Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.C([O-])(=O)C.[Na+].[NH2:10][CH2:11][C:12]([OH:14])=[O:13].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1>C1(C)C=CC=CC=1>[N:10]1([CH2:11][C:12]([OH:14])=[O:13])[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: COC1CCC(OC)O1
Reactant: NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)Cn1cccc1
Reaction time: 0.03 h
Yield: 33.6 %

Procedure:
To a 1 liter flask fitted with a condenser, a magnetic stirrer and a nitrogen inlet tube is added acetic acid (glacial, 300 ml) and sodium acetate (32.8g; 0.4 mole). The system is purged with nitrogen and a positive nitrogen pressure is maintained. Then glycine (15.0g; 0.2 mole) is added and the solution is heated to reflux. To the refluxing, clear solution is added 2,5-dimethoxytetrahydrofuran (29 ml, 0.2 mole) over a period of 2 - 3 minutes; refluxing is continued an additional 2 minutes. The reaction mixture is cooled in an ice bath and most of the acetic acid is removed under vacuum. The residue is taken up in water and extracted with four portions of ether. The ether extracts are washed with water, dried over anhydrous magnesium sulfate, filtered and the ether is evaporated to yield a slurry. The slurry is taken up into toluene, filtered through celite and crystallized by cooling to give 8.41g. (33.6%) of the title compound. M.P. 88°-90° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[N:28]2[CH:29]=[C:30]([CH2:33][CH2:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1)=[O:23].[CH3:38][Mg]Br>C1COCC1>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]2[N:28]([C:24]([C:22]([NH:21][C:3]3[CH:4]=[C:5]([C:8]4[N:12]=[C:11]([CH:13]5[CH2:14][N:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16]5)[O:10][N:9]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:23])=[CH:25][N:26]=2)[CH:29]=1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCC(C)=O)cn45)c3)no2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCC(C)(C)O)cn45)c3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of methyl 3-(3-(4-methyl-3-(6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F65) (10 mg, 0.0199 mmol) in anhydrous THF (1 mL) at −78° C. under a stream of Argon was added methylmagnesium bromide (27 uL, 0.080 mmol). The reaction was stirred to room temperature for 15 minutes then cooled to 0° C. and quenched with 1N HCl. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(3-(6-(3-hydroxy-3-methylbutyl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F67). 1H NMR (400 MHz, d6-DMSO) δ 10.10 (s, 1H), 9.34 (s, 1H), 8.63 (s, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.84 (dd, J=1.6, 8.0 Hz, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.56-7.54 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.39-4.34 (m, 2H), 4.31-4.25 (m, 1H), 4.22-4.17 (m, 2H), 3.59 (s, 3H), 2.76-2.72 (m, 2H), 2.37 (s, 3H), 1.71-1.67 (m, 2H), 1.15 (s, 6H). MS m/z 519.23 (M+1)+.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([C@@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH2:12][OH:13])C1C=CC=CC=1.[H][H].O>[Pd].CO>[NH2:10][C@@H:11]([C@@H:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH3:15])[CH2:12][OH:13]
Reactant: C[C@H](OC(C)(C)C)[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: C[C@H](OC(C)(C)C)[C@H](N)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a round bottom flask containing benzyl((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8 mmol) was added MeOH (100 mL). Solution was degassed with nitrogen for 15 min at which time palladium on carbon (0.95 g, 0.89 mmol) in MeOH (5 mL) was added. A hydrogen atmosphere was then inserted. Resulting reaction mixture allowed to stir 40 min at room temperature at atmospheric pressure when water (2 mL) was added and once again a hydrogen atmosphere was inserted at atmospheric pressure and the subsequent reaction mixture allowed to stir 18 hr at room temperature. The reaction mixture was filtered through a pad of celite and concentrated to a brown oil. Oil redissolved in toluene and concentrated to afford (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (2.5 g, 15.5 mmol, 87% yield) as a brown oil. LCMS m/z 162.1 (M+H)+, Rt 0.41 min (Mass ion only, no UV peak).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][CH2:13][O:14][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CCO)CC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)C(CCOS(C)(=O)=O)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 g (26.0 mmol) of crude 2-(6-methoxyindan-1-yl)ethanol are dissolved in 50 ml of dichloromethane and, while cooling with ice, 3.6 g (31 mmol) of methanesulphonic acid chloride and 3.1 g (31 mmol) of triethylamine are added dropwise. The mixture is stirred at room temperature for 3 hours, the triethylammonium chloride which has precipitated is filtered off and the filtrate is extracted by shaking with ice-water. The organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation at 40° under reduced pressure. Methanesulphonic acid 2-(6-methoxyindan-1-yl)ethyl ester is obtained which can be used without further purification.
Reaction SMILES: BrC1N2N=C(F)C=CC2=NC=1.NCCC[N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21].[Br:22][C:23]1[N:27]2[N:28]=[C:29]([NH:32][CH2:33][CH2:34][CH2:35]N(C)C3C=CC=CC=3)[CH:30]=[CH:31][C:26]2=[N:25][CH:24]=1>>[Br:22][C:23]1[N:27]2[N:28]=[C:29]([NH:32][CH2:33][CH2:34][CH2:35][CH:18]3[CH2:19][CH2:20][NH:16][C:17]3=[O:21])[CH:30]=[CH:31][C:26]2=[N:25][CH:24]=1
Reactant: CN(CCCNc1ccc2ncc(Br)n2n1)c1ccccc1
Reactant: NCCCN1CCCC1=O
Agent: Fc1ccc2ncc(Br)n2n1
Product: O=C1NCCC1CCCNc1ccc2ncc(Br)n2n1
Yield: 68 %

Procedure:
The 3-bromo-6-fluoroimidazo[1,2-b]pyridazine was alkylated with 1-(3-aminopropyl)pyrrolidin-2-one, under same reaction condition as used in the synthesis of N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N3-methyl-N3-phenylpropane-1,3-diamine example 5.6.29 to obtain 68% product.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>[Pd].O1CCCC1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:4]2[C:5]([NH:10][CH2:11][CH:12]([OH:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccnc1NCC(O)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1NCC(O)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
A mixture of α-[(3-nitro-2-pyridinylamino)methyl]benzene methanol (30.8 g, 0.12 mole) and 5% palladium on carbon catalyst in 450 ml of tetrahydrofuran was hydrogenated in a large glass Parr bottle at room temperature. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. p-Chlorobenzoyl chloride (15.1 ml, 0.12 mole) and triethylamine (16.5 ml, 0.12 mole) were added simultaneously dropwise to the stirred filtrate at 12°-15° C. (ice-water bath) and the mixture was allowed to stir at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was partitioned between methylene chloride and water. The methylene chloride layer was separated and extracted with water (1×), 5% potassium hydroxide (2×), and water (2×). The methylene chloride layer was separated, dried, and evaporated to dryness. The residue was purified on a silica gel column (400 g) by eluting with 50% ethyl acetete/50% hexanes. Total recovery: 18.2 g (41.6% yield). A 5-g sample was recrystallized from ethyl acetate/hexanes to give 2.71 g of solid, mp. 157°-159° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:37])C.Cl.O>CC(C)=O>[CH:4]([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:37])=[O:3]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of 4.32 g of (RS)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 50 ml of acetone was added 5 ml of 2N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the thus formed precipitate was collected by filtration and washed with ethyl ether to obtain 2.94 g (79%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:6][C:7]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16]C)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:5]2[S:4][C:3]3[C:1]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:2][C:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[OH:16])=[N:8][C:7]=3[CH:6]=2)=[CH:20][CH:21]=1
Reactant: COc1ccccc1C(=O)Nc1cc(-c2ccc(F)cc2)sc1C#N
Reactant: C1COCCN1
Product: Oc1ccccc1-c1nc(N2CCOCC2)c2sc(-c3ccc(F)cc3)cc2n1
Temperature: 200 °C

Procedure:
A mixture of N-(2-cyano-5-(4-fluorophenyl)thiophen-3-yl)-2-methoxybenzamide (0.10 g, 0.57 mmol) and morpholine (0.20 mL) was heated in a microwave oven at 200° C. for 5 min. The reaction was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(6-(4-fluorophenyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol. LC/MS: m/z 408 (M+H)+ at 4.76 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[CH:2]([CH2:11][CH2:12][CH3:13])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([NH2:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3]1[N:22]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:21][C:2]=1[CH2:11][CH2:12][CH3:13])[CH3:9]
Reactant: CCCC(Br)C(=O)CC(=O)OCC
Reactant: NC(=O)c1ccccc1
Product: CCCc1oc(-c2ccccc2)nc1CC(=O)OCC

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from ethyl 4-bromo-3-oxo-heptanoate (2.83 g, 11.4 mmol) and 5.51 g (45 mmol) of benzamide to give 820 mg of Intermediate IC: TLC Rf=0.70 (2/1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ7.98 (m, 2H), 7.43-7.4 (m, 3H), 4.18 (q, 2H, J=7.2), 3.56 (s, 2H), 2.66 (t, 2H, J=7.5), 1.76-1.68 (m, 2H), 1.27 (t, 3H, J=7.2), 0.99 (t, 3H, J=7.2); low resolution MS (ES+)m/e 274.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:20]3[C:3]4[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=4[NH:1][C:2]4[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]3=4)[CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:13]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2ccc(Cl)cc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(4-chlorophenoxy)benzaldehyde in an analogous manner to that described in Example 1 to give 9-[3-(4-chlorophenoxy)-phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a beige crystalline solid of melting point 238-239° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[C:46]([F:48])[C:45]([OH:49])=[CH:44][CH:43]=2)=[C:38]([O:50][SiH:51]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:37]=1)([CH3:35])([CH3:34])[CH3:33].[CH2:64](O)[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71]>O1CCCC1>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[C:46]([F:48])[C:45]([O:49][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:44][CH:43]=2)=[C:38]([O:50][SiH:51]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(-c2ccc(O)c(F)n2)c(O[SiH](c2ccccc2)c2ccccc2)c1
Reactant: CCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(C(C)(C)C)cc2O[SiH](c2ccccc2)c2ccccc2)nc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
2.30 g (13.35 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 3.47 g (13.35 mmol) of triphenylphosphine in 100 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 3.58 g (8.10 mmol) of 6-(4-tert.-butyldiphenylsilyloxyphenyl)-2-fluoro-3-hydroxypyridine and 1.70 g (13.35 mmol) of 1-octanol are then added. After a reaction time of 1.5 hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 95:5 hexane/ethyl acetate), giving 4.43 g of 6-(4-tert.-butyldiphenylsilyloxyphenyl)-2-fluoro-3-octyloxypyridine. ##STR46##
Reaction SMILES: [CH:1]1([CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:26]#[N:27].[Na+]>CS(C)=O>[C:26]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])#[N:27]
Reactant: [C-]#N
Reactant: O=C(OCc1ccccc1)C(CCCCCCCCI)C1CCCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCCCCCCC(C(=O)OCc1ccccc1)C1CCCC1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
A mixture of the iodoester from step 2, (3.99 g, 8.7 mmol) and sodium cyanide (0.47 g, 9.6 mmol) in 15 mL of anhyd. DMSO was heated at 70°-75° C. for 30 min. After cooling, the reaction mixture was poured over ice (~ 40 g), extracted into ether and washed successively with water and saturated brine. The organic layer was concentrated to yield an oil (2.89 g). 1H NMR (300 MHz, CDCl3). δ: 7.35 (m, 5H), 5.15 (s, 2H), 2.30(t, 8 Hz, 2H), 2.20(m, 1H), 2.00(m, 1H), 1.3-1.8 (m, 22H).
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:18][CH2:17][CH2:16][O:15]3)=[CH:10][CH:9]=2)CCCCC1.[Br:25]C1C=CC(C=O)=CC=1.C(O)CO>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:25][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1
Reactant: c1cc(P(C2CCCCC2)C2CCCCC2)ccc1C1OCCO1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: c1ccccc1
Product: Brc1ccc(C2OCCO2)cc1

Procedure:
This is an example of synthesis of ligand 2. 2-(4′-Dicyclohexylphosphinophenyl)-1,3-dioxolane (Ligand 2): Part I. A solution of 4-bromobenzaldehyde (5 g, 0.027 mol), ethylene glycol (7.0 g, 0.11 mmol), and p-toluenesulfonic acid (0.1 g, 0.5 mmol) in benzene was heated at reflux for 24 h using a Dean-Stark setup to remove water. The reaction was taken up in diethyl ether (100 mL) and washed with water (5×30 mL) and brine (30 mL). The organic phase was dried over magnesium sulfate and concentrated under vacuum to afford 2-(4′-bromophenyl)-1,3-dioxolane (5.95 g). Part II. 2-(4′-bromophenyl)-1,3-dioxolane (1.0 g, 4.4 mmol) was dissolved in anhydrous diethyl ether (30 mL) and the solution was cooled to −78° C. t-Butyllithium (5.14 mL, 1.7 M solution in pentane, 8.8 mmol) was added dropwise with stirring. The reaction was stirred for 2 h at −78 ° C. Chlorodicyclohexylphosphine (1.13 g, 4.8 mmol) was added dropwise via a syringe at −78 ° C. with stirring. The reaction mixture was allowed to warm up to room temperature and stirred for an additional 18 h. To the reaction mixture was added argon purged water (25 mL) slowly. The organic phase was separated under argon and the aqueous phase was washed with diethyl ether (20 mL). The combined organic phase was concentrated under vacuum to afford a colorless oil, which was crystallized from methanol to afford ligand 2 as a white crystalline solid having the structure shown below (yield: 1.4 g, 92%). 31P{1H} NMR (CDCl3): δ2.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([CH:28]=C)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1.I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1)[CH:28]=[O:32]
Reactant: C=Cc1c(F)c(Cl)cc(C(C)Nc2ncnc3c2ncn3C2CCCCO2)c1OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
N-[1-(5-Chloro-4-fluoro-2-methoxy-3-vinylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (240 mg, 0.56 mmol) was dissolved in THF (10 mL) and 0.16 M osmium tetraoxide in water (700 μL) was added. Sodium metaperiodate (360 mg, 1.7 mmol) and water (1 mL, 60 mmol) were added. The reaction was stirred at 60° C. for 2 hours. Reagents were doubled. 0.16 M osmium tetraoxide in water (700 μL) was added. Sodium metaperiodate (360 mg, 1.7 mmol) and water (1 mL) were added and the mixture was warmed to 60° C. for another 2 hours. The mixture was evaporated and the solids were extracted with dichloromethane. The extracts were purified on silica gel using 0-60% EtOAc in hexanes to give the desired compound (50 mg, 20%). LCMS calculated for C20H22ClFN5O3 (M+H)+: m/z=434.1. found: 434.1.
Reaction SMILES: O[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.S(Cl)([Cl:33])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:33][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Yield: 81.6 %

Procedure:
To a mixture of ethyl (4-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.68 g) and toluene (50 mL) was added thionyl chloride (0.23 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (0.58 g, yield 79%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.C(N(CC)C(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](Cl)=[O:40]>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:39](=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NC(=O)c1ccccn1)N2
Temperature: 0 °C
Yield: 55.7 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (60 mg, 0.19 mmol, 1.0 eq.) and N,N-diisopropylethylamine (50 mg, 0.38 mmol, 2.0 eq.) in 4 mL of dichloromethane was added dropwise a solution of picolinoyl chloride (40 mg, 0.29 mmol, 1.5 eq.) in dichloromethane (1 mL). Then the resultant mixture was stirred at room temperature for 30 min. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=2:1) to afford 44 mg of methyl 3,3-dimethyl-2-(2-(picolinamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a gray solid; yield: 60%. MS (ESI+APCI) M+1=416.2.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[N:40]=[CH:39][C:38]([C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[C:43]([CH3:50])[CH:42]=2)=[CH:37][C:36]=1[C:51]1[N:52]=[N:53][N:54]([CH:56]([CH3:58])[CH3:57])[CH:55]=1.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CN(C=O)C>[NH2:34][C:35]1[N:40]=[CH:39][C:38]([C:41]2[CH:49]=[CH:48][C:44]([C:45]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[O:46])=[C:43]([CH3:50])[CH:42]=2)=[CH:37][C:36]=1[C:51]1[N:52]=[N:53][N:54]([CH:56]([CH3:58])[CH3:57])[CH:55]=1
Reactant: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)O
Reactant: C1COCCN1
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
Product: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
HATU (336 mg, 0.88 mmol) and DIPEA (0.30 mL, 1.77 mmol) were added to a solution of 4-(6-amino-5-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-methylbenzoic acid (200 mg, 0.59 mmol) in DMF (10.0 mL) at room temperature, after 5 min, morpholine (0.06 mL, 0.71 mmol) was added, stirred at RT for 18 h. The reaction mixture was poured into ice cold water, extracted with EtOAc (2×50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude product was purified by washing with ether to afford 148 mg of (Yield: 61.4%) of the title compound as a white solid.