Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:14][C:13]2=[O:26])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:53]=[CH:52][N:51]([CH2:54][C:55]([CH3:58])([OH:57])[CH3:56])[N:50]=1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:14][C:13]2=[O:26])[C:9]([NH:48][C:49]2[CH:53]=[CH:52][N:51]([CH2:54][C:55]([OH:57])([CH3:56])[CH3:58])[N:50]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (375 mg, 1.04 mmol) in dichloromethane (15 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (164 mg, 1.06 mmol) and 1-hydroxybenzotriazole (150 mg, 2.00 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 178 mg, 1.15 mmol). The reaction mixture was then stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (200 mg, 40%) as an off-white solid: LR-ES-MS m/z calculated for C27H36N4O5 [M]+ 496, observed [M+H]+ 497; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.69-1.35 (m, 6H) 1.05 (br. s., 3H) 1.06 (br. s, 3H) 1.49-1.89 (m, 7H) 3.81 (s, 3H) 3.89 (s, 2H) 4.10 (d, J=18.4 Hz, 1H) 4.52 (d, J=18.4 Hz, 1H) 4.68 (s, 1H) 4.71 (s, 1H) 4.82-4.96 (m, 1H) 6.44 (d, J=2.2 Hz, 1H) 6.94-7.07 (m, 1H) 7.18-7.24 (m, 1H) 7.30 (m, 2H) 7.54 (d, J=2.2 Hz, 1H) 10.77 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3]Cl.CC(CC(O)CO)C.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:26][CH3:27])(=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:20]1([C:19]([O:26][CH3:27])=[O:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:3][CH2:2]1
Reactant: ClCCCl
Reactant: COC(=O)CC(=O)OC
Agent: CC(C)CC(O)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Product: COC(=O)C1(C(=O)OC)CC1
Yield: 96.3 %

Procedure:
450.3 g of 1,2-dichloroethane (4.55 mol), 15.5 g of polyethylene glycol dimethyl ether (mean molar mass 250 g/mol) and 168.0 g of potassium carbonate (1.2 mol) were initially introduced, and the reaction mixture was heated until the 1,2-dichloroethane refluxes. 118.9 g of dimethyl malonate (0.9 mol) and 1.25 g of tetrabutylammonium bromide (3.88 mmol) were then added at the boil. The mixture was stirred using a finely dispersing stirrer (Ultra Turrax) for 6 hours. Water formed during the reaction was removed by azeotropic distillation with 1,2-dichloroethane throughout the reaction. Further work-up was carried out analogously to Comparative Example 2. The yield was 96.3%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][CH:10]=3)=[O:15])[CH2:17][CH2:18]2)=[N:23][C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: O=C1CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3)CC2)nc1C
Yield: 59.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 120 and by the reaction and treatment in the same manner as in Example 1, the title compound (234 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:22](N(OC)C)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:22]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:23]
Reactant: CON(C)C(=O)c1ccc(C)c(C)c1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(C)c(C)c2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 3,4-dimethyl-N-methoxy-N-methylbenzamide.
Reaction SMILES: [CH3:1]I.[H-].[Na+].[OH:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([I:17])=[CH:11][C:10]=1[O:18][CH3:19].O>O1CCCC1>[I:17][C:12]1[CH:11]=[C:10]([O:18][CH3:19])[C:9]([O:8][CH2:7][CH2:6][O:5][CH3:1])=[C:14]([O:15][CH3:16])[CH:13]=1
Reactant: CI
Reactant: COc1cc(I)cc(OC)c1OCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1c(OC)cc(I)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Methyl iodide (0.010 mL, 0.16 mmol) and a 50% dispersion of sodium hydride in mineral oil (12.0 mg, 0.24 mmol) were added to a solution of 4-(2-hydroxyethoxy)-1-iodo-3,5-dimethoxybenzene (39.0 mg, 0.120 mmol) in anhydrous tetrahydrofuran (1.0 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with 3.0 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 1-iodo-3,5-dimethoxy-4-(2-methoxyethoxy)benzene as a colorless oil (40.0 mg, yield: 98%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[N:32]=[C:31](B(O)O)[CH:30]=[CH:29][CH:28]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[N:32]=4)=[C:4]([CH:9]=3)[C:3]([OH:24])=[O:2])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: COc1cccc(B(O)O)n1
Product: COc1cccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)n1
Yield: 25.1 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 6-methoxypyridine-2-boronic acid (available from Combi-Blocks Inc.; 61 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(6-methoxy-pyridin-2-yl)-benzoic acid (23 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 12.95 (br s, 3H), 8.48 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.21 (dd, J=4.3, 2.3 Hz, 2H), 8.10 (dd, J=8.3, 2.0 Hz, 1H), 7.73-7.94 (m, 3H), 7.39 (d, J=7.3 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 9H).
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH3:8][C:9]1([CH3:22])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[O:10]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:15][C:13]1([CH3:14])[C:9]([CH3:22])([CH3:8])[O:10][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:6]([NH2:5])=[O:7])[CH2:20][CH:21]=2)[O:12]1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(C2=CCN(C(N)=O)CC2)OC1(C)C
Reaction time: 3 h

Procedure:
Trimethylsilyl isocyanate (0.2205 mL, 1.629 mmol) was added to a room temperature solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (200.0 mg, 0.8145 mmol) and DIPEA (0.5675 mL, 3.258 mmol) in DCM (10 mL). The mixture was stirred for 3 hours, after which, it was partioned between DCM and sat. NaHCO3. The organic layer was concentrated in vacuo to afford the title compound as a tan solid. MS (ES+): m/z 253.07 (100) [MH+]; HPLC: tR=2.61 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: OCc1cnc(-c2ccccc2)nc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cnc(-c2ccccc2)nc1Cl
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a stirred (4-chloro-2-phenylpyrimidin-5-yl)methanol (242 mg, 1.10 mmol) in CH2Cl2 (11 mL) was added Dess-Martin periodinane (553 mg, 1.43 mmol). The reaction was kept for 2 hrs and was diluted with EtOAc (10 mL).The organic layer was washed with saturated NaHCO3 solution (10 mL), and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product as a white solid (250 mg). The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexane) to give 4-chloro-2-phenylpyrimidine-5-carbaldehyde (205 mg, 82% for 2 steps) as a white solid.
Reaction SMILES: C[C@]12C34OOC5(CCC(C)(C)C[C@H]5[C@]3(C)CC[C@@H:7]1[C@@:6]1(C)[CH2:25][C@@H:26](O)[C@H:27](O)[C:28]([CH3:30])([CH3:29])[C@@H:5]1[CH2:4][CH2:3]2)C=C4.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.C(Cl)Cl>[CH3:7][C@H:6]1[C@H:5]2[CH2:4][C@H:3]3[C:28]([CH3:29])([CH3:27])[C@@H:5]([CH2:4][CH2:29][C@:28]2([CH3:30])[CH2:27][CH2:26][CH2:25]1)[C@H:6]([CH3:7])[CH2:25][CH2:26]3
Reactant: CC1(C)CCC23C=CC4(OO2)[C@@](C)(CC[C@@H]2[C@@]5(C)C[C@@H](O)[C@H](O)C(C)(C)[C@@H]5CC[C@]24C)[C@@H]3C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@@]2(C)CC[C@H]3[C@H](C)CC[C@@H](C[C@H]12)C3(C)C
Yield: 75 %

Procedure:
To a solution of baccatin IVa (79.6 mg, 0.09 mmol) and N-benzoyl-β-lactam Va-a-EE (45.8 mg, 0.14 mmol) in 3.0 mL of THF, was added NaHMDS 0.13 mL (1.2 eq, 0.85M soln. in THF) at -40° C. over the period of 30 min. TLC analysis of the reaction mixture revealed that baccatin IIIa was completely consumed. The reaction mixture was quenched with 10 mL saturated NH4Cl solution. The reaction mixture was extracted with ether (10 mL×3), then dichloromethane (10 mL), and the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel using EtOAc/hexanes (1:3) as the eluant to 2-EEO-3-phenylpropanoyl]-10-deacetyl-14-hydroxy-baccatin III (IIa-EE) as a white solid. This protected taxane IIa-EE was treated with Zn in acetic acid at 60° C. for 9 h. The reaction mixture was filtered on a glass filter and the filtrate was condensed in vacuo. The residue was redissolved in CH2Cl2, and Zn salt was removed by filtration to give the crude product. This crude product was purified by column chromatography on silica gel using EtOAc/hexanes (3:1) as the eluant to give 33.7 mg (75%) of taxane IIa as a white powder having the identification data shown below: mp 198°-202° C.; [α]D20 -13.2 (c 0.38, MeOH); 1H NMR (CDCl3) δ 1.17 (s, 3H), 1.20 (s, 3H), 1.74 (s, 3H, H19), 1.84 (m, 1H, H6b), 2.14 (s, 3H, H18), 2.17 (s, 3H, 4-OAc), 2.60, (m, 1H, H6a), 3/07 (bs, 1H, 2'-OH), 4.03 (d, J=6.6 Hz, 1H, H3), 4.14 (d, J=8.4 Hz, 1H, H20), 4.27 (m, 3H, H20, H7, 10-OH), 4.55 (m, 1H, H2'), 4.99 (bd, 1H, H5), 5.07 (m, 1H, H13), 5.17 (d, J=5.8 Hz, 1H), 5.34 (s, 1H, H10), 5.65 (d, J=5.7 Hz, 1H, H14), 5.83 (bd, 2H, H2, H3'), 6.91 (d, J=9.4 Hz, 1H, NH), 7.36-7.59 (m, 11H), 7.77 (bd, 2H), 8.15 (bd, 2H); 13C NMR (CDCl3) δ 9.53, 15.32, 20.66, 22.08, 26.03, 29.69, 37.06, 42.85, 46.50, 54.68, 58.00, 71.63, 72.06, 73.60, 75.03, 76.60, 77.12, 78.82, 80.31, 83.98, 127.10, 127.24, 128.25, 128.42, 128.84, 129.04, 130.62, 132.51, 133.59, 135.04, 137.89, 140.68, 166.49, 168.13, 170.86, 172.12, 211.58; IR (CHCl3) n 3632, 3434, 3026, 3016, 2943, 2838, 1724, 1648; Anal. Calcd for C45H49NO14 : C, 65.29; H, 5.97; N, 1.69. Found: C, 65.15; H, 6.01; N, 1.79.
Reaction SMILES: O=C1N(C2CCNCC2)CC2C(=CC=CC=2)N1.Cl[C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@@H:31]([CH2:33][C:34](=[O:52])[N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:50][C:49]5[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=5)[NH:43][C:42]4=[O:51])[CH2:37][CH2:36]3)[CH2:32][C:21]=2[CH:20]=1>>[CH3:56][C:55]([CH3:58])([CH3:57])[CH2:54][N:29]1[CH2:28][C:22]2[C:23]3[CH:24]=[N:25][NH:26][C:27]=3[CH:19]=[CH:20][C:21]=2[CH2:32][C@H:31]([CH2:33][C:34](=[O:52])[N:35]2[CH2:36][CH2:37][CH:38]([N:41]3[CH2:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][C:42]3=[O:51])[CH2:39][CH2:40]2)[C:30]1=[O:53]
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: O=C1Nc2ccccc2CN1C1CCNCC1
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Yield: 32 %

Procedure:
[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-acetic acid (75 mg, 0.23 mmol) and 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine (65 mg, 0.28 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as a white solid in 32% yield. High resolution MS m/e (M+H)+=543.3084.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Cl)[N:10]=[C:9]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=1.[N:31]1[CH:32]=[CH:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][C:35]=12.C(N(CC)CC)C.CN(C)C(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:37]2[CH2:38][CH2:39][N:34]3[CH:33]=[CH:32][N:31]=[C:35]3[CH2:36]2)[N:10]=[C:9]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=1
Reactant: c1cn2c(n1)CNCC2
Reactant: COC(=O)c1c(Cl)nc(SCc2ccccc2)nc1NCc1ccc(OC)c(Cl)c1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SCc2ccccc2)nc1N1CCn2ccnc2C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-benzylthiopyrimidine (prepared in the above (3)) 108 mg, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 57 mg, triethylamine 47 mg and N,N-dimethylacetamide 2.5 ml is stirred at 60° C. for 1 hour. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:methanol=200:1) to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-benzylthiopyrimidine as a colorless foam, 129 mg.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[N:30]1[C:34](=[O:35])[N:33]([CH3:36])[N:32]=[N:31]1>C1COCC1>[Si:5]([O:6][CH2:7][C:8]([CH3:11])([O:10][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[N:30]1[C:34](=[O:35])[N:33]([CH3:36])[N:32]=[N:31]1)[CH3:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])[CH3:12]
Reactant: CC(C)(O)CO[Si](C)(C)C(C)(C)C
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nnn(-c2cc([N+](=O)[O-])ccc2OC(C)(C)CO[Si](C)(C)C(C)(C)C)c1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
1-(Tertbutyldimethylsilyloxy)-2-methylpropan-2-ol (1.80 g, 8.81 mmol, 1.10 equiv) in THF (30 mL) under argon gas, was cooled to −78° C. Potassium tert-butoxide (1.165 g, 9.61 mmol, 1.20 equiv) was added in one portion, and the reaction mixture was stirred for 15 min at −78° C. Then a solution of 1-(2-fluoro-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (prepared according to WO2011068898, which is incorporated herein by reference; 1.915 g, 8.00 mmol, 1.00 equiv) in THF (10 mL) was added slowly, and the reaction mixture was stirred for 30 min at −78° C. and allowed to warm up to ambient temperature over 1 h. The reaction mixture was concentrated, and the residue was taken in EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc 2×. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was absorbed onto silica gel and purified by flash chromatography and eluted with heptane:EtOAc=100:0 to 30% EtOAc using 10% EtOAc increments to provide 1-(2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yloxy)-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (2.28 g, 67%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]=[C:8]1[N:12]([CH3:13])[C@H:11]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:10][CH2:9]1)=[O:6])[CH:2]=[CH2:3].Cl.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([O:4][C:5]([N:7]=[C:8]1[N:12]([CH3:13])[C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N=C1CC[C@@H](CO[Si](C)(C)C(C)(C)C)N1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N=C1CC[C@@H](CO)N1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of (2S)-5-allyloxycarbonylimino-2-t-butyldimethylsilyloxymethyl-1-methylpyrrolidine (1.0 g) in methanol (30 ml) was added conc. hydrochloric acid (1 ml) at 0° C. After stirring at ambient temperature for 12 hours, saturated aqueous sodium bicarbonate was added to the mixture and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed in turn with water and brine. The dried solution was evaporated in vacuo to give (2S)-5-allyloxycarbonylimino-2-hydroxymethyl-1-methylpyrrolidine (0.65 g).
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][C:3]=1[C:4]([NH:6][C:7](=[NH:20])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[CH2:11][CH2:10][O:9][CH2:8][C:7]1[NH:6][C:4](=[O:5])[C:3]2[CH:21]=[C:22]([CH2:25][CH3:26])[CH:23]=[N:24][C:2]=2[N:20]=1
Reactant: CCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cc(F)ccc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cnc2nc(COCCc3cc(F)ccc3F)[nH]c(=O)c2c1

Procedure:
In analogy to the procedure described in example 78.4, 2-chloro-N-{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-5-ethyl-nicotinamide was treated with potassium carbonate in DMF for 5 h at 100° C. to obtain 2-[2-(2,5-difluoro-phenyl)-ethoxymethyl]-6-ethyl-3H-pyrido[2,3-d]pyrimidin-4-one as off-white crystals. MS: m/e=346.1 [M+H+].
Reaction SMILES: Cl.[F:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([C:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:36]([N:22]1[CH2:21][CH:20]=[C:19]([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=4)=[N:14][C:13]=3[C:15]([O:25][CH3:26])=[CH:16][CH:17]=2)[CH2:24][CH2:23]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2=CCNCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C2=CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 0.12 g (0.28 mMol) 4-fluoro-N-[4-methoxy-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzothiazol-2-yl]-benzamide hydrochloride in 3 ml THF were added 0.043 ml triethyl amine. At 0° C. 0.029 ml (0.31 mMol) acetic anhydride was added dropwise and stirred for 30 min. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 15 ml water were added. After extracting with four times 25 ml ethyl acetate the combined organic phases were dried over sodium sulfate and concentrated to dryness in vacuo to yield 0.088 g (73%) N-[7-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide as an off-white solid; F.p.: 264-265° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (68 mg, 85%), MS (ISP) m/z=322.4 [(M+H)+], mp 316.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8](O[Si](C)(C)C)=[C:7](O[Si](C)(C)C)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Br.Br.[NH2:23][CH2:24][C:25]([NH2:27])=[NH:26]>>[NH2:27][C:25]1[CH:24]=[N:23][C:8]2[CH2:9][CH2:10][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][C:7]=2[N:26]=1
Reactant: CCCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)CC1
Reactant: N=C(N)CN
Agent: Br
Product: CCCN1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 1 from 2,3,6,7-tetrahydro-1-propyl-4,5-bis(trimethylsilyloxy)azepine and 2-amino-acetamidine dihydrobromide.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27].[F:29][C:30]([F:44])([F:43])[C:31]([F:42])([F:41])[C:32]([F:40])([F:39])[C:33]([F:38])([F:37])[CH:34](I)[CH3:35]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:35][CH2:34][C:33]([F:38])([F:37])[C:32]([F:40])([F:39])[C:31]([F:42])([F:41])[C:30]([F:44])([F:43])[F:29]
Reactant: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: CC(I)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C

Procedure:
276 mg of 11β-fluoro-3-hydroxy-7α-(5-(methyl-amino)-pentyl)-estra-1,3,5(10)-trien-17-one is dissolved in 3 ml of N-methylpyrrolidone, mixed with 0.6 ml of 1,1,1,2,2,3,3,4,4-nonafluor-5-iodo-hexane and heated for 1.5 hours at a bath temperature of 80° C. For working-up, the reaction mixture is cooled to room temperature, stirred into saturated common salt solution, extracted with ethyl acetate, the organic phases are washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Preparative column chromatography on silica gel with a methylene chloride-methanol gradient provides 176 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(3,3,4,4,5,5,6,6,6-nonafluoro-hexyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one.