Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=4)[C:11]=3[CH:23]=2)=[N:4][N:3]=1.O1CCC[CH2:25]1.[H-].[Na+].IC>C(OCC)(=O)C.CN(C)C=O>[CH3:25][O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[C:11]3[CH:23]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(CO)cc4)c3c2)o1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COCc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a mixture of [4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenyl]methanol (193 mg, 0.630 mmol), tetrahydrofuran (3 mL) and N,N-dimethylformamide (3 mL) was added sodium hydride (60% in oil, 37.8 mg, 0.945 mmol) at room temperature, and the resulting mixture was stirred for 10 min. Iodomethane (0.0588 mL, 0.945 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/tetrahydrofuran=2/1), and crystallized from hexane/tetrahydrofuran to give the title compound (146 mg, yield 73%) as colorless crystals.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:38]=2)[C:33]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[N:32]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:36]3[CH:35]=[C:34]4[C:39](=[CH:38][CH:37]=3)[N:31]([CH3:30])[N:32]=[C:33]4[C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1nc(-c2cccnc2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3cccnc3)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75 mg, 0.15 mmol), 1-methyl-3-(pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (60.4 mg, 0.18 mmol), Pd(PPh3)4 (17.4 mg, 15 μmol), and K2CO3 (62.2 mg, 0.45 mmol). De-gassed dioxane (1.6 mL) and water (0.4 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 70% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.67 (d, J=3.6 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J=7.7 Hz, 1H), 8.19 (dd, J=8.8, 1.0 Hz, 1H), 7.87 (s, 1H), 7.60-7.45 (m, 6H), 5.17 (s, 1H), 4.34-4.08 (m, 5H), 2.61 (s, 3H), 1.25 (t, J=7.1 Hz, 3H), 0.99 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][C@@H:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Reactant: CC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Product: CC(=O)c1cnc(Nc2ccc(C[C@H](C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(6-chloro-5-nitro-3-pyridinyl)ethanone (Paul, B. et al. J. Med. Chem., 1990, 33, 2231–2239.) and (2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:6])[O:4]C.Cl>[OH-].[Na+].CO>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:4])[OH:6]
Reactant: COP(=O)(OC)c1ccc2[nH]nc(/C=C/c3ccccc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COP(=O)(O)c1ccc2[nH]nc(/C=C/c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.6 %

Procedure:
18.5 mg of [3-((E)-Styryl)-1H-indazol-5-yl]phosphonic acid dimethyl ester are dissolved in 500 μl of 1M sodium hydroxide solution in methanol. The medium is stirred at ambient temperature for 4 hours. 100 μl of 2N hydrochloric acid are added to the mixture, which is stirred for 15 min at ambient temperature. The organic phase is extracted with 3 ml of ethyl acetate. The solvent is evaporated off under vacuum in a centrifugal evaporator to obtain 18 mg of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13](CS([O-])(=O)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].[Cl:21][C:22]1[C:23]([OH:29])=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[C:23]([O:29][CH:13]2[CH2:12][CH2:11][N:10]([C:7]3[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=3)[CH2:15][CH2:14]2)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1
Reactant: CCCc1cnc(N2CCC(CS(=O)(=O)[O-])CC2)nc1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3Cl)CC2)nc1
Temperature: 120 °C

Procedure:
A mixture of 1-(5-propylpyrimidin-2-yl)piperidin-4-ylmethanesulfonate (800 mg, 2.67 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (389 mg, 2.67 mmol, AK Scientific) and cesium carbonate (2612 mg, 8.02 mmol) in DMF (20 mL) was heated at 120° C. for 6 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and washed with H2O (3×). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The residue was purified by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2) to give the desired product as a yellow solid. MS (ESI) 379 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[N:28]([CH2:34][CH3:35])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=2[C:25]=1[O:38][CH3:39]>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[N:28]([CH2:34][CH3:35])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=3[C:25]=2[O:38][CH3:39])=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(OC)cc3-n3cccn3)n1)c2OC

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (22%); 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.61 (bs, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 7.96 (d, J=9.06 Hz, 1H), 7.83 (s, 1H), 7.64 (d, J=8.83 Hz, 1H), 7.22 (s, 1H), 7.00 (d, J=8.98 Hz, 1H), 6.95 (d, J=9.09 Hz, 1H), 6.55 (s, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 2.1-1.9 (m, 6H), 1.03 (m, 3H); MS (m/e) 534.47 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)=[CH:7][CH:8]=2)[NH:3]1>C1COCC1.[Pd]>[O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=2)[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)NC(=O)NC3)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)NC(=O)NC3)CC1
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a solution of compound 22 (0.8 g, 2.45 mmol) in THF (20 mL) was added Pd—C (10% wet basis, 0.15 g), and the mixture was subjected to hydrogenation in a Parr apparatus at 60 psi for 12 h. After filtering over the pad of celite, the solution was concentrated to get a brown oil material, which was resolved over silica column, eluting with hexanes:ethyl acetate (4:6) and then changing to (6:4) yielded 0.59 g (76%) of 23 as a light yellow gum. IR (KBr) νmax. cm−1: 3211, 3165 (NH), 3072 (Ar—H), 1698 (C═O), 1610, 1512, 1419 (C═C). 1H-NMR (500 MHz, CDCl3) δ=1.48 (s, 9H, (CH3)3C); 1.54 (m, 2H, CH2); 1.75-1.82 (m, 2H, CH2); 2.56 (m, 1H, CH); 2.76 (br. s, 2H, CH2); 4.23 (br. s, 2H, CH2); 4.44 (s, 2H, CH2); 6.58 (m, 2H, H-7, H-8); 7.30 (m, 1H, d, J=8.3 Hz, H-5); 13C NMR (125.7 MHz, CDCl3) δ=28.38 (CH3)3C), 32.50 (CH2), 42.87 (CH2), 43.30 (CH), 47.88 (CH2), 66.36 (CH2), 79.53 (CH3)3C), 93.98 (aromatic-C), 113.24 (aromatic-C), 116.97 (aromatic-C), 117.68 (aromatic-C), 132.41 (aromatic-C), 134.49 (aromatic-C), 149.82 (aromatic-C), 152.48 (C═O), 154.69 (C═O). Calculated (%) for C18H25N3O3 (331.19); C: 65.23, 7.60, N: 12.68. found (%); C: 65.12, H: 7.69, N: 12.55.
Reaction SMILES: Cl[C:2]1[CH:29]=[C:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=1)[C:8]([NH:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1)=[O:9].C(N(CC)CC)C>CO.C1COCC1.[Pd]>[CH3:35][N:33]([CH3:34])[S:30]([C:28]1[CH:29]=[CH:2][C:3]([O:4][C:5]2[CH:6]=[C:7]([CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)=[O:9])=[CH:26][CH:27]=1)(=[O:31])=[O:32]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)C)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)C)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 20 h
Yield: 32.3 %

Procedure:
To a solution of 3-{2-chloro-4-[(dimethylamino)sulfonyl]phenoxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.0 g, 1.9 mmol) in methanol (20 mL) and THF (20 mL) was added triethylamine (1.5 mL) and 10% palladium on carbon (100 mg). The resulting mixture was stirred under an atmosphere of hydrogen for 20 hours. The mixture was filtered through Celite® and evaporated under reduced pressure. The residue was dissolved in DCM (100 mL) and washed with 2M hydrochloric acid (100 mL). The organic phase was separated and the aqueous reextracted with DCM (100 mL). The combined organic extracts were dried (MgSO4) and evaporated to afford the title compound (300 mg, 32%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:9])[C:7]#[N:8].[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19](Cl)=[O:20])[C:14]=12>C(#N)C>[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:9][CH:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[C:7]#[N:8])=[O:20])[C:14]=12
Reactant: N#CC(N)c1ccco1
Reactant: O=C(Cl)c1cccn2ccnc12
Solvent: CC#N
Product: N#CC(NC(=O)c1cccn2ccnc12)c1ccco1
Yield: 10.9 %

Procedure:
α-(2-Furyl)-α-aminoacetonitrile (0.7 g, 5.5 m mols) was dissolved in acetonitrile (20 ml), and imidazo[1,2-a]pyridine-8-carboxylic acid chloride (1.0 g, 5.5 m moles) was added thereto with stirring and reacted at room temperature for 2 hours. After completion of the reaction, the solvent was removed from the reaction mixture under reduced pressure. To the residue were added water (20 ml), saturated aqueous solution of sodium. bicarbonate (50 ml) and chloroform (50 ml), and the mixture was stirred. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by column chromatography on silica gel (eluent:ethyl acetate/n-hexane=2/1) to give the object compound (0.16 g, yield 11%) as crystals. m.p. 149°-151° C.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Br>[C:25]1([O:24][C:22]2[CH:21]=[C:10]([CH:9]=[C:8]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:23]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:12])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)c2cc(Oc3ccccc3)cc(Oc3ccccc3)c2)cc1
Agent: Br
Product: O=C(c1ccc(O)cc1)c1cc(Oc2ccccc2)cc(Oc2ccccc2)c1
Reaction time: 4 h

Procedure:
14.90 g (0.038 mole) of 3,5-diphenyloxy-4′-methoxybenzophenone are dissolved under argon in a mixture of 60 ml of hydrobromic acid (48% in water) and 120 ml of hydrobromic acid (33% solution in acetic acid). The mixture is stirred for 4 hours under reflux. A further 100 ml of hydrobromic acid (330/solution in acetic acid) and 50 ml of hydrobromic acid (48% in water) are added to the reaction solution. The reaction mixture is stirred for a further 6 hours under reflux. The reaction mixture is then poured onto ice and extracted several times with diethyl ether. The organic phases are combined and extracted several times with NaOH solution (20%). The aqueous phases are combined and washed neutral with HCl solution. The neutralised aqueous phase is then extracted several times with diethyl ether. The organic phases are combined, dried over magnesium sulfate, and the solvent is removed in vacuo. The crude product is taken up in a small amount of diethyl ether and filtered over silica gel. After removing the solvent and drying the residue in a high vacuum, 11.25 g (78%) of a white solid are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][S:5]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])(=[O:7])=[O:6].N1C[CH2:20][O:19][CH2:18]C1>>[N:2]1([CH2:3][CH2:4][S:5]([C:8]2[CH:9]=[C:10]([NH:11][C:8]3[CH:9]=[CH:10][CH:12]=[CH:13][CH:14]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:6])[CH2:15][CH2:18][O:19][CH2:20][CH2:1]1
Reactant: C1COCCN1
Reactant: CN(C)CCS(=O)(=O)c1cccc(N)c1
Product: O=S(=O)(CCN1CCOCC1)c1cccc(Nc2ccccc2)c1
Yield: 98.7 %

Procedure:
This aniline was prepared with the same procedure described for the preparation of 3-(2-Dimethylaminoethylsulfonyl)-aniline, using morpholine instead of dimethylamine. 770 mg (2.137 mmol; 98.7% yield) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cccnc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-bromoacetylpyridine hydrobromide (G. B. Barlin, L. P. Davies, S. J. Ireland, M. M. L. Ngu, Aust. J. Chem., 1989, 42, 1735).
Reaction SMILES: C(OC([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]2[OH:28])=[CH:11][CH:10]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:28][C@H:16]1[C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1
Reactant: CC(C)(C)OC(=O)Oc1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
To a solution of (±)-rel-(3S,4S)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (6.5 g, 16.5 mmol) in 100 mL of methanol was added 11.42 g of potassium carbonate (83 mmol) and the reaction mixture was stirred at rt for 5 h. The organic solvent was removed under reduced pressure and the residue was partitioned between 1N HCl (300 mL) and ethyl acetate (300 mL). The layers were separated and the organic layer was dried over Na2SO4 and evaporated under reduced pressure to give (±)-rel-(3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (5 g, 15 mmol, 92% yield) which was used without further purification. LCMS (method F) RT 1.85 min, m/z 238 (M+H+−t-butyl), 279 (M+H+−t-butyl+CH3CN), 1H NMR (400 MHz, DMSO-d6) δ ppm 7.01 (d, J=8.53 Hz, 2H) 6.66 (d, J=8.53 Hz, 2H) 4.70 (d, J=5.02 Hz, 1H) 4.09 (br. s., 1H) 3.94 (d, J=11.55 Hz, 1H) 3.35-3.41 (m, 1H) 2.66-2.77 (m, 1H) 2.29-2.39 (m, 1H) 1.63 (dd, J=13.30, 3.26 Hz, 1H) 1.44-1.52 (m, 1H) 1.42 (s, 9H).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]I.C(NCC)C>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(Cl)nc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc(Cl)cn1
Yield: 28.6 %

Procedure:
1.2 ml (10 mmol) of trimethylsilylacetylene, 40 ml of diethylamine and 1.5 g (10 mmol) of 2,5-dichloropyridine are stirred at 20° under argon. To the colourless solution obtained there are added 0.1 g (0.4 mmol) of triphenylphosphine, 0.01 g (0.05 mmol) of copper-(I) iodide as well as 0.06 g (0.25 mmol) of palladium-dichloro-bis(acetonitrile). The reaction solution is subsequently heated to reflux for 5 hours while stirring. After cooling to 25° the reaction solution is evaporated at 40° under reduced pressure. 50 ml of ethanol are subsequently added to the residue and the mixture is again evaporated. The crude product is filtered over 30 g of silica gel with ethyl acetate and the eluate is evaporated, whereby 1.6 g of brown liquid remain behind. 1.0 g thereof is distilled in a bulb tube at 70°/0.1 Pa, whereby there are obtained as the main fraction 0.6 g of 2-trimethylsilylethynyl-5-chloropyridine which solidifies upon standing.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Na].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[CH2:1]([O:5][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Na]
Solvent: O
Product: CCCCOc1ccc(C#N)cc1

Procedure:
250 ml of butanol and 15.2 g (0.66 mol) of sodium are heated in a sulfonation flask under a protective-gas atmosphere until the metal has fully reacted. The mixture is cooled, p-chlorobenzonitrile is added in portions, and the reaction mixture is subsequently refluxed for about 16 hours. The cooled mixture is poured into water and extracted with ethyl acetate. The organic phase is then dried using MgSO4 and filtered, and the solvent is evaporated, giving 95% of theory of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:4].ClCCl.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[N:9]1([CH2:8][C:7]2[CH:6]=[C:5]([CH:24]=[CH:23][CH:22]=2)[C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(CN2CCNCC2)c1

Procedure:
Tert-butyl 4-(3-(methoxycarbonyl)benzyl)piperazine-1-carboxylate (1.25 g, 3.74 mmol) was stirred with a 4/1 solution of dichloromethane/trifluoroacetic acid (20 mL) for 1 hour at room temperature. The solution was then concentrated under vacuum to afford the title compound (1.73 g). MS (ESI) m/z 235.1 [M+H]+
Reaction SMILES: [OH-].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][N:5]=1.[OH:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[CH3:26]>O>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:16][CH3:17])[N:7]=[CH:6][N:5]=[C:4]2[O:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([OH:18])[CH:24]=1
Reactant: Cc1ccc(O)cc1O
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(C)c(O)c3)c2cc1OC
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
Solid potassium hydroxide (71 mg, 1.2 mmol) and then 4-chloro-6,7-dimethoxyquinazoline (0.25 g, 1.1 mmol), (prepared as described for the starting material in Example 1), were added to a melt of 2,4-dihydroxytoluene (0.6 g, 4.8 mmol) at 140° C. The mixture was stirred at 140° C. for 15 minutes, then allowed to cool. The mixture was diluted with water, and acidified to pH4 then extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The crude product was first purified by flash chromatography eluting with petroleum ether/ethyl acetate (1/9) and then by absorption HPLC eluting with trichloromethane/acetonitrile (85/15) to give 6,7-dimethoxy-4-(3-hydroxy-4-methylphenoxy)quinazoline (116 mg, 34%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:31])[NH:7][C:8]2[CH:30]=[CH:29][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[S:25][C:24]([C:26]([OH:28])=O)=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:41]([NH2:46])([CH2:44][CH3:45])([CH3:43])[CH3:42].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:31])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]4[S:25][C:24]([C:26]([NH:46][C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])=[O:28])=[CH:23][CH:22]=4)[CH2:18][CH2:19]3)=[O:13])=[CH:29][CH:30]=2)[CH2:3][CH2:2]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(=O)O)s3)CC2)cc1
Reactant: CCC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)NC(=O)c1ccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.3 %

Procedure:
5-((4-(4-(3-(Cyclopropylmethyl)ureido)benzoyl)piperazin-1-yl)methyl)-thiophene-2-carboxylic acid (100 mg, 0.226 mmol), N,N-diisopropylethylamine (99 mg, 0.127 mL, 0.452 mmol) and tert-pentylamine (39 mg, 0.452 mmol) were combined and stirred in dichloromethane. 1-Propanephosphonic acid cyclic anhydride (216 mg, 0.202 mL, 0.339 mmol, 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour at room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated under vacuum and purified by reverse phase acidic preparative HPLC to afford the title compound (5 mg). MS (ESI) m/z 512.8 [M+H]+