Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:13](F)=[C:12]3[C:7]([C:8](=[O:24])[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][N:11]3[CH:15]([CH3:18])[CH2:16][OH:17])=[C:6]([F:25])[C:5]=2[F:26])[CH2:3][CH2:2]1.[H-].[Na+].C(OCC)(=O)C.Cl>CN(C)C=O.O>[CH:1]1([C:4]2[C:5]([F:26])=[C:6]([F:25])[C:7]3[C:8](=[O:24])[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][N:11]4[CH:15]([CH3:18])[CH2:16][O:17][C:13]=2[C:12]=34)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C(C)CO)c2c(F)c(C3CC3)c(F)c(F)c2c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn2c3c(c(C4CC4)c(F)c(F)c3c1=O)OCC2C
Reaction time: 15 h
Yield: 39.2 %

Procedure:
In 1.7 ml of N,N-dimethylformamide was dissolved 170 mg of ethyl 7-cyclopropyl-5,6,8-trifluoro-1-(2-hydroxy-1-methylethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate. To the resulting solution was added 20 mg of 60% sodium hydride. The resulting mixture was stirred at 80°-90° C. for 15 hours. The reaction mixture was added to a mixture of 5 ml of ethyl acetate and 5 ml of water. The resulting mixture was adjusted to pH 1.5 with 2N hydrochloric acid. The resulting crystals were collected by filtration to obtain 63 mg (yield: 39.1%) of ethyl 10-cyclopropyl-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH:10]=[C:11]3[N:15]([C:8]=2[CH:7]=[CH:6][N:5]=1)[CH2:14][CH2:13]/[C:12]/3=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:3])=[CH2:2]>CO.[OH-].[OH-].[Pd+2]>[CH:1]([C:4]1[C:9]2[CH:10]=[C:11]3[N:15]([C:8]=2[CH:7]=[CH:6][N:5]=1)[CH2:14][CH2:13][CH:12]3[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:3])[CH3:2]
Reactant: C=C(C)c1nccc2c1cc1n2CC/C1=C\C(=O)OCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)CC1CCn2c1cc1c(C(C)C)nccc12
Reaction time: 3 h

Procedure:
To a solution of ethyl (2E)-(1-isopropenyl-6,7-dihydro-8H-pyrido[3,4-b]-pyrrolizin-8-ylidene)ethanoate (0.40 g, 1.4 mmol) in MeOH (20 mL) was added Pd(OH)2 (0.20 g). The mixture was stirred under 1 atm of H2 for 3 h. The mixture was filtered over celite and evaporated to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7]([C:9]2[S:20][C:12]3=[N:13][C:14]([OH:19])=[C:15]([Cl:18])[C:16]([CH3:17])=[C:11]3[C:10]=2[NH2:21])=[O:8])[CH2:5][CH2:4]1.[Br-].[Li+].[CH2:24](I)[CH3:25]>COCCOC.CN(C=O)C>[CH:3]1([NH:6][C:7]([C:9]2[S:20][C:12]3=[N:13][C:14]([O:19][CH2:24][CH3:25])=[C:15]([Cl:18])[C:16]([CH3:17])=[C:11]3[C:10]=2[NH2:21])=[O:8])[CH2:5][CH2:4]1
Reactant: Cc1c(Cl)c(O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: CCI
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCOc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 8 %

Procedure:
Sodium hydride (0.037 g, 0.925 mmol) is suspended in anhydrous 1,2-dimethoxy-ethane (5.0 ml) under nitrogen. The suspension is cooled to 0° C. To this cold suspension is added via cannula a solution of 3-amino-5-chloro-6-hydroxy-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.300 g, 1.01 mmol) in anhydrous DMF (5.0 ml). The ice bath is removed, and the reaction is warmed to room temperature. After the reaction is stirred 25 minutes at room temperature, lithium bromide (0.175 g, 2.02 mmol) is added as a solid, and the reaction is stirred for an additional two hours. Finally, ethyl iodide is added (0.24 ml, 0.47 g, 3.00 mmol), and the reaction is stirred for 36 hours at room temperature. At the completion of the reaction time, the mixture is quenched with water. The solid is collected by filtration, then purified by flash chromatography (hexanes:EtOAc gradient) to give the title compound as a white solid (24.3 mg, 8% yield). Mass (m/z): 326.0 (M+), 324.0 (M−).
Reaction SMILES: [Cl-].[NH4+].ClCCl.[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.Cl[C:15]([CH3:23])([CH2:17][CH2:18][C:19](Cl)([CH3:21])[CH3:20])[CH3:16]>O>[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[C:10]2[C:15]([CH3:23])([CH3:16])[CH2:17][CH2:18][C:19]([CH3:21])([CH3:20])[C:11]=2[CH:12]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Temperature: 25 °C

Procedure:
13.40 g (100.0 mmol) of ammonium chloride and 100 ml of dichloromethane are introduced into a three-necked flask under an argon atmosphere. A solution composed of 34.60 g (199.0 mmol) of 3-bromophenol, 89.00 g (486.0 mmol) of 2,5-dichloro-2,5-dimethylhexane and 300 ml of dichloromethane is added dropwise. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is poured into water and extracted with dichloromethane, the extract is washed with water and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 80% heptane and 20% dichloromethane. After evaporating the solvents, 30.00 g (53%) of the expected compound are collected in the form of white crystals with a melting point of 93° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, 4-bromoaniline (15.75 g, 91.6 mmol) was dissolved in anhydrous dichloromethane (220 ml) in a 500-ml flask. Triethylamine (14.1 ml, 100 mmol) was added to the solution. The mixture was cooled in an ice bath and 3-(trifluoromethyl)benzoyl chloride (21 g, 100 mmol) was added slowly through a syringe. The reaction mixture was allowed to warm to room temperature with stirring overnight. Deionized water was added to the mixture and the solution was transferred to a separatory funnel. The organic layer was separated and washed one more time with deionized water. The water was discarded, and the organic layer contained a suspension that was collected and heated to 40° C. to afford dissolution. After cooling to room temperature, a solid formed. The solid was collected by filtration and was triturated in dichloromethane (100 ml). The solid was then filtered and dried under high vacuum oven at 65° C. Pure product was obtained (28 g, 90% yield). M/Z of [M−H]−=343. 1H NMR (DMSO) δ=7.6 (2H), 7.8 (3H), 7.95 (1H), 8.3(1H), 10.6 (1H).
Reaction SMILES: Br.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]=2[CH2:9][O:8]1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:25][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[NH:17])=[CH:15][C:10]=2[CH2:9][O:8]1
Reactant: C1CCNC1
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: Br
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C(=N)N3CCCC3)ccc21
Temperature: 80 °C
Yield: 40 %

Procedure:
Using 100 mg of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile hydrobromide (citalopram HBr) and pyrrolidine (1.2 equiv) gave, after heating at 80° C. for 14 h, title product (58 mg, 40% yield) as a light yellow solid.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])O.[Na+].[Na+].[NH3:12].C(O)(=O)C(CC(O)=O)O>>[NH2:12][C@H:2]([C:1]([OH:9])=[O:8])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: N
Reactant: O=C([O-])CC(O)C(=O)[O-]
Agent: O=C(O)CC(O)C(=O)O
Agent: [Na+]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 0 h

Procedure:
The concentrations of the substrates prior to entering the reactor were 0.168 M for sodium malate and 1.797 M for aqueous ammonia. The reaction time was 0.181 second, and the aqueous solution obtained after the reaction was examined with a high performance liquid chromatography/mass spectroscopy apparatus, which confirmed that an amino group had been introduced into the malic acid, and that aspartic acid had been produced. The aspartic acid concentration was 4.2 mM, and the reaction yield thereof was 2.5%.
Reaction SMILES: [CH2:1]=[CH:2]C(NCCO)=O.O1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][CH2:17][OH:18]>C(O)COCCO>[CH2:10]([O:15][CH2:16][CH2:17][OH:18])[C:11]1[CH:2]=[CH:1][CH:14]=[CH:13][CH:12]=1
Reactant: C=CC(=O)NCCO
Reactant: OCCOC1CCCCO1
Solvent: OCCOCCO
Product: OCCOCc1ccccc1

Procedure:
A synthetic pathway to compounds of the invention is depicted in scheme 1. Protected HEAA derivatives 3 and 10 were prepared respectively starting from 2-(tetrahydro-2H-pyran-2-yloxy)ethanol 1 (commercially available or obtained from THP selective monoprotection of diethylene glycol) and commercially available 2-(benzyloxy)ethanol 8. Fully protected 3 was obtained by a two steps procedure including formation of acid 2 by reaction of alcohol 1 with bromoacetic acid, followed by DIC/DMAP promoted coupling with benzyl alcohol. Further removal of THP protecting group afforded alcohol 4 which was coupled with acid 2 to give dimer 5 with 82% yield. Final deprotection by acidic treatment led to the obtention of desired alcohol 6, first building block for key trimer compound 11 obtention. This conversion also led to the formation of small amounts of alcohol 7, thus reflecting the instability of this latter in these conditions (probable intramolecular transesterification of the dimer alcohol 6). Attempts to obtain pure dimer 6 by flash chromatography gave only poor yields and crude residue was finally used for next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:19].[K+].[K+].OO>CS(C)=O.C(Cl)Cl>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:15])=[O:19])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1cnc(Oc2ccc(C=O)cc2)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 47.4 %

Procedure:
Dissolve 5-(4-formylphenoxy)pyrazine-2-carbonitrile (1.87 g, 8.30 mmol) and K2CO3 (0.573 g, 4.15 mmol) in DMSO (21 mL). Add 30% H2O2 (2.4 mL, 20.8 mmol) and stir at room temperature for 22 hours. Add additional K2CO3 (0.573 g, 4.15 mmol) and heat at 55° C. for about 2.5 hours. Cool the reaction mixture and dilute with CH2Cl2 (200 mL). Wash with water (1× 100 mL) and saturated aqueous NaHCO3 (1× 100 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 0-50% ethyl acetate in dichloromethane to give the title compound (0.478 g, 23.7%): TOF MS ES+ 244.1 (M+H)+, HRMS calcd for C12H10N3O3 244.0722 (M+H)+, found 244.0709, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.2 min, 100% purity.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9]C=1C.[C:17]([OH:20])(=[O:19])[CH3:18]>O.[O-2].[O-2].[O-2].[Cr+6]>[F:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:18]=1[C:17]([OH:20])=[O:19]
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1cccc([N+](=O)[O-])c1F
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (195 ml) was added carefully with stirring to a solution of 2-fluoro-3-nitrotoluene (100 g, 645 mmol) in acetic acid (1000 ml). The mixture was warmed up to 95° C. and the solution of chromium trioxide (226 g, 2.25 mol) in water (200 ml) was added dropwise with stirring over 2 h. After addition the mixture was heated with stirring for another 3 h, allowed to cool down to room temperature and poured into water (3 L). The mixture was extracted with ethyl acetate (3×1 L), the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford a light green solid, which was washed with dichloromethane (3×300 ml) and dried under vacuum to afford the title compound was obtained as a light yellow solid (75 g, 62.8%). 1H NMR (300 MHz, DMSO) δ ppm 8.27 (m, 1H), 8.15 (m, 1H), 7.48 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=O)C.[CH3:41][NH2:42]>CO.C1COCC1>[CH3:41][NH:42][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 8-indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 27 (b), 20 mg, 0.037 mmol) in 1 mL methanol was added a solution of methylamine in THF (2N, 2 mL). The mixture was stirred at 80° C. for 4 hours. The solvent was removed by vacuum to leave a yellow solid (17 mg, 87%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.60 (br, 1H), 9.29 (s, 1H), 8.78 (s, 1H), 7.75 (s, 1H), 7.60 (br, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.20 (m, 2H), 7.12 (d, J=7.6 Hz, 1H), 6.87 (br, 2H), 3.69 (br, 4H), 3.01 (t, J=7.3 Hz, 2H), 2.94 (m, 5H), 2.65 (br, 2H), 2.49 (br, 6H), 2.17 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H32N6O3: 525.25 (M+H), Found 525.0.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])#[CH:19]>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([C:18]#[CH:19])[CH:21]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Reactant: C#Cc1cccc(N)c1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OC(C)=O)cc23)c1
Temperature: 83 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (4.31 g), 3-ethynylaniline (3.00 g) and isopropanol (65 mL) was stirred at 83° C. overnight. The reaction mixture was cooled to room temperature and filtered, the residue was washed with 100 mL of isopropanol and dried to afford the desired compound as a solid (4.89 g, 85.90%)
Reaction SMILES: [NH2:1]/[C:2](=[CH:17]/[CH3:18])/[C:3](/[S:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=O)=[CH:4]\[CH3:5].COC(=O)C1C=C(F)C=CC=1S/C(=C/C)/C(/N)=C\C>>[F:16][C:13]1[CH:14]=[CH:15][C:7]2[S:6][C:3]3[CH:4]=[CH:5][CH:18]=[CH:17][C:2]=3[NH:1][C:9](=[O:11])[C:8]=2[CH:12]=1
Reactant: C/C=C(N)\C(=C/C)Sc1ccc(F)cc1C(=O)O
Agent: C/C=C(N)\C(=C/C)Sc1ccc(F)cc1C(=O)OC
Product: O=C1Nc2ccccc2Sc2ccc(F)cc21

Procedure:
Thus, 2-aminobenzenethiol may be reacted with 2,5-difluoro-benzoic acid methyl ester to form a 2-[(E)-2-amino-1-eth-(E)-ylidene-but-2-enylsulfanyl]-5-fluoro-benzoic acid methyl ester intermediate that can be converted by treatment with alkali to 2-[(E)-2-amino-1-eth-(E)-ylidene-but-2-enylsulfanyl]-5-fluoro-benzoic acid. The benzoic acid can be cyclized to form 2-fluoro-10H-dibenzo[b,f][1,4]thiazepin-11-one, that may be converted to 11-chloro-2-fluoro-dibenzo[b,f][1,4]thiazepine, that may be further reacted with piperazine to form the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][N:14]=[C:13]([NH2:16])[N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[CH:17]([NH:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=1)([CH3:19])[CH3:18].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]([NH:20][C:21]1[N:22]=[C:23]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][N:14]=[C:13]([NH2:16])[N:12]=4)[CH:9]=3)[NH:4][CH:3]=2)[CH:24]=[N:25][CH:26]=1)([CH3:19])[CH3:18]
Reactant: Nc1noc(-c2ccc3[nH]cc(I)c3c2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(NC(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Product: CC(C)Nc1cncc(-c2c[nH]c3ccc(-c4nc(N)no4)cc23)n1
Temperature: 90 °C
Yield: 9.7 %

Procedure:
To a solution of 5-(3-iodo-1H-indol-5-yl)-1,2,4-oxadiazol-3-amine (0.15 g, 0.460 mmol) and isopropyl-(6-tributylstannanyl-pyrazin-2-yl)-amine (0.235 g, 0.549 mmol) was bubbled N2 gas for 15 min. To the mixture was added Cut (0.070 g, 0.366 mmol) and Pd(PPh3)4 (0.053 g, 0.043 mmol) and N2 gas was bubbled for another 15 min. The reaction was heated at 90° C. for 1 h. The mixture was cooled to RT, quenched with H2O (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified with preparative HPLC (eluent: 10-60% AcCN in H2O with 0.01% TFA) to give 5-(3-(6-(isopropylamino)pyrazin-2-yl)-1H-indol-5-yl)-1,2,4-oxadiazol-3-amine (0.015 g, 10%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 336.2 (M+1); 1H-NMR (400 MHz, CD3OD): δ 9.34 (s, 1H), 8.09 (s, 1H), 8.04 (d, J=0.8 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 4.39 (m, 1H), 1.38 (dd, J=6.8, 1.2 Hz, 6H).
Reaction SMILES: CO[C:3]([C:5]1[C:10]([Br:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1>>[CH3:18][C:16]1[N:17]=[C:13]([NH:12][C:3]([C:5]2[C:10]([Br:11])=[N:9][CH:8]=[CH:7][N:6]=2)=[O:4])[S:14][CH:15]=1
Reactant: COC(=O)c1nccnc1Br
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)c2nccnc2Br)n1

Procedure:
The title compound, MS: m/e=301.0 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-bromo-pyrazine-2-carboxylic acid methyl ester (Example A) and 2-amino-4-methylthiazole.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[H][H]>>[F:1][C:2]([F:9])([F:8])[CH:3]([F:7])[CH:4]([F:6])[F:5]
Reactant: [H][H]
Reactant: FC(F)=C(F)C(F)(F)F
Product: FC(F)C(F)C(F)(F)F

Procedure:
According to a particularly preferred embodiment (FIG. 1) of the invention, (i) hexafluoropropylene (1) is reacted continuously with hydrogen (2) in the gas phase in a superstoichiometric amount, in an adiabatic reactor (100), in the presence of a catalyst, to give 1,1,1,2,3,3-hexafluoropropane, and a portion (13) of the gaseous output stream resulting from this reaction is recycled; (ii) the nonrecycled part (3) of the output stream resulting from stage (i), comprising 1,1,1,2,3,3-hexafluoropropane, is reacted with potassium hydroxide (4) present in an aqueous reaction medium (200), in an amount of between 20 and 75% by weight and preferably of between 55 and 70% by weight, with respect to the weight of the water and KOH mixture of the reaction medium, maintained at a temperature of between 80 and 180° C., preferably of between 145 and 165° C., to give 1,2,3,3,3-pentafluoro-1-propene and potassium fluoride; (iii) the 1,2,3,3,3-pentafluoro-1-propene (6) obtained in stage (ii) is reacted with hydrogen (2) in the gas phase in a superstoichiometric amount, in an adiabatic reactor (300), in the presence of a catalyst, to give 1,1,1,2,3-penta-fluoropropane and a portion (14) of the gaseous output stream resulting from this reaction is recycled; (iv) the nonrecycled portion (7) of the output stream resulting from stage (iii), comprising 1,1,1,2,3-pentafluoropropane, is subjected to a purification stage (400) in order to remove impurities (8) and thus to obtain 1,1,1,2,3-pentafluoropropane, with a purity preferably of greater than 98% by weight; (v) the 1,1,1,2,3-pentafluoropropane obtained after the purification of stage (iv) is reacted with potassium hydroxide (4) present in an aqueous reaction medium (500), in an amount of between 20 and 75% by weight and preferably of between 55 and 70% by weight, with respect to the weight of the water and KOH mixture of the reaction medium, maintained at a temperature of between 80 and 180° C., preferably of between 145 and 165° C., to give 2,3,3,3-tetrafluoro-1-propene and potassium fluoride; and (vi) the gas stream (9) resulting from the dehydrofluorination stage (v), comprising HFO-1234yf, the unreacted HFC-245eb and the by products, is subjected to a purification stage (600) in order to obtain HFO-1234yf (12) having a purity of greater than 99.5% by weight, preferably of greater than 99.8% by weight. The light by products (10) separated from HFO-1234yf can be subjected to a treatment and the unreacted HFC-245eb (11) can be recycled in (500).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>>[F:12][C:13]([F:17])([F:16])[CH2:14][O:15][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cnc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a mixture of methyl 5-chloropyrazine-2-carboxylate (1 g, 5.79 mmol) and 2,2,2-trifluoroethanol (2.111 ml, 29.0 mmol) was added potassium carbonate (0.801 g, 5.79 mmol). The reaction was stirred at ambient temperature for 16 hrs. The reaction was partitioned between ethyl acetate and water. The organic portion was concentrated and purified in 10-60% EtOAc/Heptane to give the title compound (1.1 g, 4.66 mmol, 80%). MS m/z=237.1 (M+H).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)=[O:2].[F:12][C:13]1[C:22]([F:23])=[CH:21][C:16]2[N:17]=[C:18]([SH:20])[NH:19][C:15]=2[CH:14]=1.C(N(C(C)C)CC)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC.O>[F:23][C:22]1[C:13]([F:12])=[CH:14][C:15]2[N:19]=[C:18]([S:20][CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH2:4][CH2:5]3)[NH:17][C:16]=2[CH:21]=1
Reactant: Fc1cc2nc(S)[nH]c2cc1F
Reactant: O=CN1CCN(CCO)CC1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=CN1CCN(CCSc2nc3cc(F)c(F)cc3[nH]2)CC1
Temperature: 92 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
1-Formyl-4-(2-hydroxyethyl)piperazine (1.11 g, 7.0 mmol), 5,6-difluoro-2-mercaptobenzimidazole (1.30 g, 7.0 mmol), and diisopropylethylamine (3.62 g, 28.0 mmol) were dissolved in propionitrile (50 mL), and cyanomethyltrimethylphosphonium iodide (6.80 g, 28.0 mmol) was added thereto, followed by stirring for one hour at 92° C. under argon. The reaction mixture was allowed to cool and then poured in water (100 mL), followed by extraction with chloroform (100 mL×3). The organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, and the product was concentrated under reduced pressure. The crude product was crystallized from acetone-ether, to thereby yield 1-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]-4-formylpiperazine (1.78 g, yield 78%) as a yellow crystalline powder.