Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]([CH3:12])([CH3:11])[C:7]#[C:8][C:9]#[CH:10].[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].O>CCOCC>[CH3:5][C:6]([CH3:12])([CH3:11])[C:7]#[C:8][C:9]#[C:10][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#CC#CC(C)(C)C
Agent: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCCC[Sn](C#CC#CC(C)(C)C)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
(5,5-dimethyl-1,3-hexadiynyl)tri-n-butylstannane was synthesized as follows a solution containing ethylmagnesium bromide (19.3 millimoles) and 5,5-dimethyl-1,3hexadiyne (19.3 millimoles) in 50 milliliters of ether was refluxed for 5 hours under nitrogen, then cooled to -78° C. To this solution, 18.6 millimoles of tri-n-butyltin chloride in 10 milliliters of ether was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Water was added to form a two-phase mixture, the phases were separated, and the aqueous phase was washed with ether. The ether wash was combined with the organic phase from the initial phase separation, and evaporated under reduced pressure to yield a crude oil. Distillation in vacuo produced 2.92 grams of pure (5,5-dimethyl-1,3-hexadiynyl)tri-n-butylstannane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:6](Cl)[N:5]=[C:4](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[N:5]=[C:4](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: OCCCc1c(Cl)nc(/C=C/c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc(/C=C/c2ccccc2)nc2c1CCCO2
Temperature: 60 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
To 3-{4,6-dichloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}-1-propanol (275 mg, 0.89 mmol) in DMF (4 mL) was added K2CO3 (0.50 g, 3.6 mmol). The suspension was warmed to 60° C. and allowed to stir 16 h under nitrogen. The reaction was cooled to rt, concentrated to remove most of the DMF and the residue was partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc (2×), washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) using an EtOAc/hexanes gradient to yield the desired compound as a yellow solid (0.21 g, 88%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:34](Cl)(=O)[NH2:35].[C:38](=[O:41])(O)[O-:39].[Na+].C(Cl)Cl.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>C1COCC1>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[OH:50][C:48]([C:47]([F:52])([F:51])[F:46])=[O:49].[OH:50][C:48]([C:47]([F:52])([F:51])[F:46])=[O:49].[CH3:1][N:2]([CH2:3][CH2:34][NH2:35])[C:38](=[O:41])[OH:39]
Reactant: O=C([O-])O
Reactant: NC(=O)Cl
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN)C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Oxycodone free base (6.5 g, 20.6 mmol) was dissolved in dry, degassed tetrahydrofuran (120 mL), and the mixture was cooled to −10° C. using dry ice/acetone bath. Potassium bis(trimethylsilyl)amide (KHMDS) (103.0 mL, 51.6 mmol, 0.5 M in toluene) was added via cannula. The mixture was stirred under N2 at below −5° C. for 30 min. N,N-Bis(tert-butyl)N′-2-(chlorocarbonyl(methyl)amino)ethylcarbamate (8.0 g, 23.7 mmol), (E-8) prepared as described in the Example herein, in THF (30 mL) was then added via cannula over 15 min. The mixture was stirred at −5° C. for 30 min. Another portion of carbamoyl chloride (4.0 g, 11.9 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature for 2 h. Sodium bicarbonate (10 mL, sat. aq.) was added. The mixture was concentrated in vacuo to half of its initial volume. EtOAc (50 mL) was added and layers were separated. The organic phase was further washed with water (3×20 mL), brine (40 mL) and then was concentrated. The residue was purified by silica gel chromatography, using DCM/MeOH (gradient 100/1 to 100/15) to afford a white foam in 55% yield (7.0 g, 13.4 mmol). This material was dissolved in a 1:1 mixture of DCM/trifluoroacetic acid (TFA) (20 mL/20 mL) at room temperature and stirred for 1 h. The solution was then concentrated in vacuo to afford oxycodone 6-(N-methyl-N-(2-amino)ethylcarbamate-2TFA as a thick oil (7.3 g, 11.4 mmol, 99% purity). MS: (m/z) calc: 415.2, observed (M+H+) 416.5. The oxycodone 6-(N-methyl-N-(2-amino)ethylcarbamate-2TFA (E-9) was used without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[N:24]3[CH:25]=[N:26][CH:27]=[C:23]3[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[N:24]3[CH:25]=[N:26][CH:27]=[C:23]3[CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1)=[O:11]
Reactant: OCc1ccc(C2CCCc3cncn32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(C2CCCc3cncn32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.16 ml of dimethylsulfoxide in 16 ml of methylene chloride is cooled to -70° under nitrogen and 0.17 g of oxalyl chloride is added dropwise. The reaction mixture is stirred for 30 min and 0.24 g of 5-(p-hydroxymethylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 4 ml of methylene chloride is added slowly. The reaction mixture is stirred for 2 h at -70°, 0.8 ml of triethylamine is added dropwise, and the reaction mixture is allowed to warm slowly to room temperature. The reaction mixture is diluted with 20 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated to yield the title compound which is purified by conversion to the furmaric acid salt, m.p. 131°.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.O=[CH:22][C@@H:23]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[BH4-].[Na+].Cl[Si](C)(C)C>C(O)C>[CH3:22][CH2:23][O:8][C@H:7]1[O:9][C@@H:10]2[O:16][C:15]3([CH3:19])[O:17][O:18][C@@:11]42[C@@H:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[C@@H:12]4[CH2:13][CH2:14]3)[C@H:6]1[CH3:20]
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 21.5 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
Artemisinin (1 g.) and polyhydroxy catalyst, dextrose (4 g.) were stirred in ethanol (15 ml). Sodium borohydride (500 mg.) was added slowly for 10 minutes and the reaction mixture was stirred for 30 minutes at room temperature (20-23° C.). After completion of the reduction step, chlorotrimethysilane (3.5 ml) was added and the reaction mixture was further stirred for 1.5 hours at room temperature. After usual work up and purification through column chromatography (1:5 ratio) a mixture of alpha and beta arteether (0.805 g., 80.5% w/w) were obtained.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].CN(C)[CH:19]=[O:20].P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>ClC(Cl)C>[CH:19]([C:14]1[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][C:12]=2[Cl:15])[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[O:20]
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Combine 2-carboethoxy-4,6-dichloroindole (10.0 g, 0.039 mol), and dimethylformamide (4.5 mL, 0.057 mol) in dichloroethane (20 mL). Add phosphoryl chloride (8.9 g, 0.058 mmol). Heat to 80° C. After 18 hours, cool the reaction mixture to ambient temperature and combine with aqueous 1 M sodium acetate solution and stir. After 18 hours, filter, rinse with water, and dry to give 3-formyl-2-carboethoxy-4,6-dichloroindole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].[H-].[Na+].[CH3:13][N:14]([CH3:28])[S:15]([NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)(=[O:17])=[O:16].Cl>C1COCC1.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][O:6][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][S:15]([N:14]([CH3:28])[CH3:13])(=[O:17])=[O:16])=[O:27])=[CH:21][CH:22]=1
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: CN(C)S(=O)(=O)NC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)NC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dichlorobenzyl alcohol (500 mg, 2.8 mmol) in THF (20 mL) was added sodium hydride (113 mg, 2.8 mmol, 60% dispersion in mineral oil) and stirred at room temperature for 2 hours and then at 50° C. for 30 minutes. Cooled to room temperature and the solvent removed in vacuo to afford an orange solid. This was dissolved in DMSO (5 mL) to which was added a solution of N-[(dimethylamino)sulfonyl]-4-fluorobenzamide (Preparation 11, 580 mg, 2.3 mmol) in DMSO (10 mL) slowly. The dark red solution was heated at 50° C. for 18 h then 120° C. for 2 hours. The mixture was cooled and poured onto water (50 mL) containing 2M HCl (30 mL) and extracted with EtOAc (2×30 mL), washed with 1M HCl (30 mL) and dried over MgSO4, filtered and solvent removed in vacuo to give 1.9 g of crude residue that was purified using reverse phase preparative HPLC to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C@@H:19]3[CH3:31])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[BrH:32].CC(O)=O>>[BrH:32].[Br:32][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]3[CH3:31])=[CH:16][N:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Cl)nn3ccnc23)nc1
Agent: Br
Solvent: CC(=O)O
Product: C[C@H]1CNCCN1c1ccc(Nc2cc(Br)nn3ccnc23)nc1
Temperature: 150 °C
Yield: 65 %

Procedure:
An autoclave was charged with 115c (1.60 g, 3.6 mmol) and HBr/AcOH (60 mL). It was heated at 150° C. for 18 h. The reaction mixture was concentrated under reduced pressure to give black oil. The oil was recrystallized with methanol (30 mL)/dichloromethane (30 mL)/petroleum ether (90 mL) to afford 115d as a yellow solid (1.1 g, 65%). MS-ESI: [M+H]+ 388.1
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCCOc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OCCOc2ccc(N)cc2)cc1
Reaction time: 6 h

Procedure:
68.4 g (0.22 M) of methyl 4-[2-(4-nitrophenoxy)ethoxy]benzoate and 1.3 g of palladium-on-charcoal are added to a mixture of 800 ml of methanol and 200 ml of tetrahydrofuran in a 2000 ml reactor, and the mixture is then maintained under ambient pressure of hydrogen at 60° C. with vigorous stirring for 6 hours.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9](N3CCCCC3)=[CH:8]2)=[CH:2]1.[CH2:22]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32][N:12]2[CH2:13][CH2:14][CH:15]([C:9]3[C:10]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:7]([CH2:6][C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[CH:8]=3)[CH2:10][CH2:11]2)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])[CH3:23]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: c1cnc2c(c1)c(N1CCCCC1)cn2Cc1ccoc1
Product: CCOC(=O)c1cc(CN2CCC(c3cn(Cc4ccoc4)c4ncccc34)CC2)ccc1OC
Yield: 182.4 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 0.62 g (2.2 mmol) of 1-furan-3-ylmethyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine and 0.79 g (2.9 mmol) of 5-bromomethyl-2-methoxybenzoic acid ethyl ester. After standard work-up and purification, 0.95 g (91% of yield) of the expected ester were obtained.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2)([CH3:7])[C:3](OC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][C:2]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2)([CH3:1])[CH2:3][OH:4]
Reactant: COC(=O)C(C)(C)c1cccc2ccc(C)nc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2cccc(C(C)(C)CO)c2n1
Temperature: 0 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
To a solution of methyl 2-methyl-2-(2-methylquinolin-8-yl)propanoate (0.57 g, 2.3 mmol) in THF (10 mL) was added 1 N LAH (5.9 mL, 5.9 mmol) in THF at 0° C. and stirred at 0° C. for 6 hours. Sodium sulfate decahydrate (2.0 g) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The solid was removed by filtration and washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate) to give 2-methyl-2-(2-methylquinolin-8-yl)propan-1-ol (0.43 g, 85%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=1[CH3:22].C(N(CC)C(C)C)(C)C.C(Cl)Cl>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=2[CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc(/C=C/C#N)cc(C)c1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Cl)n1
Temperature: 145 °C
Yield: 61.1 %

Procedure:
To a mixture of 2,4-dichloropyrimidine (5 gm) and (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (6 gm) was added N,N-diisopropylethylamine (60 ml) under stirring. The mixture was then heated to 140 to 150° C. and stirred for 55 to 60 hours. The solution was then cooled to room temperature and the solvent was distilled off under reduced pressure to provide a residual solid. To the residual solid was added methylene chloride (300 ml) and water (250 ml). The reaction mass was stirred for 30 minutes at room temperature and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrates to provide 5 gm of (E)-3-(4-(2-chloropyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile.
Reaction SMILES: [CH2:1]([C:4]1([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]#[N:26])=[CH:15][CH:14]=2)[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].NN.C1COCC1>CCO.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([C:4]1([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]#[N:26])=[CH:15][CH:14]=2)[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C=CCC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21
Agent: [Cu+2]
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(5-allyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-5-yl)biphenyl-3-carbonitrile (35′ mg, 0.103 mmol) in EtOH (2 mL) at ambient temperature is added H2NNH2/THF (1.0 M, 15 mL, 15 mmol) and saturated aqueous CuSO4 (0.1 mL). The reaction mixture is stirred at ambient temperature overnight. The mixture is concentrated and dissolved in EtOAc, which is washed with water, dried over anhydrous Na2SO4 and concentrated to give the crude oil, which is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 342 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm (HCl salt) 0.95 (t, J=7.2 Hz, 3H), 1.21-1.33 (m, 2H), 1.80-1.90 (m, 2H), 1.90-2.02 (m, 1H), 2.09-2.37 (m, 3H), 2.59-2.68 (m, 1H), 2.71-2.85 (m, 1H), 6.81-6.88 (m, 1H), 6.90-6.98 (m, 2H), 7.19-7.25 (m, 1H), 7.27-7.39 (m, 3H), 7.43 (d, J=1.8 Hz, 1H), 7.71 (dd, J=8.3, 2.0 Hz, 1H), 8.10-8.18 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3([CH3:28])[CH2:17][CH2:16][CH2:15][N:14]3C(OCC3C=CC=CC=3)=O)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[CH3:28][C:13]1([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:17][CH2:16][CH2:15][NH:14]1
Reactant: CC1(c2nc3cccc(C(N)=O)c3o2)CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(c2nc3cccc(C(N)=O)c3o2)CCCN1
Yield: 44.1 %

Procedure:
A mixture of benzyl 2-(7-carbamoylbenzo[d]oxazol-2-yl)-2-methylpyrrolidine-1-carboxylate (144 mg, 0.37 mmol), 10% Pd/C (20 mg) in methanol (10 mL) was stirred at room temperature over 1 atm hydrogen for 3 h. Then the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography. 40 mg of yellow oil of 2-(2-methylpyrrolidin-2-yl)benzo[d]oxazole-7-carboxamide was obtained, yield 43%. 1H-NMR (400 MHz, DMSO-d6): δ 1.58 (s, 3H), 1.76-1.87 (m, 3H), 2.47-2.49 (m, 1H), 2.86-2.91 (m, 1H), 2.97-3.02 (m, 1H), 7.41-7.44 (t, J=6.4 Hz, 1H), 7.69 (s, 1H), 7.74-7.76 (d, J=5.6 Hz, 1H), 7.82 (s, 1H), 8.85-8.87 (d, J=6.4 Hz, 1H). LC-MS (ESI) m/z: 246 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:3]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([N:17]3[CH2:21][CH2:20][C@@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18]3)=[C:11]([NH2:25])[CH:10]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:70]([Zn]C#N)#[N:71].CC(N(C)C)=O>CCOC(C)=O.[Zn].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]>[NH2:25][C:11]1[C:12]([N:17]2[CH2:21][CH2:20][C@@H:19]([N:22]([CH3:23])[CH3:24])[CH2:18]2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:2]([C:70]#[N:71])=[CH:7][N:6]=2)[CH:10]=1
Reactant: N#C[Zn]C#N
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(C#N)c(-c2cn(C)c3ccccc23)n1
Temperature: 95 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A mixture of N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethyl-aminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 85, 324 mg, 0.66 mmol), zinc powder (4.3 mg, 0.07 mmol), tris(dibenzylideneacetone)-dipalladium(0) (60.3 mg, 0.07 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 62.8 mg, 0.13 mmol), and dicyanozinc (46.4 mg, 0.40 mmol) was placed in a reaction tube under N2 and then degassed DMA (1.75 mL) was added. The resulting suspension was heated to 95° C. and stirred for 2 h. The mixture was then diluted with EtOAc and washed 5 times with water, and then with brine. The solution was the dried (MgSO4) and concentrated in vacuo. The residue was dissolved in CH3OH and was allowed to pass through a stratospheres SPE cartridge PL-Thiol MP SPE (available from Polymer Laboratories) under gravity. The resulting solution was concentrated in vacuo and the resulting residue was triturated with diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether to give the title compound (184 mg, 58%) as a yellow solid; 1H NMR: (100° C.) 1.8-1.88 (1H, m), 2.03-2.11 (1H, m), 2.24 (6H, s), 2.92-2.99 (1H, m), 3.01-3.05 (1H, m), 3.06-3.11 (1H, m), 3.20 (2H, ddd), 3.69 (3H, s), 3.90 (3H, s), 4.17 (2H, br s), 6.73 (1H, s), 7.04 (1H, s), 7.10 (1H, t), 7.26 (1H, t), 7.50 (1H, d), 8.31 (1H, d), 8.42 (1H, s), 8.60 (1H, s), 8.62 (1H, s); m/z: ES+ MH+ 483.31.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[S:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)CCC>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.C1(C)C=CC=CC=1>[C:13]([C:11]1[C:5]2[S:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(Br)cc2c1SCC2(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2ccco2)cc2c1SCC2(C)C
Temperature: 25 °C
Yield: 40.1 %

Procedure:
A mixture of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]thiophene (1.20 g, 4.0 mmol), 2-(tributylstannyl)furan (1.71 g , 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.46 g, 0.4 mmol), and 20 mL of toluene is heated under argon at reflux for 30 min. The reaction mixture is cooled to room temperature, concentrated in vacuo, diluted with ether, washed with 10% aqueous ammonium hydroxide solution and with brine, dried over anhydrous magnesium sulfate, and concentrated to give a dark oil. Purification by flash column chromatography on silica gel (1% ethyl acetate-hexane) yields about 0.46 g (40%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].C([Sn](CCCC)(CCCC)[C:15]([O:17]CC)=[CH2:16])CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.[F-].[K+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:15](=[O:17])[CH3:16]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(Br)c(F)c1
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.5 %

Procedure:
54 mL solution of 5.0 g 1-bromo-2-fluoro-4-methylbenzene, 10 g tributyl(1-ethoxyvinyl)tin and 1.53 g tetrakis (triphenylphosphine) palladium in toluene was heated at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, 10% aqueous potassium fluoride solution was added thereto and stirred for 30 minutes, and formed insolubles were filtered off through Celite. The organic layer was washed with water, then hydrolyzed by vigorously stirring it together with 5 N aqueous hydrochloric acid, and the organic layer was further washed with water and brine. The solution was dried over anhydrous sodium sulfate, then the solvent was removed, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 4.61 g of 2′-fluoro-4′-methylacetophenone (yellow oil) as a crude product. From 4.61 g crude 2′-fluoro-4′-methylacetophenone, 4.1 g of the title compound (yellow oil) was obtained by the same method as in Production Example 3.