Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[O:5][CH:6]=1.COC(Cl)[Cl:13]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:13])=[O:9])[O:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)co1
Reactant: COC(Cl)Cl
Product: O=C(Cl)c1cc(Br)co1
Temperature: 25 °C

Procedure:
The crude 4-bromofuran-2-carboxylic acid was placed in a 250 mL round bottom flask equipped with a magnetic stirring bar and a reflux condenser, and the flask was alternately evacuated and filled with nitrogen several times. To the stirred solid was carefully added α,α-dichloromethyl methyl ether (50 mL, 563 mmol). The addition was accompanied by vigorous gas evolution and was very exothermic, bringing the temperature of the resulting brown frothy mixture nearly to reflux. The gas evolution was allowed to subside, then the brown mixture was slowly heated to reflux using a heating mantle. The thick, partially solidified reaction mixture was then diluted with additional α,α-dichloromethyl methyl ether (20 mL, 225 mmol) to afford a dark brown solution containing some large black solid chunks. After heating at reflux for 135 minutes, the reaction was allowed to cool to ambient temperature, and then concentrated under reduced pressure. The resulting dark brown semi-solid was held under high vacuum to remove the last traces of solvents. While being held under vacuum at ambient temperature, some large colorless prisms appeared on the upper walls of the flask. The crude 4-bromofuran-2-carbonyl chloride was obtained as a dark brown semi-solid, and was used in the next step without purification.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][C:3]=2[O:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:24]([CH:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:11][N+:12]([O-:14])=[O:13])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)c1ccc(OC)cc1)C(C[N+](=O)[O-])c1ccc2c(c1)OCO2

Procedure:
Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene and 24 L ethyl acetate. A solution of 5.355 kg (24.1 moles) ethyl 3-(4-methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:8])[CH2:6][SH:7])[CH2:3][CH2:2]1.C[O-].[Na+].Cl[C:13]1[N:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[C:18]([Cl:25])=[C:17]([CH3:26])[C:14]=1[C:15]#[N:16].ClC1C(Cl)=NC(OC(C)C)=C(C=1C)C#N>CO.CCOC(C)=O.CCCCCC.O>[CH:1]1([NH:4][C:5]([C:6]2[S:7][C:13]3=[N:20][C:19]([O:21][CH:22]([CH3:23])[CH3:24])=[C:18]([Cl:25])[C:17]([CH3:26])=[C:14]3[C:15]=2[NH2:16])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(CS)NC1CC1
Reactant: Cc1c(Cl)c(OC(C)C)nc(Cl)c1C#N
Agent: C[O-]
Agent: Cc1c(Cl)c(Cl)nc(OC(C)C)c1C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(OC(C)C)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-cyclopropyl-2-mercapto-acetamide (0.498 g, 3.80 mmol) in MeOH (5 ml) is added sodium methoxide solution (25% wt. in MeOH)(0.652 ml, 2.85 mmol). The resulting solution is stirred at room temperature for 30 minutes, then treated with a 1:1 mixture of 2,5-dichloro-6-isopropoxy-4-methyl-nicotinonitrile and 5,6-dichloro-2-isopropoxy-4-methyl-nicotinonitrile (0.400 g, 1.63 mmol). The reaction vessel is sealed, heated at 100° C. for 2.5 hours, and cooled to room temperature. The reaction mixture is poured over water (60 ml), then extracted with EtOAc (2×40 ml). The combined organic layers are washed with brine (50 ml), dried (anhydrous magnesium sulfate), filtered, and concentrated to give a yellow-brown solid. Flash chromatography (1.5:1 hexane:EtOAc) affords the title compound as a tan solid (20 mg). Mass (m/z): 340.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH3:16][N:17]([CH2:26][C:27]([OH:29])=O)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(OCC)C.C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:27](=[O:29])[CH2:26][N:17]([CH3:16])[C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Reactant: CN(CC(=O)O)C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(C(=O)CN(C)C(=O)c1ccccc1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.075 g, 0.34 mmol), 2-(N-methylbenzamido)acetic acid (0.098 g, 0.51 mmol), and DMAP (0.062 g, 0.51 mmol) in dry diethyl ether (1.0 mL) and dry CH2Cl2 (1.1 mL) was cooled to a temperature of about 0° C. under N2. DCC (0.17 g, 0.81 mmol) was added, and the reaction was slowly warmed up to room temperature under N2, then stirred at room temperature overnight. The reaction mixture was filtered using additional CH2Cl2 (0.5 mL) to remove solids and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0%-10% MeOH/CH2Cl2 to afford the title compound F83 as a white solid (0.12 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:20]1[C:21]2[N:22]([N:27]=[CH:28][N:29]=2)[C:23](Br)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:36]([Sn:40](Cl)([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH3:39]>C1COCC1>[C:1]([O:5][C:6](=[O:30])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:20]1[C:21]2[N:22]([N:27]=[CH:28][N:29]=2)[C:23]([Sn:40]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:24][N:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(Br)n2ncnc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2ncnn12
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (370 mg, 0.78 mmol) in THF (12 mL), are added 2M isopropylmagnesium chloride in THF (0.78 mL, 1.56 mmol), and after 5 minutes stirring, tributyltin chloride (0.42, 1.56 mmol) is added. The reaction mixture is stirred at −78° C. for 15 minutes and at room temperature for an additional 15 minutes. After removing the solvent, the residue is purified by silica gel column chromatography eluting with 5:1 petroleum ether:ethyl acetate followed by 1:1 petroleum ether:ethyl acetate. The title compound is isolated (105 mg, 20%).
Reaction SMILES: [2H]C1C([2H])=C([2H])C(B(O)O)=C([2H])C=1[2H].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.[C:68]1(=[O:77])[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH:70]=[CH:69]1>O1CCOCC1.O.[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh]>[C:68]1(=[O:77])[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH2:70][CH2:69]1
Reactant: O=C1C=Cc2ccccc21
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1CCc2ccccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of compound A (57 g) in tetrahydrofuran (600 mL) was added triethylamine (30 mL) dropwise over 30 min. The reaction mixture was kept at room temperature for 3 hours. The precipitated solid was filtered and the filtrate was concentrated in vacuo. The residue was reprecipitated from diethyl ether to afford compound B (31 g) as a yellow solid. To a solution of compound phenyl-d5-boronic acid (25 g) in 1,4-dioxane/water (900 mL/90 mL) was added [Rh(ndb)2]BF4 (1.3 g), racemic BINAP (2.1 g) and triethylamine (14 mL), then the reaction mixture was kept at room temperature for 2 hours under N2. Then compound indenone (19 g) was added, and the resulting mixture was heated to 100° C. for 3 hours. The precipitated solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography to afford indanone C (10 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:20]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)([CH3:19])[CH2:9][O:10][C@@:11]([C:17]#[N:18])([CH3:16])[C:12]([F:15])([F:14])[F:13])[C:5]([F:33])=[CH:4][CH:3]=1.C(N[C@H](C(O)=O)CS)(=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:19])[CH2:9][O:10][C@@:11]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:17]([NH2:18])=[N:20]2)[C:5]([F:33])=[CH:4][CH:3]=1
Reactant: C[C@](C#N)(OC[C@](C)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F)C(F)(F)F
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@]1(c2nc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 80 °C
Reaction time: 72 h
Yield: 74.4 %

Procedure:
A solution of N—[(R)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-4-nitro-benzenesulfonamide (9.18 g, 16.53 mmol) and N-acetylcysteine (5.40 g, 33.10 mmol) in 92 ml ethanol was evacuated and flushed with nitrogen. K2CO3 (4.57 g, 33.1 mmol) was added and the mixture was stirred at 80° C. for 3 days. The reaction mixture was concentrated in vacuo to about ¼ of the original volume and partitioned between water and TBME. The organic layer was washed with 10% aq. K2CO3 solution, dried over Na2SO4, filtered and evaporated to give a yellow oil. Column chromatography on silica (hexanes/14-50% (EtOAc:MeOH 95:5)) gave 4.55 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: COC(=O)C=C1CCC(c2ccc(O)cc2)CC1
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 0 °C

Procedure:
[4-(4-hydroxyphenyl)cyclohexylidene]acetic acid methyl ester (29 g, 0.12 mol) and 10% pd/c (2.9 g) were put into ethyl acetate and stirred under 25° C. hydrogen gas for 24 hours. The reaction mixture was filtered with celite and concentrated in the vacuum to obtain a yellow solid. The mixture was dissolved in hot ethyl acetate (29 mL) and cooled to reach ambient temperature. The reaction mixture was cooled with ice water again, a filtrate was filtered and washed with ethyl acetate (15 mL) to obtain trans [4-(4-hydroxyphenyl)cyclohexyl]acetic acid methyl ester as a white solid (12.6 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:32]([Mg]Cl)[CH2:33][CH2:34][CH3:35].C(OCC)(=O)C.C(OC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH2:32][CH2:33][CH2:34][CH3:35])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reactant: CCCC[Mg]Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CCCCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 313, the title compound was synthesized using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde and a solution (2M) of n-butylmagnesium chloride in THF. Crystals (ethyl acetate-diisopropyl ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[N:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[CH:3]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
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+]
Product: CC(C)C(O)(c1cccc(-c2ccncc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 94.5 %

Procedure:
By the reaction in the same manner as in Example 29-(i) using 1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.20 g), 4-pyridylboronic acid (754 mg), 2M aqueous sodium carbonate solution (2.23 ml) and tetrakis(triphenylphosphine)palladium(0) (155 mg), the pale-yellow amorphous title compound (1.13 g) was obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][N+:8]([O-])=O)C>CCOC(C)=O.CCO.[Ni]>[CH2:20]([O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[CH:6]1[CH2:7][NH:8][C:4](=[O:3])[CH2:5]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1ccc(OC)cc1OCc1ccccc1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C2CNC(=O)C2)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 72.4 %

Procedure:
3-(2-Benzyloxy-4-methoxyphenyl)-4-nitro-butyric acid ethyl ester (5.2 g) was dissolved in 20 mL EtOAc and 30 mL of EtOH. Raney Ni was added and the mixture was stirred under H2 for 10 h. The mixture was filtered through celite, heated at 90° C. for 20 h and then cooled down to r.t. The mixture was then concentrated and purified on silica gel to give 3 g of the desired product. Yield: 72%.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH2:15][NH:16][CH:17]=[O:18])=[CH:4][C:3]=1[CH2:21][O:22]C1CCCCO1.[B:29]1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:30]1.C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:19]=[CH:20][C:2]3[B:29]([OH:30])[O:22][CH2:21][C:3]=3[CH:4]=2)=[C:8]([CH2:15][NH:16][CH:17]=[O:18])[CH:9]=1)#[N:12]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: N#Cc1ccc(Oc2ccc(Br)c(COC3CCCCO3)c2)c(CNC=O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(CNC=O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-(formylaminomethyl)benzonitrile (1.44 g, 3.24 mmol), bis(pinacolato)diboron (905 mg, 3.56 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (87 mg, 3 mol %), and potassium acetate (1.01 g, 10.3 mmol) in 1,4-dioxane (25 mL) was stirred under nitrogen atmosphere at 80° C. overnight. The mixture was filtered through a Celite pad, and the solvent was removed under reduced pressure. The residue was passed short silica gel column (4:6 hexane/ethyl acetate). The crude product was dissolved in tetrahydrofuran (20 mL) and was added 6 M HCl (2 mL), and the mixture was stirred at room temperature overnight. The mixture was poured into ethyl acetate/water. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (4:6 hexane/ethyl acetate to ethyl acetate to 2:1 ethyl acetate/methanol) followed by trituration with water to give 5-[4-cyano-2-(formylaminomethyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (685 mg, 68%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-formylbenzonitrile was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[CH3:28][C:29]([CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:30][CH2:31]CCO.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][CH:5]1[O:4][CH2:1][CH2:2][CH2:31][CH:30]=[C:29]([CH3:28])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])(=[O:10])[CH3:9]
Reactant: CC(=CCCCO)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1OC(OCCCC=C(C)CCCC(C)CCCC(C)CCCC(C)C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
3.0 g (7.7 mmol) of β-D-Glucose pentaacetate and 3.24 g (9.99 mmol) of 5,9,13,17-tetramethyloctadec-4-en-1-ol were dissolved in dry acetonitrile (8 mL). 1.95 mL (15.4 mmol) of boron trifluoride diethyl etherate complex was added to the solution with cooling on ice. The reaction mixture was allowed to warm up slowly to room temperature while being stirred overnight before addition of 3.2 mL (23 mmol) of triethylamine at 0° C. The resulting solution was diluted with ethyl acetate, and washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over sodium sulfate. After filtration, the filtrate was concentrated to obtain 1-O-(5,9,13,17-tetramethyloctadec-4-enyl)-D-glucopyranoside tetraacetate as a crude product.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([O:29]CC)=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CO.[OH-].[Na+]>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([OH:29])=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccccc1CCc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1csc(-c2cc3cc(CCc4ccccc4C(=O)O)ccc3o2)n1
Yield: 54.3 %

Procedure:
To a solution of 4-tert-butyl-2-[5-{2-(2-ethoxycarbonylphenyl)ethyl}benzofuran-2-yl]thiazole (170 mg) in methanol (5 ml), 1N aqueous sodium hydroxide (1.58 ml) was added. The resulting mixture was heated under reflux for 9 hours. After being cooled, 1N hydrochloric acid was added. The resulting precipitates were collected by filtration, and washed by water to give 4-tert-butyl-2-[5-{2-(2-carboxyphenyl)ethyl}benzofuran-2-yl]thiazole (86.3 mg).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Na]>CO>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][CH2:4][CH2:5][CH2:6][CH2:7][C:2]#[N:3]
Reactant: Sc1ccccn1
Agent: [Na]
Solvent: CO
Product: N#CCCCCSc1ccccn1

Procedure:
10 g of 2-mercaptopyridine and 20 g of 6-bromo-valeronitrile are added successively to a solution of 2.26 g of sodium in 200 ml of methanol. After heating under reflux for 3 hours, the mixture is concentrated in vacuo. The residue is taken up with 200 ml of ether. The solution is washed with water and then dried and concentrated; this gives 15 g of the expected nitrile, which is characterized by an Rf of 0.39 in thin layer chromatography on silica (silica gel 60 F 54: Merck) with isopropyl ether as the eluent.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH2:7]1)(=O)=O.[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:36][SH:37].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:15]([O:14][C:13]([NH:12][CH:9]1[CH2:8][CH2:7][CH:6]([S:37][CH2:36][C:22]2[N:23]=[C:24]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)[O:25][C:21]=2[CH3:20])[CH2:11][CH2:10]1)=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CSC3CCC(NC(=O)OC(C)(C)C)CC3)c(C)o2)cc1
Yield: 27.3 %

Procedure:
A solution of tert-butyl N-[4-(methanesulfonyloxy)cyclohexyl]carbamate (2.24 g, 7.64 mmol, 1.00 equiv), methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (3.0 g, 11.39 mmol, 1.20 equiv) and cesium carbonate (5.55 g, 16.98 mmol, 2.00 equiv) in N,N-dimethylformamide (30 mL) was stirred at 50° C. under nitrogen atmosphere for 3 h. Water (100 mL) was added to quench the reaction. The resulting solution was extracted with 3×80 mL of ethyl acetate. The combined organic layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:15-2:1) to give 960 mg (27%) of methyl 4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 461 [M+H]+, 405, 271, 230, 102.