C:21]([O-:24])(=[O:23])C.[K+].CN(C)C=O>O>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([CH:3]([CH3:2])[C:21]([OH:24])=[O:23])[CH:13]=[CH:12]2
Reactant: COc1ccc2cc(C(OC)(OC)C(C)Br)ccc2c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Reaction time: 48 h
Yield: 97 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propane (3.39 g; 10 mmol), potassium acetate (1.2 g; 12 mmol), N,N-dimethylformamide (14 ml) and of water (8 ml) is heated at 100° C. under stirring for 48 h. The reaction mixture is worked up as described in example 1a to provide 2-(6-methoxy-2-naphthyl)-propionic acid (2.23 g; 9.7 mmol; yield 97%), m.p. 155°-157° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl[CH2:20][C:21]([NH:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH3:2])=[C:5]([CH:6]=1)[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:20][C:21]([NH:23][CH3:24])=[O:22])[CH2:15][CH2:14]1)#[N:9]
Reactant: COc1ccc(C#N)cc1OC1CCNCC1
Reactant: CNC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)CN1CCC(Oc2cc(C#N)ccc2OC)CC1
Temperature: 20 °C
Yield: 96.2 %

Procedure:
4-Methoxy-3-(piperidin-4-yloxy)benzonitrile hydrochloride salt (3, 28.36 g, 95.82 mmoles), 2-chloro-N-methylacetamide (12.37 g, 114.98 mmoles) and potassium carbonate (33.11 g, 239.55 mmoles) were suspended in acetonitrile (161.36 g). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to 20° C. and water (386.26 g) was charged. The reaction was heated to 75° C. and the volume reduced by distillation. Upon cooling crystallisation occurred. The resulting solid was isolated by filtration, washed twice with water (77.25 g and 128.75 g) and then dried to give the title compound (27.95 g, 94% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (m, 2H) 1.91 (m, 2H) 2.29 (m, 2H) 2.61 (d, J=4.7 Hz, 3H) 2.67 (m, 2H) 2.88 (s, 2H) 3.83 (s, 3H) 4.41 (tt, J=8.3, 4.0 Hz, 1H) 7.11 (d, J=8.4 Hz, 1H) 7.40 (dd, J=8.4, 1.9 Hz, 1 h) 7.47 (d, J=1.9 Hz, 1H) 7.68 (q, J=4.7 Hz, 1H); Mass Spectrum: m/z (M+H)+ 304.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[OH-].[Li+].[O-:17][C:18]#[N:19].[Na+].Cl>O>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[C:6](=[CH:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:7](=[O:9])[NH:19][C:18]1=[O:17]
Reactant: N#C[O-]
Reactant: O=C(O)c1ccc(Cl)cc1NCCO
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(=O)n(CCO)c2cc(Cl)ccc12
Temperature: 40 °C
Yield: 120.7 %

Procedure:
To a suspension of 2-(2-hydroxyethylamino)-4-chlorobenzoic acid (5.0 g) in water (50 ml) was added lithium hydroxide (1.0 g), was further added sodium cyanate (1.05 g) with maintaining the temperature at about 40° C. The resulting solution was reacted for 2 hours, adjusting the pH 6.0-7.0 with concentrated hydrochloric acid. Then, to the reaction solution was added lithium hydroxide (1.3 g), was further added sodium cyanate (2.1 g) at the same temperature, the resulting solution was reacted for one hour. Then, the reaction mixture was reacted for further 4 hours with adjusting the pH in the same manner as above. After the reaction, to the reaction solution was added lithium hydroxide (1.7 g) and was reacted for further 3 hours. Concentrated hydrochloric acid (5 ml) was added to this reaction solution, the resulting crystal was collected by filtration to give 4.69 g of 1-(2-hydroxyethyl)-7-chloro-2,4(1H, 3H)-quinazolinedione (yield, 84.1%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Cl)=[CH:15][N:14]=1)=[O:12].[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.Cl[Pd]Cl>[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:15][N:14]=1)=[O:12]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnc(Cl)cn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnc(-c2ccccc2)cn1
Temperature: 90 °C
Yield: 13.2 %

Procedure:
Na2CO3 (140 mg, 1.32 mmol) was added to a stirred solution of 5-chloro-pyrazine-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (200 mg, 0.44 mmol) in DMF (3 mL). PdCl2 (dppf) (96 mg, 0.13 mmol) and phenyl boronic acid (64 mg, 0.52 mmol) were then added and the reaction mixture was heated at 90° C. overnight. The reaction mixture was filtered, filtrate was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to afford 29 mg (13.3% yield) of 5-phenyl-pyrazine-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 93.2%. 1H NMR (CDCl3): δ 9.4 (d, 1H), 9.0 (d, 1H), 8.7-8.6 (m, 1H), 8.1-8.0 (m, 2H), 7.8-7.7 (d, 1H), 7.7-7.5 (m, 5H), 7.4-7.3 (d, 1H), 4.46-4.18 (m, 2H), 4.46-4.18 (m, 2H), 4.1-3.86 (m, 2H), 3.8-3.5 (m, 4H), 3.5-3.4 (m, 1H), 3.3-3.2 (m, 2H).