Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].C1C=CC2N(O)N=[N:19][C:17]=2C=1.CN(C=O)C.CN.C1COCC1>O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:19][CH3:17])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C#N)cc1F
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
4-cyano-2-fluorobenzoic acid (1.20 g), HOBt (1.47 g), WSC•monohydrochloride (2.10 g) and DMF (20 ml) were mixed with one another and stirred for 30 minutes. 2M methylamine-THF solution (11 ml) was added thereto, followed by stirring for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting solid was washed with n-hexane, to obtain 4-cyano-2-fluoro-N-methylbenzamide (1.03 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:22]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[ClH:41].CO>C(Cl)(Cl)Cl>[ClH:1].[ClH:41].[Cl:1][C:2]1[C:3]([CH:22]([S:31]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)(=[O:32])=[O:33])[C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NC2CCNCC2)ncc1Cl
Reaction time: 2 h
Yield: 84 %

Procedure:
To t-butyl 4-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]piperidine-1-carboxylate (41 mg, 0.067 mmol) was added a 20% hydrochloric acid-methanol solution. The resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in chloroform, followed by further concentration. The amorphous substance thus obtained was dried under reduced pressure to afford the title compound (34 mg, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19]>CN(C=O)C>[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:6][CH:7]=1)#[N:19]
Reactant: N#CCCCCCBr
Reactant: OCCCc1ccc(O)cc1
Solvent: CN(C)C=O
Product: N#CCCCCCOCCCc1ccc(OCCCCCC#N)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of 3-(4hydroxyphenyl)-1-propanol (2.0 g, 13.1 mmole) in DMF (5 mL) was added to a solution of DMF (35 mL) containing Nail (1.31 g, 60% in mineral oil) at 0° C. under nitrogen atmosphere. The reaction mixture was slowly warmed to 80° C. After stirring for 1 h at 80° C., the reaction mixture was cooled to 0° C., and 6-bromohexanenitrile (5.78 g,.32.83 mmole) was added. The final mixture was re-heated to 80° C., and stirred for 24 h. The reaction mixture was quenched with saturated NaCl solution (200 mL), and the product was extracted with EtOAc (300 mL). The organic layer was washed with brine solution, dried with Na2SO4, and evaporated to dryness, yielding a pale yellow solid. Purification of the crude product by flash silica column chromatography: 4/1 to 1/1 hexane/EtOAc provided 6-{3-[4-(5-cyanopentyloxy)phenyl]propoxy}hexanenitrile in 30% yield (1.33 g). Rf=0.63 in 1/1 EtOAc/hexane. 1H-NMR (CDC3, 299.96 MHz): δ (ppm) 7.09-7.07 (d, 2H), 6.81-6.78 (d, 2H), 3.96-3.92 (t, 2H), 3.42-3.37 (m, 4H), 2.64-2.58 (t, 2H), 2.39-2.32 (m, 4H), 1.87-1.52 (m, 14H).
Reaction SMILES: [C:1]([NH:6][N:7]=[C:8]([CH3:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:18]Cl.[OH-].[Na+].Cl.C(N(CC)CC)C.Cl>C(N(CC)CC)C.CCCCC>[C:1]([N:6]=[N:7][C:8]([Cl:18])([CH3:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: C=CCOC(=O)CCC(C)=NNC(C)(C)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: C=CCOC(=O)CCC(C)(Cl)N=NC(C)(C)CC
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a 1 liter 3-neck round bottom flask, equipped with a mechanical stirrer, thermometer, chlorine inlet tube and condenser was added 96.0 grams (0.4 mole) of allyl levulinate t-amylhydrazone, 400 mls of pentane and 41.5 grams of triethylamine. The resulting solution was cooled to 5° C. and and with stirring 28.4 grams (0.4 mole) of chlorine was slowly added over 30 minutes, holding the temperature at 5° to 15° C. After the addition was complete the mixture was stirred for 10 minutes at 10° C. before adding 164 grams of 10% NaOH to neutralize the triethylamine hydrochloride that had formed. The mixture was stirred until the hydrochloride dissolved and then the aqueous layer was separated. The pentane layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane and triethylamine stripped off on a rotary evaporator under reduced pressure. The residue was a yellow liquid weighing 109 grams (99% crude yield). The product was used as an intermediate in preparing the following azo compounds.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][C@@H:30]([CH2:33][CH3:34])[CH2:31][OH:32]>>[CH2:33]([C@H:30]([NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:26])[CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1)=[O:28])[CH2:31][OH:32])[CH3:34]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Reactant: CC[C@H](N)CO
Product: CC[C@@H](CO)NC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Yield: 79 %

Procedure:
By the same procedure as described in the example 31, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin4-yl-carbonyl]benzoic acid methyl ester and using (S)-(+)-2-amino-1-butanol. Then, the product was recrystallized using acetonitrile and isopropyl ether to give the desired compound.
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:4])=[O:3].[NH3:14]>C(Cl)(Cl)Cl>[S:2]([C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:4])(=[O:3])[NH2:14]
Reactant: N
Reactant: COC(=O)c1cscc1S(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cscc1S(N)(=O)=O
Reaction time: 3 h

Procedure:
39.9 g (0.166 mole) of methyl 4-chlorosulfonylthiophene-3-carboxylate (VIII) is dissolved in 400 ml of absolute chloroform; ammonia is passed in at room temperature until the mixture has an alkaline reaction. After the mixture has been stirred for a further 3 hours (care being taken that the solution remains alkaline) it is extracted with water and the organic phase is dried and evaporated. The crystalline residue can be recrystallized from ethanol; however, for further use, digestion with ether is sufficient.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[C:22]2[C:17](=[C:18]([O:23]C)[N:19]=[CH:20][CH:21]=2)[N:16]([CH3:25])[CH:15]=1.Cl>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[C:22]2[CH:21]=[CH:20][NH:19][C:18](=[O:23])[C:17]=2[N:16]([CH3:25])[CH:15]=1
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)cc2F)c2cc[nH]c(=O)c21
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of Example 2C (1.133 g, 2.75 mmol) in dioxane (35 mL) was treated with 4 N HCl in dioxane (35 mL, 140 mmol) and stirred at 70° C. overnight. The solution was cooled, diluted with 200 mL ethyl acetate, then washed with 200 mL of 1:1 saturated aqueous sodium chloride/sodium bicarbonate and dried over anhydrous sodium sulfate. Filtration and solvent removal provided 1.085 g of the product as a yellow solid.
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:10][CH:11]1[CH2:23][C:22]2[C:14](=[CH:15][C:16]3[CH2:20][CH2:19][O:18][C:17]=3[CH:21]=2)[CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C(O)=O.[OH-].[Na+]>[CH2:3]([N:10]([CH:11]1[CH2:23][C:22]2[C:14](=[CH:15][C:16]3[CH2:20][CH2:19][O:18][C:17]=3[CH:21]=2)[CH2:13][CH2:12]1)[CH3:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CNC2CCc3cc4c(cc3C2)OCC4)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CN(Cc1ccccc1)C1CCc2cc3c(cc2C1)OCC3
Temperature: 0 °C

Procedure:
44 ml of 37% strength formaldehyde solution in water are added to a solution of 21 g of the compound of Example 7 in 26 ml of concentrated formic acid maintained at 0° C. After 2 hours under reflux, the cooled reaction medium is diluted with 40% strength sodium hydroxide solution in water and extracted with methylene chloride. The organic phase is washed, dried and then evaporated under vacuum. The residue, purified by passage through a silica column, leads to the production of an oil. The elution solvent used is a mixture of methylene chloride and ethyl acetate (85:15 V/V)
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:29])[N:9]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[F:12])[N:6]=[CH:7][C:8]2=[O:29])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)c(F)c32)CC1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)cnc3ccc(F)c(F)c32)CC1

Procedure:
tert-Butyl {1-[2-(7,8-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 154, 320 mg, 0.78 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 240 mg (quantitative) of the crude product as an oil.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:22]=1[CH3:23])=[CH:19][C:18](N)=[CH:17][CH:16]=3)=[O:9])[CH3:6].[Cu][C:26]#[N:27]>S(=O)(=O)(O)O.[C-]#N.[Na+]>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:22]=1[CH3:23])=[CH:19][C:18]([C:26]#[N:27])=[CH:17][CH:16]=3)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Reactant: N#C[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [C-]#N
Product: CCOC(=O)c1ncc2[nH]c3ccc(C#N)cc3c2c1C
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 25 %

Procedure:
5 ml of 2 molar aqueous sodium nitrite solution is added dropwise, while cooling intensively with ice, to a suspension of 2.7 g of 6-amino-4-methyl-β-carbolin-3-carboxylic acid ethyl ester in 15 ml of 3N sulphuric acid. After 20 minutes, the diazotizing solution is quickly added dropwise to a solution at 60° C. of 1.2 g of copper (I) cyanide in 8 ml of 4.5 molar sodium cyanide solution. After heating for 30 minutes at 60° C., the solution is allowed to stand at room temperature for 2 hours and is then suction-filtered. The filter residue is extracted by boiling with methanol. The combined filtrates are concentrated by evaporation and chromatographed on silica gel with chloroform/ethanol (95:5). 6-Cyano-4-methyl-β-carbolin-3-carboxylic acid ethyl ester of melting point 268°-276° C. (decomposition) is obtained in 25% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=O)=[C:4]([Cl:11])[N:3]=1.[CH3:12][NH:13][NH2:14]>CCO>[Cl:11][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]2[N:13]([CH3:12])[N:14]=[CH:9][C:5]=12
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CNN
Solvent: CCO
Product: Cn1ncc2c(Cl)nc(Cl)nc21
Reaction time: 0.5 h

Procedure:
To a solution of 2,4,6-trichloro-pyrimidine-5-carbaldehyde (3.7 g, 17.5 mmol) in EtOH (50 mL) cooled to −78° C. was added methyl hydrazine (0.93 mL, 17.5 mmol) and TEA (8 mL). The mixture was stirred for 30 minutes at −78 C then 2 hr at 0 C. The solution was concentrated in vacuo without heating. To the reduced volume solution was added EtOAc and the solution washed with a sat NaHCO3 solution and concentrated in vacuo without heating. Filtration over a small silica gel plug (2:1 EtOAc:Hex) and concentration afforded the desired product as a yellow solid. It should be noted that the reaction with aromatic hydrazine compounds can be conducted at 0° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].Cl>[Pd].CO>[NH2:2][CH2:1][C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(C#N)nc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(CN)nc1
Reaction time: 2.5 h
Yield: 98.8 %

Procedure:
A mixture of methyl 3-(6-cyanopyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.24 g, 0.81 mmol), palladium (10% on carbon, 93 mg), concentrated hydrochloric acid (0.19 mL), and methanol (7 mL) was stirred under hydrogen (balloon) for 2.5 hr. The mixture was then filtered. The filtrate was concentrated to remove methanol. The residue was made basic with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (4×10 mL). The combined ethyl acetate extracts were washed with brine (5 mL), dried (Na2SO4) and concentrated to give methyl 3-(6-(aminomethyl)pyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.24 g, 0.80 mmol, 99% yield) as a solid. MS found: (M+H)+=299.31.
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[C:7]=2[CH2:6][CH2:5][O:4]1)=O.Cl.[N:16]1([CH2:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]3[C:28](=[O:31])[O:29][CH2:30][C:26]=3[CH:25]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[O:31]=[C:28]1[C:27]2[CH:32]=[CH:33][C:24]([CH2:23][CH2:22][N:16]3[CH2:21][CH2:20][N:19]([CH2:1][CH:3]4[C:12]5[CH:11]=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[C:7]=5[CH2:6][CH2:5][O:4]4)[CH2:18][CH2:17]3)=[CH:25][C:26]=2[CH2:30][O:29]1
Reactant: N#Cc1cccc2c1CCOC2C=O
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc2c1CCOC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-formyl-3,4-dihydro-1H-isochromene-5-carbonitrile (65 mg, 0.35 mmol), 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride (100 mg, 0.35 mmol), DIEA (45 mg, 0.35 mmol), AcOH (21 mg, 0.35 mmol) in 3 mL of DCM was stirred 30 min at room temperature and then NaBH(OAc)3 (440 mg, 2.1 mmol) was added. The mixture was stirred over night at room temperature. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by prep-HPLC to give 1-({4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-3,4-dihydro-1H-isochromene-5-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1
Reactant: COc1cc(C#N)nc(-c2ccccn2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CN)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Over a solution of 4-Methoxy-[2,2′]bipyridinyl-6-carbonitrile (5.0 g, 23.7 mmol) in tetrahydrofuran (25 mL), a 1.0 M solution of LiAlH4 in tetrahydrofuran (75 mL, 75.0 mmol) was slowly added and the reaction mixture was stirred for 2 h at 25° C. The reaction was then cooled to 0° C., water (2.5 mL) followed by a 15% aqueous solution of NaOH (2.5 mL) were slowly added and stirred at 25° C. for 16 hours. The reaction mixture was filtered through celite, washed with tetrahydrofuran and the organic solvent removed under reduced pressure. The aqueous residue was extracted with dichloromethane, the organic solvent dried with sodium sulphate anhydrous, filtered and removed under reduced pressure to afford C-(4-Methoxy-[2,2′]bipyridinyl-6-yl)-methylamine as an orange oil (3.5 g, aprox 68%) that was used in the next step without purification.
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>O1CCCC1>[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)[OH:22]
Reactant: CCOC(OCC)n1ccnc1
Reactant: O=Cc1cccc(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ncc[nH]1)c1cccc(F)c1F
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a solution of 1-(diethoxymethyl)-1H-imidazole (1.65 ml, 10.1 mmol) in tetrahydrofuran (15 ml), at −60° C. and under nitrogen, was added n-butyllithium (2.5 M in hexanes, 4.03 ml, 10.1 mmol). The reaction mixture was stirred at −60° C. for 1 h, before addition of 2,3-difluorobenzaldehyde (1.00 ml, 9.2 mmol), and then allowed to warm to room temperature over 18 h. The mixture was concentrated in vacuo and to the residue was added ethyl acetate (50 ml) and hydrochloric acid (3M, 50 ml). The two layers were separated and the aqueous phase was basified with aqueous sodium hydroxide solution (20%) and extracted with ethyl acetate (3×100 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo and the residue was re-crystallised from 2-propanol to give the title compound (1.25 g)
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1.C1(C)C=CC=CC=1.C(#N)C>[C:9]1([CH3:8])[CH:14]=[CH:13][C:12]([S:15]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CC(C)(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Under a nitrogen atmosphere, 3-methylbutane-1,3-diol (300 g) was dissolved in pyridine (900 ml), and a solution of 4-methylbenzenesulfonyl chloride (500 g) in toluene (900 ml) and acetonitrile (125 ml) was added dropwise over 2 hr. The reaction mixture was stirred at room temperature for 4 hr, and toluene (500 ml) and water (1800 ml) were added to allow for layer separation. The obtained organic layer was washed successively with aqueous sulfuric acid and water (twice). The solvent in the obtained organic layer was evaporated, and the residue was azeotropically evaporated with toluene (500 ml) to give the title compound (535 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[N:12]1([CH2:11][CH2:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(CCN2CCCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCN2CCCCC2)c1
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 1-[2-(3-Nitro-phenyl)-ethyl]-piperidine in ethanol was added a catalytic amount 10% activated palladium on carbon and excess hydrogen gas. This mixture was allowed to stir overnight, then filtered and concentrated. The product was clean enough for the next reaction. 60% yield. MH+=205.1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: Fc1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(F)cc2)[C@@H]1O
Yield: 68.8 %

Procedure:
The title compound (650 mg, 48%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (800 mg, 2.84 mmol) and 4-fluorophenyl-1H-imidazol-2-ylmethylamine (380 mg, 2.0 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[CH2:10])[N:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[O:15][CH3:16].O.[OH-].[Li+]>C1COCC1.CO.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[CH2:10])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[O:15][CH3:16]
Reactant: C=Cc1nc(C(=O)OC)c(OC)c(N)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=Cc1nc(C(=O)O)c(OC)c(N)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
To a solution of methyl 4-amino-5-fluoro-3-methoxy-6-vinylpicolinate (140.0 mg, 0.619 mmol) in THF (1.2 mL), MeOH (1.200 mL), Water (0.600 mL), lithium hydroxide hydrate (78 mg, 1.857 mmol) was charged as a solid. The reaction was allowed to stir at room temperature for 18 hrs. The reaction was concentrated to dryness. The resulting residue was diluted with 2 N HCl and MeOH. The product was purified (C18 10-80% ACN in H2O 12 CV) to yield 4-amino-5-fluoro-3-methoxy-6-vinylpicolinic acid (79 mg, 0.372 mmol, 60.2% yield). ESIMS for m/z 213 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H), 5.50 (dd, J=11.0, 2.2 Hz, 1H), 6.20 (dd, J=17.3, 2.2 Hz, 1H), 6.35 (s, 2H), 6.83 (ddd, J=17.3, 10.9, 1.7 Hz, 1H), 12.98 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ −145.09.
Reaction SMILES: [OH:1][CH:2]([CH2:42][N:43]1[C:47](=[O:48])[C:46]2([CH2:53][C:52]([CH3:55])([CH3:54])[N:51]([CH3:56])[C:50]([CH3:58])([CH3:57])[CH2:49]2)[NH:45][C:44]1=[O:59])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:41])[CH2:23][N:24]3[C:28](=[O:29])[C:27]4([CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([CH3:37])[C:31]([CH3:39])([CH3:38])[CH2:30]4)[NH:26][C:25]3=[O:40])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1>C(OC(=O)C)(=O)C>[C:2]([O:41][CH:22]([CH2:23][N:24]1[C:28](=[O:29])[C:27]2([CH2:34][C:33]([CH3:35])([CH3:36])[N:32]([CH3:37])[C:31]([CH3:38])([CH3:39])[CH2:30]2)[NH:26][C:25]1=[O:40])[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([O:1][C:5](=[O:4])[CH3:6])[CH2:42][N:43]3[C:47](=[O:48])[C:46]4([CH2:53][C:52]([CH3:55])([CH3:54])[N:51]([CH3:56])[C:50]([CH3:58])([CH3:57])[CH2:49]4)[NH:45][C:44]3=[O:59])=[CH:10][CH:9]=2)([CH3:13])[CH3:12])=[CH:15][CH:16]=1)(=[O:1])[CH3:3]
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COc1ccc(C(C)(C)c3ccc(OCC(O)CN4C(=O)NC5(CC(C)(C)N(C)C(C)(C)C5)C4=O)cc3)cc1)C2=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(COc1ccc(C(C)(C)c2ccc(OCC(CN3C(=O)NC4(CC(C)(C)N(C)C(C)(C)C4)C3=O)OC(C)=O)cc2)cc1)CN1C(=O)NC2(CC(C)(C)N(C)C(C)(C)C2)C1=O

Procedure:
A mixture of 4.0 g of 2,2-bis{4-[2-hydroxy-3-(7,7,8,9,9-pentamethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)propoxy]phenyl}propane, obtained as described in Example 1, and 100 ml of acetic anhydride was heated at 120°-130° C. for 6 hours. The reaction mixture was then treated substantially as described in Example 13, to give the desired Compound No. 35 in the form of white crystals melting at 229°-237° C.