Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]([C:11]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])=[C:4]2[C:3]=1[F:29].[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[C:16]([O:15][C:14]([N:13]([CH3:21])[C:11]([C:10]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:8][N:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:31]=3[CH3:30])[C:35]([OH:37])=[O:36])=[C:3]([F:29])[C:4]=12)=[O:12])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)c(F)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccn2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1F
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a degassed solution containing tert-butyl 5-chloro-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate (0.10 g, 0.24 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.078 g, 0.30 mmol), sodium carbonate (0.075 g, 0.71 mmol), dioxane (2.0 mL) and water (0.40 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.008 g, 0.007 mmol). The mixture was stirred at 95° C. for 18 h. The solution was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1 N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2×15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.467 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 522 (MH+).
Reaction SMILES: [I-].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C(#N)C>[CH2:17]([O:16][P:15]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:18]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=O)(Cc1ccccc1C(F)(F)F)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium iodide (3.85 g, 25.6 mmol, 1 equiv.) in acetonitrile at room temperature under argon is added neat 1-chloromethyl-2-trifluoromethyl-benzene (commercially available from Acros Organics USA). To the resulting milky suspension is added freshly distilled triethyl phosphite (4.26 g, 25.6 mmol, 1 equiv.) and the resulting solution is stirred overnight at room temperature. After that time further triethyl phosphite (2.13 g, 12.9 mmol, 0.5 equiv.) is added and the reaction mixture heated at reflux for 1 hour. After cooling down to room temperature all volatiles were evaporated under reduced pressure. The residue is taken-up in dichloromethane and filtered through paper and the filtrate is concentrated under reduced pressure to yield the desired material as a clear oil pure enough to be used in the following step without further purification (7.46 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](OCC)(OCC)OCC)[CH3:10]>C(OCC)(=O)C>[CH2:9]([O:11][C:12]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1)[CH3:10]
Reactant: CCOC(OCC)(OCC)OCC
Reactant: Nc1cccnc1N
Solvent: CCOC(C)=O
Product: CCOc1nc2cccnc2[nH]1
Temperature: 130 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
2,3-Diaminopyridine (7.84 g, 71.9 mmol) and tetraethoxymethane (35 mL, 167 mmol) were mixed, and the mixture was stirred at 130° C. for 2 hr. The mixture was cooled to room temperature, ethyl acetate (100 mL) was added thereto and the precipitated solid was collected by filtration to give the title compound (4.17 g, 36%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:9]O>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccnc1
Reactant: OO
Solvent: CC(=O)O
Product: N#Cc1ccc[n+]([O-])c1
Yield: 58.3 %

Procedure:
5.21 g of 3-cyanopyridine are completely dissolved in 50 ml of glacial acetic acid at 40° C., with stirring. Then 9.8 ml of a 30% aqueous solution of H2O2 are added and the mixture is heated, with stirring, to 100° C. for 2 hours. Thin-layer chromatography shows that the reaction is complete. The solvent is cautiously removed by evaporation and the beige solid is treated with 25 ml of ethanol, cooled and and filtered. The residue is dried at 35° C. under vacuum, affording 3.5 g (58.3% of theory) of 3-cyanopyridine-N-oxide as a white solid with a melting point of 172°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:12][CH:13](Br)[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][CH2:13][CH2:14][CH2:15][O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CCC(Cl)Br
Reactant: COc1cc(O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)cc(OCCCCl)c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A mixture of 3,5-dimethoxyphenol 100.0 g (0.6486 mole), chlorobromopropane 148.0 g (0.96 mole) and potassium carbonate 89.6 g (0.96 mole) was heated overnight at gentle reflux in 600 ml of acetone. The reaction mixture was cooled at room temperature, filtered, and stripped to dryness via a rotary evaporator. The resulting oil was dissolved in chloroform and the solution extracted with 5% aqueous sodium hydroxide; removal of chloroform gave a dark brown oil. A 5-g sample of the oil was pumped in vacuo overnight at 80° C. This produced 3.23 g (53.2% yield based on the aliquot taken) of dark brown oil. H1 (CDCl3): δ 2-2.14 (quintuplet, center methylene protons, 2H), 3.6-4.2 (m, aliphatic protons, 4H), 3.8 (s, OCH3, 6H), 6.1 (s,aromatic protons, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: NCCCO
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(NCCCO)nc21

Procedure:
The title compound, m.p. 222°-224° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-aminopropanol using procedures analogous to those described above, except that the mixture was heated in a pressure bottle at 210° C. for 40 min., and the product was crystallized from ethyl acetate.
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>ClC(Cl)C>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:9][C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2])=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 76 %

Procedure:
tert-Octylamine (51.7 g, 0.4 mol) and triethylamine (61.2 ml, 0.44 mol) in 260 ml of dichloroethane are introduced into a reactor. The mixture is heated to 70° C. and then 4-nitrobenzoyl chloride (77.9 g, 0.42 mol) is added in small portions in 50 minutes. The mixture is refluxed for 4 hours. The reaction mixture is poured into ice-cold water; the product is extracted with dichloromethane, drying is carried out, and the solvent is evaporated off. The beige precipitate obtained is recrystallized from a mixture of isopropyl ether and ethanol (10:1 ratio). After drying under vacuum, 84.6 g (yield: 76%) of 4-nitro-N-(tert-octyl)benzamide are obtained in the form of an off-white powder, which is used as it is in the following stage.
Reaction SMILES: C(O[C:4](=O)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>C1COCC1>[CH3:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)NC1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN[C@H]1CCCc2ccccc21
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(1,2,3,4-Tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester (5.0 g, 22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH4 (2.6 g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C. with stirring for 2 hours. On cooling, Na2SO4.10H2O (15.0 g) and ether (100 mL) are added to the mixture. The resulting mixture is stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1 N HCl (20 mL) and ether (20 ML) are added to the residue. The organic layer is separated and discarded. The aqueous layer is basified with 1 N NaOH and extracted with CH2Cl2 (2×25 mL). The combined extract is washed with water (2×), dried (Na2SO4) and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine as an oil. [α]RT=−10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30 (m, 1H), 7.06-7.20 (m, 3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:19]([OH:20])[C@@H:18]2[C@:5]3([N:9]([CH2:10][CH2:11][C:12]4[C:17]2=[CH:16][C:15]2[O:21][CH2:22][O:23][C:14]=2[CH:13]=4)[CH2:8][CH2:7][CH2:6]3)[CH:4]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C@@H:19]([OH:20])[C@@H:18]2[C@@:5]3([N:9]([CH2:10][CH2:11][C:12]4[C:17]2=[CH:16][C:15]2[O:21][CH2:22][O:23][C:14]=2[CH:13]=4)[CH2:8][CH2:7][CH2:6]3)[CH:4]=1
Reactant: COC1=C[C@@]23CCCN2CCc2cc4c(cc2[C@@H]3[C@@H]1O)OCO4
Solvent: ClC(Cl)Cl
Product: COC1=C[C@]23CCCN2CCc2cc4c(cc2[C@@H]3[C@@H]1O)OCO4

Procedure:
Batch A: 1H NMR 400 MHz (CDCl3) (d ppm): 6.06 (1H, OCH2O (+)-cephalotaxine) and 5.82 (1H, OCH2O (+)-cephalotaxine); 5.99 (1H, OCH2O (−)-cephalotaxine) and 5.76 (1H, OCH2O (−)-cephalotaxine). Presence of 11±5% de (+)-cephalotaxine. [a]22=−134,02° (c=0,214; CHCl3): calculated rate 25±5% Batch B: slightly racemized (1%) [a]19=−173,3° (c=0,208; CHCl3)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:12]([OH:14])=O)=[CH:5][C:6]2[N:10]=[N:9][NH:8][C:7]=2[CH:11]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH:28]1[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>>[N:30]12[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31]1)[CH:28]([NH:27][C:12]([C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:7]3[NH:8][N:9]=[N:10][C:6]=3[CH:5]=1)=[O:14])[CH2:29]2
Reactant: COc1cc2[nH]nnc2cc1C(=O)O
Reactant: NC1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1cc2[nH]nnc2cc1C(=O)NC1CN2CCC1CC2

Procedure:
Following the procedure of Example 22, 6-methoxy-1H-benzotriazole-5-carboxylic acid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH:34]=[O:35])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].CC(C)=O>C(O)C>[O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH2:34][OH:35])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:26])([CH3:27])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:17])([CH3:16])[CH3:18])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(C=O)nc2[N+](=O)[O-])CO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(CO)nc2[N+](=O)[O-])CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
107 mg (0.20 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-formyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 3.0 mL of ethanol, 10 mg (0.24 mmol equivalents) of sodium borohydride was added thereto, and the mixture was stirred at room temperature (25° C.) for 10 minutes. After completion of the reaction, acetone was added dropwise, and the mixture was concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/1) to give 101 mg (0.19 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-{(4-hydroxymethyl-2-nitro-1H-imidazol-1-yl)methyl}-1,3-dioxane.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([N:11]1[C:19]2[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[CH2:9][CH3:10])(=O)=O.[CH3:32]O[Na]>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:8]([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)([CH2:9][CH3:10])[CH2:7][CH2:6][O:5][CH3:32])=[CH:26][CH:27]=1
Reactant: CCC(CCOS(C)(=O)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CO[Na]
Solvent: CO
Product: CCC(CCOC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 40 °C

Procedure:
To a mixture of 3-(4-chlorophenyl)-3-(4-(methylsulfonamido)-1H-indol-1-yl)pentyl methanesulfonate (10 mg, 0.02 mmol), as described in Example 40 Step I, in methanol (2 mL) was added CH3ONa (21 mg, 0.4 mmol) at room temperature. Then the mixture was heated to 40° C. for 2 h. The solution was quenched with saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by Prep-HPLC (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title compound as a white solid. LC/MS m/z=421.1 [M+H]+.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C(N(CC)CC)C.[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](Cl)=O)[CH2:19][CH2:18]1)=[O:16]>O1CCCC1>[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)[CH2:19][CH2:18]1)=[O:16]
Reactant: CC(N)=NO
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](c2nc(C)no2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of acetamide oxime (0.19 g, 2.6 mmol) and triethylamine (0.36 ml, 2.6 mmol) in tetrahydrofuran (24 ml) was added trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (0.50 g, 2.4 mmol) at 0-5° C. After completed addition the cooling bath was removed, and the mixture was stirred for 30 minutes. The precipitated ammonium salts were removed by filtration and washed with tetrahydrofuran. The filtrate was concentrated to dryness. The residue was redissolved in 1,4-dioxane (24 ml). The mixture was treated with a catalytic amount of toluene-4-sulfonic acid monohydrate and heated at reflux over night (16 h). The solvent was evaporated. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.48 g, 88%) as light brown oil. MS m/e: 225 ([M+H]+)
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:23][O:24][C:25]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])([CH2:8][O:9][C:10]([C:19]([F:22])([F:21])[F:20])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH2:6][OH:7])=[N+:2]=[N-:3].CC(C)=[O:40].OS(O)(=O)=O.O=[Cr](=O)=O>CC(O)C>[N:1]([CH2:4][C:5]([CH2:8][O:9][C:10]([C:11]([F:14])([F:13])[F:12])([C:15]([F:18])([F:17])[F:16])[C:19]([F:21])([F:22])[F:20])([CH2:23][O:24][C:25]([C:30]([F:31])([F:32])[F:33])([C:26]([F:27])([F:28])[F:29])[C:34]([F:35])([F:36])[F:37])[C:6]([OH:40])=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)=O
Reactant: [N-]=[N+]=NCC(CO)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: [N-]=[N+]=NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of alcohol 11 (19.0 g, 31.8 mmol) at 0° C. was added dropwise a solution of Jones reagent (2.7 N, 31 mL). After addition, the reaction mixture was stirred at room temperature for 1 hour and 2-propanol (10 mL) was slowly added. The solvent was removed under vacuo and the residue was dissolved in ether. Washing the ether solution with water, separation the layers and the aqueous lay was extracted with ether. The combined organic lay was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give the acid 12 as a solid (18.5 g, 95%). mp. 97-98° C.; 1H NMR (400 MHz, CD3OD) δ 3.62 (s, 2H), 4.25 (d, J=8.8 Hz, 2H), 4.33 (d, J=8.4 Hz, 2H); 19F NMR (376 MHz, CD3OD) δ −71.16 (s); 13C NMR (100.7 MHz, CD3OD) δ 50.9, 53.6, 67.5, 81.2 (m), 121.6 (q, J=292.6 Hz), 171.9; MS (CI) m/z 612 (M++1, 100), 584 (80); HRMS (CI) Calcd for C13H8F18N3O4: 612.0227, Found: 612.0204.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 98 %

Procedure:
A solution of the ester of Step A (3.9 g, 15.2 mmol) in tetrahydrofuran (50 mL) was treated with 1 N sodium hydroxide (31 mL, 31 mmol) and then heated at reflux overnight. After cooling, the reaction mixture was concentrated in vacuo. The residue was acidified with 2N hydrochloric acid to give a white solid which was collected by filtration and dried under vacuum to provide the title compound (3.4 g, 98.0%) as a white solid, m.p. 250-254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:15][CH3:16])([CH2:12][CH:13]=[CH2:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:24]Cl>CN(C)C=O>[CH3:32][O:31][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH3:19])[C:28]=1[O:29][CH3:30])[CH2:24][O:11][CH2:10][C@:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([NH:15][CH3:16])[CH2:12][CH:13]=[CH2:14]
Reactant: C=CC[C@](CO)(NC)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@](COCc1cc(OC)c(OC)c(OC)c1)(NC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Under argon, a solution of 2-(S)-(3,4-dichlorophenyl)-2-methylamino-4-penten-1-ol (8.5 g) in anhydrous N,N-dimethylformamide (50 mL) was added to a suspension of sodium hydride (1.5 g) in anhydrous N,N-dimethylformamide (50 mL) under cooling with ice, and the mixture was stirred for 1 hour at room temperature. A solution of 3,4,5-trimethoxybenzyl chloride (7.8 g) in anhydrous N,N-dimethylformamide (30 mL) was added to the reaction mixture under cooling with ice, and the resultant mixture was stirred overnight at room temperature. The reaction mixture was poured into ice-water, extracted with ether, sequentially washed with water and saturated brine, and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 2:1→ethyl acetate), to thereby give the title compound (11.8 g, 81.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[H-].[Na+].CI.[C:47](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][CH3:47])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (1 ml), then thereto is added sodium hydride (63%,11 mg) under ice-cooling, and the mixture is stirred at 0° C. for 30 minutes. Methyl iodide (23 μl) is added thereto, and the mixture is stirred for 2 hours under ice-cooling. To the reaction mixture is added 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=4:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methoxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (120 mg). MS (m/z): 614 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]2[C:18]=1[CH:17]=[N:16][CH:15]=[CH:14]2.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:19][C:11]2[CH:12]=[C:13]3[C:18](=[C:9]([Br:8])[CH:10]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Oc1cc(Br)c2cnccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(Br)c3cnccc3c2)cc1
Reaction time: 15 h
Yield: 70.9 %

Procedure:
Triethylamine (0.137 mL) was added to a dichloromethane (5 mL) solution of Intermediate 7 (100 mg) and p-toluenesulfonic acid chloride (66 mg; WAKO) at room temperature and the resulting mixture was stirred as it was for 15 hours. The resulting mixture was diluted with dichloromethane and washed with water, the organic layer was dried, then the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (Yamazen; n-hexane/ethyl acetate) to give the title compound (92.9 mg).