Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A mixture of [4-(methylsulfonyl)phenyl]boronic acid (540 mg, 2.7 mmol), 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (1 g, 2.7 mmol), Pd(PPh3)2Cl2 (190 mg, 0.27 mmol), DME (10 mL) and 2M Na2CO3 (5 mL) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, charged with water, and extracted with Et2O. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The aqueous phase was further extracted with CH2Cl2. The CH2Cl2 extracts were combined with the Et2O extracts, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 1.5% MeOH/CH2Cl2, followed by recrystallization from MeOH. The recrystallized material and the mother liquor were combined, then concentrated to give 705 mg (58%) of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as an off-white solid. This material contained a minor impurity which was carried on to the next step. 1H NMR (400 MHz, CDCl3): δ 8.41 (d, 1H, J=2.7 Hz), 8.14 (d, 2H, J=8.4 Hz), 8.01 (d, 2H, J=8.4 Hz), 7.75 (d, 1H, J=8.7 Hz), 7.34 (d, 1H, J=8.2 Hz), 4.26-4.10 (m, 2H), 3.92 (d, 2H, J=6.3 Hz), 3.07 (s, 3H), 2.83-2.66 (m, 2H), 2.10-1.94 (m, 1H), 1.84 (d, 2H, J=12.82 Hz), 1.46 (s, 9H), 1.38-1.21 (m, 2H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[N:34]=[C:33](Cl)[C:32]([Cl:36])=[CH:31][N:30]=1>CS(C)=O>[Cl:28][C:29]1[N:34]=[C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:13]3[CH2:14][CH2:15][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:18]3)=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]3)[C:32]([Cl:36])=[CH:31][N:30]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)N1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ncc3Cl)c3c2CN(C)C3=O)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a suspension of 7-amino-4-(4-isopropyl-piperazin-1-yl)-2-methyl-2,3-dihydro-isoindol-1-one (1.62 g, 5.6 mmol) and potassium carbonate (2.55 g, 8.7 mmol) in dimethylsulfoxide (30 mL), 2, 4, 5-trichloropyrimidine (970 μL, 8.4 mmol) is added and stirred at 70° C. for 4 hours. To the mixture is added 2,4,5-trichloropyrimidine (650 μL, 5.6 mmol) and the mixture is stirred at 70° C. for 6 hours. The mixture is cooled and then extracted twice with dichloromethane. The organic layer is successively washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography to afford 7-(2,5-dichloro-pyrimidin-4-ylamino)-4-(4-isopropyl-piperazin-1-yl)-2-methyl-2,3-dihydro-isoindol-1-one (1.95 g) as yellow solids in 80% yield. Rf=0.26 (MeOH/AcOEt=1/4). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.13 (s, 3H), 1.14 (s, 3H), 2.87-2.69 (m, 5H), 3.18-3.08 (m, 4H), 3.22 (s, 3H), 4.40 (s, 2H), 7.20 (d, 1H), 8.20 (s, 1H), 8.66 (d, 1H), 11.0 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C:10]([NH2:13])=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](N)=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:13][C:10]2[CH2:11][CH2:12][N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:9]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: NC1=NN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Product: COc1ccc(NC2=NN(Cc3ccccc3)CC2)cc1

Procedure:
4,5-dihydro-1-phenylmethyl-1H-pyrazol-3-amine (24 g) (prepared by the method of H. Dorm, A. Otto, Chem Ber. 103 2505 (1970), p-anisidine (17.5 g) and p-toluenesulphonic acid (100 mg) was heated at 170° under dry nitrogen until evolution of ammonia ceased. The reaction mix was cooled, purified by chromatography on SiO2 eluting with ether:pentane 1:1 to give the sub-title compound as colourless cubes (13.3 g).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]([C:22]1[CH:27]=[C:26]([N:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=1[Cl:31])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:11])=[O:10])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:23]1[CH:24]=[CH:25][C:26]([N:28]([CH3:29])[CH3:30])=[CH:27][C:22]=1[N:8]([CH2:7][C:6]([OH:32])=[O:5])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)OC(C)(C)C)c2cc(N(C)C)ccc2Cl)cc1OC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)c2cc(N(C)C)ccc2Cl)cc1OC

Procedure:
To a solution of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy-benzenesulfonyl)-amino]-acetic acid tert-butylester (1.160 g) in dry DCM (5.5 mL) were added successively triethylsilane (0.423 mL) and TFA (4.8 mL).
Reaction SMILES: [OH:1][C:2]1(C(C)(C)C)[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15](C3C=NOC=3C)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]1[C:23]([CH3:26])([CH3:25])[CH3:24].[OH-:31].[Na+].Cl>O1CCCC1>[OH:1][C:2]1[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]([CH2:6][C:5]([C:8]#[N:9])=[C:4]([OH:31])[CH3:3])=[O:16])[O:10][N:9]=2)=[CH:4][C:3]=1[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1oncc1C(=O)NCc1cc(C2=CC(C(C)(C)C)C(O)(C(C)(C)C)C=C2)no1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)=C(C#N)CC(=O)NCc1cc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)no1

Procedure:
4.0 g (0.01 mol) of the product from Example 52 were dissolved in 50 ml of absolute tetrahydrofuran, and 20 ml of 1N NaOH were added while cooling with ice; once the reaction was complete (monitoring by TLC), the mixture was acidified with 22 ml of 1N HCl and extracted with dichloromethane; this was followed by washing, drying and concentration. The remaining residue was crystallized from tert-butyl methyl ether/petroleum ether. Yield: 3.3 g.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[CH3:11].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)OC1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(C)c(Br)s1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(-c2ccnn2C)s1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 5-bromo-4-methyl-2-thiophenecarboxylate (1 g, 4.25 mmol) in dioxane/H2O (5:1, 20 mL) was added K2CO3 (2.3 g, 17 mmol), bis(tri-t-butylphosphine)palladium(0) (108 mg, 0.213 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g, 5.52 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.24 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification: LCMS (ES) m/z=237 (M+H)+.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][O:38][C:39](=[O:63])[NH:40][C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])=[C:43]([CH2:53][N:54]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH3:55])[CH:42]=2)=[C:32]([CH2:64][CH3:65])[CH:31]=1>>[C:59]([O:58][C:56]([N:54]([CH2:53][C:43]1[CH:42]=[C:41]([NH:40][C:39]([O:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([B:25]([OH:27])[OH:26])=[CH:31][C:32]=2[CH2:64][CH3:65])=[O:63])[CH:46]=[CH:45][C:44]=1[S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])[CH3:55])=[O:57])([CH3:62])([CH3:61])[CH3:60]
Reactant: CCc1cc(Br)ccc1CCOC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCc1cc(B(O)O)ccc1CCOC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Yield: 59 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 43A (650 mg, 1.1 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 43B (362 mg, 59%) as a brown oil. MS (ESI) m/z 563.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[CH:7]1)[CH2:4][OH:5])[CH3:2].[OH-].[Na+].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.CO>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:5][CH2:4][CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[CH:7]1)[CH2:1][CH3:2]
Reactant: Clc1cccc(CBr)c1
Reactant: CCC(CO)n1cnc2cnc3ccccc3c21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCC(COCc1cccc(Cl)c1)n1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
2-Ethyl-2-(1H-imidazo[4,5-c]quinolin-1-yl)-1-ethanol (3.0 g, 12.43 mmol), dichloromethane (40 mL), aqueous sodium hydroxide (40 mL of 50%), benzyltrimethylammonium chloride (0.01 g) and 3-chlorobenzyl bromide (2.81 g, 13.67 mmol) were combined and the resulting solution was stirred at ambient temperature overnight. Analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete. The reaction was diluted with dichloromethane (100 mL) and water (100 mL). The layers were separated. The aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel eluting with ethyl acetate) to provide 4.22 g of 1-(1-{[(3-chlorobenzyl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinoline as a light orange oil.
Reaction SMILES: C(C(C)=O)C.O.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16](=[O:33])[N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:20]=1)#[N:8].[C:34]([OH:43])(=[O:42])[C@@H:35]([C@H:37]([C:39]([OH:41])=[O:40])[OH:38])[OH:36].CCCCCCCC>O1CCCC1>[C:39]([CH:37]([CH:35]([C:34]([OH:43])=[O:42])[OH:36])[OH:38])([OH:41])=[O:40].[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16](=[O:33])[N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:20]=1)#[N:8]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Solvent: C1CCOC1
Solvent: CCC(C)=O
Solvent: CCCCCCCC
Product: O=C(O)C(O)C(O)C(=O)O
Reaction time: 13 h

Procedure:
Methyl ethyl ketone (7 mL) was added to 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate (258.17 mg, 0.71 mmol), and completely resolved under reflux by using oil bath. Then, tetrahydrofuran solution of L(+)-tartaric acid (6 mL, containing 0.77 mmol of tartaric acid) was added, and the heating of the oil bath was stopped. Then, n-octane (22 mL) was added to the mixture, solid was precipitated, and subsequently allowed to stand for about 13 hours and a half in the oil bath. The obtained solid was collected by filtration, washed by n-octane (small amount), dried under reduced pressure at 60° C., for about 5 hours to provide 283.86 mg of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:15]([C:17]1[O:21][C:20]([C:22](Cl)=[O:23])=[CH:19][CH:18]=1)#[N:16].CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([NH:8][C:22]([C:20]2[O:21][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: Nc1cccc(Cl)c1N1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2cccc(Cl)c2N2CCCCC2)o1
Yield: 10 %

Procedure:
Using a procedure similar to Example 3, step (d), 3-chloro-2-piperidin-1-yl-phenylamine (54 mg, 0.25 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (55.8 mg, 0.360 mmol) in the presence of DIEA (95 μL, 0.55 mmol) to afford 8.4 mg (10%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 10.70 (br s, 1H), 8.42 (dd, 1H, J=1.4, 8.1 Hz), 7.30 (dd, J=1.5, 3.7 Hz), 7.24 (d, 1H, J=3.7 Hz), 7.17 (t, 1H, J=8.1 Hz), 7.07 (dd, 1H, J=1.4, 8.1 Hz), 3.58-3.52 (m, 2H), 2.85-2.82 (m, 2H), 2.02-1.99 (m, 1H), 1.89-1.72 (m, 4H), 1.52-1.38 (m, 1H), Mass spectrum (ESI, m/z): Calcd. for C17H16ClN3O2, 330.0 (M+H), found 330.1.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1)C.O.[OH-].[Li+]>O1CCOCC1.O>[C:15]1([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:21])=[O:3])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CCCOc1cccc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCOc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a solution in 2:1 dioxane/water (36 mL) of 4-(3-phenylphenoxy)butanoic acid ethyl ester (3.42 g, 12 mmol), prepared as in step 1, was added lithium hydroxide hydrate (1.42 g, 33.8 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo and the resulting solid was mostly dissolved in aqueous Na2CO3. The aqueous solution was decanted from a small amount of residual solid and extracted with ethyl ether. The ether extract was discarded and the aqueous phase was taken to pH 2 with HCl and extracted with ethyl acetate. The ethyl acetate extract was dried over MgSO4, filtered, and concentrated in vacuo to give 4-(3-phenylphenoxy)butanoic acid (3.17 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A179) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:26]=[C:27]([CH2:31]O)[CH:28]=[CH:29][CH:30]=3)=[N:23][CH:24]=2)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:22]4[N:23]=[CH:24][C:19]([N:16]5[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]5)=[CH:20][N:21]=4)[CH:26]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCN(C)CC5)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
67 mg (0.44 mmol) of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one and 125 mg (0.44 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}methanol are suspended in 5 ml of DMF with 222 mg (0.67 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g), and the mixture is shaken at room temperature for 30 min. 156 mg (0.67 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 15 h. The reaction mixture is filtered, the residue is evaporated, and the residue is purified by column chromatography on silica gel, giving 67 mg of “A125”; HPLC: Rt=2.20 min (method B); ESI: 418 (M+H);
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH:54][C:55](=[O:66])[C:56]3[CH:61]=[CH:60][C:59]([C:62]([CH3:65])([CH3:64])[CH3:63])=[CH:58][CH:57]=3)[C:42]([NH:44][C@@H:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH3:46])=[O:43])=[CH:36][CH:35]=2)=[N:32][CH:33]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CC#N>[C:62]([C:59]1[CH:58]=[CH:57][C:56]([C:55]([NH:54][C@@H:41]([CH2:40][C:37]2[CH:36]=[CH:35][C:34]([C:31]3[N:30]=[CH:29][C:28]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)=[CH:33][N:32]=3)=[CH:39][CH:38]=2)[C:42]([NH:44][C@@H:45]([C:47]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:48])[CH3:46])=[O:43])=[O:66])=[CH:61][CH:60]=1)([CH3:63])([CH3:64])[CH3:65]
Reactant: OB(O)c1ccc(O)cc1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 83 %

Procedure:
To a 10 ml flask were added (4-hydroxyphenyl)boronic acid (317.23 mg, 2.30 mmol), sodium carbonate decahydrate (138.0 mg, 2.3 mmol), tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoyl)-D-alaninate INT-32 (700.0 mg, 1.15 mmol), Pd(dppf)Cl2 (87.8 mg, 0.12 mmol), THF (10 mL), CH3CN (10 ml) and water (5 mL). The solution was degassed using N2 bubbling for 10 min. The reaction mixture was heated to 80° C. for 2 hours. The mixture was extracted with DCM (3×20 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. The final compound was purified by column chromatography (40% DCM in hexane) to afford 595.0 mg (83%) of tert-butyl ((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-45 as solid. LCMS-ESI (m/z) calculated for C37H42N4O5: 622.3. found 623.3 [M+H]+, tR=3.635 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 9.11 (s, 2H), 8.50 (d, J=8.7 Hz, 1H), 8.41 (d, J=7.2 Hz, 1H), 8.30 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.6 Hz, 2H), 4.85 (td, J=9.9, 4.6 Hz, 1H), 4.17 (p, J=7.1 Hz, 1H), 3.24-3.00 (m, 2H), 1.46-1.34 (m, 9H), 1.32-1.19 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)[CH:5]=[N:6][CH:7]=1.[NH2:15][C:16]([CH3:29])([CH3:28])[C:17]#[C:18][CH:19]([O:24][SiH:25]([CH3:27])[CH3:26])[C:20]([CH3:23])([CH3:22])[CH3:21].Cl.CN(CCCN=C=NCC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:13][CH3:14])[C:10]([NH:15][C:16]([CH3:29])([CH3:28])[C:17]#[C:18][CH:19]([O:24][SiH:25]([CH3:27])[CH3:26])[C:20]([CH3:22])([CH3:23])[CH3:21])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCC(Oc1cncc(Cl)c1)C(=O)O
Reactant: C[SiH](C)OC(C#CC(C)(C)N)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(Oc1cncc(Cl)c1)C(=O)NC(C)(C)C#CC(O[SiH](C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(5-Chloro-3-pyridyloxy)butyric acid (2.26 g), 4-amino-1-tert.-butyldimethylsilyloxy-4-methylpent-2-yne (2.27 g) and 4-dimethylaminopyridine (0.010 g) in dry dichloromethane (50 ml) were stirred at ambient temperature and N-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (2.11 g) was added. The mixture was stirred at ambient temperature for 3 hours, stored for 18 hours, diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate (twice) then water (twice). The organic phase was dried over magnesium sulphate and evaporated under reduced pressure to give a dark yellow oil, 4.4 g, containing the required product.
Reaction SMILES: CN[O:3][CH3:4].[C:5]1([Mg]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CNOC
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
The benzophenone derivative 70 was prepared using chemistry outlined in Scheme 13. Weinreb amide 69, derived via coupling of the acid chloride of the corresponding acid intermediate 62 with N,O-dimethylhydroxylamine, was treated with phenylmagnesium bromide to afford 70. Subsequent reduction of compound 70 with sodium borohydride provided alcohol 71, which was further reduced in the presence of trifluoroacetic acid to give the diphenylmethane derivative 72.
Reaction SMILES: [CH2:1]([PH2:7])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH:8]([CH:10]=[O:11])=[O:9]>O1CCCC1>[CH2:1]([P:7]1[CH:8]([OH:9])[CH:10]([OH:11])[P:7]([CH2:1][CH2:2][C:3]([CH3:4])([CH3:6])[CH3:5])[CH:8]([OH:9])[CH:10]1[OH:11])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)CCP
Reactant: O=CC=O
Solvent: C1CCOC1
Product: CC(C)(C)CCP1C(O)C(O)P(CCC(C)(C)C)C(O)C1O
Yield: 90 %

Procedure:
Following the procedure of Example 2, mononeohexyl phosphine (200 parts) in tetrahydrofuran, is reacted with 250 parts of glyoxal and 256 parts (90% yield) of 1,4-dineohexyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, m.p. 186°-210° C., are isolated.