Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(F)cc2)cc1
Yield: 49.8 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 4-fluoro-benzyl bromide (150 mg, 0.75 mmol) to afford the title product (100 mg, 50% yield); LCMS; 100% APCI+, Calcd: 401.48; Found: 402.34 m/z (M+1); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.10 (m, 4H), 3.39 (br, 2H), 3.70-3.90 (m, 1H), 4.02-4.19 (m, 2H), 4.97 (s, 2H), 6.82-6.89 (m, 2H), 7.06 (t, J=8.0 Hz, 2H), 7.23-7.28 (m, 2H), 7.35-7.42 (m, 2H).
Reaction SMILES: [C:1]([NH:10][OH:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(O[CH:15](OCC)[CH2:16][CH2:17][CH2:18]Cl)C>C(O)(=O)C>[O:11]1[N:10]2[CH:18]([O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]2=[O:9])[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(CCCCl)OCC
Reactant: O=C(NO)c1ccccc1O
Solvent: CC(=O)O
Product: O=C1c2ccccc2OC2CCCON12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Salicylhydroxamic acid (30 g.) and 36 g. of 4-chlorobutyraldehyde diethyl acetal were allowed to react in acetic acid as described in Example 1. The reaction mixture was transferred to an ice-water mixture, stirred well, and decanted to remove the aqueous layer. The oil was washed again with water and allowed to stand at room temperature whereupon crystallization occurred. Aqueous solution of ammonium hydroxide was added, mixture was warmed and stirred and then allowed to stand overnight at room temperature. The aqueous solution was decanted from the partially crystallized oil and the latter was triturated with ethanol yielding 9.5 g. of solid melting at 137.5°-139.5° C. After recrystallization from methanol, the product (7 g.) melted at 139°-141° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]1([C:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[SH:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH3:52][C:53]([CH3:78])([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]2[CH:64]=[C:65]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[N:66]=[C:60]2[CH:59]1[CH2:75][CH2:76]O)=[O:57])[CH3:54]>C1COCC1>[CH3:54][C:53]([CH3:78])([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]2[CH:64]=[C:65]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[N:66]=[C:60]2[CH:59]1[CH2:75][CH2:76][S:39][C:38]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:57])[CH3:52]
Reactant: COc1ccccc1-c1cn2c(n1)C(CCO)N(C(=O)OC(C)(C)C)CC2
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 111 %

Procedure:
Triphenylphosphine (4.08 g, 15.5 mmol) was dissolved in THF (25 ml), cooled to about 0° C. under N2 and Diethylazodicarboxylate (2.45 ml, 15.54 mmol) was added at a dropwise rate so that the reaction temperature was maintained at about <3° C. Stirring was continued for about ½ hour at 0° C. A mixture of the triphenylmethanethiol (4.30 g, 15.54 mmol) and the product from Step 13.e. (2.90 g, 7.77 mmol) in THF (25 ml) was added at a dropwise rate. The resulting mixture was stirred for about 1 hour at about 0° C. and then allowed to warn to room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in ether (40 ml) and allowed to stand overnight. The solid was filtered off and the filtrate was concentrated then purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc and then 4:1/hexanes:EtOAc as eluants. The product fractions were combined and concentrated under reduced pressure to obtain a pale yellow foam (5.49 g, 111%) which was used without further purification. Mass spec. 632.4 MH+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](F)[N:17]=2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH:23]1([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CS(C)=O>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:30][CH2:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:17]=2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: NCC1CCCCC1
Reactant: N[C@H]1CC[C@H](Nc2ncc(Cl)c(-c3cccc(F)n3)n2)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2ncc(Cl)c(-c3cccc(NCC4CCCCC4)n3)n2)CC1
Temperature: 105 °C
Reaction time: 24 h

Procedure:
A mixture of trans-N1-(5-chloro-4-(6-fluoropyridin-2-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (12 mg, 0.037 mmol), cyclohexylmethanamine (42.2 mg, 0.373 mmol), and DMSO (0.35 ml) was stirred at about 105° C. for about 24 hours. The excess cyclohexylmethanamine was removed under vacuum to yield a residue. The residue was mixed with 0.5 ml DMSO, filtered, purified by prep HPLC and then lyapholized to yield 9.4 mg of the title compound as a TFA salt. LCMS (m/z): 415.3 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, METHANOL-d4, 45° C.) δ ppm 0.89-1.07 (m, 2H) 1.10-1.30 (m, 3H) 1.30-1.54 (m, 4H) 1.55-1.65 (m, 2H) 1.69 (d, J=12.91 Hz, 2H) 1.76 (d, J=12.91 Hz, 2H) 1.96-2.14 (m, 4H) 2.98-3.10 (m, 1H) 3.18 (d, J=6.65 Hz, 2H) 3.71-3.82 (m, 1H) 7.03 (d, J=9.00 Hz, 1H) 7.49 (br. s., 1H) 7.83 (t, J=8.22 Hz, 1H) 8.35 (s, 1H)
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(Cl)Cl>[I:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1
Reactant: O=c1c2ccccc2oc2ccccc12
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccccc2oc2ccc(I)cc12
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A solution of xanthen-9-one (1.96 g, 10.0 mmol; Aldrich) in trifluoroacetic acid-CH2Cl2 (1:1, 40 mL) was chilled to 0° C. and treated with N-iodosuccinimide (NIS; 2.25 g, 10.0 mmol; Lancaster), added portionwise over 1 h. After an additional 1 h at 0° C., the ice bath was removed and stirring continued for 8 h. Residual oxidant was quenched with aq. NaS2O3 and the mixture was extracted with CH2Cl2. The organic phase was washed with NaHCO3, dried over MgSO4, and the residue purified by flash chromatography (120 g silica gel, 10-100% CH2Cl2-hexanes) to afford the title compound (1.75 g, 5.43 mmol; 54% yield): 1H NMR (300 MHz, CDCl3) δ ppm 8.66 (d, J=2 Hz, 1H), 8.34 (dd, J=8, 2 Hz, 1H), 7.98 (dd, J=9, 2 Hz, 1H), 7.75 (ddd, J=9, 7, 2 Hz, 1H), 7.50 (dd, J=8, 1 Hz, 1H), 7.40 (ddd, J=8, 7, 1 Hz, 1H), 7.28 (d, J=9 Hz, 1H); MS (DCl/NH3) m/z 323 (M+H)+, 340 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]([CH:12]=[CH2:13])[C:9]([NH2:11])=[S:10])[CH:5]=[CH:4][CH:3]=1.[CH2:14](N)[CH:15]=[CH2:16]>>[CH2:16]([NH:11][C:9](=[S:10])[CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[CH:12]=[CH2:13])[CH:15]=[CH2:14]
Reactant: C=CC(C(N)=S)c1cccc(C)n1
Reactant: C=CCN
Product: C=CCNC(=S)C(C=C)c1cccc(C)n1

Procedure:
Reacting 2-(6-methyl-2-pyridyl)-3-thiobutenamide with allylamine by the procedure of Example 7 gives N-allyl-2-(6-methyl-2-pyridyl)-3-thiobutenamide.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:16](O)[CH3:17]>S(=O)(=O)(O)O>[C:1]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1cccc2ccccc12
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1cccc2ccccc12

Procedure:
A stirred solution of 50 grams (0.25 mole) of 3-(naphth-1-yl) propanoic acid and 20 drops (catalyst) of concentrated sulfuric acid in 250 mL of ethanol was heated at reflux for about 24 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether, and the solution was washed with two 150 mL portions of an aqueous solution saturated with sodium bicarbonate and then with 150 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 56.0 grams of ethyl 3-(naphth-1-yl)propanoate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.Cl.[C:11]([NH:15][NH2:16])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1.CCO>[C:11]([NH:15][NH:16][C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NN
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 2,4-dichloro-5-fluoro-pyrimidine (1.84 g, 11.00 mmol) and tert-butylhydrazine hydrochloride (1.25 g, 10.00 mmol) in THF (50 mL) and EtOH (5 mL) was added triethylamine (4.18 mL, 30.00 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove triethylamine HCl salt and the filtrate concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc/Hexanes) to afford 1.7 g of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=2.8 Hz, 1H), 6.47 (s, 1H), 4.60 (d, J=5.8 Hz, 1H), 1.09 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.19 minutes (M+H) 218.81.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[CH2:31][C:32]#[N:33])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.CO.N1CCCCC1.[CH:43](=O)[C:44]([CH3:47])([CH3:46])[CH3:45]>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([C:31](=[CH:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:32]#[N:33])=[O:34])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(C)(C)C=O
Reactant: N#CCC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
A mixture of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.33 mmol, 1.00 equiv), methanol (15 mL), dichloromethane (5 mL), piperidine (56 mg, 0.66 mmol, 2 equiv) and pivalaldehyde (142 mg, 1.66 mmol, 5 equiv was stirred for 48 h at 30° C. in a 25-mL sealed tube. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (100/1) to give 45 mg (26%) of (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile as a white solid. MS (ESI, pos. ion) m/z: 522 (M+1) 1HNMR (300 MHz, CDCl3, ppm) 8.396 (1H, s), 7.684˜7.656 (2H, d, J=8.4), 7.440˜7.388 (2H, t), 7.222˜7.092 (5H, m), 6.956 (1H, s), 5.613 (2H, s), 5.006˜4.909 (1H, m), 4.626˜3.290 (4H, m), 2.419˜1.732 (4H, m), 1.275 (9H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][C:2]1=[O:6].[CH2:7]1[O:11][CH:8]1CC.[CH2:12](O)[CH2:13]CC>>[C:8]([CH:3]1[CH2:4][CH:5]([CH2:12][CH3:13])[O:1][C:2]1=[O:6])(=[O:11])[CH3:7]
Reactant: CCC1CO1
Reactant: CCCCO
Reactant: O=C1CC=CO1
Product: CCC1CC(C(C)=O)C(=O)O1

Procedure:
Sodium hydroxide (82.5 g, 205 moles) in 82.5 g H2O was added over a period of 65 minutes to a stirring solution of n-butylacetoacetate (308.6 g, 1.875 moles), 1,2-butylene oxide (108 g, 1.5 moles) and H2O (102 g) in a one liter, four-neck flask equipped with a thermometer, mechanical stirrer, addition funnel, and condenser. The reaction was stirred at about 25° C. for 10 hours. The mixture was transferred to a separatory funnel and acidified with 31% hydrochloric acid to pH 6. The organic phase and aqueous phase separated cleanly. The organic phase (377 g) was distilled as in the preceding examples to obtain three fractions with fraction 3, boiling point 110° C.-120° C., yielding 151.9 g lactone when analyzed by gas chromatography. Fractions 1 and 2 comprised principally butyl alcohol and unreacted starting materials in addition to a small amount of lactone. Total yield of lactone was 150.4 g or 64.2%. 1,2-Butylene oxide conversion was 87.0% with a selectivity to the desired furanone of 77.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.O1CCCC1.Cl[C:58]1[O:59][C:60]2[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:61]=2[N:62]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:50])([CH3:51])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37]([C:58]4[O:59][C:60]5[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:61]=5[N:62]=4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Clc1ccc2nc(Cl)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5o4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 85 °C
Yield: 43.6 %

Procedure:
A dried pressure tube was consecutively charged with [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.1) (100 mg, 127 μmol), tetrahydrofuran (3 ml), 2,6-dichlorobenzo[d]oxazole (31.6 mg, 165 μmol), cesium carbonate (165 mg, 507 μmol) and water (1.5 ml). The tube was flushed with argon, thereafter [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (11 mg, 12.7 μmol) was added, the tube was sealed and the reaction mixture heated at 85° C. for 64 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzo oxazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (41 mg, 44% yield) was obtained as a white solid. MS (ISP): m/z=740.4 [M+H]+ and 742.3 [M+2+H]+.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[C:10]([NH:12][CH:13]3[CH2:15][CH2:14]3)[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:18][C:2]1[C:3]2[N:11]=[C:10]([NH:12][CH:13]3[CH2:15][CH2:14]3)[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ncnc2cnc(NC3CC3)nc12
Solvent: CN(C)C=O
Product: Clc1ncnc2cnc(NC3CC3)nc12

Procedure:
1.7 g of 4-hydroxy-6-(cyclopropylamino)-pyrimido[5,4-d]pyrimidine are heated under reflux with 50 ml of thionyl chloride with the addition of 4 drops of dimethylformamide for 1.5 hours. The reaction mixture is concentrated, methylene chloride is added and the mixture is concentrated again. The residue is then partitioned between methylene chloride and an aqueous potassium carbonate solution. The aqueous phase is extracted twice more with methylene chloride and the combined organic phases are dried and concentrated. The product is reacted further without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.B(Br)(Br)Br>>[ClH:1].[NH2:25][CH:23]([CH3:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:33])=[CH:17][CH:18]=1
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CC(C)NC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: CC(N)Cc1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 120.8 %

Procedure:
Following General Procedure F, a tert-butyl 1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propan-2-ylcarbamate (55 mg, 0.11 mmol) was reacted with BBr3 (1.0 M in CH2Cl2, 2 mL, 2 mmol) to afford the desired product (28 mg, 66%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.61 (d, J=5.4 Hz, 1H), 7.47 (dd, J=22.8, 7.8 Hz, 2H), 7.36-7.29 (m, 3H), 6.08 (d, J=5.4 Hz, 1H), 3.65 (dd, J=13.7, 6.9 Hz, 1H), 3.05 (ddd, J=34.9, 13.6, 7.3 Hz, 2H), 1.39 (d, J=6.6 Hz, 3H): ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC >99% (AUC), tR=8.77 min.
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]2[S:21][C:20]3[C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1.[F:35][C:36]1[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[C:38](I)[CH:37]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.C(O)(C)C>[F:1][C:2]1[C:3]([C:17]2[S:21][C:20]3[C:22]([C:38]4[C:39]([CH2:42][OH:43])=[CH:40][N:41]=[C:36]([F:35])[CH:37]=4)=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1
Reactant: OCc1cnc(F)cc1I
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCN5CCNC5=O)ncc4F)sc23)OC1(C)C
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1CCNc1ncc(F)c(-c2cc3cccc(-c4cc(F)ncc4CO)c3s2)n1
Temperature: 100 °C
Yield: 20.7 %

Procedure:
Combine 1-(2-{5-fluoro-4-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-2-yl]-pyrimidin-2-ylamino}-ethyl)-imidazolidin-2-one (120 mg, 0.25 mmol), (6-fluoro-4-iodo-pyridin-3-yl)-methanol (100 mg; 0.32 mmol), (1,1′-bis(di-phenylphosphino)ferrocene)palladium(II) chloride (10.14 mg; 0.01 mmol), 2-(di-tert-butylphosphino)biphenyl (2 mg, 0.01 mmol) and sodium carbonate (2 M, 0.2 mL, 0.4 mmol) in 5 mL of dioxane in a pressure tube. Heat the mixture at 100° C. overnight in oil bath. Cool the mixture down to room temperature, dilute it with chloroform-isopropyl alcohol (3/1). Wash the organic phase with saturated aqueous sodium chloride, dry it over sodium sulfate and concentrate it to an oily residue. Purify the crude by flash column chromatography (10% methanol in dichloromethane) to afford the title compound (25 mg, 21%). MS (ES) m/z 483 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([C:32]([OH:41])=[O:31])=[CH:34][CH:35]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Product: O=C(O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-formyl-benzoic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 527.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCCCCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 9.5 g. of p-n-hexylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 14.4 g. of a brownish oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-hexylbenzyliden)amino]benzonitrile which is obtained has a melting point of 32.2°-33.0°C. and a clearing point of 64.5°C. UV (ethanol): ε281 = 23500 (shoulder at 310 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.[CH3:20][CH2:21][CH:22]([OH:25])[CH2:23][CH3:24]>>[CH2:21]([CH:22]([O:25][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1)[CH2:23][CH3:24])[CH3:20]
Reactant: Cc1cc(C)c(Cc2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CCC(O)CC
Product: CCC(CC)Oc1nc(C)nc(Cc2c(C)cc(C)cc2C)c1C

Procedure:
The title compound was prepared by the method analogous to that in Example 32 starting with 4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine and 3-pentanol. White crystals. mp. 82-84° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O.[CH3:9][CH2:10][CH2:11]CCCC.[CH3:16]C(C)=O>>[CH3:9][C:10]1([CH3:11])[O:6][C:5]2([CH3:16])[CH2:7][CH2:8][CH:1]1[CH2:3][CH2:4]2
Reactant: CCCCCCC
Reactant: CC(C)=O
Reactant: Oc1ccc(O)cc1
Product: CC12CCC(CC1)C(C)(C)O2
Temperature: 25 °C

Procedure:
Crystalline anhydrous hydroquinone (19.5 g) was added to a 1 cm diameter jacketed glass chromatography column filled with heptane. The heptane was then drained to the level of the top of the packed hydroquinone, cold acetone poured into the jacket to chill the column contents below -10° C., and Unitene-D (20 g) added. The column contents were then eluted with heptane (about 250 ml) with continued chilling over 2 hours. This removed most of the undesirable components of the feed. The jacket was then drained of coolant and the column warmed to room temperature. Continued elution with heptane provided a solution of 1.8-cineole (1.8 g) of 92.8% purity (solvent-free basis). This represents a 50% yield of 1,8-cineole present in the feedstock mixture.