Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:21][CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([OH:21])[CH2:23]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: OC1CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCCC(O)C3)sc2Br)s1

Procedure:
4-[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonylchloride, prepared as in Step III of Example 23 (136 mg; 0.33 mmol; 1 eq), is dissolved in DCM (10 ml). 3-hydroxy piperidine (0.20 ml; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added under a nitrogen atmosphere. After 2 hours reaction, solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is purified by reverse preparative HPLC, affording N-(5-{2-bromo-5-[(3-hydroxypiperidin-1-yl)sulfonyl]-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide as an oil (31 mg; 20%).
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)C.C(C1C=CC(OCC[O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=CC=1)(=O)CCC>>[NH2:17][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[CH:12][CH:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Product: CCCC(N)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 25 except that (2-(2-(2-(4-butyrylphenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (44) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-one (21). This produced the crude product which was purified by flash silica gel column chromatography, eluting with ethyl acetate, to give 45 (730 mg, 73%) as a clear oil: MS (ES+) m/z 497.3 (M+H)+.
Reaction SMILES: [CH:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].Cl[C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1>C(#N)C>[CH3:2][CH:1]([NH:5][C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=1)[CH2:3][CH3:4]
Reactant: O=C(OCc1ccccc1)c1sc(Cl)nc1C(F)(F)F
Reactant: CCC(C)N
Solvent: CC#N
Product: CCC(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2)s1
Yield: 30.3 %

Procedure:
By the procedure of Example 39, a stirred mixture of 20 ml acetonitrile, 3.65 g (49.8 mmol) of sec-butylamine, and 8 g (24.9 mmol) of benzyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506), was heated at reflux for 16 hours. The product was separated and then triturated in hexane to yield 2.70 g of an off-white solid product (m.p.=56°-57° C.) identified in Table I.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[S:7][CH2:6][CH2:5][O:4]1)[OH:2].[CH3:11][N:12]=[C:13]=[O:14].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>CCOCC>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]1[C:8]([CH3:10])([CH3:9])[S:7][CH2:6][CH2:5][O:4]1)=[O:14]
Reactant: CC1(C)SCCOC1=NO
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Product: CNC(=O)ON=C1OCCSC1(C)C

Procedure:
A quantity of 3.2 grams of crude 2-oximino-3,3-dimethyl-1,4-oxathiane was caused to react with 4 ml of methyl isocyanate in 75 ml of ether containing 5 drops of dibutyltin diacetate at room temperature for twenty hours. The excess methyl isocyanate and solvent were evaporated, and the residue taken up in ethyl acetate. After rinsing this solution with 100 ml of saturated brine and back-extraction with 100 ml of ethyl acetate, the combined organic solutions were dried over magnesium sulfate, filtered, and the solvent evaporated. The resulting thick oil was triturated with about 30 ml of a 3:1 isopropyl ether/ethyl acetate mixture at room temperature. Filtration afforded 0.7 g of pure 2-(methylcarbamoyloximino)-3,3-dimethyl-1,4-oxathiane, mp 67.0°-68.0°; structure confirmed by spectral analysis.
Reaction SMILES: [CH:1]([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1)([CH3:3])[CH3:2].[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:1]([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:28][CH2:27][O:26][CH2:25][CH2:24][Br:23])[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1(c2ccccc2O)Sc2ccccc2N(C)C1=O
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)C1(c2ccccc2OCCOCCBr)Sc2ccccc2N(C)C1=O

Procedure:
9.4 g (30 mmol) of 3,4-dihydro-2-isopropyl-4-methyl-2-(2-hydroxyphenyl)-2H-1,4-benzothiazin-3-one are boiled for 8 hours under reflux with 22 g (94 mmol) of 1,5-dibromo-3-oxapentane and 12.9 g (90 mmol) of potassium carbonate in 75 ml of 2-butanone. The mixture is then filtered with suction, and the filtrate is concentrated, finally in a high vacuum. This gives 12.4 g of an almost colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:10])[CH3:9])[NH:4][N:3]=1.[I:11](O)(=O)=O.II>C(O)C>[I:11][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[NH:7][C:8](=[O:10])[CH3:9]
Reactant: [O-][I+2]([O-])O
Reactant: CC(=O)Nc1cc(C)n[nH]1
Agent: II
Solvent: CCO
Product: CC(=O)Nc1[nH]nc(C)c1I
Temperature: 50 °C
Yield: 231.4 %

Procedure:
A suspension of N-(3-methyl-1H-pyrazol-5-yl)acetamide (29.6 g, 0.213 mol), iodic acid (9.3 g, 0.053 mol) and iodine (32.5 g, 0.128 mol) in ethanol (300 mL) was heated at 50° C. for 3 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and taken up in ethyl acetate. The solution was washed twice with 2 M Na2S2O3 followed by brine solution. The organic layer was dried (magnesium sulphate), filtered and concentrated in vacuo. The residue was triturated from diethyl ether, filtered and dried to provide the title compound as a white solid (32.5 g).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+].[C:41]([O:45][C:46]([N:48]1[CH2:52][CH2:51][C@H:50]([O:53][C:54]2[C:55]3[CH2:63][NH:62][CH2:61][CH2:60][C:56]=3[N:57]=[CH:58][N:59]=2)[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42].Br[C:65]1[CH:66]=[C:67]([CH3:73])[C:68]([O:71][CH3:72])=[N:69][CH:70]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(OC)(C)C.CO.CC(OC)(C)C>[C:41]([O:45][C:46]([N:48]1[CH2:52][CH2:51][C@H:50]([O:53][C:54]2[C:55]3[CH2:63][N:62]([C:65]4[CH:70]=[N:69][C:68]([O:71][CH3:72])=[C:67]([CH3:73])[CH:66]=4)[CH2:61][CH2:60][C:56]=3[N:57]=[CH:58][N:59]=2)[CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Reactant: COc1ncc(Br)cc1C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COC(C)(C)C
Solvent: CO
Solvent: C1COCCO1
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C
Temperature: 120 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
X-Phos (0.96 g, 2.01 mmol, 0.3 eq.), Pd2(dba)3 (0.615 g, 0.672 mmol, 0.1 eq.), Cs2CO3 (4.38 g, 13.44 mmol, 2 eq.) were combined and flushed 10 min with Argon. To this mixture, a solution of (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 7) (2.15 g, 6.72 mmol) in dioxane (6 mL) and 5-bromo-2-methoxy-3-methylpyridine (1.76 g, 8.73 mmol) were added at rt and the reaction mixture was stirred at 120° C. for 2 h. The reaction was cooled down to rt, the reaction mixture filtered over Hyflo, AcOEt was added and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was dissolved in dioxane (6 mL) and added to a glass vial containing 5-bromo-2-methoxy-3-methylpyridine (1.76 g, 8.73 mmol), X-Phos (0.96 g, 2.01 mmol), Pd2(dba)3 (0.615 g, 0.672 mmol), Cs2CO3 (4.38 g, 13.44 mmol). The vial was capped and the reaction mixture was stirred at 120° C. for 2 h. The reaction was cooled down to rt, the reaction mixture filtered over Hyflo, AcOEt was added and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography on silica gel (CH2Cl2 then TBME then TBME/MeOH 99/1 to 90/10) gave (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow foam (2.05 g, 69% yield). 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.35-1.44 (br.s., 9H) 2.07-2.23 (m, 2 H), 2.14 (s, 3 H), 2.87-2.93 (m, 2 H), 3.39-3.68 (m, 6 H), 3.81 (s, 3 H), 4.03-4.08 (m, 2 H), 5.56-5.63 (m, 1 H), 7.41-7.46 (m, 1 H), 7.67-7.73 (m, 1 H), 8.60 (s, 1 H). LCMS: [M+H]+=342.2, Rt(2)=0.94 min.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([O:13]CC)=[O:12])[C:5]2[CH:26]=[CH:27][NH:28][C:4]=2[C:3]1=[O:29].[OH-].[Na+].O.Cl>O1CCOCC1>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([OH:13])=[O:12])[C:5]2[CH:26]=[CH:27][NH:28][C:4]=2[C:3]1=[O:29]
Reactant: CCOC(=O)c1ccc(Oc2ccccc2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(C(=O)O)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A mixture of Example 9b (0.23 g, 0.59 mmol) and sodium hydroxide (0.89 mL of 2.0 M aqueous solution) in dioxane (10 mL) was heated at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). After addition of concentrated HCl (5 mL), the mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford 0.21 g (98%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 3.55 (s, 3H), 6.24-6.25 (m, 1H), 6.94 (d, J=8.54 Hz, 1H), 7.05 (d, J=7.63 Hz, 2H), 7.16 (t, J=7.32 Hz, 1H), 7.27 (t, J=2.9 Hz, 1H), 7.35-7.40 (m, 3H), 7.92 (dd, J=8.7, 2.29 Hz, 1H), 8.04 (d, J=2.14 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 361.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:31]=[C:18]3[N:19]=[C:20]([CH3:30])[C:21]([CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])=[C:22]([Cl:23])[N:17]3[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:31]=[C:18]3[N:19]=[C:20]([CH3:30])[C:21]([CH:24]([O:29][C:2]([CH3:7])([CH3:3])[CH3:1])[C:25]([O:27][CH3:28])=[O:26])=[C:22]([Cl:23])[N:17]3[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(OCc4ccccc4)c3)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3cccc(OCc4ccccc4)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a suspension of methyl 2-(2-(3-(benzyloxy)phenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate. (80 mg, 0.18 mmol) in tert-butyl acetate (5 mL) at room temperature was added CH2Cl2 (10 mL) followed by perchloric acid (27 mg, 0.26 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (80 mg, 92%). Used as is in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]1([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1>>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C:19]2([NH:18][C:14]([C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:20][CH2:21]2)=[CH:23][CH:24]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 78.2 %

Procedure:
The title compound (D53) (650 mg) was prepared according to the general procedure for amides preparation (Method A) starting from (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (500 mg, available from Sigma Aldrich #516341), and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (470 mg). Reaction time: 18 hrs.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].O.[CH3:22][CH2:23]OCC>CN(C)C=O.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:1]([C:3]1[C:7]([CH:22]=[CH2:23])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: CCOCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodopyrazole (58 g) in dimethylformamide (350 ml) containing yinyltri-n-butyltin (116 ml) and tetrakis(triphenylphosphine)palladium(0) (3.5 g) was stirred at 75° C. for 3 hours. The reaction nixture was poured into water (600 ml) and ether (600 ml). The organic layer was washed with water (5 times), brine (700 ml) and dried over sodium sulphate. Removal of the solvent in vacuo was followed by recrystallisation of the residue from propan-2-ol, to give the title compound as a pale brown solid, m.p. 75-6° C.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=CO[CH:8]=2)=[CH:3][CH:2]=1.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[N:26]1[C:32](=[O:40])[CH2:33][N:34]1C=C(I)C=[N:35]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C2C=CC=CC=2)C=CC(B(O)O)=CC=1>>[CH2:18]([C@H:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[N:26]1[C:32](=[O:40])[CH2:33][N:34]1[CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:6][CH:5]=2)[CH:11]=[N:35]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cn1cc(I)cn1
Agent: OB(O)c1ccc(-c2ccccc2)cc1
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cn1cc(-c2ccc(-c3ccccc3)cc2)cn1
Yield: 39 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, 1-(4(S)-benzyl-2,2-dimethyl-oxazolidinyl)-2-(4-iodopyrazol-1-yl)-ethanone was coupled to 4-biphenylboronic acid to provide in 39% yield 1-(4(S)-benzyl-2,2-dimethyl-oxazolidinyl)-2-(4-biphenyl-4-yl-pyrazol-1-yl)-ethanone as a white solid, mp 150-1° C. 1H NMR: δ 7.83 (s, 1H), 7.68 (s, 1H), 7.62-7.52 (m, 6H), 7.47-7.28 (m, 8H), 4.83, 4.38 (AB quartet, 2H, J=15.6 Hz), 4.22-4.18 (m, 1H), 3.94 (m, 2H), 3.09 (dd, 1H, J=6.4, 13.0 Hz), 2.97 (dd, 1H, J=8.5, 13.2 Hz), 1.79 (s, 3H), 1.55 (s, 3H). Anal. Calculated for C29H29N3O2 : C, 77.14; H, 6.47; N, 9.31. Found: C, 77.04; H, 6.52; N, 9.37.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]=1[OH:25])([CH3:14])([CH3:13])[CH3:12].O>C(O)=O.C(O)(=O)C>[C:21]([C:17]1[CH:18]=[C:19]([CH2:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:20]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:16]=1[OH:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: OCC=Cc1ccccc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CC(=O)O
Solvent: O
Solvent: O=CO
Product: CC(C)(C)c1cc(CC=Cc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
Cinnamyl alcohol (134 g.) was added to a suspension of 2,6-di-t-butylphenol (206 g.) in 88% aqueous formic acid (470 ml.) and glacial acetic acid (200 ml.), and the mixture was refluxed for 1.5 hours. Warm water (2000 ml.) was added and the oily layer which formed on top of the mixture was collected. The oil was distilled and gave a fraction (179 g.), b.p. 190°-200° C. at 0.5 mm Hg. The oil crystallized upon treatment with Skelly F (a mixture of petroleum hydrocarbons boiling between 30°-60° C.) to give glistening, colorless needles, m.p. 93° C. (Found: C, 85.7; H, 9.20. Calc. for C23H30O: C, 85.7; H, 9.38). The nuclear magnetic resonance (nmr) spectrum of this compound at 100 MHz in deuterated chloroform (CDCl3) exhibited absorbances as follows: a singlet (9 protons) at δ 1.41; a singlet (9 protons) at δ 1.45; a singlet (2 protons) at δ 3.48; a singlet (1 proton) at δ 5.07; a multiplet (2 protons) at δ 6.18-6.58; and a multiplet (7 protons) at δ 6.96-7.46.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[C:14]([CH3:20])[C:11]=1[CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:20][C:14]1[C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:10]([CH3:9])[C:11]=1[CH2:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Cc1cc(C)c(C)c(CCl)c1C
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C)c(C)c(COc2ccc(Br)cc2)c1C
Yield: 79 %

Procedure:
In acetone (50 ml), a mixture of 4-bromophenol (7.8 g), 2,3,5,6-tetramethylbenzyl chloride (6.3 g) and potassium carbonate (6.5 g) was heated at reflux for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and successively washed with 3% aqueous sodium hydroxide solution, water and saturated brine. The solvent was evaporated under reduced pressure, thereby giving 8.7 g of the desired compound.
Reaction SMILES: C(S)C.B(F)(F)F.CCOCC.C([O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH2:31][C:32]#[C:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])C1C=CC=CC=1.O>C(Cl)Cl.CCOCC>[OH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH2:31][C:32]#[C:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)CCCC#CCc1ccc2ccccc2c1OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCC#CCc1ccc2ccccc2c1O
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
A solution of ethanethiol (12.0 mL, 0.162 mole) and boron trifluoride etherate (6.0 mL, 0.049 mole) was stirred at room temperature. A solution of methyl 7-(1-benzyloxy-2-naphthyl)-5-heptynoate (2.05 g. 0.006 mole) in methylene chloride (8 mL) was added and the mixture was stirred for 1.5 hours, then poured into water. The crude product was isolated by extraction with ether, and chromatographed with 2:1 ether/hexane. The title compound (1.09 g, 71%) was obtained as a colorless oil. Mass spectrum: m/z=282.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH2:13].[H-].[Na+]>CN(C)C=O>[N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([CH2:13][CH:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:11]([O:20][CH3:21])=[O:19])[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: Nc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(Cn1cnc2c(N)ncnc21)C(=O)OC
Temperature: 120 °C
Reaction time: 192 h
Yield: 76.4 %

Procedure:
A mixture of adenine (5.40 g, 0.040 mol), dimethyl itaconate (8.00 g, 0.051 mol), sodium hydride (55% in oil, 0.2 g) and dry N,N-dimethylformamide (125 ml) was warmed to 120° C. and then kept with stirring at room temperature for 8 days. The precipitate was filtered, washed with dichloromethane (3×15 ml) and dried in vacuum to yield 8.96 g (76 g) of dimethyl 2-(adenin-9-ylmethyl)-succinate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:14])[NH:7]2.[H][H]>CN1CCCC1=O.[OH-].[Pd+2].[OH-]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:14])[NH:7]2
Reactant: [H][H]
Reactant: COc1ccc(O)c2ccc(=O)[nH]c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1ccc(O)c2c1NC(=O)CC2
Yield: 98.2 %

Procedure:
5-Hydroxy-8-methoxycarbostyril (12.5 g) in 200 ml of N-methylpyrrolidinone with 500 mg of palladium hydroxide (20%) were hydrogenated at 50° C. under 1,2 bar hydrogen. The catalyst was removed by filtration through Celite and the solvent evaporated to give 12.4 g of 5-hydroxy-8-methoxy-3,4-dihydrocarbostyril (mp=190° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].Cl[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=1.C([O-])(O)=O.[Na+]>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.O1CCOCC1>[NH2:22][C:17]1[N:16]=[C:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=2)[CH:20]=[C:19]([CH3:21])[N:18]=1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Reactant: Cc1cc(Cl)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(F)c(C=O)c(F)c2)nc(N)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To (3,5-difluoro-4-formylphenyl)boronic acid (5.0 g, 26.9 mmol) and 4-chloro-6-methyl-2-pyrimidinamine (3.86 g, 26.9 mmol) were added 1,4-dioxane (100 mL) and saturated aqueous NaHCO3 (40 mL). The mixture was degassed with nitrogen for 10 minutes. Pd(Ph3P)4 (1.0 g, 0.87 mmol) was added and the reaction mixture was stirred overnight at 100° C. The reaction mixture was cooled to room temperature, poured onto water and filtered. The solid was washed with water and EtOAc to provide a pale yellow solid (2.4 g). The combined filtrates were poured into a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was chromatographed on a SiO2 column (gradient: 100% CHCl3 to 90:10:1 CHCl3/CH3OH/NH4OH). Loading of the material into the column was complicated by the poor solubility properties of the residue. Hot dioxane was used to help solubilize the residue. Part of the material co-eluted with the solvent front. All the fractions containing the product (including the ones that co-eluted with the solvent front) were combined, concentrated and triturated with ˜1:1 mixture of EtOAc and hexanes to provide desired product as a yellow solid (1.6 g). This material was combined with the pale yellow solid obtained from the initial filtration and used without further purification. LC-MS (ES) m/z=250 [M+H]+.