Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Clc1cccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Clc1cccc2c1cnn2C1CCCCO1
Temperature: 45 °C
Yield: 94.6 %

Procedure:
To a 1 L flask with mechanical stirrer was added 4-chloro-1H-indazole (75.0 g, 0.492 mol), pyridinium p-toluenesulfonate (1.24 g, 4.92 mmol), CH2Cl2 (500 ml) and 3,4-dihydro-2H-pyran (98.6 ml, 1.08 mol). With stirring, this mixture was heated to 45° C. for 16 hours. Analysis of reaction mixture shows production of both isomers of product. Cooled reaction to 25° C. and added CH2Cl2 (200 ml). Washed the solution with water (300 ml) and saturated NaHCO3 (250 ml). Dried the organics with MgSO4 and concentrated to dryness. Purified the crude product by dissolving in EtOAc/Hexanes (4:6, 1 L) and adding SiO2 (1.2 L). The mixture was filtered and the cake was washed with EtOAc/Hexanes (4:6, 2 L). The organics were concentrated in vacuo to yield 110.2 g 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (95%) as an orange solid. Isomer 1: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=1 Hz, 1H), 7.50 (dd, J=9 Hz, 1 Hz 1H), 7.29 (dd, J=9 Hz, 8 Hz 1H), 7.15 (dd, J=8 Hz, 1 Hz 1H) 5.71 (dd, J=9 Hz, 3 Hz 1H) 4.02 (m, 1H) 3.55 (m, 1H) 2.51 (m, 1H) 2.02 (m, 2H) 1.55 (m, 3H). LCMS (ESI pos) m/e 237 (M+1); Isomer 2: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=1 Hz, 1H), 7.62 (dd, J=9 Hz, 1 Hz 1H), 7.20 (dd, J=9 Hz, 8 Hz 1H), 7.06 (dd, J=8 Hz, 1 Hz 1H) 5.69 (dd, J=9 Hz, 3 Hz 1H) 4.15 (m, 1H) 3.80 (m, 1H) 2.22 (m, 2H) 2.05 (m, 1H) 1.75 (m, 3H). LCMS (ESI pos) m/e 237 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:30]=[C:31]([O:36][CH2:37][CH3:38])[C:32]=1[O:33][CH2:34][CH3:35])[C:7]([N:9]1[CH2:13][CH2:12][C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)([CH2:14][CH2:15]S(C)(=O)=O)[CH2:10]1)=[O:8])[CH3:2].C(N(C(C)C)CC)(C)C.ClC1C=CC=CC=1.[F:55][C:56]1[CH:79]=[CH:78][C:59]([CH2:60][N:61]2[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=3[N:63]=[C:62]2[C:70]([CH:72]2[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]2)=[O:71])=[CH:58][CH:57]=1>C(OCC)(=O)C.CO.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:30]=[C:31]([O:36][CH2:37][CH3:38])[C:32]=1[O:33][CH2:34][CH3:35])[C:7]([N:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:75]2[CH2:76][CH2:77][CH:72]([C:70]([C:62]3[N:61]([CH2:60][C:59]4[CH:58]=[CH:57][C:56]([F:55])=[CH:79][CH:78]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=4[N:63]=3)=[O:71])[CH2:73][CH2:74]2)([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:10]1)=[O:8])[CH3:2]
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: CCOc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(OC)c(OC)c3)C2)cc(OCC)c1OCC
Solvent: CO
Solvent: Clc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(OC)c(OC)c3)C2)cc(OCC)c1OCC
Reaction time: 4 h

Procedure:
Combine 1-(3,4,5-triethoxy-benzoyl)-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.31 g, 0.55 mmol), diisopropylethylamine (0.14 g, 1.1 mmol), chlorobenzene (5 mL), and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.28 g, 0.83 mmol) Heat to 120° C. After 4 hours, partition the reaction mixture between ethyl acetate and water. Extract 2 times with water and a 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 3/1 ethyl acetate/hexane and then 10/1/0.1 ethyl acetate/methanol/concentrated aqueous ammonia to give the title compound: Rf=0.60 (silica gel, 10/1/0.1 ethyl acetate/methanol/concentrated aqueous ammonia); mp; 155-160° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])[O:11][CH2:12][CH3:13])[CH2:9][CH2:8]2)[CH:6]=1.[CH3:15][O:16]C1C=NN(CC#N)C=1>>[CH3:15][O:16][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])[O:11][CH2:12][CH3:13])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: COc1cnn(CC#N)c1
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Product: CCOC(=N)C1(n2cc(OC)cn2)CC1

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 56, but using 2-(4-methoxy-1H-pyrazol-1-yl)acetonitrile as the starting material. 1H NMR (500 MHz, CDCl3) δ 1.37 (t, 3H), 1.63-1.72 (m, 4H), 3.76 (s, 3H), 4.16 (q, 2H), 7.17 (s, 1H), 7.35 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1Br.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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]>[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[NH:7][C:6]1[CH:8]=[CH:9][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: CCc1ccc(N)cc1
Reactant: Fc1ccc(F)c(Br)c1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCc1ccc(Nc2c(F)ccc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 1.21 g of 4-ethylaniline, 1.10 g of 2,3,6-trifluoro-bromobenzene in 10 g of toluene is added consecutively 350 mg BINAP and 300 mg of bis-dibenzylideneaceton-palladium (0) [Pd(dba)2) in 3 ml of toluene and 0.9 g of sodium tert.-butoxide in 3 ml toluene. The mixture is flushed with nitrogen and heated for 6 h under reflux. After cooling to room temperature, water (30 ml), concentrated hydrochloric acid (10 ml) and hyflo (1 g) are added and stirring is continued for 1 h. The mixture is filtered and the filtrate is separated into its phases. The organic phase is washed three times with water, dried using magnesium sulfate and evaporated to dryness. The residue can be used as such in the following step or purified by flash chromatography on silica using toluene as the eluent affording 1.13 g of N-(2′,3′,6′-trifluorophenyl)-4-ethylanilin.
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:3]/[CH:4]=[CH:5]/[C@H:6]1[C@H:10]([CH3:11])[O:9][C:8](=[O:12])[N:7]1[CH2:13][CH2:14][S:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([O:23]CCCC)=[O:22])[N:20]=1.[OH-].[Na+].Cl>CO>[OH:1][C:2]([CH3:33])([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:3]/[CH:4]=[CH:5]/[C@H:6]1[C@H:10]([CH3:11])[O:9][C:8](=[O:12])[N:7]1[CH2:13][CH2:14][S:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=1
Reactant: CCCCCC(C)(O)C/C=C/[C@H]1[C@H](C)OC(=O)N1CCSc1nc(C(=O)OCCCC)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(C)(O)C/C=C/[C@H]1[C@H](C)OC(=O)N1CCSc1nc(C(=O)O)cs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
To a solution of the compound 44 (3.7 g) in methanol (37 mL) was added dropwise 2N aqueous sodium hydroxide solution (11 mL) at 0° C. The solution temperature was risen to room temperature and the solution was stirred for 45 minutes. After the reaction solution was cooled to 0° C., 2N hydrochloric acid was added thereto and the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by flush column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (2.95 g) having the following physical data.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=5)=[CH:22][N:21](C5CCCCO5)[N:20]=4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.P([O-])([O-])([O-])=O>CO.O1CCOCC1>[CH3:31][S:30][C:26]1[N:25]=[C:24]([C:23]2[C:19]([C:17]3[CH:18]=[C:13]4[CH:12]=[CH:11][N:10]([S:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)(=[O:8])=[O:9])[C:14]4=[N:15][CH:16]=3)=[N:20][NH:21][CH:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CSc1nccc(-c2cn(C3CCCCO3)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Product: CSc1nccc(-c2c[nH]nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.4 %

Procedure:
To a solution of the 1-Benzenesulfonyl-5-[4-(2-methylsulfanyl-pyrimidin-4-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (C-1-2) (750 mg, 1.41 mmol) in MeOH (1 mL) was added a solution of HCl in Dioxane (˜4N, 0.1 mL). After stirring at ambient temperature for 45 minutes, the solution was dropped into phosphate buffer (pH 7, 15 mL). The resulting precipitate was collected by filtration, rinsed with water and air dried to give 5-{4-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazol-3-yl}-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (C-1-3) (622 mg, 98%) which was carried on without further purification. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 11.51 (br. s., 1H), 8.47 (d, J=2.02 Hz, 1H), 8.34 (d, J=5.05 Hz, 1H), 8.23 (br. s., 1H), 8.14 (d, J=7.58 Hz, 2H), 8.10 (d, J=1.77 Hz, 1H), 7.84 (d, J=2.78 Hz, 1H), 7.68 (t, J=7.45 Hz, 1H), 7.57 (t, J=7.71 Hz, 2H), 7.07 (d, J=4.80 Hz, 1H), 6.75 (d, J=3.79 Hz, 1H), 1.81 (s, 3H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([NH:36][NH2:37])=[CH:35][C:30]=2[O:29][CH2:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: NNc1ccc2c(c1)OCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc4c(c3)OCO4)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=466.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:4]/[C:3]2[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=2[F:1])/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1c(F)ccc(F)c1F
Product: COc1ccc(/C(C#N)=C/c2c(F)ccc(F)c2F)cc1OC
Yield: 86.1 %

Procedure:
2,3,6-Trifluorobenzaldehyde (320 mg) and 3,4-dimethoxybenzyl cyanide (354 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (549 mg, yield: 86%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:16]([CH3:31])[CH:15]=[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[N:13]=1)C1C=CC=CC=1.Cl.CO>CO.[Pd]>[OH:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:16]([CH3:31])[CH:15]=[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=2)[N:13]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(OCCOCc2ccccc2)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(OCCO)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 83.8 %

Procedure:
A solution of 0.22 g (0.4 mmol) of [2-(2-benzyloxy-ethoxy)-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 52) in 10 ml of MeOH was treated with 0.04 g (0.04 mmol) of Pd—C (10%) and 0.5 ml of HCl/MeOH (1 molar). The reaction mixture was hydrogenated at RT and ambient pressure until the absorption of H2 stopped (1 hour). After filtration with the aid of Dicalite, the filtrate was poured into crashed ice, the pH was adjusted to 8-9 with the help of sodium carbonate solution and the reaction mixture was extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography [CH2Cl2 (sat. with NH3)/MeOH 98:2 to 4:1] to give 0.16 g (86%) of the title compound as colorless oil. MS: 478.2 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5].[CH:7]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16](=[O:19])[CH:17]=[CH2:18])([CH3:9])[CH3:8].[NH4+].[Cl-]>C1COCC1>[CH:7]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16](=[O:19])[CH2:17][CH2:18][CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5])([CH3:9])[CH3:8]
Reactant: C=CC(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: C=C(C)CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)CCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
47 mg (1.9 mmol) of Mg chips is stirred at room temperature (or while being heated intermittently) in 1.5 ml of absolute THF with 283 mg (1.9 mmol) of 4-bromo-2-methyl-1-butene, until all Mg has gone into solution. This Grignard solution is mixed at -30° C. with a suspension of 197 mg (1.00 mmol) of CuBr--Me2S in 1.5 ml of absolute THF. It is stirred for 30 minutes at this temperature; 117 mg (0.64 mmol) of 20 on 2 ml of absolute THF is added; it is stirred for 16 hours at -10° C. and hydrolyzed with 10 ml of saturated NH4Cl solution. It is extracted three times with 20 ml of Et2O each. After drying on MgSO4, the solvent is removed. By flash-chromatographic purification with pentane/Et2O (15:1), 128 mg (0.51 mmol, 79%) of 21a is obtained.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[N:5]=[C:6]([S:26](Cl)(=[O:28])=[O:27])[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:8]=1[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>CC(C)=O.C1COCC1>[Cl:3][C:4]1[N:5]=[C:6]([S:26]([NH2:2])(=[O:28])=[O:27])[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:8]=1[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCc1c(Cl)nc(S(=O)(=O)Cl)n1COCC[Si](C)(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1c(Cl)nc(S(N)(=O)=O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Ammonium hydroxide (5.0 mL, 128 mmol) was added to a 0° C. solution of 4-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonyl chloride (1.33 g, 2.8 mmol) in acetone (4.5 mL) and THF (2.5 mL). The reaction mixture was stirred at RT for 30 min and evaporated. The residue was taken up in EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered, evaporated, and purified by silica gel chromatography (0-25% EtOA/hexanes) to give the title compound (0.95 g, 74%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.71 (s, 2H), 5.37 (br. s., 2H), 4.75 (s, 2H), 3.59-3.70 (m, 2H), 0.92-0.97 (m, 2H), 0.91 (s, 9H), 0.11 (s, 6H), 0.02 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([O:6][CH2:7]Cl)=[CH:4][CH:3]=1.[K].[Cl:12][C:13]1[CH:14]=[N:15][C:16](=[S:19])[NH:17][CH:18]=1>COCCOC>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([O:6][CH2:7][S:19][C:16]2[N:17]=[CH:18][C:13]([Cl:12])=[CH:14][N:15]=2)=[CH:4][CH:3]=1
Reactant: S=c1ncc(Cl)c[nH]1
Reactant: ClCOc1ccc(Cl)cc1
Agent: [K]
Solvent: COCCOC
Product: Clc1ccc(OCSc2ncc(Cl)cn2)cc1
Yield: 70 %

Procedure:
A mixture of p-chlorophenoxymethyl chloride (6 mmol) and the potassium salt of 5-chloropyrimidine-2-thione (5 mmol) in 1,2-dimethoxyethane (25 ml) was stirred at room temperature for 10 h, the solvent distilled off at reduced pressure, the residue extracted with chloroform (70 ml), the chloroform (70 ml), the chloroform solution washed with 1 M NaOH (2×10 ml) and water (10 ml), and the dried (MgSO4) solution evaporated. The residual sulfide was recrystallized from iPrOH; yield 70%, m.p. 120° C. 1H NMR (DMSO-d6): δ5.90 (SCH2), 6.98 and 7.31 (Ph), 8.78 (H-4, H-6).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[SH:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].CN1CCOCC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:12][CH:13]=1)[NH:6][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[N:34][C:26]=1[SH:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1cccnc1S
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)c1cccnc1S
Yield: 92.8 %

Procedure:
A solution of O-(2,6dichlorobenzyl)-L-tyrosine methyl ester hydrochloride (2.50 g, 6.4 mmol), 2-mercaptonicotinic acid (0.99 g, 6.4 mmol) and NMM (1.41 ml, 1.29 g, 12.8 mmol) in DMF (10 ml) was stirred at room temperature for 64 h. Solvent was removed in vacuo and the residue partitioned between DCM (30 ml) and water (25 ml). The aqueous layer was extracted with DCM (30 ml) and the combined organic layers were washed with 10% NaHCO3 solution (30 ml), dried over MgSO4 and the solvent removed in vacuo to give a brown oil which was purified by chromatography (SiO2; gradient elution, 4:1 EtOAc/hexane to 100% EtOAc) to give the title compound as a yellow foam, (2.92 g, 93%). δH (CDCl3) 8.71 (1H, dd, J 1.8, 7.6Hz), 8.05 (1H, s), 7.61 (1H, dd, J 1.8, 6.1 Hz), 7.35 (2H, m), 7.33-7.19 (2H, m), 6.94 (2H, d, J 8.7Hz), 5.22 (2H, s), 4.97 (1H, m), 3.74 (3H, s) and 3.21 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[CH3:17])[CH3:2].C(OC(=O)CO[C:25]1[C:34]2CCCCC=2C=C[CH:26]=1)C>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[C:8]2[CH2:17][CH2:34][CH2:25][CH2:26][C:9]=2[C:10]([S:13]([Cl:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CCOC(=O)COc1cccc2c1CCCC2
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 10.2, using compound 22.1 as the starting material. 1H NMR (400 MHz) (CDCl3) δ 7.93 (1H, d, J=8.9 Hz); 6.62 (1H, d, J=9.0 Hz); 4.73 (2H, s); 4.29 (2H, q, J=7.1 Hz); 3.27-3.24 (2H, m); 2.81-2.78 (2H, m); 1.85-1.82 (4H, m); 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[CH2:56]([CH:58]1[CH2:62][CH2:61][C:60]([CH2:63]O)=[CH:59]1)[CH3:57]>C1COCC1>[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:63][C:60]3[CH2:61][CH2:62][CH:58]([CH2:56][CH3:57])[CH:59]=3)=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCC1C=C(CO)CC1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCC3=CC(CC)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecylpyrimidin-2-yl)phenol and 3-ethyl-1-cyclopenten-1-yl-methanol (prepared by LiAlH4 reduction of methyl 3-ethyl-1-cyclopentene-1-carboxylate as described by Takeda, Bull.Chem.Soc.Jpn. 50 (7), 1831 (1977)). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH2:11])([CH3:10])[CH3:9].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[N:14]=1>CC(CC)=O>[CH:8]([NH:11][C:17]1[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[N:14]=[C:13]([Cl:12])[N:18]=1)([CH3:10])[CH3:9]
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)N
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: COc1c(Cl)nc(Cl)nc1NC(C)C

Procedure:
42 ml of triethylamine, 25 ml of isopropylamine, 250 ml of methylethylketone and 32 g of 2,4,6-trichloro-5-methoxypyrimidine (prepared as indicated by Budesinsky et Coll., Ceskoslov. Farm. 10, 241-247, 1961) were stirred together at 20° C. for 6 hours. The reaction mixture was then evaporated under reduced pressure and the residue fixed on a silica gel column. This was followed by elution with a 95/5 toluene-diethylamine mixture. In this way were isolated 20.2 g of 4-isopropylamino-2,6-dichloro-5-methoxypyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23]>>[NH2:16][C:15]1[CH:14]=[C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:12]([O:11][CH3:10])=[CH:18][C:17]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COCCOc1cc(N)ccc1OC
Product: COCCOc1cc(N)c(C(=O)c2ccccc2Cl)cc1OC

Procedure:
(2-amino-5-methoxy-4-(2-methoxyethoxy)phenyl)-(2-chlorophenyl)-methanone (Xgg) was prepared by reacting 2-chlorobenzaldehyde with 0.0296 moles of 4-methoxy-3-(2-methoxyethoxy) aniline in a manner analogous to Example 1. MH+/Z=336.
Reaction SMILES: Br.C(O)(=O)C.C1(=O)[N:10]([CH2:11][C:12]2[N:13]=[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C(=O)C2=CC=CC=C12.[OH-].[Na+]>O>[NH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)oc1-c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NCc1nc(-c2ccccc2)oc1-c1ccccc1

Procedure:
A mixture made up of 20 ml of 48% hydrobromic acid, 20 ml of glacial acetic acid and 10 g of 4-phthalimidomethyl-2,5-diphenyloxazole, was heated under reflux until a clear solution resulted (3 hrs.). The solvent was pulled off under vacuum until dryness. The residue was dissolved in 100 ml of water, made basic with 1N NaOH and extracted with ethyl acetate. The ethyl acetate solution was washed with water until neutral and dried over sodium sulfate. The solvent was pulled off under vacuum and the residue was recrystallized from ethyl acetate and hexane.
Reaction SMILES: [Al+3:1].[Cl-].[Cl-].[Cl-].[C:5]1([Mg]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O(CCCC)CCCC>[C:5]1([Al:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [Al+3]
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Solvent: CCCCOCCCC
Product: c1ccc([Al](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of AlCl3 (133 mg; 1.0 mmol) in Bu2O (4.0 mL) was added phenylmagnesium bromide (1.2 mL, 3.1 mmol, 2.6 M in Et2O) at ambient temperature. After stirring at ambient temperature overnight, the product mixture was purged with a strong stream of nitrogen gas to evaporate the THF and Et2O. Bu2O (5.0 mL) was added to the residue and the mixture was stirred overnight, then filtered and the filtrate was purged with a strong stream of nitrogen gas to provide Ph3Al as a solid.