Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5](COCC[Si](C)(C)C)[C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.7 %

Procedure:
To a solution of 8-chloro-1-methyl-7-(2-propen-1-yl)-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3,7-dihydro-1H-purine-2,6-dione (2.99 g, 8.08 mmol) in DCM (20 ml) was added TFA (10 ml) and the reaction stirred for 2.5 hours at room temperature. The reaction mixture was then concentrated and the residue treated with further DCM and evaporated once more. Purification by SPE (Si) eluting 1:9-4:1 ethylacetate/cyclohexane afforded impure product (1.31 g), which was dissolved in methanol (20 ml) and treated with sat. potassium carbonate aq. (20 ml). After stirring overnight the mixture was partitioned between water containing 2M HCl (1 ml) and ethyl acetate. The organic extract was separated, washed with brine, dried (MgSO4) and concentrated to afford the title compound 0.87 g (45%); m/z 241.1 [MH+].
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:28])[NH:16][C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])=[N:18]3)=[C:13]([CH2:29][CH3:30])[N:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:32].[K+].[K+].ClCCl>C(O)C.O>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:28])[NH:16][C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]([NH2:24])=[O:32])=[N:18]3)=[C:13]([CH2:29][CH3:30])[N:12]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(C#N)c3)[nH]c(=O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(C(N)=O)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.25 mmol) cis-3-[7-(4-tert-butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl]benzonitrile (Example 40A) are dissolved in 5 ml ethanol and 10 ml water. 342 mg (2.48 mmol) potassium carbonate and 281 mg (2.48 mmol) hydrogene peroxide are added. The reaction mixture is stirred at room temperature for 18 hours. Dichloromethane is added, the organic phase separated, dried over sodium sulfate and evaporated to dryness in vacuo.
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][C:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(#N)C.O.O.O.O.O.O.[Co](Cl)Cl>[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:13][C:11]2([CH3:14])[O:12][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:10]2)=[CH:18][CH:17]=1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Reactant: Nc1ccc(I)cc1
Agent: Cl[Co]Cl
Solvent: O
Solvent: CC#N
Product: CC1(CNc2ccc(I)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
2-Bromo-1-(2-methyl-oxiranylmethyl)-4-nitro-1H-imidazole (prepared as described by Goto, F.; et al: WO 2004035547; 0.54 g, 2 mmol), 4-iodoaniline (1.31 g, 6 mmol) and cobalt (II) chloride hexahydrate were suspended in 15 mL acetonitrile and stirred at 60° C. for 3 hours. The resulting mixture was filtered through a Celite pad and washed with EtOAc. Upon removing solvent, brown solid precipitated out. The precipitate (˜200 mg) was dried and dissolved in 5 mL DMF. The solution was cooled to −78° C. before NaH (20 mg, 60% in mineral oil) was added quickly. The resulting mixture was warmed up to room temperature and stirred for one hour, before it was quenched with 1 mL water and partitioned in 50 mL EtOAc/50 mL water. The organic layer was washed with brine and dried over Na2SO4. The concentrated residue was purified by aolumn chromatography (EtOAc/Hexanes, v/v, 1/1 to 4/1) to give the titled product (90 mg) as yellow solid. ESI MS m/z 401 (M+H). 1H NMR (400 MHz, MeCN-d3) δ 7.66 (s, 1H), 7.39 (d, J=5.2 Hz, 2H), 6.52 (d, J=5.2 Hz, 2H), 4.75-4.91 (m, 1H), 4.20 (d, J=10.4 Hz, 1H), 4.02 (d, J=10.4 Hz, 1H), 3.37-3.58 (m, 2H), 1.63 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16](Br)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH2:22][CH3:23]>C1COCC1.C(OCC)C>[CH2:21]([C:16]1[CH:15]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[N:18][CH:17]=1)[CH2:22][CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of 5-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-3-bromopyridine (1.50 g, 4.37 mmol, Example 12a above) in THF (30 mL) at 0° C. was added [1,3-bis(diphenylphosphino)-propane]nickel(II) (14.0 mg) followed by propylmagnesium chloride (5.50 mL of a 2 M solution in diethyl ether, Aldrich). The reaction mixture was refluxed for 3 h, cooled to ambient temperature and then quenched with saturated aqueous ammonia chloride. The desired product was extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 1:1) to afford 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as an oil (292 mg, 22%): MS (CI/NH3) m/z: 307 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ0.95 (t, J=8.3 Hz, 3H), 1.42 (s, 4.5H), 1.46 (s, 4.5H), 1.60-1.70 (m, 2H), 2.22-2.40 (m, 2H), 2.56 (t, J=8.3 Hz, 2H), 3.70-3.80 (m, 2H), 3.90 (m, 1H), 4.13 (m, 1H), 4.51 (m, 1H), 7.04 (s, 1H), 8.06 (s, 1H), 8.18 (d, J=3.3 Hz, 1H). To a 0° C. solution of 5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (290 mg, 0.950 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). After stirring for 30 min the reaction mixture was basified with 15% aqueous NaOH and extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by chromatography (silica gel; CH2Cl2/MeOH, 10:0.5) afforded the free base of the title compound as an oil (103 mg, 53%): MS (CI/NH3) m/z: 207 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ0.94 (t, J=8.3 Hz, 3H), 1.58-1.70 (m, 2H), 2.30-2.48 (m, 2H), 2.55 (t, J=8.3 Hz, 2H), 3.57 (m, 1H), 3.76 (q, J=8.3 Hz, 1H), 4.04-4.10 (m, 2H), 4.39 (m, 1H), 7.03 (t, J=3.0 Hz, 1H), 8.04 (s, 1H), 8.14 (d, J=3.3 Hz, 1H). The free base was dissolved in Et2O and a saturated solution of HCl in Et2O was added dropwise carefully. The solvent was removed, and the resultant solid was recrystallized from MeOH/Et2O to afford the title compound as a yellow hygroscopic solid: mp 79-80° C.; MS (CI/NH3) m/z: 207 (M+H)+; 1H NMR (D2O, 300 MHz) δ1.01 (t, J=3.05 Hz, 3H), 1.68-1.80 (m, 2H), 2.62-2.78 (m, 2H), 2.80 (t, J=7.1 Hz, 2H), 4.04-4.21 (m, 3H), 4.44-4.60 (m, 2H), 7.40 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H). Anal. Calcd for C12H18N2O.2 HCl.H2O: C, 48.49; H, 7.46; N, 9.43. Found: C, 48.35; H, 7.23; N, 9.48.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH:9]([CH3:11])[CH3:10])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13].[P:15]([O-:23])([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([O:23][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH:9]([CH3:11])[CH3:10])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13])=[O:16])[CH3:19]
Reactant: CC(C)C1C(=O)N(CCl)S(=O)(=O)N1C
Reactant: CCOP(=O)([O-])OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)OCN1C(=O)C(C(C)C)N(C)S1(=O)=O
Yield: 48 %

Procedure:
2-Chloromethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g) was added to a solution of diethyl phosphate (Formula III: A=B=Et) (0.48 g) in methylene chloride containing triethylamine (0.31 g), and the mixture was allowed to reflux for 48 hours and then cooled. The mixture was concentrated in vacuo and the residue purified by silica gel flash chromatography (ethyl acetate/hexane) to afford 0.36 g (48%) of 2-(diethoxyphosphinyloxymethyl)-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =H; R2 =isopropyl; R3 =CH3 ; A=B=Et) as an oil.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])(=O)C.[Na+].Cl[CH2:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23].O>CS(C)=O.C(OCC)(=O)C>[CH3:26][C:21]([CH3:27])([CH2:20][CH2:19][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(C)(C)CCCl
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)CCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a stirred solution of 83.2 grams (0.51 mole) of N-hydroxyphthalimide in 500 ml of dimethyl sulfoxide was added 41.8 grams (0.51 mole) of sodium acetate. Upon completion of addition the reaction mixture was stirred for one hour at ambient temperature. After this time 84.2 grams (0.51 mole) of methyl 4-chloro-2,2-dimethylbutanoate was added dropwise. The reaction mixture was then heated to 100° C. where it stirred for 16 hours. The reaction mixture was cooled and 300 ml of water and 1000 ml of ethyl acetate were added. The mixture was shaken and the organic layer separated. The organic layer was washed with three 200 ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with 1:3 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to a residual oil. The oil was dissolved in 500 ml of diethyl ether and washed with two 100 ml portions of aqueous 1N sodium hydroxide. The ether layer was concentrated under reduced pressure to give 90.3 grams of methyl 2,2-dimethyl-4-(phthalimidooxy)butanoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14](C)[C:13]2[CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=[CH:19][C:12]=2[N:11]=1.Cl.[CH3:24][C:25]1([CH3:32])[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.[CH3:33]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:24][C:25]1([CH3:32])[CH2:30][CH2:29][CH:28]([NH:31][C:20]([C:17]2[CH:18]=[CH:19][C:12]3[N:11]([CH3:33])[C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:14][C:13]=3[CH:16]=2)=[O:21])[CH2:27][CH2:26]1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(C(=O)O)cc21
Reactant: CC1(C)CCC(N)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)NC3CCC(C)(C)CC3)ccc21

Procedure:
Prepared analogously to example 3c from 2-(2,6-dichloro-phenylamino)-1-methyl-1H-benzimidazole-6-carboxylic acid, 4,4-dimethyl-cyclohexylamine hydrochloride, TBTU and NMM in DMF; mp: 189-190° C., Rf value: 0.56 (silica gel; petrol ether/ethyl acetate=2:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:22]#[N:23])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1([C:22]#[N:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(F)cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(F)cc2F)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To 4-Cyano-4-(2,4-difluorophenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.720 g, 2.42 mmol) in 5 ml of dichloromethane, 2 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.484 g (90%) of 4-(2,4-difluorophenyl)-piperidine-4-carbonitrile which was used as such for the subsequent step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([CH:20]3[CH2:23][NH:22][CH2:21]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([CH:20]3[CH2:21][N:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH2:23]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2C2CNC2)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (51) (318 mg, 1 mmol) and 2-chloro-quinoline (52) (163 mg, 1 mmol) in DMF was added Cs2CO3 (650 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give (53) (346 mg, 0.78 mmol, yield 77.8%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13](Br)[N:12]=2)=[O:10])[NH:6][N:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:12]=2)=[O:10])[NH:6][N:7]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Nc1nc(C(F)(F)F)c(N2CCCC2)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1

Procedure:
To a stirred solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide (Example 1) (40 mg, 0.095 mmol) in dry THF (2 ml) was added pyrrolidine (7.89 μL, 0.095 mmol). The resulting mixture was heated using microwave radiation at 120° C. for 35 minutes. The reaction mixture was partitioned between EtOAc (50 ml) and water (30 ml) and the organic portion was separated, (MgSO4) and concentrated in vacuo to give the crude product as an orange oil. The crude product was purified using preparative TLC eluting with DCM: 1% MeOH to afford the title compound as an orange solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([NH:7][NH2:8])=O)[CH3:3].Cl.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][N:17]=[C:18]=[S:19]>CCO>[CH3:1][N:2]([CH2:4][C:5]1[N:17]([CH3:16])[C:18]([SH:19])=[N:8][N:7]=1)[CH3:3]
Reactant: CN(C)CC(=O)NN
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CN(C)Cc1nnc(S)n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
N,N-dimethylglycine hydrazide hydrochloride (50 g, 0.263 mol) was stirred for 5 min in EtOH (525 mL). To this suspension was added Cs2CO3 (62.5 g, 0.192 mol) and the mixture was stirred at room temperature for 15 min. Methyl isothiocyanate (19.25 g, 0.263 mol) in EtOH (270 mL) was added to the pot and the reaction mixture was brought to reflux. The reflux condenser was removed and the EtOH was allowed to evaporate under atmospheric pressure (oil bath temperature 105–110° C.) over 3 h to give a purple paste. The reaction was removed from heat and allowed to sit at room temperature overnight (18 h), during which time the paste became a solid. The solid was mixed with CH2Cl2 (1.5 L) and filtered. The organic filtrate was concentrated under reduced pressure to give 31 g of a crude yellow oil. The oil was purified by column chromatography through silica gel, eluting with 4:1 CH2Cl2/MeOH to afford 15.3 g (34.9%) of the desired product.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:8]=[N:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1.N([O-])=[O:16].[Na+]>O.C(OCC)(=O)C>[OH:16][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[N:9][CH:8]=1
Reactant: N#Cc1ccc(N)cn1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O)cn1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Concentrated sulfuric acid (21.0 mL) was added to a suspension of 3-amino-6-cyanopyridine (5.00 g, 42.0 mmol) in water (75.0 mL), and then a 1.6 M aqueous solution of sodium nitrite (29.0 mL, 46.4 mmol) was slowly added dropwise thereto under ice water cooling. This suspension was stirred for 6 hours at 100° C. The reaction mixture was cooled to room temperature, and then was diluted with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1, v/v). Thus, the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]O)=[CH:23][CH:22]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:15]2[C:16](=[O:17])[C:8]3([CH2:7][C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH2:9]3)[NH:13][C:14]2=[O:18])=[CH:23][CH:22]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)NC3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.4 g, 5.66 mmol, described in Intermediate 6), 4-methoxybenzyl alcohol (0.94 g, 6.80 mmol), diethyl azodicarboxylate (1.48 g, 8.49 mmol), and triphenylphosphine (2.23 g, 8.49 mmol) in THF (15 mL) was stirred at ambient temperature for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (15 mL) and CH2Cl2 (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40, to give the title compound. MS: m/z=368 (M+1).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[C:13]([O-])(=[O:15])C.[Na+]>CN(C=O)C>[CH3:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][C:11]=1[CH:13]=[O:15]
Reactant: Cc1ccc(C)s1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)c(C)s1
Temperature: 25 °C

Procedure:
To DMF (100 mL) stirred in an ice bath was added POCl3 (25 mL) drop wise followed by the addition of 2,5-dimethyl-thiophene (5 mL). The solution was warmed to room temperature and then was heated at 80° C. overnight. The reaction was cooled to room temperature and was slowly added to ice. Sodium acetate was added to bring the pH to between 5 and 6. The aqueous portion was extracted with ethyl acetate, and the organic portion was dried over sodium sulfate, concentrated under reduced pressure and purified on a silica gel column (eluent: 10:1:hexanes:EtOAc→4:1:hexanes:EtOAc to yield 2,5-dimethyl-thiophene-3-carboxaldehyde (1.5 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3F)[CH2:13][CH2:12]2)[C:5]([O:8]C)=[N:6][CH:7]=1.[C:26]([O:29][CH2:30][CH3:31])(=[O:28])C.Cl.[C:33](=[O:36])([O-:35])[O-].[Na+].[Na+]>C(O)C>[C:26]([OH:29])(=[O:28])[C:33]([OH:35])=[O:36].[O:8]=[C:5]1[C:4]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:36][CH2:33][CH:31]3[CH2:30][CH2:4][CH2:3][CH2:2][CH2:7]3)[CH2:13][CH2:12]2)=[CH:3][CH:2]=[CH:7][NH:6]1
Reactant: COc1ncc(Cl)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)O
Product: O=c1[nH]cccc1CN1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1

Procedure:
In ethanol (12 ml) was dissolved 221 mg of 1-[(5-chloro-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine. To the mixture was added 12 ml of a 4N-hydrogen chloride-ethyl acetate solution, followed by heating under reflux for 11 hours. An aqueous sodium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. Ether was added to the obtained oil, to crystallize. The title compound (176 mg) was obtained as a light pink powder.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:32]([O:35]CC)(=[O:34])[CH3:33].Cl.[C:39]([O:42]CC)(=[O:41])[CH3:40]>CO>[C:39]([OH:42])(=[O:41])/[CH:40]=[CH:33]/[C:32]([OH:35])=[O:34].[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 5 h

Procedure:
To a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (2.48 g) in ethyl acetate (10 mL) and methanol (10 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (20 mL) at room temperature. After stirring for 5 hr, the mixture was concentrated under reduced pressure. The residue was basified with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (10 mL) and added to a solution of (10 mL) fumaric acid (350 mg) in methanol. The solvent was evaporated under reduced pressure and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as colorless crystals (yield 793 mg, 29%).