Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([C@:26]([OH:63])([CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[C:27]([N:29]1[C@H:33]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[CH2:40][C@H:32]2[O:31][C:30]1([CH3:42])[CH3:41])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([C@:26]([OH:63])([CH2:43][CH2:44][OH:45])[C:27]([N:29]1[C@H:33]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[CH2:40][C@H:32]2[O:31][C:30]1([CH3:42])[CH3:41])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@@](O)(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@@](O)(CCO)Cc1ccccc1
Reaction time: 3 h
Yield: 71.7 %

Procedure:
TBAF (0.278 g, 1.06 mmol, 1M in THF) was added to a solution of (S)-2-benzyl-4-(tert-butyl-diphenyl-silanyloxy)-1-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-2-hydroxy-butan-1-one (21f) (0.33 g, 0.53 mmol) in THF (20 mL) at room temperature and stirred for 3 h. Solvent was evaporated and the residue dissolved in dichloromethane and washed with water, brine, dried and evaporated. The product purified by flash chromatography using petroleum ether:acetone (4:1) to get 0.145 g of the title product in 69% yield from two steps.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=O)[CH2:3][CH:4]=O.[NH2:10][C:11]1[S:12][CH:13]=[C:14]([CH3:16])[N:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[CH:6]=[CH:7][N:10]([C:11]2[S:12][CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:4]=[CH:3]1
Reactant: CC(C)(CC=O)CC=O
Reactant: Cc1csc(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1csc(N2C=CC(C)(C)C=C2)n1
Reaction time: 5 h

Procedure:
In 170 ml of benzene, 4.45 l g (0.035 mole) of 3,3-dimethylglutaraldehyde was combined with 3.96 (0.035 mole) of 2-amino-4-methylthiazole under nitrogen. The reaction mixture was brought to reflux and water azeotroped off via a Dean-Stark trap. After 21 hours 0.20 g (0.001 mole) of p-toluenesulfonic acid monohydrate was added to the reaction mixture and heating continued an additional 5 hours after which the solvent was evaporated in vacuo. The crude product was purified by silica gel flash chromatography eluting with a 1% ethyl acetate/hexane solution. The eluate was evaporated in vacuo to yield 2.67 g of the title compound as a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1>[Pd].CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:14])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(-n2cccn2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(-n2cccn2)c1

Procedure:
1-(5-Methoxy-2-nitro-phenyl)-1H-pyrazole was treated under standard hydrogenation conditions (H2, EtOH, 10% Pd/C) to yield desired 4-Methoxy-2-pyrazol-1-yl-phenylamine as a crude solid, which was used for the subsequent reaction without further purification; TLC: 1:1 EtOAc/Hexane Rf 0.6, homogeneous; SM Rf 0.7; MS (m/e) 190.12 (M+H).
Reaction SMILES: OC1C=C(CCC[N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])C=CC=1.ClC1C=CC(CO)=CC=1>>[C:12]1(=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[NH:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Agent: OCc1ccc(Cl)cc1
Product: O=C1NC(=O)c2ccccc21

Procedure:
Mitsunobu coupling of phenol 58 with 4-chlorobenzylalcohol followed by flash chromatography (5 to 30% EtOAc-hexanes gradient) gave 2434344-chlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione as a colorless oil. Yield (2.82 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.79-7.82 (m, 2H), 7.67-7.69 (m, 2H), 7.31-7.38 (m, 4H), 7.15 (t, J=8.0 Hz, 1H), 6.79-6.81 (m, 2H), 6.70-6.73 (m, 1H), 4.99 (s, 2H), 3.72 (t, J=7.2 Hz, 2H), 2.65 (t, J=8.0 Hz, 2H), 2.02 (dddd, J=7.2 Hz, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>O1CCCC1.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.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cccc(Br)n1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1cccc(C=O)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 6-bromo-2-pyridinecarboxaldehyde (3.0 g) in tetrahydrofuran (10 ml), was added sequentially bis(triphenylphosphine)palladium(II) chloride (0.178 g), copper(I)iodide (0.024 g), 1-dodecyne (3.25 ml), and triethylamine (2.12 ml). The solution was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, charged again with bis(triphenylphosphine)palladium (11) chloride (0.024 g), copper (I) iodide (0.024 g), and triethylamine (2.12 ml), and 1-dodecyne (3.25 ml), and tetrahydrofuran (5.0 ml), and heated at 40° C. for 5 hrs. The reaction mixture was again cooled and recharged as above, and heated at 40° C. for 24 hrs. The cooled mixture was concentrated, taken up in ethyl acetate (100 ml), washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was taken up in ethyl acetate (100 ml) and filtered. The filtrate wets combined with material from a similar reaction run 1.43 g of the carboxaldehyde and proportionate amounts of the catalysts, 1-dodecyne, and solvent. The filtrate was concentrated. The residue was purified by flash chromatography using 1.5% ethyl acetate/hexane followed by 1% ethyl acetate/hexane as eluents. The appropriate fractions were collected and concentrated to yield 2.24 g (29%) of product, as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:6]=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:4]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].CC(N(C)C)=O>O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[CH:6]=[C:5]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[N:4]=[C:3]([CH2:2][N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])[N:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cccnc1N1CCN(c2cc(-c3cccc(Cl)c3)nc(CBr)n2)CC1
Reactant: CCNCC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(CC)Cc1nc(-c2cccc(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 25 °C

Procedure:
Combine 2-bromomethyl-4-(3-chloro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (32 mg, 0.06 mmol), diethylamine (0.5 mL), DMA (2 mL) and heat at 80° C. for 3 hours. Let cool to room temperature and add water (5 mL). Extract with EtOAc (10 mL), wash with water (10 mL), dry (Na2SO4) and evaporate. Purify by column chromatography (1:1 hexanes/EtOAc) to obtain {4-(3-chloro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-ylmethyl}-diethyl-amine as a yellow solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:14])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].[S]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1)[CH3:2]
Reactant: Nc1ccccc1O
Reactant: CCCCC(CC)Cn1c(C)nc2ccccc21
Agent: [S]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c(-c2nc3ccccc3o2)nc2ccccc21
Temperature: 25 °C

Procedure:
24.4 g (0.1 mol) of 1-(2-ethylhexyl)-2-methylbenzimidazole (prepared by heating N-2-ethylhexyl-o-phenylenediamine in acetic acid/hydrochloric acid), 10.9 g (0.1 mol) of o-aminophenol and 9.6 g (0.3 mol) of sulfur in 100 ml of pyridine are heated under reflux for 18 hours. After cooling to room temperature, the crude product is precipitated by addition of water. Multiple recrystallization from n-hexane with addition of active charcoal gives 5.7 g (16% of theory) of product, which according to melting point, EPLC and UV determination is identical to the compound obtained in Example 7.
Reaction SMILES: [OH-].[Na+:2].[O:3]=[C:4]([CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([O-:7])=[O:6].[Na+].[CH3:22]I.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[O:3]=[C:4]([C:8]([CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([O-:7])=[O:6].[Na+:2]
Reactant: CI
Reactant: CCCCCCC(C(=O)C(=O)[O-])c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C(=O)C(=O)[O-])c1ccccc1
Yield: 58 %

Procedure:
A 3N aqueous solution (0.50 ml) of sodium hydroxide and 2.0 ml of tetrahydrofuran were added to 0.205 g (0.76 mmoles) of sodium 2-oxo-3-phenylnonanoate, and the mixture was stirred until a completely uniform solution formed. Then, 0.09 ml (1.8 mmoles) of methyl iodide and 20 mg of triethylbenzylammonium chloride were added, and the mixture reacted at room temperature for 23 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ether. The ether layer was dried over magnesium sulfate. The drying reagent was separated by filtration, and the solvent was evaporated. The NMR spectral analysis of the resulting oily product led to the determination that the desired 2-oxo-3-methyl-3-phenylnonanoic acid formed in a yield of 52%. Then, 1.0 ml of a 1N aqueous solution of sodium hydroxide was added to this product, and the mixture was concentrated under reduced pressure. Ether was added, and the precipitated white solid was isolated by filtration to give sodium 2-oxo-3-methyl- 3-phenylnonanoate (0.065 g; 0.229 mmole) in a yield of 58 %.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[N:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[N:21]=3)=[N:3][CH:4]=[CH:5][C:6]2=[N:10]1
Reactant: Cc1cc(N)nc(C)n1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(C)n1
Yield: 86.1 %

Procedure:
A suspension of 4-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (200 mg, 0.57 mmol), 4-amino-2,6-dimethylpyrimidine (95 mg, 0.77 mmol), Pd2(dba)3 (16 mg, 0.018 mmol), Xantphos (39 mg, 0.067 mmol) and cesium carbonate (437 mg, 1.34 mmol) in dioxane (5 mL) was sealed in a microwave vial, purged with nitrogen and irradiated at 150° C. for 25 minutes in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (60-80% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (189 mg, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.52 (br s, 1H), 9.16 (s, 1H), 8.34 (s, 1H), 7.99 (d, J=6.4 Hz, 1H), 7.83 (d, J=1.0 Hz, 1H), 7.81 (s, 1H), 7.71 (dd, J=9.0, 7.3 Hz, 1H), 7.21 (d, J=6.4 Hz, 1H), 3.32 (s, 3H), 2.41 (s, 3H). LCMS (Method B): RT=2.93 min, m/z: 385 [M+H+].
Reaction SMILES: [CH3:1][C:2]([NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=3[O:16][C:15]=2[CH:23]=1)(=[O:10])=[O:9])([CH3:6])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.Cl.[NH2:31][OH:32].C(=O)(O)[O-].[Na+]>ClCCCl.CN(C)C=O.O1CCCC1>[OH:32][NH:31][C:3](=[O:4])[C:2]([CH3:6])([NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=3[O:16][C:15]=2[CH:23]=1)(=[O:10])=[O:9])[CH3:1]
Reactant: NO
Reactant: CC(C)(NS(=O)(=O)c1ccc2c3c(oc2c1)CCCC3)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(NS(=O)(=O)c1ccc2c3c(oc2c1)CCCC3)C(=O)NO
Temperature: 25 °C

Procedure:
2-Methyl-2-(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino)-propionic acid (387 mg, 1.15 mmol) was suspended in 1,2-dichloroethane (22 mL), then oxalyl chloride (438 mg, 3.45 mmol) was added dropwise. N,N-dimethylformamide (2 drops) was added and a gas evolved from the solution. The reaction was stirred until the solids were dissolved. The reaction mixture was concentrated by evaporation, washed with hexane, concentrated again, and dissolved in tetrahydrofuran (20 mL), then added to an aqueous tetrahydrofuran solution (1:1, 34 mL, 5° C.) of hydroxylamine hydrochloride (800 mg, 11.5 mmol) and sodium bicarbonate (1.8 g, 17.25 mmol). The reaction was stirred, warming up to room temperature, overnight. The tetrahydrofuran was removed from the reaction mixture in vacuo. To the residue, 1 M HCl and dichloromethane were added. The organic phase was separated from the organic phase, dried (over MgSO4), and concentrated. The crystals were rinsed with ethyl acetate, then collected by filtration to give N-hydroxy-2-methyl-2-(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino)-propionamide (a compound of general Formula IX) (235 mg, 58%), the structure of which is shown below. The melting point of this compound was determined to be 175-176° C. 1HNMR (CDCl3): δ10.0 (s, 1H), 7.6 (s, 1H), 7.4 (d, 1H), 7.2 (m, 2H), 2.6 (m, 2H), 2.4 (m, 2H) 1.6 (m, 4H), 1.0 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12](Cl)([Cl:17])[C:13]([F:16])([F:15])[F:14]>CN(C=O)C.Cl.[Zn]>[Cl:11][C:12]([Cl:17])([C:13]([F:16])([F:15])[F:14])[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[OH:5]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: OC(c1cccc(Cl)c1Cl)C(Cl)(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A suspension of 35.0 g of 2,3-dichlorobenzaldehyde, 41.2 g of 1,1,1-trichloro-2,2,2-trifluoroethane and 16.4 g of zinc powder in 360 ml of DMF is stirred for 66 h at RT, and subsequently taken up in a mixture of 600 ml of 10% hydrochloric acid and 600 g of ice. By extraction with ether, drying, and concentration of the organic extracts by evaporation, there is obtained (2,2-dichloro-3,3,3-trifluoro-1-hydroxypropyl)-2,3-dichlorobenzene in the form of a yellow oil (compound No. 5.10).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[CH:17]=[CH:18][O:19][C:12]=23)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:21]1([CH2:27][C:28]2[S:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:31]2[S:32][C:28]([CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:29][CH:30]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[CH:18][O:19][C:12]=12)=[O:9]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccnc2ccoc12
Product: Nc1ncc(-c2ccc(CN3CCOCC3)s2)cc1C(=O)Nc1ccnc2ccoc12

Procedure:
Reaction of 2-amino-5-bromo-N-furo[3,2-b]pyridin-7-yl-pyridine-3-carboxamide (synthesis described above) with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A29”;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([C:19](O)=[O:20])[NH:13][CH2:14]2.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:19][OH:20])[NH:13][CH2:14]2
Reactant: O=C(O)[C@H]1Cc2c(Br)cccc2CN1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@H]1Cc2c(Br)cccc2CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
Add lithium aluminum hydride (2 L, 2.00 mol, 1M in THF) to (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (325.4 g, 1.11 mol) in tetrahydrofuran (4.88 L) at −35° C. in an appropriate vessel, then warm to 25° C. over 60 minutes and stir. After 3 hours, cool the mixture to −5° C. then add water (76 mL), 15% w/w aqueous sodium hydroxide (76 mL) and water (228 mL). Heat the mixture to 25° C., add anhydrous magnesium sulfate (750 g) and stir. Filter the mixture and concentrate under reduced pressure to give a solid. Add dichloromethane (690 mL) to the solid and slurry for 30 minutes before filtration to give a solid. Dry the solid under vacuum at 35° C. to give the title compound (148.9 g, 0.55 mol). MS (m/z): 242(M+1 (79Br)), 244(M+1 (81Br)).
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[O:45]1C=[CH:48][CH:47]=[C:46]1[C:50]([C:52]([CH2:54][CH2:55][CH2:56]C)=O)=O.P([O-])([O-])([O-])=O.[OH-].[Na+]>C(OCC)C.CCCCCC.CC(O)C>[CH3:48][CH2:47][C@@H:46]([OH:45])[CH2:50][CH2:52][CH2:54][CH2:55][CH3:56]
Reactant: CCCCC(=O)C(=O)c1ccco1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCCCC[C@H](O)CC
Temperature: 25 °C

Procedure:
A reaction mixture was formed by admixing (i) 50 mg NAD, (ii) 4 ml of 2-propanol and (iii) 5 mmoles of (R)-3-octanone, Compound 13, in a liquid medium containing 1 gm of lyophilized PED alcohol dehydrogenase preparation, 75 ml of 50 mM phosphate buffer, pH 7.1, and 25 ml of hexane. The pH value of the reaction was maintained constant by addition of 1N NaOH. The reaction mixture was maintained at room temperature until product formation stopped. When product formation stopped, (R)-3-octanol, Compound 13a, was isolated by removal of the hexane layer and extraction of the aqueous layer with ethyl ether (3×75 ml).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2OC(=O)[S:12][N:11]=2)=[CH:6][CH:5]=1.[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:19]>CCCCCCCCCCCC>[CH2:23]([O:22][C:20]([C:18]1[S:12][N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:1])[F:17])=[CH:9][CH:8]=2)[N:19]=1)=[O:21])[CH3:24]
Reactant: O=c1oc(-c2ccc(OC(F)(F)F)cc2)ns1
Reactant: CCOC(=O)C#N
Solvent: CCCCCCCCCCCC
Product: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)ns1
Temperature: 150 °C
Yield: 12.3 %

Procedure:
To a solution of 5-(4-trifluoromethoxyphenyl)-[1,3,4]oxathiazol-2-one (0.74 g, 2.81 mmol) in n-dodecane (0.50 ml) was added ethyl cyanoformate (1.10 ml, 11.24 mmol). The resulting reaction mixture was refluxed for 24 h at 150° C. After the completion of the reaction (TLC monitoring), added ice-cold water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 2% EtOAc-Hexane) to get the product (0.11 g, 12%).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[B:15]([O:24][CH:25]([CH3:27])[CH3:26])([O:20][CH:21]([CH3:23])[CH3:22])OC(C)C.OC(C(O)(C)C)(C)C.Cl>O1CCCC1.C(OCC)C.O1CCOCC1>[CH3:27][C:25]1([CH3:26])[C:21]([CH3:22])([CH3:23])[O:20][B:15]([C:2]2[S:1][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=2)[O:24]1
Reactant: c1cc2sccc2cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC1(C)OB(c2cc3cnccc3s2)OC1(C)C
Temperature: -72.5 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a −70° C. solution of thieno[3,2-c]pyridine (21.6 g) in 400 mL of dry tetrahydrofuran under nitrogen gas was added n-butyl lithium (99.9 ml of a 1.6 molar solution in hexanes) over about 15-20 minutes keeping the temperature below −65° C. The solution became cloudy and dark brown. After 45 minutes tri-isopropyl borate (33.06 g) was added and the mixture became homogeneous. The mixture was stirred at −70 to −75° C. for 2 hours. The mixture was allowed to warm to −30° C., then a solution of pinacol in 100 mL of diethyl ether was added over 4 minutes. The reaction mixture became an orange homogeneous solution. The temperature was allowed to warm to 5° C. and held at that temperature for 1 hour. The reaction mixture was neutralized (pH 7) very slowly with 40 mL of 4M hydrochloric acid in 1,4-dioxane, keeping the temperature below 10° C. A precipitate formed. The reaction mixture was stirred for 1 hour and then the solid was collected by filtration. The solid was dried under vacuum at 40° C. for 16 hours. The dry solid (36 g) was stirred with 400 mL of water for 1.5 hours. The slurry was filtered and the solid collected. The solid was dried under a flow of air for 60 hours to give the desired product (34.5 g). 1H NMR (400 MHz, Chloroform-d) δ ppm 1.21 (s, 12H) 7.66-7.70 (m, 1H) 7.80 (d, J=0.78 Hz, 1H) 8.28 (d, J=5.65 Hz, 1H) 8.98 (d, J=0.97 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][CH:39]([NH:41][CH2:42][CH2:43][NH2:44])[CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][CH2:42][NH:41][CH:39]([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: CC(C)NCCN
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCNC(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N-(1-methylethyl)-1,2-ethanediamine by following the procedures in Example 79c. LC-MS m/z 576 (M+H)+; 1H-NMR (MeOD) 1.02 (d, J=6.0 Hz, 6H), 2.31 (m, 3H), 2.72 (m, 3H), 3.23 (m, 1H), 3.55 (m, 1H), 6.36 (d, J=8.8 Hz, 1H), 7.13 (m, 1H), 7.24 (m, 2H), 7.47 (m, 2H), 7.56 (m, 2H), 8.00 (s, 1H), 8.10 (d, J=7.6 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4].[CH2:17]([OH:20])[C:18]#[CH:19].O>C(N(CC)CC)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.[Cu]I>[OH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([C:19]#[C:18][CH2:17][OH:20])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4]
Reactant: C#CCO
Reactant: CC(C)(CO)NC(=O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(CO)NC(=O)c1ccc(C#CCO)cc1F
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 113.1 %

Procedure:
To a solution of N-(2-hydroxy-1,1-dimethylethyl)-4-bromo-2-fluorobenzamide (0.29 g, 1.0 mmol) in triethylamine (5 ml), dichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.05 mmol), copper(I) iodide (0.009 g, 0.05 mmol) and 2-propyn-1-ol (0.085 g, 1.5 mmol) were added and stirred at 50° C. for 3.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate and dried over Na2SO4. After the solvent was evaporated under a reduced pressure, the residue was subjected to silica gel chromatography (hexane/ethyl acetate=1/2) to give the title compound (0.30 g, 94%).