Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].Br[CH2:15][CH2:16][C:17](Cl)([Cl:19])[Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][C:17]([Cl:19])=[CH:16][CH2:15][O:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH2:9][CH2:10][OH:11])=[C:6]([Cl:12])[CH:5]=1
Reactant: ClC(Cl)(Cl)CCBr
Reactant: OCCOc1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 95 °C
Yield: 35.5 %

Procedure:
A solution of 7.0 grams (0.386 mole) of 3,5-dichloro-4-(2-hydroxyethoxy)phenol in 60 mL of DMF was stirred, and 2.8 grams (0.039 mole) of 3-bromo-1,1,1,-trichloropropane was added, followed by 10.0 grams (0.08 mole) of potassium carbonate. Upon completion of addition the reaction mixture was heated at 95° C. during a six-hour period. After this time the reaction mixture was cooled to ambient temperature, diluted with 250 mL of water and extracted with two 150 mL portions of ethyl acetate. The extracts were combined, washed with an aqueous 10% hydrochloric acid, solution, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 75:25 heptane:ethyl acetate as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:12]2[N:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[CH:16]=[CH:15][C:13]=2[N:14]=1.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=[O:39].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:36][C:37]([F:42])([CH3:41])[C:38]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:12]2[N:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]3)[CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:39]
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Nc4ccccc4N)nc(N4CCOCC4)c3n2)CC1
Reactant: CC(F)(F)C(=O)O
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: CC(F)(F)C(=O)Nc1ccccc1Nc1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
2-(1-((2-(2-aminophenylamino)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol was reacted with 2,2-difluoropropanoic acid (2 eq), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.5 eq) and DIPEA (4 eq) in DMF (4 mL) for 1 hr (hour). The reaction mixture was extracted with EtOAc and bicarbonate solution and the organic layer was dried with Magnesium sulfate, filtered, evaporated and purified via flash column chromatography to get 50 mg of 2,2-difluoro-N-(2-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-ylamino)phenyl)propanamide. This intermediate was reacted with acetic acid (1.6 mL) over one week to yield 4.1 mg of 120 following reverse phase HPLC purification. MS (Q1) 552.3 (M)+
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][NH:28][CH3:29]>O1CCCC1.O>[CH3:27][N:28]([CH3:29])[C:2](=[O:3])[NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2
Reactant: COC(=O)CC/C(C)=C/Cc1c(N=C=O)c2c(c(C)c1OC)COC2=O
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC/C(C)=C/Cc1c(NC(=O)N(C)C)c2c(c(C)c1OC)COC2=O

Procedure:
A solution of 0.65 g (1.8 mmol) of methyl (E)-6-(1,3-dihydro-4- isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 10 ml of tetrahydrofuran was treated with 5 ml of a solution of 40% dimethylamine in water. After 1 hour the reaction was partitioned between water and ethyl acetate. The organic phase was washed with water three times, dried over magnesium sulfate, and concentrated under reduced pressure to give 0.4 g of methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)- 6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate, mp 116°-118° C.
Reaction SMILES: [C:1]([O:4][CH:5]([C:23](=[O:34])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]=[N+]=[N-])[CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])(=[O:3])[CH3:2]>C(O)C.[Ni]>[C:1]([O:4][CH:5]([C:23](=[O:34])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH2:31])[CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCN=[N+]=[N-]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCN
Reaction time: 4 h

Procedure:
In a hydrogenation apparatus, a suspension of 1.12 g of 2,3,4-triacetoxy-1-{2-[2-(2-azido-ethoxy)ethoxy]acetyl}5-hydroxypentyl acetate and 1.0 g of Raney-Nickel in 100 ml of ethanol is shaken under an atmosphere of hydrogen for 4 h. The reaction solution is filtered and concentrated. The residue contains 23:
Reaction SMILES: CC1C=CC(S([O:11][CH:12]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]2)(=O)=O)=CC=1.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22](O)=[CH:21][C:20]=1[CH3:27]>>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:11][CH:12]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]2)=[CH:21][C:20]=1[CH3:27]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(O)C2)cc1
Product: Cc1cc(OC2CCC(O)C2)cc(C)c1Br

Procedure:
The title compound is prepared from 3-hydroxycyclopentyl 4-methylbenzenesulfonate and 4-bromo-3,5-dimethylphenol following a procedure analogous to that described in Step 3 of Intermediate 2. LC (method 7): tR=1.07 min; Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH2:13])([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCCCP(=O)(CCCN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCP(=O)(CCCNCc1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.14 g of 3-aminopropyl(n-butyl)phosphinic acid ethyl ester are mixed with 2.51 g of p-chlorobenzaldehyde, and first 1.2 g of glacial acetic acid and then a solution of 0.42 g of sodium cyanoborohydride in 5 ml of methanol are added, whereupon an exothermic reaction takes place. The mixture is then stirred at room temperature for 2.5 hours and adjusted to pH 8, and the volatile constituents are removed under reduced pressure. The residue is dissolved in dichloromethane, washed with water, dried over sodium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel, yielding 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acid ethyl ester; 1H-NMR spectrum (in CDCl3): δ=7.30-7.32 (4H,m); 4.02 (2H,q); 3.74 (2H,s); 2.67 (2H,t); 2.5-2.22 (1H,S); 1.79-1.64 (6H,m); 1.53 (2H,m); 1.42 (2H,m; 1.31 (3H,t); 0.81 (3H,t); 31P-NMR spectrum (in CDCl3 ): δ=58.16.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[NH2:17][C:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:29][CH:28]=2)=[N:25][CH:26]=1)([CH3:20])[CH3:19].CCN(CC)CC>O=S(Cl)Cl.C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:29][CH:28]=3)=[N:25][CH:26]=2)([CH3:19])[CH3:20])=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(-c2ccc(C(C)(C)N)cn2)cc1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(-c2ccc(C(C)(C)NC(=O)c3cnc(-c4cccnn4)nc3O)cn2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (200 mg, 0.92 mmol) was dissolved in SOCl2 (5 ml). The mixture was stirred at 60° C. for 4 hours, then concentrated under vacuo. The residue was dissolved with 5 ml of DCM, and added dropwise to a solution of diethyl 4-(5-(2-aminopropan-2-yl)pyridin-2-yl)phenylphosphonate, 33-g, (353 mg, 0.92 mmol) and Et3N (371 mg, 3.7 mmol) in DCM (10 ml) at 0° C. The mixture was stirred at room temperature for 5 hours and then washed with brine, dried, and concentrated under vacuo to give diethyl 4-(5-(2-(4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido) propan-2-yl)pyridin-2-yl)phenylphosphonate (220 mg, 44%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18](Cl)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([S:32][CH3:31])[CH:34]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1cncc(B(O)O)c1
Reactant: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Oc2nc(-c3cncc(SC)c3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 71.6 %

Procedure:
To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 1e (4.0 g; 9.20 mmol), 5-(methylthio)pyridin-3-yl boronic acid (Compound 1f) (2.32 g; 13.7 mmol), K2CO3 (2.50 g; 18.1 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (0.45 g, 0.55 mmol) in a mixture of ethanol (18 mL) and H2O (4.5 mL) was irradiated in a microwave reactor at 130° C. for 30 min. The resultant mixture was diluted with EtOAc, washed with saturated NH4Cl(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 1g (3.45 g; 72% yield) as pale-yellow solid. 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.40 (d, 1H), 8.21 (s, 1H), 7.99 (br. s, 1H), 7.12-7.18 (m, 2H), 6.93-6.96 (m, 2H), 5.77 (br. s, 0.6H), 4.90 (br. s, 0.4H), 4.22-4.32 (m, 1H), 3.86 (s, 3H), 3.18-3.56 (m, 4H), 2.47 (s, 3H), 1.80-2.15 (m, 4H), 1.46-1.52 (m, 9H); MS: m/z 524.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[CH3:12][C:4]1[N:3]=[C:2]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: COc1ccc(Nc2nc(C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (108 mg, 0.605 mmol) and 4-methoxy-phenylamine (89.4 mg, 0.73 mmol) by a procedure similar to Example 72b. 1H NMR (DMSO-d6): 11.28 (brs, 1H), 8.73 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.5 Hz, 1H), 7.85-7.78 (m, 2H), 7.66 (d, J=9 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]([CH3:22])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([Cl:21])[CH:13]=3)[CH:7]=[N:8][CH:9]=1)[CH3:3].[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24].C(N(CC)CC)C>ClCCl>[Cl:21][C:14]1[CH:13]=[C:12]2[C:17]([C:18]([C:19]#[N:20])=[C:10]([C:6]3[CH:5]=[C:4]([CH:2]([NH:1][S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH3:3])[CH:9]=[N:8][CH:7]=3)[N:11]2[CH3:22])=[CH:16][CH:15]=1
Reactant: CC(N)c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC(C)c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile (0.072 g, 0.209 mmol) and dichloromethane (3 mL). Ethanesulfonyl chloride (0.060 g, 0.525 mmol) and triethylamine (0.059 mL, 0.417 mmol) are added and the reaction is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford ethanesulfonic acid {1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethyl}-amide as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 1.32 (t, J=7.5 Hz, 3H), 1.65 (d, J=7.1 Hz, 3H), 2.96-3.15 (m, 2H), 3.84 (s, 3H), 4.75-4.86 (m, 1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 8.20 (t, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 403.1005 [(M+H)+ Calcd for C19H20N4O2SCl: 403.0996].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-])=O)[C:8]([O:13][CH3:14])=[C:9]([CH2:11][OH:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:15][C:7]1[C:8]([O:13][CH3:14])=[C:9]([CH2:11][OH:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: COc1c(CO)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (5-tert-butyl-2-methoxy-3-nitrophenyl)methanol (0.250 g, 1.04 mmol) in ethyl acetate (10.4 mL), 10% palladium/activated charcoal (0.025 g) was added and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 14 hours. After completion of the reaction, insoluble materials were filtered through a Celite pad, and the solvent was washed with ethyl acetate. The solvent of the filtrate was evaporated under reduced pressure to obtain 0.219 g (quantitative) of the crude product containing the captioned compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2C=CC=CC=2N=N1.C1(CC(N2CC3C(=CC=CC=3)C2=O)C(O)=O)CCCC1.NC1SC=CN=1.[CH:54]1([CH2:60][C@@H:61]([N:70]2[CH2:78][C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[C:71]2=[O:79])[C:62]([NH:64][C:65]2S[CH:67]=[CH:68][N:69]=2)=[O:63])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>>[CH:54]1([CH2:60][C@H:61]([N:70]2[CH2:78][C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[C:71]2=[O:79])[C:62]([NH:64][C:65]2[CH:12]=[N:8][CH:67]=[CH:68][N:69]=2)=[O:63])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nccs1
Agent: O=C(O)C(CC1CCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1cnccn1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O

Procedure:
BOP coupling of (3-Cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step A; 273 mg; 1.00 mmol) and 2-aminothiazole (100 mg; 1.00 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 40% ethyl acetate/hexanes) 132 mg (37%) of 3-Cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as a white solid: ES-HRMS m/e calcd for C19H21N3O2SNa (M++Na+) 378.1247, found 378.1250.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH:11]=[CH2:12])[CH:7]=[C:6]([C:13]2[CH:18]=[C:17]([CH2:19][CH:20]=[CH2:21])[C:16]([OH:22])=[C:15]([CH2:23][CH:24]=[CH2:25])[CH:14]=2)[C:5]=1[OH:26])[CH:2]=[CH2:3]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[CH:7]=[C:6]([C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][CH3:25])[C:16]([OH:22])=[C:17]([CH2:19][CH2:20][CH3:21])[CH:18]=2)[C:5]=1[OH:26])[CH2:2][CH3:3]
Reactant: C=CCc1cc(CC=C)c(O)c(-c2cc(CC=C)c(O)c(CC=C)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(CCC)c(O)c(-c2cc(CCC)c(O)c(CCC)c2)c1
Yield: 73.3 %

Procedure:
A solution was prepared by dissolving 0.2 g of 3,3',5,-5'-tetraallyl-2,4'-biphenyldiol in 10 ml of ethyl acetate. The solution was catalytic reduced with 50 mg of 5% palladium-carbon catalyst at room temperature under normal pressure. The catalyst was filtered out, and the filtrate was concentrated and purified by a silica gel column-chromatography (n-hexane:ethyl acetate=5:1) to yield 0.15 g of 3,3',5,5'-tetrapropyl-2,4'-biphenyldiol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][N:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Clc1ccncn1
Product: C[C@@H](c1ccc(-c2ccncn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-chloropyrimidine in Step 4. LC-MS Method 2 tR=1.172, m/z=392.1; 1H NMR (CDCl3) 1.28-1.40 (m, 1H), 1.52 (m, 3H), 1.64 (m, 2H), 1.81-1.99 (m, 2H), 2.09-2.37 (m, 3H), 2.90 (m, 1H), 3.51 (t, 2H), 5.68 (m, 1H), 6.88-7.07 (m, 3H), 7.16-7.28 (m, 3H), 7.58 (m, 1H), 7.79 (d, 2H), 8.61-8.80 (d, 1H), 9.18 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1>C(OC(=O)C)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:11][C:12](=[O:14])[O:18][C:16](=[O:17])[CH2:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CC(CC(=O)O)c1ccc2c(c1)OCO2
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2ccc3c(c2)OCO3)CC(=O)O1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
3-(1,3-benzodioxol-5-yl)pentanedioic acid (2 g, 7.9 mmoles) was suspended in acetic anhydride (50 ml) and refluxed for two hours. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was triturated with ether to give the product (1.3 g, 70%). 1H NMR (DMSO-d6) δ 6.91 (m, 1H), 6.89 (m, 1H), 6.72 (m, 1H), 6.01 (s, 2H), 3.53–3.41 (m, 1H), 3.07–2.89 (m, 4H).
Reaction SMILES: [CH2:1]([N:4]([C@@H:17]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21]1)=[O:19])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.O>CN(C)C=O>[CH2:1]([NH:4][C@@H:17]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([C:29]([CH3:31])([CH3:32])[CH3:30])([CH3:27])[CH3:28])[CH2:21]1)=[O:19])[CH:2]=[CH2:3]
Reactant: C=CCN([C@H](C(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN[C@H](C(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a stirred solution N-allyl-N-{2-[3-(S)-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-2-oxo-1-(S)-phenyl-ethyl}-2-nitro-benzenesulfonamide (8.73 g, 15.6 mmol) in anhydrous dimethylformamide (45 cm3) was added potassium carbonate (6.50 g, 46.8 mmol). The mixture was stirred at ambient temperature for 10 minutes and thiophenol (2.25 cm3, 21.8 mmol) was added dropwise over 10 minutes. The mixture was stirred for 16 hours at ambient temperature and poured into water (500 cm3) and extracted with ethyl acetate (3×150 cm3). The combined ethyl acetate extracts were washed with water (2×100 cm3), brine (1×100 cm3), dried over sodium sulfate, vacuum filtered and the volatile fractions removed in vacuo to a foul smelling yellow oil. The crude product was purified by column chromatography (silica, eluting with hexane-ethyl acetate 1:1 to 0:1) to afford the title compound as a yellow viscous oil (5.67 g, 97.1%) with a positive ion ESI (M+H)+375.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([F:27])[CH:23]=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:17][CH2:18]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)ccc2OCC2CC2)OC1(C)C
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-5-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A39) the title compound is obtained as colorless solid.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].[C:17]1([PH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.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>[C:24]1([P:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=[O:12])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1ccccc1Br
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1P(c1ccccc1)c1ccccc1
Reaction time: 12 h

Procedure:
After 5.9 ml of triethylamine (43 mmol) and 334 mg of tetrakis(triphenylphosphine)palladium have been added, 5 ml of 2-bromobenzaldehyde (43 mmol) and 11.15 ml of diphenylphosphine (64.5 mmol) are refluxed in 150 ml of absolute toluene under a protective gas atmosphere in a three-necked flask equipped with a reflux condenser. Triethylamine hydrobromide precipitates as a white solid over the course of the reaction. After 12 hours, the reaction solution is filtered, washed three times with saturated ammonium hydrochloride solution and saturated sodium chloride solution and the solvent is removed in a rotary evaporator. The resultant crude product is recrystallised from methanol. Yield 10.61 g (85% of theoretical).