Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15][O:16][C:17]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:49]([CH2:51][CH2:52][O:53][P:54](Cl)[N:55]([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57])#[N:50].CN1C=CN=C1>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@H:13]([O:14][P:54]([O:53][CH2:52][CH2:51][C:49]#[N:50])[N:55]([CH:56]([CH3:57])[CH3:58])[CH:59]([CH3:60])[CH3:61])[C@@H:12]([CH2:15][O:16][C:17]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: COc1ccc(C(OC[C@H]2OC[C@H](OCc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cn1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H]2OC[C@H](OCc3ccccc3)[C@@H]2OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
To a cooled solution (0° C.) of 1,4-anhydro-2-O-benzyl-5-O-[bis(4-methoxyphenyl)(phenyl)methyl]D-ribitol (1.60 g, 3.04 mmol) and N,N-diisopropylethylamine (1.59 mL, 9.11 mmol) in DCM (20 mL), 2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (1.44 g, 6.08 mmol) and 1-methylimidazole (0.12 mL, 1.519 mmol) were added. The reaction mixture was warmed to ambient temperature and stirred for 90 min. The reaction was then quenched with methanol (5 mL) and stirred for 5 min. The solvent was then removed in vacuo, and the residue was purified by flash chromatography using 20% ethyl acetate in hexane to obtain 0.94 g (1.293 mmol, 42.6%) of the pure product. LCMS: for C42H51N2O7P calculated 726.3. found 727.3 [M+H]+ and 749.4 [M+Na]+. 31P NMR (400 MHz, CD3CN) δ: 149.94, 149.70.
Reaction SMILES: [C:1](=[O:19])([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[O:14][C:15]([F:18])([F:17])[F:16])[O:2][CH3:3]>C(OCC)(=O)C.[Pd]>[C:1](=[O:19])([O:2][CH3:3])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:14][C:15]([F:18])([F:17])[F:16]
Reactant: COC(=O)Oc1ccc([N+](=O)[O-])cc1OC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Oc1ccc(N)cc1OC(F)(F)F
Yield: 71.7 %

Procedure:
A solution of methyl 4-nitro-2-(trifluoromethoxy)phenyl carbonate (70 mg, 0.25 mmol) in ethyl acetate (10 mL) was stirred in presence of 10% Pd (27 mg) under H2 atmosphere for 4 h. The reaction was filtered through a pad of Celite and concentrated in vacuo to provide 4-amino-2-(trifluoromethoxy)phenyl methyl carbonate (45 mg, 72% yield). 1H NMR (400.0 MHz, CDCl3) δ 7.02 (d, J=8.7 Hz, 1H), 6.62-6.60 (m, 1H), 6.56 (dd, J=2.7, 8.7 Hz, 1H), 3.90 (s, 3H), 3.78 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[NH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([OH:17])[C:6]=2[CH:18]=1.[CH3:19]I.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:11])(=[O:12])[N:9]([CH3:19])[C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([OH:17])[C:6]=2[CH:18]=1
Reactant: COC(=O)C1=C(O)c2cc(Cl)ccc2S(=O)(=O)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(O)c2cc(Cl)ccc2S(=O)(=O)N1C
Yield: 81.3 %

Procedure:
14.5 gm (50 millimols) of methyl 6-chloro-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide were reacted with 21.3 gm (150 millimols) of methyl iodide and 50 ml of 1N sodium hydroxide in 165 ml of methanol, yielding 12.35 gm (81% of theory) of methyl 6-chloro-4-hydroxy-2-methyl-2H-1, 2-benzothiazine-3-carboxylate-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A 250 ml two-necked round-bottomed flask equipped with a magnetic bar, a thermometer and a reflux condenser is charged with DMF (30 ml), 4-chloro-3-trifluoromethyl-phenol (4.5 g), 2-chloro-4-methyl-5-nitro-pyridine (4.0 g) and potassium carbonate (6.4 g). The reaction mixture is stirred at ambient temperature for 1 hour, poured into water (300 ml), acidified with HCl 5 molar (15 ml) and then extracted with ethylacetate (4×50 ml). The combined organic layers are washed with brine (100 ml), dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification by flash chromatography over silica gel with hexane/ethyl acetate 7:3 (v:v) gives 7.03 g of the compound as a red solid (MP: 75-80° C.).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[C:6]([OH:14])[CH:5]=1.Br[CH2:16][C:17]#[CH:18]>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[C:6]([O:14][CH2:18][C:17]#[CH:16])[CH:5]=1
Reactant: CCC(=O)c1ccc(F)cc1O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(F)ccc1C(=O)CC
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a mixture of NaH (95%, 278 mg, 11 mmol) in DMF (20 mL) at 0° C., was added 1-(4-fluoro-2-hydroxy-phenyl)-propan-1-one (1.68 g, 10 mmol) in DMF (5 mL). After 15 min at 0° C., was 3-bromo-propyne (3.02 g, 20 mmol) added to the reaction mixture. After 1 h at 0° C., was the reaction mixture allowed to assume room temperature. The reaction mixture was extracted with H2O (100 mL). The H2O phase was washed with Et2O 3×100 mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, CH2Cl2), to give 1.40 g (68%) of 1-(4-fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]2[C:12](=O)[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=1.P(Cl)(Cl)([Cl:18])=O>O1CCOCC1>[Cl:18][C:12]1[C:13]2[NH:14][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=c1[nH]cnc2cc(-c3ccco3)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Clc1ncnc2cc(-c3ccco3)[nH]c12
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
A mixture of 6-(2-furyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (2.20 g) and phosphoryl chloride (10.7 g) was stirred at 100° C. for 20 min, dioxane (30 mL) was added, and the mixture was stirred at 100° C. for 3 hrs. After concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate-acetone (155 mL×4). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue washed with ethyl acetate-diethyl ether, and dried under reduced pressure at 60° C. to give the title compound (2.19 g).
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30](O)=[O:31])[CH:23]=[CH:24][CH:25]=1.S(Cl)(Cl)=O>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([N:1]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: O=C(CNc1ccccc1)OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OCc2ccccc2)c2ccccc2)c1
Yield: 21.8 %

Procedure:
The procedure is similar to that described in Example 28, but starting with benzyl 2-anilinoacetate (3.6 g), 2-[3-(3-methylphenyl)ureido]acetic acid (3.1 g) and thionyl chloride (1.65 g). The product obtained is purified by chromatography on silica gel (0.063-0.200 mm; 60 g) contained in a column 2 cm in diameter [eluant: cyclohexane/ethyl acetate (50:50 by volume)], collecting 20-cc fractions. Fractions 5 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, benzyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate (1.4 g), m.p. 140° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[OH:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2C1(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 18.15 g of 5-chloroisatin in 45 ml of THF is cooled to +4° C., 200 ml of a 2M solution of cyclohexylmagnesium chloride in ether are added dropwise and the mixture is stirred for 3 hours at RT. 900 ml of a saturated solution of ammonium chloride are added and the solvents are concentrated under vacuum. The aqueous phase is extracted with AcOEt, the organic phase is washed with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 4 g of the expected product after crystallization from a THF/AcOEt mixture.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].ON1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>C(Cl)Cl>[OH:27][CH2:26][C:25]([NH:24][C:2](=[O:3])[O:4][CH2:5][CH3:6])([CH3:29])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(N)CO
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl chloroformate (3 g, 0.027 mol.) and N-hydroxysuccinimide (3.8 g, 0.033 mol.) in 10 mL of DCM at 0° C. under nitrogen atmosphere was added N,N-Diisopropylethylamine (7.0 mL, 0.04 mol). The progress of the reaction was monitored by thin layer chromatography (TLC). After stirring for 3 hrs at room temperature. DCM was evaporated and the residue was dissolved in 10 mL of acetonitrile, cooled in an ice-bath and then added dropwise a solution of 2-amino-2-methyl-1-propanol (3.1 mL, 1.2 eq). The resulting mixture was stirred at ice-bath temperature for 1 h and then overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was filtered, and the precipitate was washed with 2×10 mL DCM and dried over sodium sulfate. After removing the solvent under reduce pressure, the residue was purified by silica gel column chromatography to give ethyl (1-hydroxy-2-methylpropan-2-yl)carbamate as a colorless oil
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:35]([OH:37])=[O:36])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=4[O:41][CH3:42])[C:35]([OH:37])=[O:36])=[CH:26][C:11]=3[C:12]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3OC)cc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a 150 mL sealed tube was added 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.252 g, 3 mmol), 3-borono-4-methoxybenzoic acid (0.882 g, 4.50 mmol), cesium carbonate (1.466 g, 4.50 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.069 g, 0.060 mmol), dioxane (18 mL) and water (3.60 mL). The vial was sealed and heated in an oil bath over night at 85° C. The reaction mixture was then filtered through celite and concentrated in vacuo. Cold 0.5N HCl was then added and the heterogeneous mixture was stirred for 30 minutes. The resulting product, a white solid was filtered, washed with water and dried overnight to give a quantitative yield of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxy benzoic acid which was carried on without further purification. LCMS m/z 420.88 (M+H), Rt 2.002 min., 88% purity.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:43])[C@H:17]([O:21][C:22]1[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:38])=[C:27]1[CH3:39])[CH:18]([CH3:20])[CH3:19]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:24]2[CH:23]=[C:22]([CH:42]=[CH:41][CH:40]=2)[O:21][C@H:17]([CH:18]([CH3:20])[CH3:19])[C:16]([O:15][CH3:14])=[O:43])[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(C)C
Agent: Cl
Product: COC(=O)[C@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:16])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=2[O:12][CH3:13])[N:5]=[C:4](Cl)[N:3]=1.[NH2:18][NH2:19]>CO>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:16])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=2[O:12][CH3:13])[N:5]=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: NN
Reactant: COc1cc(Cl)c2nc(Cl)nc(N)c2c1OC
Solvent: CO
Product: COc1cc(Cl)c2nc(NN)nc(N)c2c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
A mixture of 4-amino-2,8-dichloro-5,6-dimethoxyquinazoline (1.5 g, 0.0054 moles), anhydrous hydrazine (5 ml, 0.16 moles) and methanol (100 ml) was heated at reflux for 8 hours and stirred at room temperature for 16 hours. The mixture was cooled to 0° C. and the precipitate which formed was collected by filtration. Recrystallization of the solid from methanol followed by drying under vacuum at 55° C. afforded the product (1.12 g), mp 168°-169° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[N:20]1([CH:2]=[C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][CH:4]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: c1c[nH]cn1
Reactant: O=C1C(=CO)C(c2ccccc2)Oc2ccccc21
Solvent: CCO
Product: O=C1C(=Cn2ccnc2)C(c2ccccc2)Oc2ccccc21

Procedure:
A solution containing 1 g 3-hydroxymethylidene-flavanone and 0.3 g imidazole in 10 ml absolute ethanol is refluxed for 10 minutes then cooled on an ice bath. After evaporation the oil is dissolved in methylene chloride and purified by acidic extraction. The resulting oil is crystallized in a mixture of hexane and ethyl acetate. Pure 3-(1-imidazolyl)methylidene-flavanone is obtained as white crystals; m.p. 129°-131° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[F:17])[CH2:29][CH2:28]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)nn1C(C)(C)C

Procedure:
93 mg (97%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(2-fluorophenyl)piperazine (41 mg, 0.225 mmol), DIPEA (0.060 mL, 0.338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:33]([O:35]CC)=[O:34])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:33]([OH:35])=[O:34])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=3)[CH2:19][CH2:20]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)c(F)c(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCOc4cc(F)c(F)c(F)c4)CC3)c2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
A mixture of 0.8 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluoro-phenoxy)ethyl]piperidine-4-carboxylate in 50 cm3 of dioxane, 50 cm3 of methanol and 4.4 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 18 hours. A further 4.4 cm3 of aqueous 5N sodium hydroxide solution were added to the reaction mixture, which was stirred for 6 hours in the region of 70° C. After cooling to about 20° C., the reaction mass was concentrated to dryness under reduced pressure (1.1 kPa) at a temperature in the region of 5° C. The residue was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 4 cm; height 20 cm), eluting with a mixture of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and collecting 60-cm3 fractions. Fractions 8 to 19 were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and oven-dried under reduced pressure (10 kPa) at about 50° C. 0.59 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid melting at about 120° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:15]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:8][C:7]=2[C:6](=O)[NH:5][N:4]=1.P(Cl)(Cl)([Cl:21])=O.[OH-].[Na+]>>[Cl:21][C:6]1[C:7]2[CH:8]=[C:9]3[N:14]([C:15]=2[C:3]([C:2]([F:18])([F:17])[F:1])=[N:4][N:5]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(C(F)(F)F)c2c1cc1ccccn12
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1nnc(Cl)c2cc3ccccn3c12
Temperature: 25 °C
Yield: 100 %

Procedure:
Compound II (2.62 g, 10.3 mmol) and phosphorus oxychloride (3.18 mL, 34 mmoL) were combined and heated under reflux for 2 days. After cooling to room temperature, the reaction mixture was poured into ice water and made basic with aqueous sodium hydroxide (pH>7). The product was collected by filtration and dried in a vacuum oven overnight to give 2.82 g (100%) of 1-chloro-4-trifluoromethylpyridazino[4,5-b]indolizine (III)
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.Cl.[N:16]([O-])=[O:17].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[N:16]=[O:17]
Reactant: C=C(C)Cn1c(N)cc(=O)n(C)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=C(C)Cn1c(N)c(N=O)c(=O)n(C)c1=O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Methallylamine (211 g, 2.97 mol) is added to a solution of concentrated hydrochloric acid (250 ml) in water (1.91), followed by portionwise addition of potassium cyanate (240 g, 2.97 mol). The reaction is then heated for 2 hours at 80° C., prior to cooling and evaporation to afford (2-methyl-allyl)-urea (244.5 g), mp 114-115° C. The urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride (536 ml) and the reaction is heated at 70° C. for 1 hour, cooled to 0° C. and diluted with ether. The resultant solid is collected by filtration, washed with ether, suspended in water (2.21) and heated to 75° C. 2M aqueous sodium hydroxide solution is then added portionwise over 30 min to maintain pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 ml), further cooled to 10° C. and the resultant solid is collected by filtration, washed with cold water and dried to afford 6-amino-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 267-269° C. The uracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20° C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour. After standing overnight, the reaction is cooled to 5° C. and the solid collected by filtration to give 6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 162-163° C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.55 l) and concentrated hydrochloric acid (72 ml). A solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30 minutes and the reaction is stirred at 20° C. for 3 hours. The solid is collected by filtration, washed successively with water, methanol and ether to afford 6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyrimidine-2,4-dione, mp 213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water (950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69 mol) is added portionwise. After cooling to room temperature, the solid is collected by filtration to afford 5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 152-153° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[C:17]([CH2:20]P(=O)(OC)OC)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9](/[CH:10]=[CH:18]/[C:17](=[O:19])[CH3:20])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Reactant: COP(=O)(CC(C)=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)/C=C/c1cccc(Oc2ccc(F)cc2)c1

Procedure:
A mixture of the product from step (c) (8.9 g). dimethyl acetylmethylphosphonate (6.84 g), anhy. potassium carbonate (11.37 g) and dry THF (100 ml) was heated under N2 at 50°-55° C. for 20 hours. The mixture was then cooled and filtered, the residue washed with THF, and the filtrate and washings combined and stripped to give a pale orange oil which was eluted through a silica gel column using ether/40-60 pet. ether (1:2) and the eluate stripped and dried under high vacuum to give the desired product as a very pale yellow, viscous oil (5.59 g).