Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:22](OB(C=C)OCCCC)[CH2:23]CC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[CH3:17][NH:16][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([CH:22]=[CH2:23])[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]=2[CH3:18])=[CH:9][CH:10]=1)=[O:15]
Reactant: C=CB(OCCCC)OCCCC
Reactant: CNC(=O)c1ccc(-c2cc(Cl)c([N+](=O)[O-])cc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(-c2ccc(C(=O)NC)cc2)c(C)cc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
To a mixture of 5′-chloro-N,2′-dimethyl-4′-nitrobiphenyl-4-carboxamide (Step 2, 100 mg, 0.33 mmol), vinylboronic acid dibutyl ester (90 mg, 0.5 mmol) and sodium carbonate (245 mg, 2.31 mmol) in THF/H2O (8/2 mL) is added dichlorobis(triphenylphospine) palladium (II) (12 mg, 5% mmol). The reaction tube is sealed, the mixture is purged with N2 for 3 min and then heated at 90° C. under N2 for overnight. The reaction is cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture is extracted with ethyl acetate (3×15 mL). The organic extracts are combined, washed with brine and concentrated. The crude product is purified with silica gel column chromatography (30% ethyl acetate in DCM) to afford N,2′-dimethyl-4′-nitro-5′-vinylbiphenyl-4-carboxamide as a yellow solid. The obtained solid is dissolved in methanol (20 mL). To this solution is added Pd/C (10%). The reaction mixture is degassed and purged with H2 for several times and stirred under atmospheric hydrogen overnight. The mixture is filtered and concentrated to afford 4′-amino-5′-ethyl-N,2′-dimethylbiphenyl-4-carboxamide as a yellow solid. ESMS m/z 269.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][CH:5]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][C@@H:23]([CH3:25])[NH:22][CH2:21][C@@H:20]1[CH3:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][C@@H:23]([CH3:25])[N:22]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][N:6]=2)[CH2:21][C@@H:20]1[CH3:26])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: COC(=O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]2C)nc1

Procedure:
A mixture of 6-fluoronicotinic acid methyl ester (200 mg, 1.29 mmol) and (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was heated at 120° C. in DMSO (2.0 mL) with potassium carbonate (178 mg, 1.29 mmol) for 2 h. The reaction mixture was partitioned between ethyl acetate (20.0 mL) and water (5.0 mL). The organic layer was washed with water (2×5.0 mL), dried over sodium sulfate, filtered and concentrated to give the title intermediate as a yellowish oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][O:35][CH2:36][CH3:37]>CN(C)C=O>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:33][CH2:34][O:35][CH2:36][CH3:37])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:24]=[O:25])=[CH:6][N:7]=1)[CH3:23]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc2c(C=O)cnc(Cc3cccc(OCC)c3)c2cc1OC
Temperature: 85 °C
Yield: 87.6 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (60 g, 0.17 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (234 mg, 1.70 mmol) and 1-bromo-2-ethoxy-ethane (0.095 mL, 0.85 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-(2-ethoxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil (61 mg, 88% yield).
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>C1C=CC=CC=1>[CH:19]([NH:23][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9])([CH2:21][CH3:22])[CH3:20]
Reactant: CCC(C)N
Reactant: Cc1c(C(F)(F)F)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Solvent: c1ccccc1
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(C)c1[N+](=O)[O-]

Procedure:
A nitration mixture, consisting of 16.1 ml. of H2SO4 (d 1.84) and 1.9 ml. of HNO3 (d 1.5), is heated to 55° C. and 3.5 grams of 5-chloro-2-(trifluoromethyl)toluene is slowly added. The mixture is heated for one hour at 55° C. followed by one hour at 110° C. The reaction mixture is cooled and poured onto ice to give 5-chloro-2-(trifluoromethyl)-4,5-dinitrotoluene as a cream-colored solid. The product is crystallized from cyclohexane to give 3.6 grams of cream-colored crystals, melting point 81° C. to 82° C. 1.8 Grams of 5-chloro-2-(trifluoromethyl)-4,6-dinitrotoluene is refluxed for 15 minutes with 3 ml. of mono-sec-butylamine and 30 ml. of benzene, cooled, filtered, washed with water until neutral, dried, and vacuum stripped to give 1.5 grams of N-sec-butyl-3-methyl-2,6-dinitro-4-(trifluoromethyl)aniline as a yellow solid, melting point 38° C. to 39° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([NH2:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[P-](F)(F)(F)(F)F.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCO>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13](=[NH:15])[NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:10]([CH3:12])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 201.6 %

Procedure:
To a stirred solution of Boc-D-Valine amide (10 g, 46 mMol) in CH2Cl2 (200 mL) was added Triethyloxoniuim hexafluorophosphate (13.0 g, 48 mMol). (The reaction started out as a suspension which gradually cleared.) The reaction was stirred for 48 h at RT, poured into a separatory funnel, washed with 1 N Na2CO3, dried (Na2SO4), filtered and concentrated under vacuum. To the remaining oil was added Benzylamine (5.0 mL, 23 mMol) and EtOH (20 mL). The reaction was stirred at 60° C. for 24 h. After cooling to RT the reaction was evaporated under vacuum. The title compound (14.16 g, >95% pure by LCMS) was obtained without purification as a pale yellow oil which eventually solidified to a waxy solid: MS (ES) m/e 306.4 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([OH:9])=O)[C:2]=1[C:10]([OH:12])=[O:11].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:13]([NH:25][C:7]([C:3]1[C:2]([C:10]([OH:12])=[O:11])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCN
Reactant: O=C(O)c1nccnc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCNC(=O)c1nccnc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
Pyrazine-2,3-dicarboxylic acid (624 mg, 4.0 mmol), 1-dodecylamine (740 mg, 4.0 mmol), benzotriazole-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (2.6 g, 4.8 mmol) and 4-dimethylaminopyridine (488 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature overnight. The reaction mixture was poured into water, then extracted three times with ethyl acetate. The isolated organic phase was dried with anhydrous Na2SO4. The solvent was removed by vaporizing under reduced pressure. The residue was purified by silica column chromatography (developing agent: dichloromethane/methanol=30/1) to produce 3-(dodecylcarbamoyl)pyrazine-2-carboxylic acid (650 mg).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@@H:21]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[N:22]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18](O)=[O:19])=[CH:13][C:12]=1[F:35].Cl.Cl.[CH3:38][C@H:39]1[C:47]2[C:46]([N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[N:45][CH:44]=[N:43][C:42]=2[C@H:41]([OH:54])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@H:21]2[N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:23]([CH3:26])([CH3:27])[CH2:24][CH2:25]2)[C:18]([N:51]2[CH2:52][CH2:53][N:48]([C:46]3[C:47]4[C@H:39]([CH3:38])[CH2:40][C@@H:41]([OH:54])[C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:49][CH2:50]2)=[O:19])=[CH:13][C:12]=1[F:35]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)c(F)c2)CCC1(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)c(F)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (0.045 mL, 0.26 mmol) was added to a solution of (S)-2-(4-bromo-3-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.035 g, 0.081 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.025 g, 0.081 mmol; see Example 3, Step 12), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.031 g, 0.081 mmol) in DCM (5 mL). The reaction was stirred overnight at room temperature. The reaction was then quenched with H2O, washed with H2O (3×30 mL), dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography to give (S)-tert-butyl 5-((S)-1-(4-bromo-3-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (23% yield). LCMS (APCI+) 648.2 m/z [M+H]+; Retention time=4.28 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:11][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Yield: 56.9 %

Procedure:
A solution of 1-(2-methoxyphenyl)piperazine (41.2 mmol) in 100 mL of acetonitrile and 12 mL of dimethylformamide was combined with N-(2-bromoethyl)phthalimide (43.3 mmol) and potassium carbonate (61.8 mmol). The mixture was heated to reflux for 8 hours. After cooling, the reaction mixture was quenched with water, extracted with dichloromethane. The organic phase was washed with brine, water, and dried over magnesium sulfate. Filtration and evaporation of the solvents gave a yellow oily residue that was purified by flash chromatography using hexanes and ethyl acetate (1:1) to give 1-(2-methoxyphenyl)-4-[(2-phthalimido)ethyl]piperazine (8.56 g, 57%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8].[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=2[CH3:8])[CH:17]=[CH:16][N:15]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])nc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(Cl)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 18.8 %

Procedure:
3-Bromo-2,4-dimethyl-6-nitropyridine (2.2 g, 9.5 mmol) and 2-chloro-4-hydroxypyridine (2.5 g, 19 mmol) were combined in DMA (10 mL) and the solution was sonicated and sparged with Ar for 10 min. K2CO3 (4.0 g, 29 mmol) was added and the reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was poured into water (200 mL) and the precipitated solids were isolated by filtration. The solids were washed with ½ sat. K2CO3 (aq) (3×50 mL) and water (3×50 mL) and dried under high vacuum for 5 h. The crude product was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-((2-chloropyridin-4-yl)oxy)-2,4-dimethyl-6-nitropyridine (0.50 g, 19%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.33-8.30 (m, 2H), 7.15 (d, J=2.3 Hz, 1H), 7.01 (dd, J=5.8, 2.3 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H); MS (ESI) m/z: 280.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][C:4]#[C:5][C:6]1[NH:32][C:9]2=[N:10][CH:11]=[C:12]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:13]=[C:8]2[CH:7]=1.[H][H]>CO.[Pd]>[CH3:33][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[NH:32][C:9]2=[N:10][CH:11]=[C:12]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:13]=[C:8]2[CH:7]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C#CCN(C)C)cc3c2)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(CCCN(C)C)cc3c2)c1F
Yield: 42.9 %

Procedure:
A solution of N-(2-(3-(dimethylamino)prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (30 mg, 63 mmol) in MeOH (10 mL) was treated with 10% Pd/C and allowed to stir under a balloon atmosphere of hydrogen for 4 hours. The mixture was filtered through GF/F paper, rinsing with MeOH. The filtrate was purified by silica gel chromatography (eluting with 10% MeOH/DCM containing 1% NH4OH) to afford N-(2-(3-(dimethylamino)propyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (13 mg, 27 mmol, 43%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 11.50 (s, 1H), 10.77 (s, 1H), 9.80 (br s, 1H), 8.27-8.18 (m, 2H), 7.56-7.49 (m, 1H), 7.26-7.20 (m, 1H), 6.19-6.17 (m, 1H), 3.12-3.08 (m, 2H), 2.76-2.71 (m, 2H), 2.32-2.27 (m, 2H), 2.17 (s, 6H), 1.87-1.72 (m, 2H), 1.01-0.97 (m, 3H); m/z (APCI-pos) M+1=480.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1ccccc1
Solvent: CCCCO
Product: CCC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Temperature: 100 °C

Procedure:
The operation is carried out as in Stage 2 of Example 3 and 161 mg of the product obtained in Stage 1 above, 3 ml of butanol and 0,132 ml of benzylamine are mixed together and the reaction medium is heated to a temperature of approximately 90 to 110° C. for approximately 5 hours, then left to return to ambient temperature. After leaving to crystallize, the reaction medium is diluted with 10 ml of isopropanol, followed by separating, washing with 10 ml of isopropanol and drying under vacuum at approximately 50° C. After chromatography on silica eluting with methylene chloride/ethyl acetate in a proportion of 50/50, In this way 179 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(O)C>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Yield: 87 %

Procedure:
To 1.9 g of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 30 mL of absolute ethanol was added 1.6 mL of 3-bromoaniline. After refluxing the reaction under an inert atmosphere for 8 hours, the reaction mixture was cooled to 0° C. and the product was filtered and washed with cold ethanol. Drying in vacuo yielded 2.7 g (87%) of 4-(3-bromo-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile as an off-white solid: melting point 185-195° C.; mass spectrum (m/e): M+H 343.0, 345.1.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(OC)cc2)cc1)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(O)cc2)cc1)c1ccccc1

Procedure:
Prepared by treating 1t with boron tribromide (3 eq) in CH2Cl2 at room temperature. Yield (29%); 1H NMR (d6-DMSO) δ 11.95 (br s, 1H), 10.57 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.38–7.07 (m, 13H), 6.85 (t, J=8.8 Hz, 4H), 6.38 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 510 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23](O)=[O:24])=[N:5][CH:4]=1.C1[CH:31]=[N:30][C:29]2N(O)N=NC=2C=1.CNC>C1COCC1.C(Cl)CCl>[CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23]([N:30]([CH3:31])[CH3:29])=[O:24])=[N:5][CH:4]=1
Reactant: On1nnc2cccnc21
Reactant: COc1ccc(CN2CCc3c(C(=O)O)ncc(OC)c3C2=O)cc1
Agent: CNC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3c(C(=O)N(C)C)ncc(OC)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 250 mL THF suspension of 4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic acid (11.0 g), 8.0 g EDC, 5.7 g HOAT, and 11.2 mL TEA was stirred at room temperature for 20 minutes, followed by addition of 45 mL of a 2M THF solution of dimethylamine and then stirring for 1.5 hours. The reaction was quenched with 200 mL of 1N aq HCl and stirred vigorously for 30 minutes. After concentrating in vacuo until an oil formed on the water layer, 200 mL chloroform was added. The water layer was washed again with chloroform then the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to pure product by HPLC/MS and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:15][C:3]=1[C:4]([O:6]CC1C=CC=C(Cl)C=1)=[O:5].[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:15][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(OCc1cccc(Cl)c1)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A solution of (3-chlorophenyl)methyl 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoate (970 mg, 2.3 mmol) in dioxane (30 ml) and water (15 ml) was treated with lithium hydroxide (monohydrate) (145 mg, 3.5 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then evaporated in vacuo, the residue take up into water (50 ml) and washed with ether (100 ml). The aqueous layer was then acidified with 2M HCl the extracted with ether (2×150 ml). Organic layers combined, washed with brine, dried and evaporated in vacuo to afford the title product as a white solid (600 mg). MS (ES−) m/z 295 [M−H]− (C14H1035Cl2O3). 1H-NMR (400 MHz, d6-DMSO) δ 5.17 (2H,s), 7.17-7.20 (1H, m), 7.38-7.53 (6H,m), 13.4 (1H, s).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1C=CC=CC=1.[O:15]([CH2:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:15]([CH2:22][C:23]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)[C@@H]1CCCN1C(=O)COc1ccccc1
Temperature: 25 °C

Procedure:
2.53 grams (g) of L-proline and 20 milliliters (ml) of anhydrous pyridine are mixed in a flask cooled by an ice bath, and 3.42 g of phenoxyacetyl chloride is added dropwise over about a 20-minute period. The mixture is warmed by water bath to room temperature, and the solvent evaporated under reduced pressure (in vacuo), leaving a viscuous syrup. The syrup is dissolved in 15 ml water and the water is evaporated in vacuo. The residue is dissolved in 20 ml water, and the resulting solution is filtered, and subsequently treated with 10 ml of 2 N hydrochloride. The resulting precipitate, crude phenoxyacetyl-L-proline, is purified on a chromatographic column containing 80 g of silica gel. The column is eluted with a solvent mixture composed of equal volumes of isopropanol and toluene to provide phenoxyacetyl-L-proline.
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][O:12][C:13]([CH3:22])([C:18]([F:21])([F:20])[F:19])[C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CO>O>[C:1]1([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][O:12][C:13]([CH3:22])([C:18]([F:19])([F:20])[F:21])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(C)(OCc1ccc(-c2ccccc2)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(OCc1ccc(-c2ccccc2)cc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42 %

Procedure:
A mixture of (±)-methyl 2-[(4-phenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate (28.1g.), potassium hydroxide (5.6g.), methanol (200ml.) and water (25ml.) is stirred at ambient temperature for 2.5 hours. The suspension is separated by filtration and the filtrate evaporated in vacuo. The residue is mixed with water, and the solution is washed with light petroleum (b.p. 60°-80° C). The aqueous phase is acidified with concentrated hydrochloric acid then extracted with ether. The extracts are dried (Na2SO4) and evaporated. The residue is crystallised from light petroleum (b.p. 80-100° C.) to give (±)-2-[(4-phenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acid (11.3g.), m.p. 132°-134° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8].[H][H]>[C].[Pd].C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:2]([F:1])=[C:3]([CH:10]=1)[NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: [H][H]
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Nc1cc(N)ccc1F
Yield: 80.5 %

Procedure:
100.3 mg (10 wt %) of 5% palladium carbon (containing water) was added to a mixture of 1.00 g (4.39 mmol) of ethyl 2-fluoro-5-nitrocarbanilate and 20 ml of ethanol, and the resultant mixture was stirred until 309 ml of hydrogen was absorbed. The reaction mixture was filtered to remove the catalyst, and the solvent was then distilled off under a reduced pressure. Thus, 700 mg of the objective product (yield: 81%) was obtained in the form of light brown crystals.