Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]=[CH:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of (S)-tert-butyl 1-hydroxy-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamate (1.7 g, 6.6 mmol) in CH2Cl2 (20 mL) was added Dess-Martin periodionane (3.4 g, 7.9 mmol). The reaction was stirred at r.t. for 1 h. Tlc showed the starting material had disappeared. The mixture was poured into Et2O (100 mL) and K2CO3 (5 g) was added. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by chromatography to give (S)-tert-butyl 1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamate (1.2 g, 71%). 1H NMR (CD3OD) δ 1.45 (s, 9H), 2.07 (m, 2H), 3.90 (m, 3H), 4.30 (b, 1H), 5.0 (b, 1H), 9.55 (s, 1H).
Reaction SMILES: C[Mg]Cl.O1CCCC1.[CH:9](=O)/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH3:17].BrCBr.C([Mg]Cl)(C)(C)C.C([O:30][CH2:31][CH3:32])C>>[CH:14](/[CH:15]1[CH2:17][CH:16]1[CH:31]([OH:30])[CH3:32])=[CH:13]\[CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCC/C=C/C=C/C=O
Reactant: CCOCC
Agent: CC(C)(C)[Mg]Cl
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: BrCBr
Product: CCCC/C=C/C1CC1C(C)O
Reaction time: 18 h
Yield: 87.7 %

Procedure:
Prepared as described in Example 1 (System B) from methyl magnesium chloride 3M in tetrahydrofuran (7.3 ml, 21 mmol), (2E,4E)-nona-2,4-dienal (3 g, 21 mmol), dibromomethane (15 g, 87 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (43 ml, 87 mmol) at 0°-10° C. Work-up after 18 h and bulb-to-bulb distillation at 80° C./0.05 mbar gave 3.1 g (77%) of a colorless oil (syn/anti=83:17). Odour: fruity, pear, green. 1H NMR (CDCl3): δ 1H NMR (CDCl3): δ 0.5 (m, 1H), 0.7 (m, 1H), 0.8-1 (2H), 0.9 (t, 3H), 1.2-1.4 (6H), 1.8-2.0 (3H), 3.2 (m, 1H), 5.0 (m, 1H), 5.5 (m, 1H) ppm. 13C-NMR (CDCl3) syn-isomer: δ 11.5 (t), 13.9 (q), 18.8 (d), 22.2 (d), 22.5 (q), 28.1 (d), 31.7 (t), 32.1 (t), 71.5 (d), 128.9 (d), 131.7 (d). 13C-NMR (CDCl3) anti-isomer: δ 10.8 (t), 14.0 (q), 19.6 (d), 22.2 (d), 22.5 (q), 28.3 (d), 31.7 (t), 32.1 (t), 72.0 (d), 128.7 (d), 132.0 (d). syn-configuration assigned by GC retention time. MS (EI): m/z (%) 168 ([M]+, 1), 150 ([M-H2O]+, 7), 113 (48), 95 (47), 82 (33), 81 (80), 68 (72), 67 (100), 57 (43), 55 (45), 54 (80), 45 (75), 43 (56), 41 (64). IR (film): 3340 (br, OH), 2958 (m), 2925 (m), 2871 (m), 2858 (m), 1455 (m), 1414 (w), 1366 (m), 1290 (w), 1180 (w), 1103 (m), 1076 (m), 1029 (m), 959 (s), 897 (m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](Br)[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B1OC(C([O-])=O)C=CO1)#[N:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:9]1[C:10]([O:13][CH3:14])=[N:11][CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:8]=1)#[N:17]
Reactant: COc1ncc(-c2ccccn2)cc1Br
Reactant: N#Cc1ccccc1B1OC=CC(C(=O)[O-])O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncc(-c2ccccn2)cc1-c1ccccc1C#N
Temperature: 140 °C
Reaction time: 5 h

Procedure:
Tetrakistriphenylphosphine palladium (0.15 g) was added to a mixed solution of 0.50 g of 5-(2-pyridyl)-3-bromo-2-methoxypyridine, 0.42 g of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 0.82 g of cesium carbonate and 20 ml of dimethylformamide and the mixture was stirred at 140° C. in a nitrogen atmosphere for 5 hours. After cooling to room temperature, ethyl acetate was added thereto, the mixture was washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:3) to give 0.36 of the title compound as pale yellow powder.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:56]2[N:57]=[C:58]([NH:61]C(OC(C)(C)C)=O)[S:59][CH:60]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][CH2:46][CH2:45][CH2:44][C:43]([NH:42][CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:56]3[N:57]=[C:58]([NH2:61])[S:59][CH:60]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)=[O:55]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((4-((tert-butoxycarbonyl)amino)butanamido)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (47 mg, 48 μmol), DCM (0.5 mL), and TFA (0.2 mL, 2.87 mmol) for 2 h. The reaction mixture was concentrated in vacuo, and the residued was partitioned between DCM and ice water. The water layer was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; AcN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound LCMS: Rt=0.53 min, m/z=615.3 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O): δ 7.63 (s, 1H), 7.05 (s, 1H), 5.58-5.49 (m, 1H), 4.96-4.83 (m, 3H), 4.41 (br s, 2H), 3.06-2.90 (m, 2H), 2.44-2.28 (m, 2H), 1.98-1.83 (m, 2H), 1.38-1.04 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:23])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(Br)c3O2)cc1
Reactant: OB(O)c1ccccc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccccc4)c3O2)cc1
Yield: 93 %

Procedure:
Treatment of 2-bromo-4-methylphenol (19.09 g, 102 mmol) with potassium carbonate (56.0 g, 400 mmol) and allyl bromide (15.96 g, 130 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-methylphenol. Treatment of 2-allyl-6-bromo-4-methylphenol (5.21 g, 23.0 mmol) with 3-chloroperoxybenzoic acid (9.13 g, 34.50 mmol, 77%) followed by potassium carbonate (7.9 g, 57.5 mmol) generally according to the procedure described for Intermediate 9 afforded 2.14 g (43%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (2.41 g, 10.0 mmol) with p-toluenesulfonyl chloride (2.1 g, 11.0 mol) generally according to the procedure described for Intermediate 10 gave 3.31 g (84%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.25 g, 0.63 mmol) and phenylboronic acid (0.23 g, 1.89 mmol) generally according to the procedure described for Intermediate 154 afforded 0.23 g, (93%) of (±)-(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.15 g (97%) of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.297 g, 1.13 mmol) according to the procedure described in Example 21 afforded 0.106 g (61%) of (±)-[(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 227-228° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[NH:17](C(OC(C)(C)C)=O)[C@@H:18]([C:27](O)=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:27]([N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][N:2]([CH3:16])[CH3:1])[CH2:11][CH2:12]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CN(C)Cc1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Yield: 94.4 %

Procedure:
(2R)-2-Amino-1-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-3-(4-chlorophenyl)propan-1-one was prepared according to the procedure described in Preparation V using dimethyl[(2-piperazinylphenyl)methyl]amine (Step 3)(0.35 g, 1.4 mmol), Boc-p-Cl-D-Phe-OH (Peptech Corp.) (0.53 g, 1.8 mmol) in CH2Cl2 (7 mL), EDC (Aldrich Chemical Company) (0.37 g, 1.9 mmol) and HOBT (used in place of HOAT) (Bachem) (0.27 g, 1.8 mmol). After workup as described in Preparation V, the crude compound was dissolved in CH2Cl2 (10 mL) and treated with TFA (5 mL). After stirring the reaction at RT for 1 h, the solvent was concentrated in vacuo and the residue was partitioned between CH2Cl2 and satd NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give (2R)-2-amino-1-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-3-(4-chlorophenyl)propan-1-one as a yellow oil (0.53 g). MS m/z: 401 (M+H). Calc'd for C22H29ClN4O: 400.94.
Reaction SMILES: Cl[C:2]1[N:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([F:11])=[CH:6]2.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN1CCCC1=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:3]2[C:2]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]3[C:5]([CH:6]=[C:7]([F:11])[CH:8]=[CH:9]3)=[N:4]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc2c(Cl)n(-c3ccc(Cl)cc3)nc2c1
Reactant: NC1CCCCC1
Solvent: CN1CCCC1=O
Product: Fc1ccc2c(NC3CCCCC3)n(-c3ccc(Cl)cc3)nc2c1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-6-fluoro-2H-indazole was reacted with cyclohexylamine ([108-91-8]) in N-methyl 2-pyrrolidone for 72 h at 150° C. in a sealed tube to give the title compound as yellow solid. MS: m/e=344.5 [M+H+].
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(O)C>[Br-:12].[C:15]1([CH2:14][CH2:13][N+:5]2[CH:6]=[CH:7][C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][CH:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccncc1
Reactant: BrCCc1ccccc1
Solvent: CC(C)O
Product: CCOC(=O)c1cc[n+](CCc2ccccc2)cc1
Product: [Br-]
Yield: 80.3 %

Procedure:
A mixture of 5.00 g (33 mmol) of ethyl isonicotinate, 6.12 g (33 mmol) of 2-bromoethylbenzene and 25 mL of 2-propanol were heated at reflux for 17 hours. The mixture was evaporated to dryness and triturated 3×75 mL with ether. The excess ether was removed by evaporation and there was obtained 8.91 g of 1-(2-phenylethyl)-4-carboethoxypyridinium bromide as a yellow solid. NMR (CDCl3) 58.97 (d, 2H); 8.34 (d, 2H); 7.13-7.2 6 (m, 5H); 5.35-5.42 (m, 2H); 4.41-4.50 (q, 2H); 3.39-3.47 (t, 2H); 2.58-2.65 (m, 2H); 1.37-1.46 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].CS[C:18](SC)=[C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[C:20]1=[O:41]>C1(C)C=CC=CC=1>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[C:20](=[O:41])[C:19]=1[C:18]1[NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=2[S:7](=[O:8])(=[O:9])[N:10]=1
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(N3C(=O)c4ccccc4C3=O)c1=O)N2
Yield: 61.1 %

Procedure:
The product of Example 309G (32.6 mg, 0.13 mmol) and the product of Example 350C (53 mg, 0.13 mmol) were reacted in toluene (3 mL) at 100° C. for 3 hours. The resulting precipitate was collected by filtration and washed with methanol and diethyl ether to give the title compound (45 mg, 61.5%). 1H NMR (300 MHz, DMSO-d6) δ 3.32 (s, 3 H), 4.61 (s, 2 H), 4.70 (s, 2 H), 7.28 (s, 1 H), 7.42 (m, 1 H), 7.70 (d, J=4.04 Hz, 2 H), 8.06 (m, 2 H), 8.11 (m, 2 H), 8.22 (d, J=8.09 Hz, 1 H). MS (ESI−) m/z 565 (M−H)−.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH:3]1[N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[C:5](=[O:11])[O:4]1.[Li+].[CH3:15]C([N-]C(C)C)C.C1COCC1.CCCCCCC.ICI>C1COCC1>[CH3:15][C@:6]12[CH2:10][CH2:9][CH2:8][N:7]1[CH:3]([C:2]([Cl:1])([Cl:12])[Cl:13])[O:4][C:5]2=[O:11]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1OC(C(Cl)(Cl)Cl)N2CCC[C@H]12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ICI
Solvent: CCCCCCC
Product: C[C@]12CCCN1C(C(Cl)(Cl)Cl)OC2=O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of (7aR)-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (D1) (0.2 g, 0.82 mol) in THF (10 ml) cooled at −78° C. LDA 2M sol in THF/heptane (0.58 ml, 1.17 mol) was added and the mixture stirred 30 min. Diiodomethane (0.185 ml, 2.97 mol) was added and the temperature was allowed to warm to −40° C. over a period of 2 hrs then left at this temperature for an additional hour. The resulting mixture was partitioned between DCM and H2O. The aqueous phase was extracted with DCM (2×10 ml); the organic phases were collected, dried over Na2SO4 and evaporated in vacuo. The residue was purified by SPE-Si cartridge (25 g) eluting with DCM. Collected fractions after solvent evaporation afforded title compound (D2) in mixture (4:1) with starting material (110 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[C:17](Cl)[N:16]=[C:15]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[N:14]=1>>[Cl:12][C:13]1[N:14]=[C:15]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[N:16]=[C:17]([NH:11][S:8](=[O:10])(=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: NS(=O)(=O)Nc1ccccn1
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccccn1
Yield: 71.8 %

Procedure:
According to the procedure described in referential Example 1e), pyridine-2-sulfamic acid amide (60 mg, Referential Example 21) was reacted with 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (100 mg, Referential Example 1d)) to give pyridine-2-sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-amide (100 mg). tR=3.83 min (LC); [M−H]+=483.33 (ES−);
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]>>[Cl:1][C:2]1[N:3]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Product: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1[N+](=O)[O-]
Yield: 35 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-methyl-3-nitrophenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-methyl-3-nitrophenyl)-1H-indole-3-carboxaldehyde (35% yield) as a light cream solid. ESI/MS 315 (M+H); 356 [(M+1+CH3CN) adduct]; RT=3.35 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cc(F)cc(F)c2)CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of tert-butyl 3-(3,5-difluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (3.38 g, 11.3 mmol) in dichloromethane (100 mL), was added trifluoroacetic acid (10 mL). The mixture was stirred for 1 h at ambient temperature after which the solvent was evaporated. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (1.04 g). MS m/z (rel. intensity, 70 eV) 199 (M+, bp), 141 (52), 127 (52), 114 (36), 113 (63).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=[CH:14]2>CC(C)=O.[OH-].[Na+]>[NH2:1][C:2]1[N:7]=[C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=[CH:14]3)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Nc1nc(Cl)cc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Temperature: 62 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6.56 g (40 mMol) 2-amino-4,6-dichloropyrimidine and 7.52 g (40 mMol) 6-hydroxy-1-naphthoic acid in 160 ml acetone and 80 ml 1 N aqueous NaOH is heated to 62° C. for 36 h. The mixture is cooled to rt, partially concentrated in vacuo and the residue poured into 1.6 l icewater. Under vigorous stirring, 20 ml 2 N HCl are added dropwise (pH≈4). After stirring the suspension for 30 min, the title compound is filtered off and washed with water; HPLC: tRet=12.8.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-n2cc(I)c3c(Cl)ncnc32)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 82.4 %

Procedure:
A mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.6 g, 20.0 mmol), 3-nitrophenylboronic acid (5.0 g, 30.0 mmol), Cu(OAc)2 (3.6 g, 20.0 mmol), pyridine (9.5 g, 120.0 mmol) and 4 Å MS (10.0 g) in dry DCM (150 mL) was purged with O2 before stirred at r.t. for 5 days. The reaction mixture was filtered through a celite pad and the filter cake was thoroughly washed with DCM. The filtrate was concentrated and purified by column chromatographic (silica gel, 0 to 50% DCM in PE during 15 min and then 0 to 20% ethyl acetate in a mixture of PE & DCM (1:1)) to afford 4-chloro-5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (16) (6.6 g, 82% yield) as a white solid. LC-MS (ESI): m/z (M/M+2) 399.9/400.9.
Reaction SMILES: N1([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])C=CN=C1.CI.[CH:25]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1>C(#N)C.C(Cl)Cl>[CH:25]1([N:29]2[CH2:34][CH2:33][N:32]([C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)=[O:7])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)n3ccnc3)CC2)cc1
Reactant: C1CC(N2CCNCC2)C1
Solvent: CC#N
Solvent: ClCCl
Solvent: CI
Product: CC(=O)c1ccc(N2CCN(C(=O)N3CCN(C4CCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-{4-[4-(imidazole-1-carbonyl)-piperazin-1-yl]-phenyl}-ethanone (8 mmol) in acetonitrile (15 mL) is added MeI (32 mmol). The mixture is stirred at rt for 24 h. Solvent is removed in vacuo to yield a light yellow solid. The solid is dissolved in DCM (40 mL), followed by the addition of 1-cyclobutylpiperazine (8 mmol) and TEA (8 mmol). The mixture is stirred at rt for 24 h, washed with aqueous sodium bicarbonate (20 mL). The organic layer is dried over MgSO4 and solvent removed to give the crude product, which is purified by column chromatography (5% MeOH in DCM) to give the pure title compound. 1H NMR (300 MHz, CDCl3) δ 7.87 (d, 2H), 6.86 (d, 2H), 3.49-3.33 (m, 12H), 2.76-2.71 (m, 1H), 2.53 (s, 3H), 2.32 (t, 4H), 2.05-2.01 (m, 2H), 1.91-1.85 (m, 2H), 1.76-1.69 (m, 2H); LC-MS (M+1) 371.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.CN(C)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].CN(C)C1C=CN=CN=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:20]([O:8][C:7]1[C:6]([Cl:9])=[N:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][C:2]=1[Cl:1])(=[O:22])[CH3:21]
Reactant: Oc1c(Cl)nc(-c2ccccc2)nc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)C
Agent: CN(C)c1ccncn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(Cl)nc(-c2ccccc2)nc1Cl

Procedure:
A solution of 3.1 g of 4,6-dichloro-5-hydroxy-2-phenylpyrimidine, 2.8 ml of trimethylamine, 1.6 ml of acetic anhydride and 0.1 g of 4-dimethylaminopyrimidine in 50 ml of toluene is stirred for 4 hours at 20°-25° C. The reaction solution is subsequently diluted with ethyl acetate, washed with water and dried. On concentration by evaporation, there crystallise 4.3 g of 5-acetoxy-4,6-dichloro-2-phenylpyrimidine, m.p. 145°-147° C. (compoud No. 36).