Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-])=O.C(N(CC)CC)C.O>O1CCCC1.CO.[C].[Pd]>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:26]([C:25]2[CH:29]=[CH:30][C:22]([NH2:19])=[CH:23][CH:24]=2)=[O:27])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.00 g, 3.42 mmol), 4-nitrobenzoyl chloride (0.761 g, 4.1 mmol) and triethylamine (1.67 mL, 12.0 mmol) in tetrahydrofuran (25 mL) was stirred at room temperature for overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a solid. A mixture of the obtained solid and 10% of palladium-carbon (100 mg) in tetrahydrofuran (30 mL) and methanol (100 mL) was stirred at room temperature under hydrogen atmosphere (5 atm). After being stirred for 3 h, the reaction mixture was filtrated and concentrated to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 0:100) and the title compound was obtained as a solid (1.28 g, quant.).
Reaction SMILES: BrN1C(=O)CCC1=O.[CH3:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[S:13](=[O:22])(=[O:21])[C:12]([C:23]([O:25][CH3:26])=[O:24])=[N:11]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(Cl)Cl>ClC(Cl)C.CN(C=O)C>[CH3:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:19][C:14]=2[S:13](=[O:22])(=[O:21])[C:12]([C:23]([O:25][CH3:26])=[O:24])=[N:11]1
Reactant: COC(=O)C1=NN(C)c2ccc(C)cc2S1(=O)=O
Reactant: C1COCCN1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1=NN(C)c2ccc(CN3CCOCC3)cc2S1(=O)=O
Reaction time: 0.42 h
Yield: 58.2 %

Procedure:
N-Bromosuccinimide (0.239 g) and methyl 1,6-dimethyl-1H-4,1,2-benzothiadiazine-3-carboxylate 4,4-dioxide (Preparation 40, 0.30 g) are dissolved in dichloroethane (100 mL). The solution is exposed to light from a 650 W sunlamp with stirring for 25 minutes. The solvent is evaporated and the crude solid obtained is dissolved in DMF (8 mL). Morpholine (0.43 g) is added and the mixture is stirred for 3 hours. The mixture is poured into CH2Cl2 (200 mL) and washed with water (3×200mL). The organic layer is dried with Na2SO4, filtered and the solvent evaporated. The crude solid is chromatographed with MeOH/CH2Cl2 (1-5%) to obtain 0.23 g (59%) of the title compound as an off-white solid. Physical characteristics: MS (ESI+) m/z 254 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[C:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:19]=[C:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:10][CH2:11][N:6]2[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A 100-mL single-neck round-bottomed flask was purged with nitrogen and charged with 205b (0.75 g, 2.80 mmol), 10% palladium on carbon (50% wet, 280 mg), and methanol (30 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 2 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 205c (524 mg, 79%). MS-ESI: [M+H]+ 239.1
Reaction SMILES: C[Li].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17]2[C:22](C#N)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC[O:28][CH2:29][CH3:30]>>[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([N:16]([CH3:25])[C:17]2[C:22]([C:29](=[O:28])[CH3:30])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(c1ncccc1C#N)C1CCN(Cc2ccccc2)CC1
Reactant: CCOCC
Agent: [Li]C
Product: CC(=O)c1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a flame-dried flask containing a mixture of methyllithium (1.5M in ether as complexed with lithium bromide, 5.2 ml) in anhydrous ether (5.2 ml) at -78° under nitrogen is added a solution of 1-benzyl-4-(N-methyl-N-(3-cyano-2-pyridyl)amino)piperidine (XXXIII, EXAMPLE 42, 1.2 g) in anhydrous ether (5.3 ml) over 5 min. The resulting mixture is allowed to warm up to 0° over approximately 2.25 hrs and is quenched with sulfuric acid (2N, 3.9 ml) and stirred at 20°-25° for 2 hrs. The biphasic mixture is then adjusted to pH 10-11 with aqueous sodium hydroxide (5%), diluted with ether (10 ml) and water (10 ml) and the phases are separated. The aqueous phase is extracted with additional ether (30 ml), and the combined organic phases are washed with saline (10 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and chromatographed (silica gel, 70-230 mesh, 50 g; ethyl acetate/hexane (50/50)) to give the title compound, mp=93°-94°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[C:22]([F:23])=[CH:21][C:12]3[O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[O:16][C:11]=3[CH:10]=2)[CH:8]=1.C1C=CC(P([N:42]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:42][C:5]1[C:4](=[O:27])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[C:22]([F:23])=[CH:21][C:12]3[O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[O:16][C:11]=3[CH:10]=2)[N:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)nc(C(=O)O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)nc(N)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1,4-dihydropyridazine-3-carboxylic acid (2.33 g, 5.91 mmol), DPPA (1.90 mL, 8.86 mmol) and Et3N (1.23 mL, 8.86 mmol) in toluene (23 mL) was heated to 100° C. for 90 min. To the mixture was added 8 M NaOH aqueous solution (7.4 mL) at 0° C. The mixture was stirred at room temperature for 2 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and on silica gel (hexane/EtOAc=80/20 to 0/100) and triturated with EtOAc/hexane to yield the title compound (1.12 g, 53% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.73 (3H, s), 6.24 (2H, s), 7.92 (1H, d, J=10.5 Hz), 7.99 (1H, d, J=6.8 Hz), 8.37 (1H, d, J=1.5 Hz).
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])=[CH:3][Cl:4].[NH2:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1>O1CCOCC1>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1)=[O:17])(=[O:13])=[O:14])=[CH:3][Cl:4]
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reactant: COc1cc(Cl)nc(N)n1
Solvent: C1COCCO1
Product: COc1cc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(Cl)=CCl)n1

Procedure:
7.4 g of 2-(1,2-dichlorovinyloxy)phenylsulfonylisocyanate and 4.0 g of 2-amino-4-chloro-6-methoxypyrimidine are heated to 70°-80° C. in 60 ml of absolute dioxane for 3 hours. After cooling the mixture is treated with activated carbon, filtered and evaporated to 1/5 of the original volume. From the residue crystallise 9.0 g of N-[2-(1,2-Dichlorovinyloxy)phenylsulfonyl]-N'-(4-chloro-6-methoxy-pyrimidin-2-yl)urea, m.p. 196°-198° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][CH2:17][O:16][CH2:15]2)[CH2:13][C:12]3=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:29]=[C:30]=[N:31][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][CH2:17][O:16][CH2:15]2)[CH2:13][C:12]3=[N:31][C:30]#[N:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC2(CCCOC2)Oc2ccc(C#Cc3ccccc3)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC2(CCCOC2)Oc2ccc(C#Cc3ccccc3)cc21
Reaction time: 1 h
Yield: 121.2 %

Procedure:
To a solution of 6-(phenylethynyl)-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (86 mg, 0.27 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.54 mL, 0.54 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.16 mL, 0.427 mmol) dropwise. The resulting mixture was stirred 80 h. The reaction mixture was quenched with ice-water (15 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 112 mg the crude desired product as light yellow solid, which was used for next step without further purification. MS ESI +ve m/z 343 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:22](Br)=[CH:21][N:20]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O>COCCOC.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:22]([C:40]4[S:39][CH:43]=[CH:42][CH:41]=4)=[CH:21][N:20]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(-c2cccs2)cn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
To a solution of 4-(7-Benzenesulfonyl-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.29 mmol) in 4 mL DME (degassed with nitrogen prior to use) was added 0.94M aqueous Na2CO3 (0.61 mL, 0.57 mmol) and Pd(PPh3)4 (66 mg, 0.057 mmol). The reaction mixture was stirred 5 minutes, then 2-thiophene boronic acid (55 mg, 0.43 mmol) was added. The reaction mixture heated to reflux and stirred 16 hours, after which it was cooled to room temperature and DME was removed by rotary evaporation. The reaction mixture was diluted with H2O and extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (8:1 to 4:1 hexanes:EtOAc) to furnish 4-(7-Benzenesulfonyl-5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (120 mg, 79%) as a beige powder. LCMS (APCI+) m/z 526 [M+H]+; Rt: 3.25 min.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([N:8]1[CH2:34][CH2:33][CH2:32][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([C:19]([C:22]([C:25]([C:28]([F:31])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.CN1CCOCC1.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][CH2:50][C:51](Cl)=[O:52])[CH:44]=1>C(Cl)Cl>[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][CH2:50][C:51]([NH:1][C@H:2]([C:6]([N:8]2[CH2:34][CH2:33][CH2:32][C@H:9]2[C:10]([NH:12][CH:13]([CH:14]([CH3:15])[CH3:16])[C:17](=[O:18])[C:19]([F:21])([F:20])[C:22]([F:23])([F:24])[C:25]([F:26])([F:27])[C:28]([F:31])([F:29])[F:30])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:52])[CH:44]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Reactant: O=C(Cl)CCc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CCc1cccnc1)C(C)C)C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Dissolve H-Val-Pro-Val-CF2CF2CF2CF3.hydrochloride (221.0 mg, 0.40 mmol) in methylene chloride (10 mL) and cool to -20° C. while stirring. Add N-methylmorpholine (0.2 mL, 2.0 mmol) and immediately follow with a dropwise addition of 3-(3-pyridyl)propanoyl chloride in methylene chloride (5 mL) at such a rate as to maintain the internal reaction temperature at -10° C. or less. After completion of the addition, allow the reaction mixture to warm to room temperature. After 1.5 hours at room temperature, dilute the reaction mixture with methylene chloride (20 mL) and wash with 1N HCl (2×20 mL), saturated NaHCO3 (2×20 mL) and brine (1×20 mL). Dry (MgSO4) and concentrate in vacuo to give the title product in crude form. Immediately purify the crude product by flash chromatograpy (2×15 cm column eluted with 1:27 MeOH--CH2Cl2) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1.CN(C)C1C=CC=CC=1.S(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:21])[C:16]=1[OH:20])[NH:12][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: O=C(O)c1cc(F)ccc1O
Solvent: CN(C)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1cc(F)ccc1O
Yield: 54.7 %

Procedure:
5Fluorosalicylic acid (5.15 g.) and 4-amino-2,6-dichlorophenol (5.88 g.) were well mixed to which was added benzene (10 ml.) and N,N-dimethylaniline (4.35 ml.). Then with stirring thionyl chloride (3.3 ml.) was added and refluxed 30 minutes. The resulting solution was evaporated and the residue was dissolved in ethyl acetate and subjected to decolorization with activated charcoal followed by washing with 2 N hydrochloric acid and 2.5% sodium bicarbonate solution. The ethyl acetate was then extracted several times with 2 N sodium carbonate solution and the aqueous extracts were combined and brought to pH 1-2 with hydrochloric acid to give a precipitate which was recrystallized from aqueous acetone to give white needle-like crystals (5.7 g.) of 3',5'-dichloro-2,4'-dihydroxy-5-fluorobenzanilide. Yield: 55%. Melting point: 227°-229° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC(C)C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)=Cc1ccc(F)c(C(F)(F)F)c1

Procedure:
4.3 g (18.2 mmol) 1-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-propan-1-ol and 1.0 g (5.3 mmol) p-toluenesulphonic acid monohydrate in 100 mL toluene are refluxed for 3 hours using the water separator. Then the reaction mixture is combined with water and made alkaline with 1 N sodium hydroxide solution. After separation of the organic phase this is washed with water, dried with sodium sulphate and evaporated down. The oil remaining is further reacted directly.
Reaction SMILES: [CH:1]1([C:5]([NH:7][C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[CH:15]=2)[CH2:9][C:10](OC)=[O:11])=[O:6])[CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl>[O:11]=[CH:10][CH2:9][C@H:8]([NH:7][C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C[C@H](NC(=O)C1CCC1)c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: O=CC[C@H](NC(=O)C1CCC1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirring solution of the methyl ester from Example 9, Step B (1.2 mmol, 330 mg) in 10 mL of DCM cooled to −78° C. was added dropwise over 20 min. diisobutylaluminum hydride (2.4 mmol, 2.4 mL of 1 M solution in DCM). The solution was stirred at −78° C. for 2 h. Methanol (2 mL) cooled to −78° C. was canulated dropwise to the reaction mixture over 5 min. After 10 min. the reaction was allowed to warm to room temperature, during which time a white precipitate formed. DCM (30 mL) was added, and the solution was poured into 2 N HCl (50 mL). The organic phase was collected and the aqueous phase was extracted with DCM (2×25 mL). The combined organic phase was dried with MgSO4 and the solvent removed under reduced pressure. The oily residue was dissolved in DCM and passed through a silica plug eluting with DCM. Removal of solvent under reduced pressure afforded the title compound as a clear oil. MS(ESI): m/z 250 (M+H). HPLC B: 1.31 min.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([O-])([O-])=O.[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].O>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:17](=[O:18])[CH2:16][Br:15])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(Br)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CBr
Yield: 37.5 %

Procedure:
To a mixture of glycine ethyl ester hydrochloride (2.0 g, 14.3 mmol) and K2CO3 (2.1 g, 15.2 mmol) in CH2Cl2 (35 ml) cooled at 0-5° C. bromoacetyl bromide (1.36 ml, 15.6 mmol) was added dropwise. The suspension was stirred at room temperature and after 3 h H2O (20 ml) was added. The phases were separated and the organic one was washed with a saturated solution of NaHCO3 (20 ml) and H2O (20 ml) and dried over Na2SO4. The solvent was evaporated obtaining 39 as white solid (1.2 g, 40%). ESI+MS: calcd for C6H10BrNO3: 224.06; found: 224.0 and 226.0 (MH+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH3:12])[C:5]2=[N:4][CH:3]=1>CO.[Pd]>[N:4]1[CH:3]=[CH:2][N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH3:12])[C:5]=12
Reactant: CNc1nccn2c(Br)cnc12
Agent: [Pd]
Solvent: CO
Product: CNc1nccn2ccnc12
Reaction time: 8 h
Yield: 158.8 %

Procedure:
To a solution of (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (Example 1) (2.4 g, 11.9 mmol) in methanol (160 ml) was added Pd-C (10% wt. 0.1 eq). The mixture was hydrogenated at rt overnight, filtered, and washed with hot methanol. The organics were combined and concentrated to afford 2.8 g of crude imidazo[1,2-a]pyrazin-8-yl-methyl-amine (M).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:10][C:11](=[O:21])[C:12]=1[O:13]CC1C=CC=CC=1)=[O:6])([CH3:3])[CH3:2].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:25])=[O:26])=[CH:10][C:11](=[O:21])[C:12]=1[OH:13])=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)NC(C)C)n2C)cc1
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(O)c(C(=O)NC(C)C)n2C)cc1
Yield: 83.3 %

Procedure:
3-Hydroxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (18-06) (190.0 mg, 83.3%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-06) (280.0 mg, 0.58 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: Br[C:2]1[C:3]([C:13]#[N:14])=[N:4][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][N:7]=1.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][SH:20])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:14][C:13]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([C:8]3[O:9][CH:10]=[CH:11][CH:12]=3)[N:4]=2)[S:20][C:19]=1[C:18]([O:17][CH2:15][CH3:16])=[O:21]
Reactant: CCOC(=O)CS
Reactant: N#Cc1nc(-c2ccco2)cnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc2ncc(-c3ccco3)nc2c1N
Temperature: -10 °C
Yield: 100 %

Procedure:
A solution of 3-bromo-6-(furan-2-yl)pyrazine-2-carbonitrile 57 (1.21 g, 4.84 mmol), ethyl-2-mercaptoacetate (0.587 mL, 0.640 g, 5.32 mmol) and sodium carbonate (0.564 g, 5.32 mmol) in ethanol (20 mL) was stirred 1 h at rt, 1 h at 40° C. and 1 h at 50° C. Cooled down to −10° C., the resulting precipitate was collected, washed with cold ethanol (5 mL) and dried to give ethyl 7-amino-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxylate 58 (1.4 g, 100%). NMR (400 MHz, DMSO-d6) 1.32 (t, J=7.0, 3H), 4.33 (q, J=14.0 and 7.0 Hz, 2H), 6.78 (dd, J=3.5 and 2.0, 1H), 7.05 (br s, 2H), 7.47 (dd, J=3.5 and 0.8 Hz, 1H), 8.00 (dd, J=2.0 and 0.8 Hz, 1H), 9.16 (s, 1H). (m/z)=290 (M+H)+.
Reaction SMILES: [OH-].[Na+].CO.C1(C)C=CC=CC=1.C([S:15][CH2:16][C:17]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]([CH3:25])[CH2:21][N+:22]([O-])=[O:23])=[O:18])(=O)C>O>[N:22](=[C:21]1[CH:20]([CH3:25])[N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:17](=[O:18])[CH2:16][S:15]1)[OH:23]
Reactant: CCCCN(C(=O)CSC(C)=O)C(C)C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)CSC(=NO)C1C

Procedure:
A solution of 6.8 g of sodium hydroxide, 125 ml of methanol, and 125 ml of toluene was charged to a flask and stirred vigorously while adding 33 g. of 2-(acetylthio)-N-butyl-N(1-nitro-2-propyl) acetamide over a 5-minute period of 30°-40° C. The reaction mixture was stirred at 40° C for 5 hours; then stirred overnight at room temperature. The mixture was stripped of solvents under reduced pressure. The solid residue was dissolved in 500 ml of cold water and the mixture was filtered and the filtrate was acidified with conc. hydrochloric acid. The resulting mixture was extracted three times with methylene chloride and the methylene chloride layer was dried with MgSO4. The methylene chloride was stripped from product under reduced pressure. The oily residue crystallized over night. This crude reaction product was recrystallized from 60/40 xylene-hexane mixture to yield 12 g of 2-oximino-3-methyl-4-butyltetrahydro-1,4-thiazin-5-one, m.p. 118°-120° C. An nmr spectrum supported the proposed structure.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:5][C:3]1=[O:4].[H][H].CCCCCC.C(OC(C)C)(C)C>C(O)C>[OH:1][C@H:2]1[C@H:7]([OH:8])[C@H:6](/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:5][C:3]1=[O:4]
Reactant: CCCCCCCCC#C[C@H]1OC(=O)[C@@H](O)[C@@H]1O
Reactant: [H][H]
Solvent: CCO
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: CCCCCCCC/C=C\[C@@H]1OC(=O)[C@@H](O)[C@@H]1O
Yield: 74.6 %

Procedure:
1.924 g (7.58 mmol) of the compound (15) obtained in step e were dissolved in 20 ml of ethanol, 40 mg of 5 wt % Pd--CaCO3 /Pb (Lindlar catalyst) were added thereto, and the resultant solution was strongly stirred in a hydrogen flow. The solid product in the reaction solution was filtered, and the solvent was distilled at a reduced pressure, thereby obtaining a colorless solid product. This solid product was recrystallized using 50 ml of a hexane/isopropyl ether solution mixture obtained by mixing hexane with isopropyl ether at a mixing ratio of 20:30 to obtain 1.45 g of a colorless fibrous compound (16) (yield:74.6%). The physical data of the resultant compound (16) were as follows.