Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][N:13]([CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1)C(OC(C)(C)C)=O)[CH2:3][CH3:4]>CO>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH2:2]([NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1)[CH2:3][CH3:4]
Reactant: CCCN(CCCN(CCCN(CCC1CCCCN1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCCNCCCNCCCNCCC1CCCCN1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
30 ml of 3N methanolic hydrochloric acid are added to a solution of 2.07 g (3.54 mmol) of 1-propyl-9-[2-(2-piperidyl)-ethyl]-1,5,9-tri-BOC-1,5,9-triazanonane in 5 ml of methanol, and the reaction mixture is stirred at room temperature for 15 hours. The crystallisate is filtered off and the filtration residue is suspended in 15 ml of hot methanol. After cooling to room temperature, filtration, washing the crystallizate with ice-cold methanol and drying under a high vacuum at 100° C., the title compound is obtained, m.p. >270° C. 1H-NMR (D2O): δ =0.92(t,3H); 1.41-2.18(m,14H); 2.90-3.42(m,15H).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH2:4][O:3]1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[N:9]1([CH2:8][CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CC1(C)OC[C@H](CCn2ccc3ccccc32)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@@H](O)CCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.3 %

Procedure:
To an ice cooled solution of 1-[2-((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl]-1H-indole (520 mg, 2.12 mmol) in THF (10 ml) was added portionwise 1N-HCl (8.48 ml). After the addition was completed, the reaction mixture was stirred at room temperature for 2.5 hours. An aqueous solution of NaHCO3 was added, and the resulting mixture was stirred for several minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated in vacuo to give (S)-4-(1-indolyl)-butane-1,2-diol (449.3 mg, 103%) as an oil. This material was used immediately without further purification. To an ice cooled solution of (S)-4-(1-indolyl)-butane-1,2-diol in DMF (10 ml) was added imidazole (433 mg, 6.36 mmol) followed by tert-butyldimethylsilylchloride (335 mg, 2.23 mmol). After 30 minutes, the ice-bath was removed and then the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by silica gel (15 g) column chromatography eluting with hexane/ethyl acetate (20:1) to give (S)-[1-(tert-butyldimethylsilyloxy)-4-(1-indolyl)]-butan-2-ol (542 mg, 80.0%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[S:9][CH:10]=[CH:11][C:6]=2[C:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:4][CH2:3]1.[Br:22]Br>N1C=CC=CC=1>[Br:22][C:10]1[S:9][C:7]2[NH:8][C:2](=[O:1])[CH2:3][N:4]=[C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=3)[C:6]=2[CH:11]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C2=NCC(=O)Nc3sccc32)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C2=NCC(=O)Nc3sc(Br)cc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
In a 20 mL dram screw-cap vial with septum was dissolved compound 493 (0.140 g, 0.466 mmol) in pyridine (3 mL) to give an orange solution. The mixture was cooled to 0° C. and bromine (0.029 mL, 0.559 mmol) was added dropwise. The reaction mixture was left to stir at 0° C. for 1 hour. The mixture was quenched with saturated thiosulfate solution and extracted with ethyl acetate. The organic layer was washed several times with water, then brine, dried over magnesium sulfate, filtered and evaporated. The residue was suspended in ether and filtered to afford title compound 494 (101 mg, 57%) as a tan solid. MS (m/z): 379.33 (M+H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[Cl:23])[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>C1COCC1>[Cl:23][C:14]1[CH:15]=[CH:16][C:17]([C:19]([F:20])([F:21])[F:22])=[CH:18][C:13]=1[C:12]([NH:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([CH2:3][OH:2])[CH2:6][CH2:7]1)=[O:24]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(N[C@H]1CC[C@H](CO)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-(2-chloro-5-trifluoromethyl-benzoylamino)-cyclohexane carboxylic acid methyl ester (step 1)(95.2 g, 0.26 mol) in dry THF (1 L) under nitrogen at 0° C. is added lithium aluminum hydride pellets (20 g, 0.53 mol) portion wise over 3 hours. The reaction mixture is stirred at 0° C. for a further 2 hours and then carefully quenched at 0° C. by the addition of water (40 mL) in THF (60 mL) followed by further THF (500 mL) to maintain a mobile suspension. Finally, 1M sodium hydroxide solution (80 mL) is added at 0° C. resulting in a yellow solution containing a colourless suspension. The reaction is filtered through a Celite® pad (filter material) to remove inorganic salts. The Celite® pad/salts are washed with EtOAc (500 mL) then with EtOAc:THF (1:1; 300 mL). The organics are combined and diluted with further EtOAc (600 mL) and then washed with saturated brine (600 mL). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure until a slurry is obtained. Et2O is added to the slurry, which is then stirred for 5 minutes before being filtered to recover a colourless solid. The solid is washed with isohexane and then dried at 35° C. under vacuum to give the required product.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:28][C@H:29]1[C@H:32]([CH3:33])[N:31]([S:34]([O-:37])(=[O:36])=[O:35])[C:30]1=[O:38])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:28][C@H:29]1[C@H:32]([CH3:33])[N:31]([S:34]([OH:37])(=[O:35])=[O:36])[C:30]1=[O:38]
Reactant: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCO
Product: C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O

Procedure:
(3S-trans)-3-[(Benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinesulfonic acid tetra-n-butylammonium salt is dissolved in 250 ml of ethanol and 0.8 g of 5% palladium on charcoal is added. Hydrogen is bubbled through the stirred mixture for 90 minutes and the catalyst is filtered out. The addition of 12 ml of formic acid causes an immediate precipitation of the title compound which is filtered and dried. A second crop of the title compound is obtained upon concentration of the filtrate and the addition of more formic acid, yielding a total of 1.3 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:14]([OH:34])([PH2:32]=[O:33])[CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[C:16](O)=[O:17])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:36][C@H:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH3:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:42]([O:41][C:39](=[O:40])[CH:37]([NH:36][C:16](=[O:17])[CH:15]([C:14]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13])([OH:34])[PH2:32]=[O:33])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1)[CH3:38])([CH3:45])([CH3:44])[CH3:43]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(NC(=O)OCc1ccccc1)C(O)([PH2]=O)C(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)C(Cc1ccc(-c2ccccc2)cc1)C(O)([PH2]=O)C(C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
The compound from step 1 (0.9 g) is solubilised in 10 ml of DMF in nitrogen, and t-butyl alaninate hydrochloride (450 mg), 2.5 ml of DIEA (6 eq) and 1.98 g of TBTU (3 eq) are successively added. The mixture is stirred for 15 min at ambient temperature and the reaction is processed as in step 4 of example 3. 1.10 g of expected product (97%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH2:16][CH2:17][CH2:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH2:18][CH2:17][CH2:16][OH:15])(=[O:21])=[O:20])=[CH:30][CH:29]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCCO)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 3-mercapto-1-propanol to afford 4-(3-hydroxypropylthio)benzonitrile. 1.8 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 4-(3-hydroxypropylthio)benzoic acid. 1.2 g of 4-(3-hydroxypropylthio)benzoic acid was reacted via Procedure R to give 4-(3-hydroxypropylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(3-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[N:6][C:5]2[N:8]=[CH:9][CH:10]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])OC(C)(C)C)=[CH:15][CH:14]=3)[C:4]=2[NH:3]1.[C:27]([C:31]1[CH:35]=[C:34]([N:36]=C=O)[N:33]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:35]=[C:34]([NH:36][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[C:4]4[NH:3][C:2](=[O:1])[CH:7]=[N:6][C:5]=4[N:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=2)=[O:26])[N:33]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4ncc(=O)[nH]c34)cc2)cc1
Yield: 64 %

Procedure:
Method F1 was used with tert-butyl 4-(2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to obtain the title compound (yield 64%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][S:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25]C)=[CH:22][CH:23]=3)[CH:18]=[C:17]([CH3:27])[C:16]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:5].B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[F:35][C:2]([F:1])([F:34])[CH2:3][S:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[CH:18]=[C:17]([CH3:27])[C:16]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:10][CH:9]=1)(=[O:5])=[O:6]
Reactant: COc1ccc2c(Oc3ccc(NS(=O)(=O)CC(F)(F)F)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(NS(=O)(=O)CC(F)(F)F)cc2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a stirring solution of 273 (0.14 g, 0.31 mmol) in CH2Cl2 (6 mL), chilled to −20° C. under N2, was added BBr3 (0.24 g, 0.94 mmol) dropwise, via syringe, over 1 minute. After 90 min at −20° C. the r×n was poured over 50 g ice followed by EtOAc (50 mL). The EtOAC layer was washed with brine (50 mL), dried (Na2SO4) and concentrated to a viscous yellow oil that was purified by column chromatography using a gradient of 100% CH2Cl2 to 1% MeOH: CH2Cl2 to yield a foam. The foam was crystallized from EtOAc/hexanes to yield the title compound 274, as a light yellow solid (72 mg, 55%). 1H NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 4.33 (q, J=9.8 Hz, 2H), 6.57 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 6.97 (dd, J1=2.4 Hz, J2=9.1 Hz, 1H), 7.12-7.30 (m, 5H), 7.53 (s, 1H), 7.55 (d, J=9.8 Hz, 1H), 9.40 (s, 1H), 9.84 (s, 1H), 10.06 (s, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[OH-].[Na+].[N:13]1([N:19]2[C:28]3[C:23](=[CH:24][C:25]([CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][CH:27]=3)[C:22](=[O:36])[C:21]([C:37](OCC)=[O:38])=[CH:20]2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:37]([C:21]2[C:22](=[O:36])[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([CH2:29][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:24]=3)[N:19]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:20]=2)=[O:38])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cn(N2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCc1ccc(Br)cc1)c1cn(N2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 190 °C
Yield: 68 %

Procedure:
4-Bromobenzylamine hydrochloride (2.22 g) is suspended in water (5 mL) and neutralized with 2N aqueous NaOH (5 mL). The free amine is extracted with dichloromethane (2×25 mL). The organic layers are combined, washed with brine (5 mL), and dried with Na2SO4. The solution is concentrated in vacuo to afford 1.48 g of a clear, colorless oil which is then combined with ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.48 g) from Preparation No. 56 and heated to 190° C. for 3 hours. The reaction mixture is allowed to cool to room temperature, and the resulting solid is recrystallized in ethyl acetate to afford 0.44 g of the title compound as a white solid.
Reaction SMILES: N[C:2]1[NH:6][CH2:5][N:4]([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2([CH3:17])[CH3:16])[C:3]=1[C:18](=[O:20])[CH3:19].N(OC(C)(C)C)=O>O1CCCC1>[CH3:16][C:8]1([CH3:17])[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]1[N:4]1[C:3]([C:18](=[O:20])[CH3:19])=[CH:2][N:6]=[CH:5]1
Reactant: CC(=O)C1=C(N)NCN1C1c2ccccc2CC1(C)C
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CC(=O)c1cncn1C1c2ccccc2CC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
13 Parts of [5-amino-3-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-1H-imidazol-4-yl]ethanone were dissolved in 167 parts of tetrahydrofuran. To the solution were added dropwise 7.7 parts of 2-methyl-2-propyl nitrite. After stirring at room temperature for 1 hour, the reaction mixture was evaporated to dryness. The residue was purified by column chromatography over silica gel. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 6.25 parts (51%) of [1-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-1H-imidazol-5-yl]ethanone; mp. 69°-70° C. (compound 1.10).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@@H:9]2[NH:12][C:11](=[O:13])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14]OS([O-])=O.[K+]>CO>[C:1]1([S:7]([CH2:8][C@@H:9]2[NH:12][C:11](=[O:13])[CH2:10]2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])OO
Reactant: O=C1C[C@H](CSc2ccccc2)N1
Agent: [K+]
Solvent: CO
Product: O=C1C[C@H](CS(=O)c2ccccc2)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 157.4 %

Procedure:
A solution of 4(R)-(phenylsulfanylmethyl)azetidin-2-one (from example 6, step A) (105 mg, 0.543 mmol) in MeOH (3 mL) was treated with an aqueous solution of oxone (167 mg, 0.272 mmol, 3 mL). After stirring at room temperature for 24 h, the reaction mixture was quenched with aqueous Na2S2O3 (10%, 1 mL) and concentrated. The concentrate was diluted with EtOAc (5 mL) and brine (5 mL) and the two layers separated. The aqueous layer was re-extracted three times with CHCl3 (20 mL) and the combined organic phases were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to afford 4(R)-(benzenesulfinylmethyl)azetidin-2-one (89.6 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ (1:1 mixture of diastereoisomers) 7.61-7.45 (m, 10H), 6.29-6.14 (bs, 1H), 5.70-5.58 (bs, 1H), 4.16-4.08 (m, 1H), 3.88-3.80 (m, 1H), 3.27-3.05 (m, 4H), 2.92 (dd, J=13.3, 9.2 Hz, 1H), 2.90 (dd, J=13.3, 3.5 Hz, 1H), 2.75-2.67 (m, 1H), 2.66-2.58 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:14])[C:5]=2[NH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c(Br)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ncnc2c(Br)c[nH]c12
Temperature: 115 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 7-bromo-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (100 mg, 0.5 mmol) and 6 mL of POCl3 under argon was warmed at 115° C. After 3 hours, the mixture was cooled to room temperature and poured over 300 mL of ice, stirred, made basic with potassium carbonate and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 101 mg (93%) of the desired 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine as beige solid which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:12][C:13]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=[N:18]2>>[Cl:23][C:22]1[C:13]([NH:12][C:9](=[O:11])[CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]1)[CH:16]=[CH:15]2
Reactant: O=C(O)CCC1CCCCC1
Reactant: CCOC(=O)C1CCN(c2ccc3c(N)c(Cl)ccc3n2)CC1
Product: CCOC(=O)C1CCN(c2ccc3c(NC(=O)CCC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 84.9 %

Procedure:
Prepared according to the method of example 62(a), using cyclohexanepropanoic acid (280 mg) and 1-(5-amino-6-chloro-2-quinolinyl)-4-piperidinecarboxylic acid, ethyl ester (Example 77(a)) (200 mg), to afford the sub-titled compound (240 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[P:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12]CC>>[C:6]1([CH2:9][P:11](=[O:12])([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])[CH:7]=[CH:8][C:3]([CH2:2][P:11](=[O:12])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:4][CH:5]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(CP(=O)(OCC)OCC)cc1)OCC
Temperature: 130 °C
Yield: 89.1 %

Procedure:
α, α′-Dibromo-p-xylene (5.28 g, 20 mmol, 1 equiv.) and triethyl phosphite (10.3 mL, 60 mmol, 3 equiv.) were placed in a flask with a magnetic stirring bar. A distillation apparatus was attached to collect ethyl bromide formed along with the reaction. The mixture was immersed in an oil bath and heated to 130° C. for 2 h. After cooling down, white crystal crushed out and recrystalized from hexane to give the product (6.74 g, 89% yield). 1H NMR (CDCl3) δ7.24 (s, 4H), 4.00 (m, 8H), 3.12 (d, 4H, J=20.2 Hz), 1.23 (t, 12H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:22]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[C:25]=2[CH:24]=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH:22]1[C:30]2[C:25](=[C:26]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[O:10][C:9]5[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=5[C:6]=4[N:7]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Cc1ccc2c(n1)oc1c(N3CCOCC3)nc(Cl)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(n1)oc1c(N3CCOCC3)nc(-c3cccc4[nH]ccc34)nc12
Temperature: 90 °C
Yield: 16 %

Procedure:
To a solution of 2-chloro-7-methyl-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine, 18 (27 mg, 0.09 mmol, leg), indole-4-boronic acid (43 mg, 0.27 mmol, 3 eq) and PdCl2(PPh3)2 (12.4 mg, 0.02 mmol, 20 mol%) in a mixture of dioxane (2 mL) and H2O (1.0 mL) was added Na2CO3 (19 mg, 0.18 mmol, 2 eq) under Ar(g). The reaction mixture was then heated in a pressure tube for 18 h at 90° C. Once cooled down, the mixture was partitioned with H2O (10 mL) and extracted with CH2Cl2 (2×10 mL) and EtOAc (2×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by SCX-3 cartridge eluting with CH2Cl2/MeOH (1:0-0:1 then +1M NH3) followed by silica gel column chromatography with hexane/EtOAc (3:1-0:1) to yield N as a pale brown solid (5.4 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[CH:29][CH:30]=[C:31]4[C:34]([O:36]C)=[O:35])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[CH:29][CH:30]=[C:31]4[C:34]([OH:36])=[O:35])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1
Reactant: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3cccc(C(=O)O)c3c2)cc1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A solution of methyl 7-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.052 g, 0.09 mmol) in tetrahydrofuran (0.9 mL) was placed in a microwave reaction tube. Methanol (0.45 mL) was added followed by 1N sodium hydroxide (0.14 mL, 0.14 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.039 g, 74% as 0.40 tetrahydrofuran) 1H NMR (DMSO-d6): 13.13 (s, 1H), 9.10 (s, 1H), 8.17-8.15 (m, 1H), 8.07 (d, J=9 Hz, 1H) 7.87 (dd, J=2, 9 Hz; 1H), 7.71 (d, J=9 Hz, 2H), 7.57-7.54 (m, 1H), 7.41 (d, J=8 Hz, 2H), 7.28-7.24 (m, J=8 Hz, 2H), 7.16 (dd, J=9, 2 Hz, 2H), 4.98 (s, 2H), 3.36 (septet, overlapping H2O, 1H), 3.23-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). HRMS C32H27NO4Cl2 m/z 560.1395 (M+H)+Cal; 560.1375 (M+H)+Obs.