Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:7]2)([O-])=O.C(=O)(O)[O-].[Na+].S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>S(=O)(=O)(O)O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([O:16][CH2:27][CH3:28])=[O:15])[CH2:7]2
Reactant: O=C(O)CC1Cc2ccc([N+](=O)[O-])cc2C1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC1Cc2ccc(N)cc2C1

Procedure:
A solution of (5-nitro-indan-2-yl)-acetic acid [2.22 g, Reference Example 9(a)] in ethanol (100 ml) containing sulfuric acid (5 drops) was refluxed for 4 hours, after which HPLC showed only a trace of free acid remaining. The mixture was treated with solid sodium bicarbonate to neutralise the sulfuric acid and then filtered. The filtrate was placed under a nitrogen atmosphere then 10% palladium on carbon (0.14 g) was added. The mixture was stirred rapidly and hydrogen was bubbled through the solution from a balloon. The reaction was monitored by HPLC until reduction was completed (4 hours) when the reaction mixture was filtered through a pad of celite. The filtrate was evaporated to give the title compound (2.16 g) as a dark red oil which was used without further purification.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11](=[O:15])[CH2:12][CH2:13][Cl:14])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:22]>Cl.O>[Cl:14][CH2:13][CH2:12][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:22])[CH:10]=2)[CH2:6][CH2:7]1)=[O:15]
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc2c(c1)N(C(=O)CCCl)CC2
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: O=C(CCCl)N1CCc2ccc(F)cc21
Temperature: 10 °C
Yield: 76 %

Procedure:
1.12 g (5.0 mmol) of 6-amino-1-(3-chloropropionyl)indoline (prepared as described in Preparation 6) were suspended in 20 ml of 6 N aqueous hydrochloric acid, and a solution of 380 mg (5.5 mmol) of sodium nitrite in 5 ml of water was added to the suspension while ice-cooling so that the internal temperature was maintained at 10° C. or lower. The mixture was then stirred while ice-cooling for 30 minutes. At the end of this time, 2.0 mg (8.4 mmol) of fluoboric acid (as a 42% w/v aqueous solution) were added to the mixture, and the resulting mixture was stirred at 0° C. for 1 hour. The precipitated salt was collected by filtration. This salt was dried over phosphorous pentoxide in a desiccator under reduced pressure by means of a vacuum pump overnight to obtain 1.23 g (3.8 mmol) of the title compound as a solid (yield: 76%).
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[C:7](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)\[CH2:8][OH:9])(=[O:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:4][CH2:5]/[C:6](/[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1)=[C:7](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)\[CH:8]=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\CO)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\C=O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
A mixture of the acetate from Example 2 (215 mg) and MnO2 (1.2 g) in 30 mL of CH2Cl2 was stirred for 12 h at r.t., and then filtered through a pad of celite. The filtrate was concentrated to give 160 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[Br:23][CH2:24][CH2:25][CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:25][CH2:24][Br:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCCBr)cc1)Oc1ccccc1
Yield: 89.2 %

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (4.0 g, 13.3 mmol) and 1,3-dibromopropane (7.0 mL, 66.6 mmol) are dissolved in methyl ethyl ketone (100 mL). Powdered K2CO3 (2.4 g, 17.3 mmol) is added. The mixture is heated under reflux for 4 h, cooled, filtered and concentrated to an oil. The crude oil is chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:4) to afford the title compound (5.0 g, 89%). MS (ESI) m/z 421 (M+H)+. Step 2.
Reaction SMILES: [CH:1]1([CH2:7][PH:8](=[O:10])[O-:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](N(CC)CC)[CH3:12].C(OC(Cl)=O)C>O1CCCC1>[CH:1]1([CH2:7][PH:8](=[O:9])[O:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[PH]([O-])CC1CCCCC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCO[PH](=O)CC1CCCCC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
19.3 g of cyclohexylmethylphosphinate are is dissolved in 60 ml of absolute tetrahydrofuran under an inert atmosphere. The solution is cooled to 0° C. and a suspension forms which is treated with 12.14 g of triethylamine. An exothermic reaction occurs. The suspension is re-cooled to 0° C. before dropwise addition of 13.02 g of ethylchloroformate. A further exothermic reaction with gas-evolution is observed together with the formation of a white precipitate. The resulting suspension is warmed to 20° and stirred for 20 hours. The solid is removed by filtration and the filtrate is evaporated to dryness. The residue is dissolved in dichloromethane and washed with water. Drying and removal of the solvent affords a pale yellow oil. Distillation under high vacuum affords ethyl cyclohexylmethylphosphinate, b.p. 120°-130° C./2×10-1 mbar. 'H-NMR (CDCl3): δ (ppm)=7.17 (1H, d, t, 5=527 MZ, P-H), 4.13 (2H, m, CH2OP), 1.95-1.58 (7H, m, 3×CH2 +CH), 1.38-0.95 (6H, m, 3×CH2).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14](Cl)=[CH2:15])[C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.C1(C)C(C)=CC=CC=1.C(=O)([O-])O.[K+]>[Cl-].[Zn+2].[Cl-].O>[NH:12]=[C:10]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH2:13][C:14](=[CH2:15])[S:11]1
Reactant: C=C(Cl)CN(C(N)=S)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: C=C1CN(c2cccc(C(F)(F)F)c2)C(=N)S1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (2.94 g) and zinc chloride (6.08 g) were added to xylene (50 ml) at room temperature, and the mixture was heated to 90° C. and stirred at the same temperature for 1.5 hour. After cooling, water was added to the reaction mixture, which was neutralized by addition of potassium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, and the residual oil was subjected to preparative liquid chromatography, which afforded 1.92 g of 2-imino-3-(3-(trifluoromethyl)phenyl)-5-methylidenethiazolidine (74% yield). From the results of analysis by liquid chromatography, the purity was determined to be not lower than 99%.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[OH-].[Na+].CO>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])[C:21]2[C:22]([CH3:28])=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:27])=[O:20])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(C)c1N(CCCCCCCC(=O)O)C(=O)c1ccc(Cl)cc1

Procedure:
As described in example 1(b), the reaction is carried out with 15.8 g (38 mmol) of 8-[4-Chloro-N-(2.6-dimethylphenyl)-benzamido]-caprylic acid methyl ester, 2.2 g (55 mmol) of sodium hydroxide, 100 cc. of methanol and 5 cc. of water. Reaction time: 20 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:26]2[C:31]([CH:32]=O)=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:32]([C:31]3[C:26]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:27][CH:28]=[CH:29][CH:30]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccnc1N1CCCC1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccnc4N4CCCC4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 32.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2-Pyrrolidin-1-yl-pyridine-3-carbaldehyde (28.6 mg, 0.163 mmol) were reacted to produce 24 mg (34%) of the title compound. mp: 190° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 8.21 (m, 1H), 8.02 (s, 1H), 7.71 (d, J=8 Hz, 1H), 6.68 (s, 1H), 7.18 (s, 1H), 7.06 (d, J=8 Hz, 1H), 6.75 (t, 1H), 6.27 (m, 1H), 6.17 (m, 1H), 5.14 (t, J=8 Hz, 1H), 3.32 (s, 3H), 3.29 (s, 2H), 3.08 (m, 2H), 2.85 (s, 1H), 2.71 (s, 1H), 2.55 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.82 (m, 2H), 1.73 (m, 2H), 1.37 (d, J=8 Hz, 1H), 1.09 (t, J=8 Hz, 1H). MS: 494, 496 (M+H), HPLC: 3.19 min (G method).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[C:24]#[N:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[BH4-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][NH2:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2′-cyano-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.545 g, 1.5 mmol) and cobalt(Π) chloride hexahydrate (0.71 g, 3.0 mmol) in MeOH (60 mL) and THF (24 mL) was added sodium borohydride (0.58 g, 15.3 mmol), and the reaction was stirred at room temperature for 2 hours. 2N Aqueous HCl (67 mL) was added, and the mixture was concentrated. 2N Aqueous NH4OH was added until the solution was basic, and the mixture was extracted twice with CH2Cl2. The combined organic layers were washed three times with H2O, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([O:13][C@@H:14]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH3:15])[C@@H:9]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C@@H:8]1[CH2:37]OS(C)(=O)=O)(=O)=O.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C>[CH2:43]([N:50]1[CH2:37][C@@H:8]2[C@H:7]([CH2:12][CH2:11][C@H:10]([O:13][C@@H:14]([C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:17]=3)[CH3:15])[C@H:9]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:6]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: C[C@@H](O[C@H]1CC[C@H](COS(C)(=O)=O)[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCO
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C

Procedure:
In a pressure tube was placed a solution of crude [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]di(methylene) dimethanesulfonate (step H) in 20 mL ethanol and 1.2 mL (˜3 equiv.) benzylamine. The pressure tube was seated and heated at 150° C. in an oil bath for 3 hr. The tube was cooled to RT and opened. The resulting mixture was transferred to a round bottom flask and the solvent removed under vacuum. The residue was diluted with 100 mL EtOAc, washed with 20 mL 5N aq. NaOH, dried over MgSO4 drying agent, filtered and the solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc to give 1.6 g of the title compound. 1H-NMR (CDCl3): δ: 7.35–7.20 (5H, m), 7.50 (2H, s), 6.97 (2H, m), 6.85 (2H, t, J=8.2 Hz), 4.42 (1H, t, J=6.0 Hz), 3.75 (2H, d, J=13.4 Hz), 3.50 (2H, d, J=13.4 Hz), 3.30 (1H, m), 2.96 (1H, m), 2.52 (3H, m), 2.19 (2H, m), 1.98 (1H, m), 1.97 (1H, m), 1.86 (2H, m), 1.57 (1H, m), 1.33 (3H, t, J=6.0 Hz), 1.30(1H, m).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].N1C=CC=CC=1.Cl.N1C=CC=CC=1C(Cl)=[O:23]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:1]([NH2:8])=[O:23]
Reactant: Nc1ccccc1N
Reactant: O=C(Cl)c1ccccn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(=O)c1ccccn1
Yield: 60 %

Procedure:
Dissolving 5.0 g (17 mmol) of (4-bromo-phenyl)-(2-nitrophenyl)-amine into 50 milliliter of tetrahydrofuran, an aqueous solution prepared by dissolving 15 g (86 mmol) of sodium dithionite into 60 milliliter of water was added. Subsequently, adding 10 milliliter of methanol, the resultant solution was stirred at room temperature for 3 hours. After recognizing that the color (orange) of the resultant solution almost disappeared, water was added, followed by extracting with ethyl acetate. After sufficiently drying an organic layer with sodium sulfate, the solvent was removed by distillation, and as a result, phenylenediamine was obtained. Dissolving the resultant phenylenediamine into 150 milliliter of ethyl acetate, an organic layer was extracted. Further, 5.4 g (68 mmol) of pyridine, 3.6 g (23 mmol) of 2-picolinic acid chloride hydrochloride and catalyst amount of 4-dimethylaminopyridine (DMAP) were added to the organic layer, and the resultant solution was stirred at room temperature for 3 hours, followed by left standing for a night. After completion of the reaction, adding water, separation with filtration was carried out for precipitated solids and then, they were sufficiently washed with water and methanol, thereby obtaining 3.8 g of 2-picolinic acid amide as white solid (yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23].O1CCCC1>[Pt]=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=2)[CH:5]=[C:4]([Cl:19])[C:3]=1[N:20]=[CH:21][N:22]([CH3:23])[CH3:24]
Reactant: COc1ccc(C=Nc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1F
Agent: O=[Pt]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1F
Reaction time: 0.25 h

Procedure:
A 4.0 g. amount of N'-[2,6-dichloro-4-[(3-fluoro-4-methoxybenzylidene)amino]phenyl]-N,N-dimethylformamidine is dissolved in 100 ml. of warm tetrahydrofuran, then 500 mg. of platinum oxide that has been wetted with water is added and the mixture is hydrogenated in a Parr apparatus for 15 minutes. The reaction mixture is filtered and washed with tetrahydrofuran. The clear yellow solution is evaporated in vacuo to crystallize a solid. The solid is recrystallized from ethanol, filtered and washed with a small amount of ether to provide 2.0 g. of the desired product as granular yellow crystals, m.p. 138°-140° C.
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([Br:19])=[CH:4][N:3]=1.C[N:21]1C(=O)CCC1>N>[Br:19][C:5]1[C:6]2[C:7](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[C:2]([NH2:21])=[N:3][CH:4]=1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Br)ncc(Br)c2n1
Reactant: CN1CCCC1=O
Agent: N
Product: Nc1ncc(Br)c2nn(-c3c(Cl)cccc3Cl)cc12
Yield: 84 %

Procedure:
A solution of 4,7-dibromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (730 mg, 1.73 mmol) in NMP (6.5 mL) and 33% aqueous ammonia (3.5 mL) was sealed in a microwave vial and irradiated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with ether to afford the title compound as a beige solid (515 mg, 84% yield). LCMS (Method C): RT=2.00 min, m/z: 357 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH:16]=[C:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:24][CH:25]=1)[C:3]1[N:4]=[CH:5][CH:6]=[CH:7][N:8]=1
Reactant: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1ncccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CN(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
5-(4-[2-(N-Methyl-N-(2-pyrimidinyl)amino)ethoxy]benzylidene)-2,4-thiazolidinedione (2.4 g) in dry 1,4-dioxan (150 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (3 g) until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (mp 150-51° C.) was obtained after crystallisation from methanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[I:11]C1(OC(=O)C)COC(=O)N1OC(=O)C>ClCCl>[IH2+:11].[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1
Reactant: CC(=O)ON1C(=O)OCC1(I)OC(C)=O
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Product: [IH2+]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-dimethyl-4,6-dioxo-1,3-dioxane (0.30 mmol) was added under argon to a solution of the iododiacetoxy oxazolidinone analog 25 (0.30 mmol) in anhydrous dichloromethane (6 mL) and the solution was stirred at room temperature overnight. The solvent was then evaporated and the product purified by flash chromatography on silica gel using 60-70% ethyl acetate in hexane as eluent to give the iodonium ylide 2,2-Dimethyl-4,6-dioxo-1,3-dioxane iodonium ylide derivative 26 as a white solid in 16% yield.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25].O.[NH2:34][NH2:35].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:26]1([CH:24]([C:23]2[C:3]3[C:4](=[O:22])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:35][N:34]=2)[CH3:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NN
Reactant: CC(C(=O)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccc1)c1n[nH]c2c1c(=O)n(-c1cccc(C(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-phenylpropionyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (119 mg, 0.27 mmol) produced in Synthesis Example 38 in DMF (1 mL) was added hydrazine monohydrate (purity of 80%, 43 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution, and an oily substance was collected. To the oily substance was added isopropyl ether, and the mixture was heated. Then the resulting matter was allowed to stand to a room temperature for crystallization. The resulting crystal was separated by filtration and dried to give 3-(1-phenylethyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (69 mg, yield 59%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:15](OC1C=CC([N+]([O-])=O)=CC=1)=[O:16]>C(OCC)(=O)C.ClCCl>[CH:15]([N:8]1[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH:9]1[C:11]([O:13][CH3:14])=[O:12])=[O:16]
Reactant: COC(=O)C1CC2(CCN1)OCCO2
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1CC2(CCN1C=O)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24 g of methyl 1,4-dioxa-8-azaspiro[4.5]decane-9-carboxylate (111 mmol) are dissolved in 80 mL of ethyl acetate and 80 mL of dichloromethane. There are added 26 g of (4-nitrophenyl) formate (155 mmol), and the whole is stirred at ambient temperature for one hour. The reaction mixture is evaporated to dryness and taken up in ethyl acetate. The organic phase is subsequently washed in succession with a 1 N NaOH solution, water, and then with a saturated NH4Cl solution until a neutral pH is reached. It is subsequently dried over magnesium sulphate, filtered and concentrated to dryness. The oil so obtained is purified by flash chromatography (heptane/ethyl acetate gradient). The title product is obtained in the form of an oil.
Reaction SMILES: [CH2:1]([N:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5](=[O:7])[O-:6])[CH:2]=[CH2:3].Br[C:13]1[CH:14]=[C:15]2[C@@H:22]([NH2:23])[CH2:21][C:20]3([CH2:26][CH2:25][CH2:24]3)[O:19][C:16]2=[N:17][CH:18]=1.C([Li])(C)(C)C.[CH:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CCOCC>[CH2:1]([N:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5](=[O:6])[O-:7])[CH:2]=[CH2:3].[OH:37][CH:32]([C:13]1[CH:14]=[C:15]2[C@@H:22]([NH2:23])[CH2:21][C:20]3([CH2:26][CH2:25][CH2:24]3)[O:19][C:16]2=[N:17][CH:18]=1)[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: N[C@H]1CC2(CCC2)Oc2ncc(Br)cc21
Reactant: CC(C)(C)C=O
Agent: C=CCN(C(=O)[O-])C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)C(O)c1cnc2c(c1)[C@@H](N)CC1(CCC1)O2
Reaction time: 0.08 h

Procedure:
A solution of N-allyl-N-t-butylcarbamate-(4′S)-6′-(bromo)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-amine (4.12 g, 10.1 mmol) in ether (80 mL) was cooled to −78° C. and then t-butyllithium (12.5 ml, 21.3 mmol) was added and stirred for 15 minutes before the pivalaldehyde (3.80 ml, 35.0 mmol) (Note: freshly distilled) was added. After 5 minutes, LC-MS shows the starting material has been consumed. The reaction was quenched with sat'd NH4Cl and the organic layer separated. The organic layer was combined with previous trial reactions and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with 0% to 30% EtOAc in hexane, to provide N-allyl-N-t-butylcarbamate-(4′S)-6′-(1-hydroxy-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-amine as a yellow oil. MS m/z: 417 (M+1).