Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[S:10][C:11]=1[CH:12]=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>CO.O1CCCC1.[C].[Pd]>[CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[S:10][C:11]=1[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1nc(-c2ccc(C)cc2)sc1C=CC(=O)c1ccc(C=CC(=O)OC)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCc1nc(-c2ccc(C)cc2)sc1CCC(=O)c1ccc(CCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
The obtained methyl 3-[4-[3-[4-hexyl-2-(4-methylphenyl)thiazol-5-yl]propenoyl]-2-methylphenyl]acrylate (112 mg, 0.230 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL). 10% palladium carbon (22 mg) was added to the solution to cause replacement of hydrogen in the system. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtrated with Celite. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (5:1, v/v) to give the desired compound (46 mg) as colorless oil (yield 41%).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH:12]=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:19]([Mg]Br)[CH3:20]>C1COCC1>[Si:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([CH:12]([OH:13])[CH2:19][CH3:20])[CH:14]=[C:15]([F:17])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(C=O)c1F
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A 200 mL round bottom flask was charged with 90.B (1.38 g, 5.1 mmol) and THF (10 mL) and cooled to −78° C. under N2. To the cold solution was added ethylmagnesium bromide (3.0 M in ether) (commercially available from Aldrich) (5.1 mL, 15 mmol) dropwise. The mixture was stirred for 30 minutes at −78° C. The cooling bath was removed, and the mixture was stirred for 30 minutes at ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The organic layers were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-15% EtOAc/hexane) to afford 90.C (0.48 g, 31% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13](Cl)=[O:14].C(N(CC)CC)C>O1CCOCC1>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: Nc1ccnc(Cl)c1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnc(Cl)c1F)c1c(F)cccc1Cl
Temperature: 50 °C
Yield: 62.7 %

Procedure:
A mixture of 2-chloro-3-fluoropyridin-4-ylamine (293 mg, 2.0 mmol), 2-chloro-6-fluoro-benzoyl chloride (400 mg, 2.07 mmol) and triethylamine (300 μL, 218 mg, 2.15 mmol) in dioxane (6 mL) was heated at 50° C. for 4 hours. After cooling to ambient temperature, triethylamine (60 μL) and 2-chloro-6-fluorobenzoyl chloride (40 μL) were added. The resultant mixture was heated under reflux for a further 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM and the resultant solid was triturated in diethyl ether, filtered, and dried to give the desired compound as a white solid (380 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.46 (br s, 1H), 8.27-8.23 (m, 2H), 7.59 (td, J=8.3, 6.2 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.42-7.37 (m, 1H). LCMS (Method C): RT=3.34 min, m/z: 303 [M+H+].
Reaction SMILES: C(OCC)(C(C(C(F)(F)F)(F)F)(F)F)(F)F.C([C:19](C(F)=O)([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])C.C(OC=C)=C.C(N(CC)CC)C>COCCOCCOC>[C:20]([CH2:19][C:24]([F:27])([F:26])[F:25])([F:23])([F:22])[F:21]
Reactant: CCC(C(=O)F)(C(F)(F)F)C(F)(F)F
Agent: C=COC=C
Agent: CCOC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: FC(F)(F)CC(F)(F)F

Procedure:
Using essentially the procedure as in Example 1, a mixture of perfluorobutyric acid fluorides (3.77 g with acyl fluoride content of 81%, 14 mmol), KF (1.02 g ,17 mmol), the ethoxyisobutene (4.56 g with purity 88%, 0.18 mmol) in 8.33 g diglyme was agitated at room temperature for four days. The reactor was vented to yield 0.67 g liquid which comprised (GC %): 88% starting acyl fluorides mixture and 8% C4F9OC2H5. The reaction solution remaining in the reactor was vacuum distilled to yield 3.0 g of a mixture which comprised (GC %): 75% C4F9OC2H5, 1.5% C2H5C(CF3)2C(O)F and 7.6% starting vinyl ether. After decarboxylation by treatment with triethylamine, the remaining diglyme solution yielded 1.45 g CF3CH2CF3 (purity 98% contaminated with 1.5% C4F9OC2H5 and 0.5% (CF3)CC2H5C(O)F). Triethylamine recovery gave 2.5 g organic liquid material with b.p. up to 101° C., consisting of (GC %): 2.5% CF3CH2CF3, 42% triethylamine, 9% starting vinyl ether and 29% diglyme. Calculated yields were: C4F9OC2H5, 72% on the consumed acid fluoride mixture, CF3CH2CF3, 75% on consumed vinyl ether.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[NH2:24])[CH:18]=[CH:19][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:24][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=3)[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: CN(C)Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I

Procedure:
3-Iodo-4-methylbenzoyl chloride (2.2 g, 7.88 mmol), dissolved in anhydrous THF (13 mL), was added dropwise to a solution of 3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1.5 g, 5.5 mmol), DIPEA (2.1 mL, 11.8 mmol) in THF (30 mL) at ˜5° C. The resultant solution was stirred at ambient temperature overnight. The solvent was removed in vacuo and the crude residue was redissolved in CH2Cl2 and washed with 1N NaOH. The organic layer was then washed with water, and brine then dried over NaSO4 before being concentrated in vacuo. The brown colored residue was then triturated in a mixture of hexanes/DCM to precipitate 1.4 g of the desired product as an off-white powder: 529 m/z (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[O:19]1[CH2:22][CH:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][N:26]3[CH2:27][CH2:28][CH:23]([CH:21]4[CH2:22][O:19][CH2:20]4)[CH2:24][CH2:25]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: C1CC(C2COC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)sc2n1
Reaction time: 6 h
Yield: 23.1 %

Procedure:
A solution of 5 -chloro-7-morpholin-4-ylthiazolo [5,4-d]pyrimidine-2-carbaldehyde (1.0 g, 3.52 mmol), 4-oxetan-3-ylpiperidine (536 mg, 4.23 mmol) and molecular sieves (4 Å, powdered, 6.56 g) in DCE (30 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (1.49 g, 7.05 mmol) was added and the mixture stirred for 6 h, then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 97:3) to afford the title compound as a cream solid (334 mg, 41%). LCMS (Method A): RT=2.48 min, M+H+=410
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH:29]([O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:3])[N:37]([C:36]4[CH:38]=[CH:39][C:33]([O:32][CH:29]([CH3:31])[CH3:30])=[CH:34][CH:35]=4)[CH2:22][CH2:21]3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: CC(C)Oc1ccc(N)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4)CC3)C2=O)cc1
Yield: 58.1 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-benzenesulfonyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.2 g), dimethylaluminium chloride in heptane (0.9 molar, 0.94 ml) and 4-isopropoxy-aniline (0.1 g) to give the desired 8-benzenesulfonyl-2-(4-isopropoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.14 g) as a yellow solid. MS (ESI): 429.18 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:17]>C(O)(C)C>[NH2:17][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OC1CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(C3CC(O)C3)nc(I)c12
Temperature: 110 °C

Procedure:
In a Parr pressure reactor 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanol (4.159 g, 0.0119 mol) was dissolved with 2.0M ammonia in isopropyl alcohol (40 mL). The mixture was cooled to −20° C. and saturated with ammonia. The reaction was heated at 110° C. for 63 h at which point it was cooled and concentrated in vacuo. The crude product was purified using HPFC Jones 25 g silica gel column eluting with 5-8% MeOH: CH2Cl2 to yield the title compounds; MS (ES+): m/z 330.88 (100) [MH+], 331.89 (10) [MH++]; HPLC: tR=0.48 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.55-2.76 (m, 2H) 3.06-3.22 (m, 2H) 3.32-3.50 (m, 1H) 4.51-4.69 (m, 1H) 6.15 (br. s., 2H) 7.24 (d, J=5.05 Hz, 1H) 7.39 (d, J=5.05 Hz, 1H).
Reaction SMILES: FC(OC1C=CC(C=CC#N)=CC=1)CC(F)(F)F.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.[F:28][C:29]([F:35])([CH:32]([F:34])[F:33])[CH2:30][OH:31]>>[F:28][C:29]([F:35])([CH:32]([F:34])[F:33])[CH2:30][O:31][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: OCC(F)(F)C(F)F
Agent: N#CC=Cc1ccc(OC(F)CC(F)(F)F)cc1
Product: N#Cc1ccc(OCC(F)(F)C(F)F)cc1

Procedure:
According to Ann. N.Y. Acad. Sci (1988), 544, pages 86 to 100 (Chem. Abstr. 111, 208650), 4-tetrafluoropropoxycinnamonitrile can be prepared in the following manner. 4-Fluorobenzonitrile is reacted with 2,2,3,3-tetrafluoropropanol to give 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile which is then reduced by complex hydrides to give 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde. The 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde leads to the 4-tetrafluoropropoxycinnamonitrile by reaction with the anion of diethyl cyanomethylphosphonate in the context of a Wittig-Horner reaction.
Reaction SMILES: CCO[C:4](/[N:6]=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19]O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)C#N>C(OCC)C>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][C:4]#[N:6])=[CH:16][CH:15]=1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: OCCc1ccc(Br)cc1
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: N#CCCc1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of 4-bromo-phenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) in diethyl ether (16 mL) at 0° C. The reaction mixture is stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (10 mL) is added. The clear orange solution is stirred for 5 minutes at 0° C. and then at 25° C. for 12 hours. The reaction mixture is then filtered, and washed with diethyl ether. The filtrate is concentrated under reduced pressure and chromatographed over silica gel (10% ethyl acetate-hexanes is used as the eluant) to provide the desired product as a pale yellow oil (2.04 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[N:9]=[CH:8]1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[O:24][CH3:25].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[N:9]=[C:8]1[C:23]([O:24][CH3:25])=[O:26]
Reactant: COCCCCn1cnc2c1CCCC2
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCCCn1c(C(=O)OC)nc2c1CCCC2
Temperature: -15 °C
Reaction time: 12 h

Procedure:
1-(4-Methoxybutyl)-4,5,6,7-tetrahydro-1H-benzimidazole (625 mg) was dissolved in acetonitrile (5 ml), and the mixture was cooled to −15° C. Triethylamine (1.25 ml) and methyl chlorocarbonate (691 μl) were added dropwise. The reaction mixture was heated to room temperature and stirred for 12 hr. The reaction mixture was again cooled to −15° C., triethylamine (1.25 ml) and methyl chlorocarbonate (691 μl) were added dropwise, heated to room temperature and stirred for 12 hr. This operation was further repeated 3 times, aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (225 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:15][C@H:14]([OH:16])[CH2:13][CH2:12][C@@H:11]1[NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.CCOCC>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][C@@H:11]1[NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
The compound benzyl (1S,2R,4R)-2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxycyclohexylcarbamate (4.15 g) in CH2Cl2 (30 mL) was added to Dess-Martin periodane (13.4 g, 31.6 mmol) in CH2Cl2 (100 mL) at 0° C. After 1 h, the ice bath was removed and the reaction aws stirred overnight. This mixture was diluted with ether (425 mL) and washed with water (2×50 mL), sat'd Na2S2O3 (2×50 mL), 1N sodium hydroxide (2×50 mL), and brine (1×50 mL). The organic layer was dried over MgSO4, filtered, and then evaporated to dryness to give benzyl (1S,2R)-2-((tert-butyldimethylsilyloxy)methyl)-4-oxocyclohexylcarbamate (4.05 g) as a clear viscous oil after drying under vacuum overnight. MS found: (M+H)+=392.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:48])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH:33]5[CH2:37][O:36]C(C)(C)[O:34]5)[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:48])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH:33]([OH:34])[CH2:37][OH:36])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4COC(C)(C)O4)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(CC(O)CO)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
To a solution of 2-[6-chloro-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (crude from Step 2) in CH2Cl2 (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 48 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 10% MeOH/CH2Cl2 to afford 22 mg (20%, 2 steps) of 2-[6-Chloro-1-(2,3-dihydroxy-propyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid. MS: (M+Na)+=545; mp=165-180° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.14 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.47 (d, J=7.6 Hz, 2H), 7.91 (s, 1H), 7.23 (d, J=6.8 Hz, 1H), 5.15 (d, J=5.3 Hz, 1H), 5.03 (dd, J=5.3, 3.0 Hz, 1H), 4.84 (t, J=5.5 Hz, 1H), 4.35-4.80 (m, 5H), 4.18-4.26 (m, 1H), 3.93-4.15 (m, 2H), 3.79-3.90 (m, 1H), 3.34-3.49 (m, 2H), 1.33-1.45 (m, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=1)(=O)C.[OH-]>CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[OH:4][C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=1
Reactant: CC(=O)Oc1ccc2ncc3c(c2c1)CCCC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: Oc1ccc2ncc3c(c2c1)CCCC3
Temperature: 60 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of Compound 274 (26.50 g, 110 mmol) in dry methanol (150 mL) was added Dowex 1x8-200 hydroxide form (0.40 g, catalytic), and tetra-n-butylammonium bromide (50 mg, catalytic), and the resulting mixutre was stirred at 60° C. for 24 hours. The reaction mixture was cooled, diluted with ethyl ether (100 mL) and filtered to give 21.47 g (98 percent) of Compound 275: white crystalline solid; mp 284°-286° C. (dec.); Rf =0.25 (silica, 50 percent ethyl acetate in dichloromethane); IR (CHCl3) νmax 2933, 2906, 2850, 2582, 1627, 1503, 1421 cm-1 ; 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1 H, OH), 8.34 (s, 1 H, H6), 7.77 (d, J=9.0 Hz, 1 H, H4), 7.19 (dd, J=9.0, 2.6 Hz, 1 H, H3), 7.12 (d, J=2.6 Hz, 1 H, H1), 2.88 (t, J=6.1 Hz, 2 H, H7 or H10), 2.78 (t, J=6.1 H, 2 H, H7 or H10), 1.87-1.74 (m, 4 H, H8 and H9); 13C NMR (125 MHz, DMSO -d6) δ 155.5, 148.8, 141.1, 138.5, 130.9, 129.4, 128.4, 120.0, 104.0, 26.5, 24.3, 22.1, 21.9; MS (FAB+) m/e (rel intensity) 200 (M+H, 100), 124 (8), 107 (14); HRMS for C13H14NO (M+H), calcd 200.1075, found 200.1079.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cccnc4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.3 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.6 mg, 0.012 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-pyridin-3-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 65% yield.
Reaction SMILES: ClS(O)(=O)=O.[NH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1.[C:12]([CH:16]([CH2:19][CH:20]=[CH2:21])[C:17]#[N:18])(=O)[CH2:13][CH3:14]>O.CC1C=CC=CC=1C>[CH2:19]([C:16]1[C:12]([CH2:13][CH3:14])=[N:6][C:7]2[N:8]([N:9]=[CH:10][N:11]=2)[C:17]=1[NH2:18])[CH:20]=[CH2:21]
Reactant: C=CCC(C#N)C(=O)CC
Reactant: Nc1nc[nH]n1
Agent: O=S(=O)(O)Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: C=CCc1c(CC)nc2ncnn2c1N
Temperature: 130 °C
Yield: 84 %

Procedure:
In a 20 l jacketed vessel fitted with reflux condenser and water separator, 14650 g of o-xylene were initially charged, and 411 g of chlorosulfonic acid were added. 2074 g of 3-amino-1,2,4-triazole and 3690 g of a solution of 2-propionylpent-4-enenitrile (87.4% in o-xylene) were added, and the mixture was heated to reflux. The mixture was stirred under reflux for 14 hours, and the water of reaction formed was removed via a phase separator. Once no more water separated off, the mixture was cooled to 130° C. and 634 g of triethylamine were added. On further cooling, the product precipitated in the form of colorless crystals. At a temperature of 100° C., 2350 g of isopropanol were added. The mixture was cooled further to 20° C., and the solid formed was separated off. The filtercake was washed with 1500 ml of a 1:1 mixture of isopropanol and water and then dried under reduced pressure. This gives 4057 g of a colorless powder. Melting point: 258° C. (decomposition), 1H-NMR: 1.35 (t, 3H); 2.88 (q, 2H); 3.45 (d, 2H); 5.09 (d, 2H); 5.20 (d, 2H); 5.6 (s, broad, 2H); 5.8-6.0 (m, 1H); 8.30 (s, 1H). Yield: 84.0%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C1C[O:16][CH2:15][CH2:14]1>C(OCC)C.O.[Zn+2].[Br-].[Br-].[Cl-].[Cl-].[Zn+2]>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][CH:15]=[O:16]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: C1CCOC1
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: O
Product: O=CC=Cc1ccccc1C(F)(F)F
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of 2-trifluoromethylbenzaldehyde (260 mg) in 5 mL THF was added 200 mg of ZnBr2. With stirring, 400 mg of α,α-bis(trimethylsilyl)-t-butylacetaldimine (7) was added, and stirring was continued overnight. The solution was cooled to 10° C., then hydrolyzed by the addition of a solution of ZnCl2 (200 mg) in diethyl ether/water (3 mL each), followed by stirring at room temperature for 1 h. The solids were removed by filtration through Celite and the filtrate extracted with diethyl ether (2×). The combined ether extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide the crude title compound as an oil. The product was purified via silica gel column chromatography to afford a white powder (130 mg): 1H NMR (CDCl3) δ 6.70 (dd, 1H, J=9.6, 4.5 Hz), 7.55 (t, 1H, J=4.5 Hz), 7.63 (t, 1H, J=4.5 Hz), 7.76 (d, 2H, J=4.8 Hz), 7.88 (br d, 1H, J=9.6 Hz), 9.77 (d, 1H, J=4.8 Hz).