Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][CH:8]([CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:9](OCC)=[O:10])=O)C.[CH3:30][NH2:31]>C(O)C>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH:14]([CH:8]1[O:7][CH2:6][C:4](=[O:3])[N:31]([CH3:30])[C:9]1=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)COC(C(=O)OCC)C(Oc1ccccc1OC)c1ccccc1
Reactant: CN
Solvent: CCO
Product: COc1ccccc1OC(c1ccccc1)C1OCC(=O)N(C)C1=O
Yield: 64 %

Procedure:
4 g of ethyl 2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxyphenoxy)propionate dissolved in 30 ml of ethanol was heated in an autoclave at 150° C. for 20 hours with 20 ml of a 10% ethanolic solution of methylamine. Cooling was allowed to take place and the solvent was removed under reduced pressure. The residue was crystallized from ethanol to obtain 2.26 g of 2-[α-(2-methoxyphenoxy)-benzyl]-4-methyl-morpholin-3,5-dione. Yield 64%.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:36](O)(=O)C(O)=O>>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][N:28]([CH3:36])[CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNC[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Reactant: O=C(O)C(=O)O
Agent: C=O
Product: CN(CC(=O)O)C[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 0.13 g of ethyl ester of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]glycine obtained in Example 40 were added 2 ml of formalin and 2 ml of oxalic acid; The mixture was heated at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was subjected to extraction with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogencarbonate, then with water, followed by drying. The solvent was distilled off under reduced pressure. The residue was dissolved in 6 ml of methanol. To the solution were added 0.2 g of potassium carbonate and 2 ml of water. The mixture was stirred for 2 hours at 60° C. The reaction mixture was concentrated under reduced pressure, to which was added water, followed by extraction with ether. The aqueous layer was acidified to pH 4 with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. From the residue was obtained 0.1 g of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]-N-methylglycine as crystals, m.p. 195°-197° C.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:18][N:17]([C:19](OC(C)(C)C)=O)[CH2:16]2)[CH2:11][CH2:10]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:6][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:16][N:17]([CH3:19])[CH2:18]2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNC1CCN(C2CN(C)C2)CC1
Yield: 83.3 %

Procedure:
To a solution of tert-butyl 3-[4-(tert-butoxycarbonylamino)piperidin-1-yl]azetidine-1-carboxylate (2.49 g) in tetrahydrofuran (100 ml) was added lithium aluminium hydride (930 mg) while stirring in an ice bath, followed by stirring under a nitrogen atmosphere in an ice bath for 10 min and at room temperature for 10 min. The reaction mixture was refluxed under a nitrogen atmosphere for 1.5 hrs. The reaction mixture was cooled in an ice bath, and then water (0.93 ml), a 5N aqueous solution of sodium hydroxide (0.93 ml), and water (4.65 ml) were added thereto in this order, followed by stirring at room temperature for 24 hrs. The insoluble portion was filtered off and washed with ethyl acetate to give a filtrate, which was concentrated to provide the titled compound (1.07 g, 83.4%) as a pale yellow oil.
Reaction SMILES: C[O-].[Na+].CO.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.Cl[CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(OCC)C.CN(C)C=O>[O:12]([CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCC1CCNCC1
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc(OCC2CCNCC2)cc1
Yield: 32.4 %

Procedure:
To a mixture of 28 ml of 30% sodium methanolate solution and 50 ml methanol, there are added 14.1 g (0.15 mole) of phenol. The reaction mixture is evaporated, mixed with 50 ml of N,N-dimethyl formamide and 7.8 g (0.05 mole) of 4-chloromethylpiperidine hydrochloride and heated for 18 hours at 70°-80° C. After cooling, the reaction mixture is mixed with diethyl ether, washed with water and dilute aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and evaporated in a vacuum. There are obtained 3.1 g of 4-phenoxymethylpiperidine (32% of theory); m.p. 41°-42° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]([CH3:17])[CH:11]2[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Cl:23][C:24]1[C:33](Cl)=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.O>COCCOCCOC>[Cl:23][C:24]1[C:33]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([O:7][CH3:6])=[CH:16][CH:15]=3)[CH:11]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]2[CH3:17])=[N:32][C:31]2[C:26]([N:25]=1)=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: COC(=O)CC1c2cc(OC)ccc2NC1C
Reactant: Clc1nc2ccccc2nc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: COC(=O)CC1c2cc(OC)ccc2N(c2nc3ccccc3nc2Cl)C1C

Procedure:
Anhydrous sodium acetate (3.6 g.) was added to a mixture of methyl 5-methoxy-2-methylindolin-3-ylacetate (8.0 g.) and 2,3-dichloroquinoxaline (6.8 g.) in diethyleneglycol dimethyl ether (150 ml.), and the mixture was heated under reflux for 12 hrs. The mixture was then cooled and poured into water (800 ml.), and the aqueous suspension was extracted with ethyl acetate (3 × 50 ml.). The combined extracts were washed successively with water (4 × 30 ml.) and a saturated aqueous solution of sodium chloride (50 ml.), and then dried (MgSO4) and evaporated. The resultant syrup was chromatographed on chromatographic silica gel (M.F.C., 300 g.) using an increasing gradient of diethyl ether in petroleum ether (b.p. 40°-60° C.) (polarity increased by incremental addition of 10% v/v ether.) The combined eluate was evaporated to give methyl 1-(3-chloroquinoxalin-2-yl)-5-methoxy-2-methylindolin-3-ylacetate, m.p. 155°-157° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>[Na+].[I-].CN(C=O)C>[C:13]([O:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])(=[O:15])[CH3:14]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)c1ccc(F)cc1F
Temperature: 20 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of NaI, and 3L of DMF. Stir the mixture at 20° C. for 18 hr. then concentrate it to 1L. Pour the residue into 6L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluting with CH2Cl-2-hexane to obtain 198 g of the title compound. ##STR100##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][N:15]=[N+:16]=[N-:17])([F:13])[CH2:10][C@H:9]1[C:18]([O:20]CC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:30][C:31]1[CH:32]=[C:33]([C@H:37]([NH2:40])[CH2:38][F:39])[CH:34]=[CH:35][CH:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][N:15]=[N+:16]=[N-:17])([F:13])[CH2:10][C@H:9]1[C:18](=[O:20])[NH:40][C@@H:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([Br:30])[CH:32]=1)[CH2:38][F:39])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@](F)(CN=[N+]=[N-])C[C@H]1C(=O)OCc1ccccc1
Reactant: N[C@H](CF)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@](F)(CN=[N+]=[N-])C[C@H]1C(=O)N[C@H](CF)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-4-azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (500 mg, 1.32 mmol) in methanol (20 mL), 1M sodium hydroxide (2.64 mL, 2.64 mmol) was added. The solution was stirred for 2 hours at RT then was diluted with water, the methanol was removed under reduced pressure. The aqueous layer was washed with Et2O (2×100 mL). The aqueous layer was acidified until pH 3 with 2N HCl and extracted with EtOAc (2×100 mL), dried with Na2SO4, filtered and concentrated. To the residue (100 mg, 0.34 mmol), (S)-1-(3-bromo-phenyl)-2-fluoro-ethylamine (described in Part C) (83 mg, 0.38 mmol) and HBTU (197 mg, 0.52 mmol) in DMF (5 mL) was added DIPEA (0.12 mL, 0.69 mmol). The reaction mixture was stirred for 16 h at RT then poured into water and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC/MS): 488 [M+H]+, 532 [M+HCOO]−; tR (HPLC conditions f): 2.32 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH:17]=O)[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OC(=O)C)C.CCCCCCC>[C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1COCCN1
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC=O)C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H]1Oc2ccc(F)cc2N(CCN2CCOCC2)C(=O)[C@H]1NC(=O)OC(C)(C)C
Yield: 75.9 %

Procedure:
0.10 mg (0.28 mmol) [(6R,7S)-2-Fluoro-6-methyl-8-oxo-9-(2-oxo-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester in 4 ml methanol was reacted with 0.036 ml (0.40 mmol) morpholine, 0.07 ml acetic acid and 0.03 g sodium cyanoborohydride at room temperature. Chromatography on silicagel with ethylacetate/heptane 1:1 yielded 0.09 g (73%) [(6R,7S)-2-fluoro-6-methyl-9-(2-morpholin-4-yl-ethyl)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester, MS m/e (%): 424.3 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:14][C:15]1[C:16](F)=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>CCO>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=1[NH:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Reactant: CCOC(=O)c1cc(CC)sc1N
Solvent: CCO
Product: CCOC(=O)c1cc(CC)sc1Nc1c(Cl)cccc1[N+](=O)[O-]

Procedure:
Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate and 3-chloro-2-fluoronitrobenzene, m.p. 67°-70° C. (EtOH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:14])=[C:6]([C:10]([OH:13])=[CH:11][CH:12]=1)[C:7]([OH:9])=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([O:34][C:35]1[C:40]([CH2:41][NH:42][CH2:43][CH2:44][OH:45])=[C:39]([CH3:46])[CH:38]=[C:37]([CH3:47])[N:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:34][C:35]1[C:40]([CH2:41][N:42]([CH2:43][CH2:44][OH:45])[C:7](=[O:9])[C:6]2[C:10]([OH:13])=[CH:11][CH:12]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=2[CH3:14])=[C:39]([CH3:46])[CH:38]=[C:37]([CH3:47])[N:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOc1ccc(O)c(C(=O)O)c1C
Reactant: Cc1cc(C)c(CNCCO)c(OCc2ccccc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(O)c(C(=O)N(CCO)Cc2c(C)cc(C)nc2OCc2ccccc2)c1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a solution of 3-ethoxy-6-hydroxy-2-methylbenzoic acid (114d, 0.168 g, 0.856 mmol) in THF (4.0 mL) was added 1,1′-carbonyldiimidazole (0.155 g, 0.91 mmol), and the reaction was stirred at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, and 2-({[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}amino)ethanol (Cpd KK, 330 mg, 1.10 mmol) was added. Heating was then continued at 60° C. for 16 hour. The reaction mixture was cooled to room temperature, and 10M NaOH (0.3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and was then poured into ethyl acetate and washed with 1M KH2PO4 and water. The organic layer was concentrated and purified by column chromatography (0-80% ethyl acetate/dichloromethane) to give N-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-3-ethoxy-6-hydroxy-N-(2-hydroxyethyl)-2-methylbenzamide (114e, 0.274 g, 69% yield) as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@:11]([C:15]([F:18])([F:17])[F:16])([OH:14])[C@H:10]([OH:19])[CH2:9]1)C1C=CC=CC=1.N>CCOC(C)=O.CO>[F:18][C:15]([F:16])([F:17])[C@:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[OH:19]
Reactant: O[C@@H]1CN(Cc2ccccc2)CC[C@@]1(O)C(F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@@H]1CNCC[C@@]1(O)C(F)(F)F

Procedure:
The product was obtained analogously to intermediate product IP 5d starting from (3R,4S)-1-benzyl-4-trifluoromethylpiperidin-3,4-diol. Yield: 665 mg (91% of theoretical); C6H10F3NO2 (M=185.144); calc.: molpeak (M+H)+: 186; found: molpeak (M+H)+: 186; Rf value: 0.35 (silica gel, EtOAc/MeOH/conc. aqueous ammonia 7:3:0.3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([CH3:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:24][C:22]1[N:23]=[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:9](=[O:16])[N:10]([CH3:15])[CH2:11][CH2:12][N:13]3[CH3:14])=[CH:6][CH:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(C)C(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Temperature: 25 °C
Yield: 56.6 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a mechanical stirrer and reflux condenser was charged with 1k (780 mg, 3.56 mmol), 1l (998 mg, 3.73 mmol), cesium carbonate (2.36 g, 7.26 mmol) and 1,4-dioxane (40 mL). After bubbling nitrogen through the resulting solution for 30 minutes, Xantphos (0.162 g, 0.281 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.15 g, 0.165 mmol) were added, and the reaction mixture was heated at reflux for 16 h. After this time the reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was absorbed onto silica gel and purified by flash chromatography to afford a 57% yield (818 mg) of 1m as an orange solid: mp 206-207° C.; 1H NMR (500 MHz, CDCl3) δ 8.27 (bs, 1H), 7.72 (dd, 1H, J=2.0, 8.5 Hz), 7.36 (dd, 2H, J=2.0, 8.5 Hz), 6.73 (s, 1H), 3.71 (m, 1H), 3.69 (s, 1H), 3.52 (s, 3H), 3.21 (m, 1H), 3.01 (m, 1H), 2.97 (s, 3H), 2.67 (m, 1H), 2.19 (s, 3H); MS (ESI+) m/z 406 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH3:19])[CH:6]=[C:5]2[CH3:20].[CH:21]1([C:24]([NH2:26])=[O:25])[CH2:23][CH2:22]1.O1CCOCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:18][C:16]1[CH:15]=[CH:14][C:13]([CH3:19])=[C:12]([C:7]2[CH:6]=[C:5]([CH3:20])[C:4]3[C:9](=[CH:10][N:11]=[C:2]([NH:26][C:24]([CH:21]4[CH2:23][CH2:22]4)=[O:25])[CH:3]=3)[N:8]=2)[CH:17]=1
Reactant: Cc1ccc(F)cc1-c1cc(C)c2cc(Cl)ncc2n1
Reactant: NC(=O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(F)cc1-c1cc(C)c2cc(NC(=O)C3CC3)ncc2n1
Temperature: 90 °C
Yield: 74.9 %

Procedure:
To a mixture of 6-chloro-2-(5-fluoro-2-methylphenyl)-4-methyl-1,7-naphthyridine (140.1 mg, 0.4886 mmol) and cyclopropanecarboxamide (85.9 mg, 1.01 mmol) in 1,4-dioxane (4.0 mL, 51 mmol) was added palladium (II) acetate (11.9 mg, 0.053 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38.8 mg, 0.067 mmol), and cesium carbonate (417.3 mg, 1.281 mmol). The reaction vial was purged with nitrogen gas and then heated at 90° C. under a nitrogen balloon for 5 hours. Cyclopropanecarboxamide (38.0 mg, 0.447 mmol), palladium (II) acetate (32.0 mg, 0.143 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (78.9 mg, 0.136 mmol) were added and the reaction heated at 100° C. for 15 hours. The reaction mixture was then diluted in ethyl acetate, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 0.1227 g (78%) of N-(2-(5-fluoro-2-methylphenyl)-4-methyl-1,7-naphthyridin-6-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=5.239, M+H=336.1, method=E; 1H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 9.21 (s, 1H), 8.65 (s, 1H), 7.79 (s, 1H), 7.38 (m, 3.6H), 7.23 (td, J=8.5, 2.8 Hz, 1H), 2.66 (s, 3H), 2.37 (s, 3H), 2.11 (s, 1H), 0.93-0.81 (m, 4H).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>ClCCl>[F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N+:5]([O-:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ncccc1C(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C(F)F)ccc[n+]1[O-]
Temperature: 5 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
27.26 g of 3-difluoromethyl-2-methylpyridine (XVI) was dissolved in 700 ml of anhydrous dichloromethane, and under cooling with ice, to which 45.19 g of 3-chloro-perbenzoic acid was added, and the resulting mixture was stirred at 5° C. for 12 hours. The resulting organic layer was washed with 5% sodium carbonate solution, and thereafter, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol=9:1) to obtain 29.82 g of 3-difluoromethyl-2-methylpyridine N-oxide (XVII).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23]C)=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(=O)O)nc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)picolinate (200 mg, 0.60 mmol) was stirred at rt in THF/MeOH (1:1, v/v). 3N NaOH (0.2 mL, 0.60 mmol) was added and the resulting mixture was stirred at rt for 5 h. TLC indicated the reaction was complete. Most of the volatile solvent was evaporated under reduced pressure. The residue was acidified with 3N aq. HCl to pH˜5, and extracted with DCM (2×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)picolinic acid as a white semi-solid (200 mg, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17]NC(C2C3C(=CC=CC=3)N=CC=2)C)=[CH:5][CH:4]=1.[CH3:31][N:32]1[C:40]2[C:35](=[C:36]([CH:41]([NH2:43])[CH3:42])[CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1.COC1C(C2C=CC(OC)=CC=2)=CC(C=O)=CC=1.C([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:43][CH:41]([C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[CH2:34][CH2:33][N:32]3[CH3:31])[CH3:42])=[CH:5][CH:4]=1
Reactant: CC(N)c1cccc2c1CCN2C
Reactant: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Agent: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(-c2cc(CNC(C)c3cccc4c3CCN4C)ccc2OC)cc1
Yield: 55 %

Procedure:
The title compound was prepared by the same procedure for (6,4′-dimethoxy-biphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from 1-(1-Methyl-2,3-dihydro-1H-indol-4-yl)-ethylamine (528 mg, 3.0 mmol), 6,4′-Dimethoxy-biphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as white solid in 55% yield (221 mg, 5.5 mmol).
Reaction SMILES: C([N:8]1[C@@H:16]2[C@@H:11]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH:8]1[C@@H:16]2[C@@H:11]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CC[C@@H]3Cc4ccccc4C[C@@H]32)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc2c(c1)C[C@H]1CCN[C@H]1C2
Reaction time: 5 h
Yield: 69 %

Procedure:
A mixture of cis-1-benzyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (1.20 g, 4.6 mmol) and palladium hydroxide (0.91 g, 8.6 mmol) in degassed methanol (90 ml) was hydrogenated at 50° C. and 50 psi pressure for 5 h. The resultant mixture was cooled and filtered through kieselguhr. The filtrate was evaporated in vacuo to give the title compound as a colourless oil (0.55 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:21]([O:23][CH3:24])=[O:22])=[N:14][C:15]([N:18](C)[CH3:19])=[CH:16][CH:17]=2)[N:4]=1>C(Cl)(Cl)Cl>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:21]([O:23][CH3:24])=[O:22])=[N:14][C:15]([NH:18][CH3:19])=[CH:16][CH:17]=2)[N:6]=1
Reactant: COC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1
Solvent: ClC(Cl)Cl
Product: CNc1ccc(Oc2nc(OC)cc(OC)n2)c(C(=O)OC)n1
Yield: 10.7 %

Procedure:
Into a photoreaction flask having a capacity of 1 l, 20.0 g (60 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(N,N-dimethylamino)picolinate and 1,300 ml of chloroform were charged and irradiated by a 400 W high pressure mercury lamp for 24 hours. Chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=6:1 to 3:7) to obtain the desired product.