Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].O>CC(C)=O>[Cl:18][CH2:19][C:20]([O:9][C:8]1[CH:10]=[CH:11][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OC(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Paracetamol [1] (15.117 g, 50 mmol) and pyridine (7.910 g, 50 mmol) were suspended in anhydrous acetone (200 ml) and chilled to 0° C. under an atmosphere of dry nitrogen. Chloroacetylchloride (11.29 g, 50 mmol) was added dropwise (violent reaction) and the resulting solution was stirred for additional 2 hours at room temperature. Water (300 ml) was added and the mixture was heated until a clear solution was obtained. The product [2] precipitated upon cooling and was collected via filtration, washed with water and dried under reduced pressure (0.01 mbar, 50° C.) to yield [2] as colourless needles in 72% yield. The product was pure according to 1H NMR and directly subjected to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[C:9]([S:10](O)(=[O:12])=[O:11])=[C:8]([CH3:14])[N:7]=[C:4]2[S:5][CH:6]=1.C([N:18](CCC)CCC)CC>O(Cl)Cl>[CH3:1][C:2]1[N:3]2[C:9]([S:10]([NH2:18])(=[O:12])=[O:11])=[C:8]([CH3:14])[N:7]=[C:4]2[S:5][CH:6]=1
Reactant: Cc1nc2scc(C)n2c1S(=O)(=O)O
Reactant: CCCN(CCC)CCC
Agent: ClOCl
Product: Cc1nc2scc(C)n2c1S(N)(=O)=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of 2.8 g of 3,6-dimethylimidazo [2,1-b]thiazole-5-sulfonic acid in 3.4 ml of phophorus oxychloride, 1.8 g of tri-n-propylamine is added under cooling and stirred for 30 minutes at 60° C. The reaction solution after cooling is poured into ice water and extracted with dichloromethane. The dichloromethane layer is collected, dried and then distilled to remove dichloromethane. The residue is dissolved in 35 ml of acetonitrile, to which 3.8 ml of aqueous ammonia is added under cooling and stirred for 30 minutes at room temperature. The acetonitrile is distilled off under reduced pressure, and to the residue is added water. The precipitated crystalline solid is collected by filtration and washed with tetrachloromethane to give 1.5 g of the title compound as colorless crystals. mp. 177°-178° C.
Reaction SMILES: [CH2:1]([C:5]1([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[O:10][C:9](=[O:11])[CH:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:19])[CH2:6]1)[CH2:2][C:3]#[CH:4].Br[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.CC(O)=O>CC#N>[CH:20]1([C:5]2([CH2:1][CH2:2][C:3]#[C:4][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)[O:10][C:9](=[O:11])[CH:8]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7](=[O:19])[CH2:6]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Oc1cccc(Br)c1
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Sc2ccccc2)C(=O)O1
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Sc1ccccc1

Procedure:
The title compound was prepared analogously to Example 6 using 6-but-3-ynyl-6-cyclopentyl-3-phenylsulfanyl-dihydro-pyran-2,4-dione (described in Example 16) in place of 6-but-3-ynyl-6-dihydro-pyran-2,4-dione and 3-bromophenol in place of iodobenzene. 1H NMR (CDCl3): δ1.40-1.82 (m, 8H); δ2.14 (t, 1H, J=7.58 Hz); δ2.21-2.33 (m, 2H); δ0.40-2.56 (m, 2H); δ0.92 (dd, J1=17.94 Hz, J2=22.99 Hz, 2H); δ0.06-7.56 (m, 9H). Anal. Calcd. for C26H26O4S.0.2 AcOH. 1 MeCN: C, 69.95; H, 6.16; S, 6.85. Found C, 70.23; H, 6.58; S, 6.09. ESIMS (M+Na+): 457.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=3)[N:12]=[CH:11][C:10]=2[F:21])[CH2:4][C@H:3]1[CH2:22][NH2:23].[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=3)[N:12]=[CH:11][C:10]=2[F:21])[CH2:4][C@H:3]1[CH2:22][NH:23][CH2:35][C:32]1[CH:33]=[CH:34][C:28]2[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=2[N:31]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@@H](CN)[C@@H](F)C3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@@H](F)C3)c2n1
Reaction time: 24 h
Yield: 43.4 %

Procedure:
To a stirred solution of (±)-[(cis-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.15 g, 0.46 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.077 g, 0.46 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.15 g, 0.69 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.10 g, 46%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.21 (d, J=9.1 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.10 (m, 2H), 4.13 (s, 2H), 4.10 (s, 3H), 3.62 (m, 2H), 3.49-3.43 (m, 6H), 3.21 (m, 2H), 2.99 (m, 2H), 2.32 (app s, 2H). LC-MS (ES) m/e 501 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].B(F)(F)F.CCOCC.CO>O1CCCC1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][CH2:17][OH:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1c2ccccc2CCc2ccccc21
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: OCCC1c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 446.4 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid in 2.2 l of tetrahydrofuran, stirred under argon and cooled with ice-water, is treated portionwise with 87.0 g of sodium borohydride. The mixture is stirred for 30 minutes and subsequently a solution of 290 ml of freshly distilled boron trifluoride etherate in 300 ml of dry tetrahydrofuran is added dropwise thereto over a period of 90 minutes at a temperature of 10°. The mixture is stirred at 0° for 1 hour and at room temperature for 16 hours, cooled to 0° and treated dropwise over a period of 30 minutes with 400 ml of methanol. The mixture is stirred further at 0° for 15 minutes and at room temperature for 15 minutes and the solution is subsequently evaporated in vacuo. The residue is poured into a mixture of ice and 1 l of water, extracted three times with 2 l of ether each time and the organic extracts are washed successively with 1 l of 1.5N hydrochloric acid, with 1 l of 1.5N potassium bicarbonate solution and with 1 l of water. The organic phases are combined, dried over magnesium sulfate and evaporated. There is obtained 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ethanol in the form of an oil which crystallizes slowly upon standing.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1.CCOC(C)=O>CS(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ccccn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)CC1
Temperature: 140 °C
Yield: 0 %

Procedure:
A solution of 2-chloropyridine (0.83 ml, 8.81 mmol), tert-butyl piperidine-4-ylcarbamate (1.85 g, 9.24 mmol) and TEA (0.98 mL, 9.69 mmol) in DMSO (5 mL) was heated at 120° C. for 4 h 45 mins and then warmed to 140° C. for 2 days. EtOAc was added and the organic phase was washed with water then brine before evaporating to dryness. The residue was purified on a Biotage Horizion HPFC system eluting with 20% EtOAc in petroleum ether (40-60° C.) to give the title compound (0.65 mg, 27%). 1H NMR (500 MHz, CDCl3): 8.19 (s, 1H), 7.48 (dd, 1H), 6.67 (d, 1H), 6.61 (t, 1H), 4.49 (bs, 1H), 4.21 (d, 2H), 3.70 (bs, 1H), 2.99 (t, 2H), 2.05 (d, 2H), 1.59-1.38 (m, 11H). 13C NMR (CDCl3): 159.5, 155.4, 148.2, 137.7, 113.3, 107.5, 79.6, 48.4, 44.6, 32.3, 28.7; Mass Spectrum: M+H 278.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:24]([O:23][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)=[CH:29][CH:28]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 81.1 %

Procedure:
A solution of compound D (31.5 g; 0.1278 mol), tert-butyl 4-aminobenzoate (48 g; 0.248 mol), N,N-diisopropylethylamine (50.3 g; 0.39 mol) in 400 mL of dioxane was refluxed for 72 h under magnetic stirring. The reaction mixture was filtered, concentrated and taken up with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=9/1) to yield compound E (41.8 g; 81%).
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([CH2:28]Cl)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([CH2:28][S:1][C:2]3[S:3][CH2:4][CH2:5][N:6]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: SC1=NCCS1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSC3=NCCS3)c2CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of 2-mercaptothiazoline (0.3 g, 2.5 mmol) in anhydrous DMF (8.5 mL) at room temperature add sodium hydride (0.1 g, 2.6 mmol, 60% dispersion in mineral oil) in portions. After stirring at room temperature for 10 min, add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.74 g, 2.3 mmol) in anhydrous DMF (5.6 mL). Stir at room temperature overnight and quench the reaction mixture with 10% aqueous NaHCO3 (14 mL). Extract the mixture twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 hexane/EtOAc over 30 min; 95:5 hexane/EtOAc over 3 min; 95:5 to 75:25 hexane/EtOAc over 30 min; 75:25 hexane/EtOAc over 3 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-(4,5-dihydro-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.77 g, 83%). MS (ES+) m/z: 413.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)C1[C:12](=CC=CC=1)[OH:13]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:12]=[O:13])[C:5]([OH:8])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: O=Cc1ccccc1O
Product: O=Cc1cc(Cl)c(F)cc1O

Procedure:
4-Chloro-3-fluorophenol (Avocado product #16029) was converted to the salicylaldehyde via a method similar to that described in Example 2, Step 1: mp 102.7–103.7° C. 1H NMR (CDCl3/300 MHz) 11.22 (d, 1H, J=1.6 Hz), 9.80 (s, 1H), 7.63 (d, 1H, J=7.9 Hz), 6.77 (d, 1H, J=10.3 Hz). 19F NMR (CDCl3/282 MHz) −100.3 (t).
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[C:18]([I:19])=[CH:17][NH:16][C:14]=2[N:15]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[C:18]([I:19])=[CH:17][N:16]([C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[C:14]=2[N:15]=1
Reactant: Clc1ncc2c(I)c[nH]c2n1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)n1cc(I)c2cnc(Cl)nc21
Temperature: 60 °C
Reaction time: 42 h
Yield: 92 %

Procedure:
Methyl 2-bromo-2-methylpropanoate (663 mL, 5.13 mmol) was added to 2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (358.1 g, 1.28 mol) (see Preparation 40), potassium iodide (21.3 g, 128 mmol) and cesium carbonate (1670 g, 5.13 mol) in DMF (7162 mL). The mixture was heated at 60° C. for 19 hours. The reaction mixture was diluted with water (7000 mL) and stirred at room temperature for 42 hours. The mixture was filtered and the solid was washed with water (500 mL) to afford the title compound as a beige solid in 92% yield, 445.8 g.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[C:19](=[S:22])([O-:21])[CH3:20].[K+].O>CC(C)=O.[I-].[K+]>[C:19]([S:22][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8])(=[O:21])[CH3:20]
Reactant: CC([O-])=S
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CSC(C)=O)c(C)o2)cc1
Yield: 104.9 %

Procedure:
A solution of methyl 4-[4-(chloromethyl)-5-methyl-1,3-oxazol-2-yl]benzoate (5 g, 18.82 mmol, 1.00 equiv), potassium ethanethioate (2.68 g, 23.47 mmol, 1.25 equiv) and potassium iodide (120 mg, 0.72 mmol, 0.04 equiv) in acetone (40 mL) was stirred at 35° C. for 30 min. Water (50 mL) was added to quench the reaction. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 6.03 g of crude methyl 4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:40])(=[O:39])[NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:28]=5)[N:20]4[N:19]=3)[CH:15]=2)[CH2:10][CH:9]1[OH:41])(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:28]=[C:29]([S:33]([NH:34][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:39])=[O:40])[CH:30]=[CH:31][CH:32]=5)[N:20]4[N:19]=3)[CH:15]=2)[CH2:10][CH:9]1[OH:41]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5c(c4)C(NC(=O)OC(C)(C)C)C(O)C5)nn23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5c(c4)C(N)C(O)C5)nn23)c1

Procedure:
The titled compound was prepared through an acid catalyzed deprotection using {6-[7-(3-tert-butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-2-hydroxy-indan-1-yl}-carbamic acid tert-butyl ester and trifluoroacetic acid in methylene chloride to provide as a light brown lyophilate. LCMS (E/I+) 493 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.05 (s, 1H), 8.50 (s, 1H), 8.45 (d, 1H, J=7.7 Hz), 8.38 (s, 3H), 7.88 (d, 1H, J=8.2 Hz), 7.83 (dd, 1H, J=7.8 Hz), 7.70 (t, 1H, J=7.8 Hz), 7.62 (broad s, 2H), 7.31 (d, 1H, J=8.3 Hz), 7.24 (d, 1H, J=4.7 Hz), 7.02 (d, 1H, J=4.7 Hz), 5.56 (s, 1H), 4.37 (s, 2H), 3.25 (dd, 1H, J=5.8, 16 Hz), 2.75 (d, 1H, J=16, 20 Hz), 1.11 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[CH:12]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24])[CH2:14][CH2:13]1.N1C=CC=CC=1.Cl.[NH+]1C=CC=CC=1>CCOCC.O>[CH:12]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:9][CH2:8][CH:7]=[CH:6][C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:24])[CH2:13][CH2:14]1
Reactant: O=C(Cl)CCCCCCCCC1CC1
Reactant: Cc1ccc(C=CCO)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C=CCOC(=O)CCCCCCCCC2CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2.5 g. p-methylcinnamyl alcohol in 50 ml. ether at 0° under nitrogen is added 4.9 g. 9-cyclopropylnonanoyl chloride and 3.6 ml. pyridine. The reaction mixture is allowed to warm to room temperature and is then stirred for ten days. Water is then added to dissolve the pyridinium hydrochloride and form a second liquid phase. This mixture is stirred for 4 hours to hydrolyze the excess acid chloride and the mixture is then diluted with a mixture of ether and water. The ether phase is separated and the aqueous phase is extracated once with ether. The combined ether phases are washed with 2N sulfuric acid, 10% potassium carbonate, water, saturated copper sulfate, water, and brine, dried over calcium sulfate and the solvent removed to yield p-methylcinnamyl 9-cyclopropylnonanoate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([F:35])([F:34])[C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[C:14]([F:36])[C:13]=2[F:37])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[K+]>O.C(O)C>[F:37][C:13]1[C:14]([F:36])=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([F:34])([F:35])[C:24]([F:32])([F:33])[C:25]([F:30])([F:31])[C:26]([F:29])([F:27])[F:28])[CH:16]=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Temperature: 25 °C

Procedure:
A solution of 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid ethyl ester (13A) (1 equi.) and potassium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h., cooled to room temperature, quenched with hydrochloric acid (5%). The resulting white solid was filtered, washed with water, and dried under vacuum to give 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid (14 A) as a white solid (80%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19]>C(OC(=O)C)(=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][N:12]=[C:13]([CH:19]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:14]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccnc(C)c1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccnc(C=Cc2ccc([N+](=O)[O-])cc2)c1
Yield: 46 %

Procedure:
A mixture of 4-nitrobenzaldehyde (30.2 g) and 2,4-lutidine (64.2 g) in acetic anhydride (100 ml) was refluxed for 11 hours under stirring. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The resultant solution was acidified to pH 0.8 with conc. hydrochloric acid and the mixture was stirred at ambient temperature for one hour. The precipitate was collected by filtration. The residue was suspended in a mixture of ethyl acetate, tetrahydrofuran and water and the resultant mixture was adjusted to pH 8.0 with aqueous 20% potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel. The fraction eluted with a mixture of ethyl acetate and diisopropyl ether (4:6 V/V) was collected and the solvent was evaporated in vacuo to give 4-methyl-2-[2-(4-nitrophenyl)vinyl]pyridine (22.1 g).
Reaction SMILES: Cl[C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[C:17]([NH:29][CH3:30])[N:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:34][NH:35][CH3:36].C(N(CC)CC)C.C(O)(C)C>C(OCC)(=O)C.O1CCCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[C:17]([NH:29][CH3:30])[N:16]=[C:15]2[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:31]=[CH:32][C:2]([N:35]([CH3:36])[CH3:34])=[N:3][CH:4]=2)[CH:10]=1
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccc(Cl)nc3)c2)c2cc(OC)c(OC)cc2n1
Reactant: CNC
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(N(C)C)nc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 130 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
225 mg of 4-[3-(6-chloronicotinoylamino)phenyl]-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 29, 122 mg dimethylamine hydrochloride and 304 mg triethylamine were suspended in a mixed solvent of 5 ml isopropanol and 5 ml tetrahydrofuran and stirred at 130° C. for 18 hours in a sealed tube. Ethyl acetate was added thereto, and it was washed with water twice and with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:3). The product was recrystallized from hexane-ethyl acetate to give 185 mg of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.N1C2C(=CC(CN)=CC=2)C=CC=1.[CH3:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.N#N>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].O>[CH3:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[N:9]=[N:10][C:5]3=[N:4][CH:3]=2)=[N:36]1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: Cn1ccc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: C1COCCO1
Solvent: O
Product: Cn1ccc(Nc2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)n1
Yield: 14 %

Procedure:
To a suspension of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (68 mg, 0.2 mmol) (prepared from quinolin-6-ylmethanamine following the procedures of Compound 1) and 1-methyl-1H-pyrazol-3-amine (20 mg, 0.22 mmol) in dioxane (5 mL) were added Cs2CO3 (72 mg, 0.22 mmol) and H2O (0.5 mL). The mixture was degassed and charged with N2 three times, then Pd2(dba)3 (0.02 mmol, 18 mg) and xantphos (0.04 mmol, 23 mg) were added. The resulting mixture was stirred at 120° C. under one atmosphere of N2 overnight, then concentrated. The resulting residue was purified by chromatography to afford the title compound (10 mg). MS (m/z): 358 (M+1)+.