Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:17]2[C@@:13]([CH3:29])([C@@H:14]([C@@:18]3([CH3:28])[O:22][CH2:21][C@@H:20]([CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])[CH2:19]3)[CH2:15][CH2:16]2)[CH2:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.CCOC(C)=O>C1COCC1>[OH:26][C:24]([CH3:27])([CH3:25])[CH2:23][C@@H:20]1[CH2:21][O:22][C@@:18]([C@@H:14]2[C@:13]3([CH3:29])[C@H:17]([C@@H:9]([OH:8])[CH2:10][CH2:11][CH2:12]3)[CH2:16][CH2:15]2)([CH3:28])[CH2:19]1
Reactant: CC(C)(O)C[C@@H]1CO[C@](C)([C@H]2CC[C@H]3[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@@]32C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C[C@@H]1CO[C@](C)([C@H]2CC[C@H]3[C@@H](O)CCC[C@@]32C)C1
Yield: 92.5 %

Procedure:
A solution of 13 (330 mg, 0.78 mmol) in dry THF (4 mL) was treated with nBu4NF (1.02 g, 3.25 mmol). The mixture was heated at reflux for 90 h. H2O (20 mL) and EtOAc (20 mL) were added. The aqueous layer was extracted with EtOAc (4×20 mL) and the combined organic layer was dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography (SiO2, 2×5.5 cm, 30% EtOAc-hexanes) to give 13a (224 mg, 93%, white solid, mp: 98° C.).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].N[CH2:35][C@@H](O)C.CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: C[C@H](O)CN
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@H](C)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 57 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (S)-(+)-1-amino-2-propanol (0.16 mL 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (387.8 mg, 57%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=1.6 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 1(m, H), 7.53 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.92 (m, 1H), 3.32 (m, 2H), 2.19 (s, 3H), 1.18 (d, 3H, J=6.4 Hz); ES-HRMS m/z 508.0661 (M+H C22H21BrF2N3O4 requires 508.0678).
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]#[C:16][CH2:17][OH:18])[C:9](=[O:13])[O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CC[O:25]CC>C(#N)C.O.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH2:1]([N:8]([CH2:14][CH2:15][C:16](=[O:25])[CH2:17][OH:18])[C:9](=[O:13])[O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CCOC(=O)N(CC#CCO)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Hg+2]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N(CCC(=O)CO)Cc1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl benzyl(4-hydroxybut-2-ynyl)carbamate (0.05 g, 0.202 mmol), mercury(II) acetate (6.44 mg, 0.020 mmol) and boron trifluoride etherate (5.12 μl, 0.040 mmol) in Acetonitrile (0.5 ml) and Water (0.250 ml) stirred at 90° C. in wheaton vial for 30 min. By HPLC-MS the main peak corresponds to expected product.
Reaction SMILES: [OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=4)[N:21]=3)=[CH:18][N:19]=2)[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[K+]>C1COCC1.CO.O>[OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[CH:30][N:29]=4)[N:21]=3)=[CH:18][N:19]=2)[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)CCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCc4cc(C(=O)O)ccc43)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of methyl 1-hydroxy-1-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylate (900 mg, 1.709 mmol) in THF (8.6 mL) was added aqueous potassium hydroxide (1.82 mL, 17.09 mmol) and the mixture was stirred at rt overnight. The reaction was diluted with MeOH (10 mL) and water (10 mL) and the organic solvents were removed under reduced pressure. The pH was adjusted to ˜3 by addition of 1 M HCl, during which time the product precipitated. Collection of the precipitate by filtration furnished racemic 1-hydroxy-1-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylic acid (749 mg, 85%) as a white solid. The racemic mixture was resolved by chiral SFC using a Chiral Technologies IA-H 3.0×25 cm, 5 uM column and a solvent system of 50% MeOH/CO2, running at 70 mL/min. Under these conditions, the two enantiomers eluted at 5.5 min and 10.5 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH:8]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:21](O)=[O:22])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[Cl:53][CH2:54][CH2:55][NH:56][CH2:57][CH2:58][Cl:59].C(N(CC)CC)C>C(#N)C>[Cl:53][CH2:54][CH2:55][N:56]([CH2:57][CH2:58][Cl:59])[C:21]([C:20]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:18]([CH:8]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH:19]=1)=[O:22]
Reactant: Cc1ccc(C(=O)O)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: ClCCNCCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCl)CCCl)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
Adapting a literature known protocol (U.S. Pat. No. 3,235,594), to a reaction mixture of 3-[3-tert-butoxy-1-[(tert-butoxycarbonylamino)methyl]-3-oxo-propyl]-4-methyl-benzoic acid (8e) (787 mg, 2.0 mmol), N-hydroxysuccinimide (NHS, HOSu) (235 mg, 2.2 mmol) in anhydrous acetonitrile (MeCN) (10 mL) is added solid dicyclohexylcarbodiimide (DCC) (433 mg, 2.1 mmol) in small portions at about room temperature. The reaction mixture is stirred for about 12 hours and the precipitated dicyclohexylurea side product is filtered off using a Biichner funnel. The filtrate is treated with commercial di-(2-chloroethyl)amine hydrochloride (2-chloro-N-(2-chloroethyl)ethanamine hydrochloride; HN(CH2—CH2—Cl)2.HCl) (393 mg, 2.2 mmol) followed by neat triethylamine (Et3N, TEA) (321 μL, 233 mg, 2.3 mmol). The reaction mixture is stirred for about 12 hours at room temperature. The reaction is followed by TLC and/or LC/MS to completion. The volatile solvents are removed under reduced pressure using a rotary evaporator. The residue is diluted with 1.0M hydrochloric acid (HCl). The aqueous phase is extracted with ethyl acetate (EtOAc) and the combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and evaporated to dryness. Purification by silica gel column chromatography using EtOAc and hexane mixtures furnishes the target compound (8f).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:9]([S:12][C:13]#N)=[CH:8][C:5]=1[C:6]#[N:7].CI.O>C(O)C>[F:3][C:4]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#CSc1ccc(F)c(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCO
Product: CSc1ccc(F)c(C#N)c1
Yield: 91.7 %

Procedure:
To a suspension of sodium borohydride (90%, 0.41 g (9.76 mmol)) in ethanol (10 ml), 2-fluoro-5-(thiocyanato)benzonitrile (0.29 g (1.63 mmol)) was added with stirring under cooling with ice. To the resulting mixture, after one hour's stirring at room temperature, methyl iodide (0.11 ml (1.71 mmol)) was added and the resulting mixture was stirred overnight at room temperature. Then, the reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (3:7) as eluent, to give 0.25 g (92%) of 2-fluoro-5-(methylthio)benzonitrile as pale yellow-white crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)(C)(C)C.[C:12]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2)([O:14][CH3:15])=[O:13]>C(OCC)C>[C:12]([N:16]1[CH:17]2[CH2:23][CH2:22][CH:21]1[CH2:20][CH:19]([OH:24])[CH2:18]2)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)N1C2CCC1CC(=O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)N1C2CCC1CC(O)C2
Reaction time: 17.5 h

Procedure:
Under nitrogen atmosphere, 11.4 mg of LiAlH4, 0.15 ml of tetrahydrofran and then 85 μl of t-butylalcohol were placed in a reaction vessel. After standing the resulting mixture for 15 min. at room temperature, a tetrahydrofran solution of N-carbomethoxy-8-azabicyclo(3,2,1)octan-3-one prepared by the method as described in Referencial Example 3 (0.1 ml/2 mg) was added to the mixture and then continued stirring for 17.5 hrs.. To the reaction mixture, a moisture contained ethyl ether was added to stop the reaction and then the reaction mixture was subjected to extraction in several times with use of ethyl acetate. The combined extract was dried with use of Na2SO4 and concentrated to obtain N-carbomethoxy-8-azabicyclo(3,2,1)octan-3-ol, in crystal form.
Reaction SMILES: CC(C)([O-:4])C.[K+].Cl.C(N([CH2:13][CH3:14])CC)C.N(CC)(CC)CC.Cl.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>C(O)(C)C>[O:26]1[CH:23]2[O:25][CH2:13][CH2:14][CH:24]2[CH:28]([OH:4])[CH2:27]1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Product: OC1COC2OCCC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a stirred solution of compound (I.5, 0.011 mol, 2.4 g, syn/anti mixture) in isopropanol (20 ml), potassium tert-butoxide (0.0132 mol, 1.5 g) was added portionwise over 30 minutes at room temperature. The basic solution was transferred to an addition funnel and added dropwise over 10 minutes to a cooled (0° C.) vigorously stirred mixture of concentrated (37%) hydrochloric acid (0.0275 mol, 2.3 ml) in isopropanol (20 ml). The reaction mixture was stirred for 2 hours at room temperature, then triethylamine (0.022 mol, 2.2 g) was added dropwise causing Et3N.HCl salts to precipitate. The reaction mixture was diluted with ethyl acetate (50 ml) and filtered to remove the salts. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (50 ml) causing more Et3N.HCl salts to precipitate. The salts were removed by filtration and the solvent was evaporated under reduced pressure. The residual oil was further purified by silica gel plug filtration with ethyl acetate as eluent to afford a mixture of compounds (7.1/7.2, 1.03 g, yield=72%) in a ratio of 78/22 (determined by 1H NMR). Analytical samples of the pure compounds (7.1, Rf7.1=0.27) and (7.2, Rf7.2=0.15) were obtained by means of silica gel chromatography using ethyl acetate as the solvent.
Reaction SMILES: [CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[CH2:25]([SiH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH3:26].[CH2:32](N(CC)CC)[CH3:33]>[Cu](I)I>[CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([C:26]#[C:25][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Reactant: CC[SiH](CC)CC
Agent: I[Cu]I
Product: CC[Si](C#Cc1ncc(C(=O)NC[C@](C)(O)C2CC2)nc1-c1ccc(Cl)cc1)(CC)CC
Temperature: 25 °C

Procedure:
A mixture of 7.0 mg bistriphenylphosphinpalladium dichloride and 4 mg copperiodide in 5 ml triethylamine was heated to reflux for 30 min. To the resulting solution was added 0.41 g 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide (example 62 a) and 0.28 g triethylsilane and the mixture was refluxed for 0.5 h. The reaction mixture was cooled to room temperature and partitioned between 10% citric acid and ethyl acetate. The organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=1:1 to yield 0.45 g of 6-(4-chloro-phenyl)-5-triethylsilanylethynyl-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide as a solidifying foam.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([NH:9][C:10]1[C:11]([CH2:19][CH2:20][CH3:21])=[N:12][N:13]([CH3:18])[C:14]=1[C:15]([NH2:17])=[O:16])=O)[CH:2]=[CH2:3].[OH-].[Na+].O>C(O)C>[CH2:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]1[NH:17][C:15](=[O:16])[C:14]2[N:13]([CH3:18])[N:12]=[C:11]([CH2:19][CH2:20][CH3:21])[C:10]=2[N:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 41.9 %

Procedure:
A mixture of 4-(2-allyloxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (1.2 g, 0.0035 mol), sodium hydroxide (0.70 g, 0.018 mol), water (34 ml) and ethanol (8 ml) was refluxed for 5 hours. After cooling, the solution was exhaustively extracted with ethyl acetate. The combined extracts were washed with brine (30 ml), dried (Na2SO4), filtered and the solvent evaporated under vacuum to give a crude product which was crystallised from ethyl acetate/hexane to afford the title compound (0.476 g, 37%), m.p. 116-119° C. Found: C, 67.00; H, 6.21; N, 17.23. C18H20N4O2 requires C, 66.65; H, 6.21; N, 17.27%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][CH2:32]Cl.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:39][CH2:38][N:37]5[CH2:32][CH2:31][NH:34][C:35](=[O:40])[CH2:36]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1CNCCN1
Reactant: ClCCBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1CN(CCN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCN1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(3-oxopiperazin-1-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1), 1-bromo-2-chloroethane and piperazin-2-one following General Procedure G.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH2:18][CH2:19][F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:21]([CH3:23])[CH3:22])[S:14]2)[C@H:10]1[O:24]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[CH3:23][N:21]([CH3:22])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([CH2:18][CH2:19][F:20])[C@@H:9]([OH:8])[C@H:10]([OH:24])[C@H:11]2[N:12]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CCF)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CCF)O[C@@H]2S1
Yield: 18.9 %

Procedure:
A solution of 108 (300 mg, 0.7 mmol) in dichloromethane (20 mL) was treated with BCl3 (7 mL, 7 mmol, 1 M in dichloromethane) for 2 hours at −60° C., then quenched by the addition of methanol (10 mL). Volatiles were distilled out under vacuum to give a residue, which was dissolved into methanol (5 mL) and neutralized by Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give the title compound as a white solid (35 mg, 20%); (ES, m/z) [M+H]+ 265.0; 1HNMR (300 MHz, D2O) δ 6.16 (d, J=6.3 Hz, 1H), 4.60 (t, J=4.8 Hz, 1H), 4.45 (t, J=4.8 Hz, 1H), 4.10 (t, J=6.0 Hz, 1H), 3.92 (t, J=4.8 Hz, 1H), 3.62-3.66 (m, 1H), 3.42-3.60 (m, 1H), 2.90 (s, 6H), 2.06-2.20 (m, 1H), 1.67-1.88 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]2=[N:15][C:14]=1[CH3:23].[Li+].CC([N-]C(C)C)C.CCCCCCC.[CH2:39]1[CH2:43][O:42][CH2:41][CH2:40]1.C(C1C=CC=CC=1)C>C1COCC1.ClCCl>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:22])[CH:20]=[C:21]([C:41](=[O:42])[CH2:40][CH2:39][CH3:43])[C:16]2=[N:15][C:14]=1[CH3:23]
Reactant: C1CCOC1
Reactant: Cc1ccc2nc(C)c(-c3sc(-c4ncnn4C)cc3Cl)n2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CCCC(=O)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A solution of 3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.20 g, 0.58 mmol), N-methoxy-N-methyl-butylamide (Wolberg, M. et. al. Chem. Europ. J. 2001, 7, 4562) (0.084 g, 0.64 mmol) in THF (3 mL) is cooled to a −78° C., and a 2.0 M solution of LDA in heptane/THF/ethyl benzene (0.58 mL, 1.16 mmol) is added. The solution is warmed to ambient temperature, diluted with dichloromethane (20 mL), and washed with a sat. NH4Cl solution (15 mL). The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by ISCO flash chromatography (20%-100% EtOAc gradient) to furnish the title compound (0.11 g, 0.27 mmol, 46%). 1H-NMR (CDCl3), δ 1.04 (t, J=7.0 Hz, 3H), 1.76-1.86 (m, 2H), 2.56 (s, 3H), 2.59 (s, 3H), 3.51 (t, J=7.1 Hz, 2H), 4.15 (s, 3H), 7.36 (s, 1H), 7.49 (s, 1H), 7.90 (s, 1H) ppm. LC/MS (m/z): calcd. for C19H19ClN6OS (M+H)+: 415.1; found: 415.3.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[C:52]([O:56][C:57](=[O:66])[CH2:58][C@@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:36][C:30]1[CH:29]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:63]([C@@H:61]3[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]3)=[O:64])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:27]=[C:26]([F:25])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (107 mg, 0.28 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (100 mg, 0.26 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (60.2 mg, 0.28 mmol) and DIEA (0.050 mL, 0.28 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate (100 mg, 0.170 mmol, 66.6%) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B(O)O)(=[O:3])[CH3:2].Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:18][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1ccccc1B(O)O
Reactant: Nc1cccc(Br)c1
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(=O)Nc1ccccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
2-acetylaminophenyl boronic acid (0.124 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-50% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.103 g in 98% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[CH3:8].[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]([CH3:22])=O>>[CH2:9]([N:1]([CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[CH3:8])[CH2:22][CH:20]=[CH2:19])[CH:10]=[CH2:11]
Reactant: C=CCBr
Reactant: Cc1nnsc1CN
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCN(CC=C)Cc1snnc1C
Reaction time: 20 h
Yield: 67 %

Procedure:
To 15 ml of acetone were added 0.50 g (3.0 mol) of 5-aminomethyl-4-methyl-1,2,3-thiadiazole ydrochloride, 1.10 g (9.0 mmol) of allyl bromide and 2.1 g (15 mmol) of potassium carbonate. The resulting mixture was stirred for 20 hours with heating under reflux. After the reaction was completed, the reaction mixture was filtered to remove the precipitated matter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.42 g of the objective compound was obtained.