Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8](/[CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])\[C:9]([OH:11])=[O:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>C(OCC)C>[CH:1](=[C:8](/[CH2:12][C:13]([N:15]1[CH2:16][C@H:17]2[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:23]1)=[O:14])\[C:9]([O:11][CH3:26])=[O:10])/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)/C(=C/c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Solvent: CCOCC
Product: COC(=O)/C(=C/c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1

Procedure:
To a solution of (E)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid (50 mg) in diethyl ether was added a solution of diazomethane in diethyl ether with stirring and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give 52 mg of methyl (E)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate as a colorless viscous oil.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.O.[C-:21]#[N:22].[Na+]>C(O)C>[C:21]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:22]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Reaction time: 24 h
Yield: 58.7 %

Procedure:
tert-Butyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (15.3 g) was dissolved in ethanol (80 mL), water (20 mL) and sodium cyanide (4.0 g, 80 mmol) were added, and stirring was conducted at 80° C. for 24 hours. Ethanol was distilled off, water and ethyl acetate were added, and then the resultant mixture was subject to Celite filtration, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by using silica gel column chromatography (hexane:ethyl acetate=3:1→2:1) to give tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (6.87 g, 77%, 3 steps) as a white solid.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])=O)C.Cl.[C:19]([NH2:22])(=[NH:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[N:21]=[C:19]([CH3:20])[NH:22][C:4](=[O:17])[CH:5]=2)[CH:13]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(C)n1
Temperature: 100 °C
Reaction time: 60 h
Yield: 66.1 %

Procedure:
A mixture of 3-(5-chloro-2-methoxy-phenyl)-3-oxopropionic acid ethyl ester (0.9 g, 3.2 mmol), acetamidine hydrochloride (448 mg, 4.7 mmol) and potassium carbonate (1.3 g, 9.6 mmol) in ethanol (15 ml) was stirred at 100° C. in thick wall tube for 60 hours. After cooling to room temperature, the mixture was poured into ice cold water. The solid was collected by filtration, washed with water and ether and dried under vacuum to provide 6-(5-chloro-2-methoxy-phenyl)-2-methyl-3H-pyrimidin-4-one (530 mg, 68% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 3.85 (s, 3H, CH3), 6.77 (s, 1H, CH, Ar), 7.15 (d, 1H, J=8.8 Hz, Ar), 7.45 (dd, 1H, J=8.8 Hz, J=2.9 Hz, Ar), 7.90 (d, 1H, J=2.9 Hz, Ar), 12.42 (s, 1H, NH).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)=O.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](=[S:26])[NH2:25])=[CH:22][CH:21]=1.C(O)(C)C>CCO>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]2[S:26][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=3)[N:25]=2)=[CH:22][CH:21]=1
Reactant: CCCCCCCOc1ccc(C(=O)CBr)cc1
Reactant: NC(=S)c1ccc(Br)cc1
Solvent: CCO
Solvent: CC(C)O
Product: CCCCCCCOc1ccc(-c2csc(-c3ccc(Br)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a stirring solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 (1.37 g, 4.38 mmol) in EtOH (10 mL) were added 4-bromobenzothioamide (0.95 g, 4.38 mmol) and isopropanol (10 mL). The reaction mixture was stirred at room temperature for 16 h. The solid was isolated by filtration, washed with EtOH (5 mL) then taken up in DCM (10 mL) and NaHCO3 (20 mL) and stirred for 1 h at room temperature. The solid was isolated by filtration, washed with water (2×10 mL) and acetonitrile (2×4 mL) then dried to afford 1.02 g (52%) of 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole as a white micro-crystalline solid. LCMS-ESI (m/z) calculated for C22H24BrNOS: 429.1. found 430.0 [M+H]+, tR=3.20 min. (Method 4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][C:18]([NH:31][C:28]3[N:29]=[CH:30][C:25]([Cl:24])=[CH:26][N:27]=3)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Cl)nc2)COC1(C)C
Reactant: Nc1ncc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ncc(Cl)cn3)nc2)COC1(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
In a pressure tube, (S)-4-[2-(6-chloro-pyridin-3-yl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.94 g), 5-chloropyrimidin-2-amine (357 mg) and cesium carbonate (1.35 g) were combined with dioxane (5 ml) to give a yellow suspension. The mixture was degassed by bubbling through argon for several minutes. Xantphos (96 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (86 mg) were then added and the tube was sealed. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; gradient: 0% to 70% EtOAc in hexane) to afford (S)-4-{2-[6-(5-chloro-pyrimidin-2-ylamino)-pyridin-3-yl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (417 mg, 35%) as a yellow solid. MS (ISP): 436.3 ([{37Cl}M+H]+), 434.4 ([{35Cl}M+H]+), 380.3 ([{37Cl}M+H—C4H8]+), 378.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:49].[ClH:49].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][NH:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CCNC2
Yield: 79 %

Procedure:
tert-Butyl 9-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (167 mg, 0.34 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (124 mg, 79%) as a yellow solid: mp 226-231° C.;
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][C:30]1[C:35]([CH3:36])=[C:34]([S:37][CH3:38])[N:33]=[N:32][C:31]=1[NH2:39].C(N(CC)C(C)C)(C)C>C(#N)CCC>[CH3:36][C:35]1[C:34]([S:37][CH3:38])=[N:33][N:32]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:39]=[C:31]2[C:30]=1[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: CSc1nnc(N)c(C)c1C
Solvent: CCCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Temperature: 125 °C
Yield: 19 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (540 mg, ˜80% purity, 0.970 mmol, 1.0 eq), 4,5-dimethyl-6-(methylsulfanyl)-pyridazin-3-amine (that was prepared in a manner analgous to that described for Intermediate Example Int-35, Step 1, 181 mg, ˜50% purity, 1.07 mmol, 1.1 eq) and N,N-diisopropylethylamine (170 μL, 0.970 mmol, 1.1 eq) in butyronitrile (4.7 mL) was heated for 4 hours at 125° C. On cooling the reaction mixture was concentrated in vacuo. The crude mixture was purified via reversed phase preparative HPLC to give 105 mg (19% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A solution of the compound of Example 47, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.98 mmol) in 20 mL of CH2Cl2 was chilled in an ice water bath. With vigorous stirring, the solution was treated with phenyl isocyanate (0.340 mL, 3.13 mmol). After 30 min, the reaction was concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) followed by recrystallization from MeOH/CHCl3/hexanes gave 529 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea as light yellow crystals.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13].[CH3:34][C:35]([CH3:39])([CH3:38])[CH:36]=[O:37].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH:36]([OH:37])[C:35]([CH3:39])([CH3:38])[CH3:34])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Reactant: CC(C)(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC(O)C(C)(C)C)c(C)c1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A 2.44 M solution of n-butyllithium in hexane (42.8 mL, 104.5 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 12.22 g, 41.8 mmol) in tetrahydrofuran (300 mL) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Trimethylacetaldehyde (13.79 mL, 125.4 mmol) was added at 0° C., and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=9/1 to 3/1) to give the title compound (13.08 g, 83%).
Reaction SMILES: C([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:10][C:9]([CH2:18][S:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:21])=[O:20])=[CH:8][CH:7]=2)(O)=O.Cl.C(OCC)(=O)C>N1C2C(=CC=CC=2)C=CC=1>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:18][S:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH:10]=2)[NH:5][CH:4]=1
Reactant: CN(C)CCc1c(C(=O)O)[nH]c2ccc(CS(=O)(=O)N3CCCC3)cc12
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CN(C)CCc1c[nH]c2ccc(CS(=O)(=O)N3CCCC3)cc12
Temperature: 190 °C
Yield: 5.4 %

Procedure:
To a solution of previously dried 1-[[2-carboxy-3-(2-dimethylaminoethyl)-5-indolyl]methanesulphonyl]pyrrolidine (1.6 g; 0.0442 moles) in anhydrous quinoline (75 ml) and under atmosphere of nitrogen, cuprous oxide (160 mg; 0.0011 moles) was added. The reaction mixture was heated to 190° C. for 15 minutes, stirred to room temperature, poured into a mixture of 1N hydrochloric acid (150 ml) and ethyl acetate (50 ml), shaken and decanted. The aqueous solution was washed several times with ethyl acetate, then solid sodium bicarbonate was added until pH=7.8, and washed with n-hexane to eliminate the quinoline. The aqueous solution was made alkaline with solid potassium carbonate and extracted with ethyl acetate. The organic solution was dried (Na2SO4), the solvent removed under reduced pressure when a dark oil was obtained (1.3 g; yield 92%). This product was purified by column chromatography with silica gel and methylene chloride:ethanol:ammonium hydroxide (60:8:1) as eluent and a white foam (0.8 g) of 1-[[3-(2-dimethylaminoethyl)-5-indolyl]methanesulphonyl]pyrrolidine was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[OH:4].O=[C:16]([CH3:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:29][O:28][C:26]([CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:16]([NH:1][CH2:2][CH:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)[OH:4])[CH3:30])=[CH:24][CH:23]=1)=[O:27]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc3ccccc23)cc1
Yield: 30.1 %

Procedure:
Following a procedure similar to that described in Example 6, but using 3 g of 2-amino-1-(1-naphthyl)ethanol (prepared as described in Preparation 10), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 3 g of sodium cyanoborohydride, 1.9 g of the title compound were obtained having an Rf=0.35 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[C:29]5[O:34][CH2:35][O:36][C:28]=45)=[N:21][CH:22]=[N:23]3)=[C:18]([O:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:32]1[C:27]([NH:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:17][C:18]=3[O:37][CH:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:23]=[CH:22][N:21]=2)=[C:28]2[O:36][CH2:35][O:34][C:29]2=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCC4CCNCC4)cc(OC4CCOCC4)c13)OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
A mixture of 7-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.25 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 93:7 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was partitioned between ethyl acetate and an aqueous ammonium hydroxide solution. The organic layer was dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.07 g); NMR Spectrum: (CDCl3 and D2O) 1.5–1.7 (m, 2H), 1.9–2.1 (m, 4H), 2.2–2.3 (m, 2H), 2.8 (m, 2H), 3.32 (d, 2H), 3.65 (m, 2H), 3.9–4.1 (m, 3H), 4.8 (m, 1H), 6.08 (s, 2H), 6.52 (br s, 1H), 6.72 (d, 1H), 6.8 (s, 1H), 6.98 (d, 1H), 8.5 (s, 1H); Mass Spectrum: M+H+ 513 and 515.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].[F:9][CH:10]([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.CN(C)C=O.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:9][CH:10]([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccc(C#Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
Into a mixture of ethynylbenzene (1.9 g, 18.5 mmol), 1-(difluoromethoxy)-4-iodobenzene (5 g, 18.5 mmol), N,N-dimethylformamide (35 mL), and triethylamine (12.8 mL, 92.6 mmol) was introduced anhydrous argon for 5 minutes. Then, copper(I) iodide (1.85 mmol, 351 mg) and dichlorobis(triphenylphosphine)palladium(II) (1.11, 0.71 g) were added into the mixture and the new mixture was stirred at 60° C. for 3 hours. The mixture cooled to room temperature, poured into water and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification on silica gel (ISCO) using hexanes/EtOAc (100/1) as the eluting solvent, gave 1-(difluoromethoxy)-4-(phenylethynyl)benzene as a clear oil (3.45 g, 76% yield). MS m/e M+ 244; 1H NMR (400 MHz, DMSO-d6) 7.2 (d, J=8.78 Hz, 2H), 7.28-7.45 (m, 4H), 7.5-7.55 (m, 2H), 7.6 (d, J=7.78 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25].O>O1CCCC1>[Cl:22][CH2:23][C:24]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:10]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution, ice cooled, of 1-(3,4-dichlorophenyl)-1H-pyrazol-3-amine (0.36 g, 1.59 mmol) and triethylamine (0.24 g, 2.38 mmol) in dry tetrahydrofurane (5 ml), 2-chloroacetyl chloride (0.2 g, 1.79 mmol) was added. The mixture was stirred overnight at room temperature, water added and the organic solvent evaporated in vacuo. The resulting suspension was filtered and dried yielding 0.45 g of 2-chloro-N-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)acetamide as a beige colour solid.
Reaction SMILES: [O-]CC.[Na+].[Na].[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:17](=[O:23])[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]([CH:16]=1)[N:12]([CH3:15])[CH:13]=O.Cl>C(O)C>[F:6][C:7]1[CH:16]=[C:11]2[C:10]([C:17](=[O:23])[C:18]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][N:12]2[CH3:15])=[CH:9][CH:8]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Reaction time: 0.5 h

Procedure:
A solution of sodium ethoxide in ethanol, prepared from sodium metal (2.3 g) and absolute ethanol (50 ml), was added dropwise over 5 minutes to a solution of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (2.7 g), prepared in a similar manner to that described in Example 11, in absolute ethanol (10 ml) at ambient temperature. The mixture was stirred at this temperature for 30 minutes then added to hydrochloric acid (1M; 100 ml), keeping the temperature below 30°. The mixture was extracted with dichloromethane (2×150 ml). The extracts were combined, dried (magnesium sulphate) and evaporated in vacuo to give the crude product (2.5 g). The crude product was crystallised from industrial methylated spirit to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 221°-222.5° (2.0 g). The product was heated to 90° with grinding to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 234°-235° (2.0 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[N:10]=[C:11]([CH2:13][CH3:14])[NH:12][C:7]2=[C:6]([CH3:15])[CH:5]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.Cl>CN(C=O)C.O>[CH3:33][O:32][C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:10]2[C:8]3=[N:9][C:4]([CH3:3])=[CH:5][C:6]([CH3:15])=[C:7]3[N:12]=[C:11]2[CH2:13][CH3:14])=[CH:23][CH:22]=1)=[O:31]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a suspension of sodium hydride (345 mg, 60% in oil, 8.6 mmol) in dry DMF (10 mL) was added 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (1.5 g, 8.6 mmol) under an atmosphere of dry nitrogen. The reaction mixture was stirred at room temperature until the evolution of gas subsided. The reaction mixture was cooled to 0° C. and a solution of methyl 4'-bromomethylbiphenyl-2-carboxylate (2.7 g, 8.84 mmol) in dry DMF (5 mL) was added dropwise. The resulting solution was stirred at room temperature overnight. The reaction mixture was poured into water (250 mL), the pH was adjusted to pH 6 by the addition of 1N HCl, and the product was extracted into ethyl acetate. Flash chromatography (silica, ethyl acetate) gave 4'-[[5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl]methyl][1,1'-biphenyl-2-yl]carboxylic acid methyl ester (2.05 g, 61%) as an amorphous solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][S:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: OCc1cccc(CBr)c1
Reactant: O=Cc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(SCc2cccc(CO)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
200 mg of 3-mercaptobenzaldehyde was dissolved in 6 ml of dimethylformamide, and 291 mg of 3-hydroxymethylbenzyl bromide and 402 mg of potassium carbonate were added. The mixture was stirred for 3 hours at room temperature. The solvent was evaporated, water and ethyl ether were added to the residue to extract it. The extract was worked up in a customary manner, and purified by silica gel column chromatography [Wakogel C-200, 10 g; eluting solvent: hexane/ethyl acetate=2/1] to give 190 mg (yield 51%) of 3-[3-(hydroxymethyl)benzylthio]benzaldehyde as a pale yellow oil.