Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24](=[O:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CCO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]1[CH:24]([OH:26])[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.50 g of 1-benzyloxycarbonyl-2-acetyl-4-tert-butyloxycarbonyl-piperazine in 150 mL of 1:1 THF-EtOH was added 1.35 g of sodium borohydride, in several portions. The mixture was stirred at room temperature for 30 min, then quenched by slow addition of 100 mL of saturated NaHCO3. The mixture was diluted with 150 mL of water and the phases were separated. The aqueous phase was extracted with 2×100 mL of EtOAc. The combined organics were washed with 100 mL of brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluting with 2:1 hexanes-EtOAc, to yield 3.05 g of diastereomer 1 and 272 g of diastereomer 2. Data for diastereomer 1. Rf 0.63 (1:1 hexanes-EtOAc). 1H NMR (500 MHz, DMSO-d6, 75° C.): δ7.24-7.40 (m, 5H), 5.10 (s, 2H), 4.52 (d, J=5.0 Hz, 1H), 4.20 (d, J=13.1 Hz, 1H), 3.71-3.92 (m, 4H), 2.76-2.96 (m, 3H),1.40 (s, 9H), 1.00 (d, J=5.5 Hz, 3H). Mass spectrum (ESI) 309.1 (M-BOC). Data for diastereomer 2. Rf 0.53 (1:1 hexanes-EtOAc). 1H NMR (500 MHz, DMSO-d6, 75° C.): δ7.23-7.40 (m, 5H), 5.08 (s, 2H), 4.41 (br s, 1H), 3.74-3.92 (m, 5H), 3.02-3.11 (m, 1H),2.98 (dd, J=3.4, 13.5 Hz, 1H), 2.28 (br t, J=11.7 Hz, 1H), 1.40 (s, 9H), 1.16 (d, J=6.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)[N:8]=[C:9]2O)=[CH:4][C:3]=1[O:23][CH3:24].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:23][CH3:24])=[C:2]([F:1])[CH:11]=2)[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[N:8]=1
Reactant: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(O)c2cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(Cl)c2cc1F
Yield: 94.6 %

Procedure:
A solution of 7-fluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinolin-1-ol (1.8 g, 5.50 mmol) in POCl3 (7.69 ml, 82 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes. The product fractions were collected and the solvent removed under vacuum to give 1-chloro-7-fluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinoline (1.8 g, 95% yield). MS: MS m/z 346.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:37][C:38]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:39]=1[CH2:40]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:40][C:39]2[C:42]([F:46])=[CH:43][CH:44]=[CH:45][C:38]=2[Cl:37])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Reactant: Fc1cccc(Cl)c1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cc3c(F)cccc3Cl)n(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
A solution of 500 mg (1.14 mmol) of the compound of example 16, step 1, in THF (8 ml) was cooled to −78° C. with an acetone/dry ice bath. Within 10 min a solution of n-butyllithium (0.55 ml, 1.36 mmol, 2.5 M in hexane) was added followed by 0.36 ml (2.27 mmol) of 2-chloro-6-fluoro-benzyl bromide. The cooling bath was removed and the reaction mixture was allowed to warm up slowly to room temperature and stirred overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC. The eluate was lyophilized overnight to give 216 mg of the title compound.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH:19]([CH3:21])[CH3:20].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:18]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CI
Reactant: COC(=O)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1OCC(C)C

Procedure:
In 100 ml of N,N-dimethylformamide are dissolved 10.0 g of methyl salicylate, 18.1 g of potassium carbonate and 11.3 ml of isobutyl iodide. The solution is heated under reflux for 1.5 hours with stirring. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2.0 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) to obtain 4.2 g of methyl 2-isobutoxybenzoate as a light yellow oily product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:35](Cl)=[O:36]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:35](=[O:36])[C:34]2[CH:33]=[C:32]([O:31][CH3:30])[C:40]([O:41][CH3:42])=[C:39]([O:43][CH3:44])[CH:38]=2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Product: COc1cc(C(=O)N[C@H]2C[C@@H](C(=O)N3CCN(c4ccccc4C#N)CC3)N(Cc3ccccc3)C2)cc(OC)c1OC
Yield: 17.9 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 3,4,5-trimethoxy-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (13.4 mg, 17.9%) as light yellow oil. MS m/e=583.7 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].ClC(OCC)=O>>[C:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:23][CH2:24][N:25]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Agent: CCOC(=O)Cl
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)Nc3ccccc3)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid m-tolylamide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and butyryl chloride for ethyl chloroformate. 1H NMR (300 MHz, CDCl3) δ 8.65 (d, 1H), 8.35 (d, 1H), 8.27 (m, 2H), 7.70 (m, 2H), 7.60 (s, 1H), 7.52 (m, 1H), 7.28 (m, 2H), 7.02 (d, 1H), 5.10 (d, 1H), 4.07 (m, 1H), 3.58 (m, 1H), 3.23 (m, 1H), 2.90 (m, 1H), 2.50 (m, 1H), 2.14 (m, 2H), 1.57 (m, 4H), 1.21 (m, 1H), 1.04 (m, 1H), 0.89 (t, 3H); LC/MS m/z 494 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.C([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])Cl)[CH2:22][CH2:23][CH3:24].[NH4+].[Cl-]>O1CCCC1>[CH3:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)[C:2]([Sn:25]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:3]1
Reactant: Cn1nc(I)c2ccc(C(F)(F)F)cc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 132.7 %

Procedure:
To a solution of 3-iodo-1-methyl-6-(trifluoromethyl)-1H-indazole (491 mg, 1.51 mmol) in dry tetrahydrofuran (20 mL) was added drop-wise isopropylmagnesium chloride (1.66 mL, 2M in THF, 3.31 mmol) at −16° C. under N2 atmosphere. After stirring for 20 minutes, tributylchlorostannane (0.49 mL, 1.81 mmol) was added drop-wise at −16° C., then it was warmed to room temperature for 2 h. NH4Cl solution (2 mL) was added and product was extracted with dichloromethane (150 mL), then washed with water (3×20 mL) and brine (2×20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford 1-methyl-3-(tributylstannyl)-6-(trifluoromethyl)-1H-indazole (0.98 g, crude) as yellow oil which was used to next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.79 (d, 1H, J=11.4 Hz), 7.70 (s, 1H), 7.32 (d, 1H, J=8.4 Hz), 1.48-1.32 (m, 6H), 1.25-1.18 (m, 12H), 0.92-0.79 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[CH3:16][Zn]C>O1CCOCC1.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 3-bromo-4-(trifluoromethoxy)benzoic acid (923 mg, 3.24 mmol) and PdCl2(dppf) (95 mg, 0.13 mmol) were stirred in 1,4-dioxane (9 mL) in a three necked flask under argon atmosphere (a condensor was added to the flask). Dimethylzinc in toluene (3.2 mL of 2.0 M, 6.4 mmol) was added very slowly (caution: the reaction was very exothermic) and the mixture was stirred at room temperature for 1 hour before it was heated at 70° C. for 18 h. The mixture was cooled to room temperature before it was charged with additional dioxane (9 mL) and PdCl2(dppf) (100 mg). The mixture was cooled to 0° C. before additional dimethyl zinc in toluene (3.0 mL, 2.0M) was added. The ice bath was removed and the mixture was heated at 70° C. overnight. The mixture was cooled to room temperature and was quenched with methanol (2 mL) very slowly. The solution was diluted with ethyl acetate and was washed with 1N HCl (3×). The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness to yield 3-methyl-4-(trifluoromethoxy)benzoic acid (56%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:37]1([CH2:43][CH2:44][CH2:45]N)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C1COCC1>[N:37]1([CH2:43][CH2:44][CH2:45][NH:18][C:16]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Reactant: NCCCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCCN3CCOCC3)cc21
Reaction time: 18 h
Yield: 70 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 3-morpholin-4-yl-propylamine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-8 as an oil in 70% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([C:15]([CH3:17])=[O:16])C(OCC)=O)[CH3:8].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])=[C:22]([F:32])[CH:21]=1>CC(C)=O>[CH2:7]([CH2:9][C:15](=[O:16])[CH2:17][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:31])[C:27]([OH:29])=[O:28])=[C:22]([F:32])[CH:21]=1)[CH3:8]
Reactant: COC(=O)C(C)c1ccc(CBr)cc1F
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(=O)CCc1ccc(C(C)C(=O)O)c(F)c1
Yield: 59.9 %

Procedure:
To a suspension of anhydrous potassium carbonate (0.86 g, 6.2 mmol) in acetone (40 mL), ethyl 2-ethylacetoacetate (0.56 mL, 3.45 mmol) was added under stirring. After stirring for 15 minutes at room temperature, compound (20) (0.95 g, 3.45 mmol) was added, and the reaction mixture was refluxed for 12 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was treated with dichloromethane (50 mL). The organic layer was washed with a sodium bicarbonate solution and saline, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (7:2) solution followed by conventional decarboxylation and hydrolysis to give 0.55 g (45%) of compound (23) of interest as clear colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][CH3:27])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCCI
Reactant: OC1(c2cc(F)cc(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCN1CCC(O)(c2cc(F)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A mixture of 3-(3-chloro-5-fluorophenyl)pyrrolidin-3-ol (1.10 g, 5 mmol), acetonitrile (20 mL), potassium carbonate (1.4 g, 10.1 mmol) and iodopropane (1.13 mg, 6.65 mmol) was stirred at ambient temperature for 2 h. The temperature was shortly raised to 40° C. twice during this period. Water was added and the aqueous phase was extracted with ethyl acetate, the combined organic phase was dried (MgSO4), and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.57 g). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 157.2° C.; MS m/z (relative intensity, 70 eV) 257 (M+, 8), 228 (bp), 198 (46), 129 (36), 84 (59).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5](I)=[CH:4][C:3]=1[Br:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1.C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:4][C:3]=1[Br:10]
Reactant: OB(O)c1ccccc1
Reactant: Brc1cc(I)c(I)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1cc(-c2ccccc2)c(-c2ccccc2)cc1Br
Temperature: 82 °C
Reaction time: 24 h
Yield: 159.8 %

Procedure:
To a 200 ml Schlenk reaction vessel were added under a nitrogen atmosphere 3.074 g (6.30 mmol) of 1,2-dibromo-4,5-diiodobenzene synthesized in Synthetic Example 3, 600 mg (0.519 mmol) of tetrakis(triphenylphosphine)palladium (manufactured by Tokyo Chemical Industry Co. Ltd.), and 1.920 mg (15.7 mmol) of phenylboronic acid (manufactured by Wako Pure Chemical Industries, Ltd.). Further, 50 ml of toluene, 13 ml of ethanol, and an aqueous solution composed of 4.007 g (37.8 mol) of sodium carbonate and 16 ml of water were added. The whole was heated to 82° C. and stirred for 24 hours. After cooling to room temperature, toluene and water were added and phase separation was conducted. The organic phase was concentrated and the resulting residue was dissolved in 26 ml of toluene. Then, 1.0 ml of a 70% tert-butyl hydroperoxide solution (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto, followed by 2 hours of stirring at room temperature. The toluene solution was washed twice with water and then the organic phase was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane) to obtain a white solid of 1,2-dibromo-4,5-diphenylbenzene (1.953 g, yield 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[S:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16]1COC[CH2:17]1>ICC>[CH2:16]([S:12][C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=2[N:9]=1)[CH3:17]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCSc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Dissolve 5-nitro-3H-benzooxazole-2-thione (10.58 g, 53.9 mmol) in anhydrous THF (300 mL). Cool the mixture to 0° C. in an ice bath. Add NaH (4.90 g, 60% dispersion in mineral oil) slowly. Stir the resulting mixture at 0° C. for 10 min. Add iodoethane (20.0 mL, 0.250 mmol) to the stirring mixture. Allow the mixture to warm to room temperature and stir overnight. Adsorb the reaction mixture onto silica gel and subject to flash column chromatography in 2 batches (330 g, 120 g columns, eluting with 10-50% ethyl acetate/n-hexane both times) to yield the desired product (4.93 g, 41%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (d, J=2.4 Hz, 1H), 8.23 (dd, J=9.2, 2.6 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 3.37 (q, J=6.8 Hz, 2H), 1.45 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][N:5](C(OCC1C=CC=CC=1)=O)[CH2:6][C:7]([OH:9])=[O:8]>C1COCC1.[Pd]>[CH3:21][O:20][CH:3]([O:2][CH3:1])[CH2:4][NH:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(CN(CC(=O)O)C(=O)OCc1ccccc1)OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(CNCC(=O)O)OC
Reaction time: 2 h
Yield: 77.1 %

Procedure:
To a solution of compound 37 (425 mg, 1.43 mmol) dissolved in 20 mL of anhydrous THF in a Parr apparatus for hydrogenation, was added 160 mg of 10% Pd/C, the system was charged with 60 psi of H2, and the bottle was shaken for 2 h. The catalyst was filtered over Celite, washed with 20 mL of ethyl acetate and the combined filtrate was concentrated in vacuo to give 38 (180 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 3.36 (s, 6H), 3.42 (s, 2H), 4.08 (d, J=5.3 Hz, 2H), 4.54 (t, J=5.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])=[CH:10][CH:9]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Cl:29][CH2:30][C:31]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:20])([F:21])[CH:17]([F:18])[F:19])=[CH:10][CH:9]=1)=[O:32]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)CNc1ccc(OCC(F)(F)C(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)CCl)c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2.1 g of the resulting N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline, 1.1 ml of triethylamine and 50 ml of dichloromethane was added dropwise a solution of 0.6 ml of chloroacetyl chloride in 6 ml of dichloromethane with ice cooling and the resulting mixture was stirred at room temperature for five hours. To the reaction solution was added 50 ml of dichloromethane and 100 ml of ice water to factionate. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane [1:2 v/v]) to give 2.4 g of N-chloroacetyl-N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline as a yellow oily substance.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:43]>C(O)(C)C>[ClH:43].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([C:38]([F:41])([F:39])[F:40])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(C(F)(F)F)cc32)CC1
Agent: Cl
Solvent: CC(C)O
Product: O=c1ccc2ncc(C(F)(F)F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 80 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-oxo-7-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 1.4 mL of isopropyl alcohol, 57 μL of concentrated hydrochloric acid was added, and the mixture was heated under reflux while stirring for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, and the solid was filtered off to obtain 70 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one hydrochloride as a light brown solid.
Reaction SMILES: [C:1]([CH:8]([CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[OH:11])[OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClCCl.C(N(CC)CC)C.[CH2:29]([O:31][P:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35])[CH3:30]>O>[CH2:29]([O:31][P:32]([O:11][C@H:10]([C@@H:8]([OH:9])[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:33][CH2:34][CH3:35])=[O:36])[CH3:30]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CC(C)(C)OC(=O)C(O)C(O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)O[C@@H](C(=O)OC(C)(C)C)[C@@H](O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.4 %

Procedure:
(Step 1) To di-tert-butyl tartrate (182 mg, 0.692 mmol), dichloromethane (1.73 mL), triethylamine (0.145 mL, 1.04 mmol), and diethylchlorophosphoric acid (0.050 mL, 0.346 mmol) were added, and the resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture, water was added, and the resulting mixture was extracted with chloroform. The organic layer was dried, over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica, gel column chromatography (ethyl acetate/n-hexane=5/95 to 30/70), whereby di-tert-butyl (2R,3R)-2-(diethoxyphosphoryloxy)-3-hydroxysuccinate (46 mg, 33%) was obtained.