Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:47])[N:9]=[C:10](SC)[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:26]=1[F:44])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.[N+:48]([C:51]1[C:52]([NH:57][NH2:58])=[N:53][CH:54]=[CH:55][CH:56]=1)([O-:50])=[O:49]>C(N(CC)CC)C>[Si:37]([O:36][CH2:35][CH2:34][O:33][C:27]1[C:26]([F:44])=[C:25]([CH:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:15][CH:14]=2)[C:10]2[NH:9][C:8](=[O:47])[N:57]([C:52]3[C:51]([N+:48]([O-:50])=[O:49])=[CH:56][CH:55]=[CH:54][N:53]=3)[N:58]=2)[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:38])[CH3:39]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Reactant: NNc1ncccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To 3 ml of a DMF solution containing 70 mg of (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester, 19 mg of (3-Nitropyridin-2-yl)hydrazine and 0.017 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 16 hours and concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 58 mg of sodium cyanotrihydroborate and 0.056 ml of acetic acid were added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 40 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (55 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][NH2:14]>CCO>[CH3:9][O:8][C:7]1[C:2]([NH:14][CH3:13])=[N:3][CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Reactant: CN
Solvent: CCO
Product: CNc1ncc([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-3-methoxy-5-nitropyridine (8.00 g, 43.4 mmol) was added portion-wise to a 35% solution of methylamine in EtOH (14 mL). After standing for 10 min the mixture was cooled to 0° C. and further 35% methylamine in EtOH (14 mL) was added. After stirring at rt for 20 min ice/water (˜28 mL) was added. The mixture was cooled to 0° C., stirred vigorously and then allowed to stand for 15 min. The resulting solids were isolation by filtration, washed with H2O and dried to yield crude 3-methoxy-N-methyl-5-nitropyridin-2-amine (7.81 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:29]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:50])[CH3:49]>C(Cl)Cl>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:25]2[CH2:26][CH2:27][CH2:28][C@@H:23]([NH:22][C:18]3[N:17]=[C:16]([C:15]4[N:14]5[C:10]([S:11][CH:12]=[CH:13]5)=[N:9][C:8]=4[C:4]4[CH:3]=[C:2]([NH:1][C:48](=[O:50])[CH3:49])[CH:7]=[CH:6][CH:5]=4)[CH:21]=[CH:20][N:19]=3)[CH2:24]2)(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
The 4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine (0.1 g, 0.177 mmol) was dissolved in DCM (5 ml) and treated sequentially with Hunig's base (46 uL, 0.265 mmol) and acetyl chloride (15 uL, 0.212 mmol). The mixture was kept at room temperature for two hours then was diluted with DCM (10 ml). The organic phase was washed with water (2×10 ml) and with an aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo, giving a yellow foam. The product was triturated in ether and filtered off, giving the title compound as a yellow solid (97 mg). M.p.=169-174° C. 400 MHz 1H NMR (DMSO-d6) δ: 9.89 (s, 1H), 8.72 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.82 (s, 1H), 7.80-7.75 (m, 2H), 7.70-7.64 (m, 3H), 7.41 (d, J=4.3 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.13 (d, J=7.4 Hz, 1H), 6.42 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.74 (d, J=8.6 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.54-2.43 (m, 1H), 2.34 (t, J=10.2 Hz, 1H), 2.05 (s, 3H), 1.94-1.81 (m, 2H), 1.65-1.53 (m, 1H), 1.44-1.34 (m, 1H). LCMS: 608 [M+H]. Calc. for C28H26N7O3S2Cl.0.38 water.0.41 dioxane: C, 54.68; H, 4.65; N, 15.06. Found C, 54.68; H, 4.32; N, 15.05.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:19]=2)=[O:14])=[CH:9][C:8]=1[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5].[H-].[Na+].[CH2:36](I)[CH2:37][CH:38]([CH3:40])[CH3:39].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][CH:2]([CH3:33])[CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[N:16]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:17]=[C:18]([C:20](=[O:25])[CH2:21][CH:22]([CH3:23])[CH3:24])[CH:19]=2)=[O:14])=[CH:9][C:8]=1[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cc(C(=O)CC(C)C)c[nH]2)ccc1OC(=O)CC(C)C
Reactant: CC(C)CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(C(=O)c2cc(C(=O)CC(C)C)cn2CCC(C)C)ccc1OC(=O)CC(C)C
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 0.9 g of 2-(3-ethoxy-3-oxopropyl)-4-{[4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}phenyl 3-methylbutanoate in 18 ml N,N-dimethylformamide are added 0.12 g of 60% sodium hydride and 0.4 ml of isopentyl iodide successively, and the mixture thus obtained is stirred at 50-60° C. for one hour. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.7 g of 2-(3-ethoxy-3-oxopropyl)-4-{[1-isopentyl-4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}phenyl 3-methylbutanoate is obtained as a white solid product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:5][N:4]=[N:3]1.OO.S([O-])(O)=[O:18].[Na+].C(OO)=O>C(O)=O.O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][S:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[O:18]
Reactant: O=S([O-])O
Reactant: Cn1nnnc1SCc1ccccn1
Agent: O=COO
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1S(=O)Cc1ccccn1
Reaction time: 5 h

Procedure:
1-Methyl-5-(2-pyridyl)methylthio-1,2,3,4-tetrazole (2.0 g) is dissolved in formic acid (20 ml), and thereto is added with stirring 30% hydrogen peroxide (1.3 g) at room temperature, and the mixture is stirred for 5 hours. Sodium hydrogensulfite is added to the mixture under ice-cooling in order to decompose excess performic acid. Water is added to the mixture and it is extracted with chloroform. Chloroform solution is washed with water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography [Wakogel C-200, eluting agent, chloroform-methanol (50:1)] to give 1-methyl-1,2,3,4-tetrazol-5-yl 2-pyridylmethyl sulfoxide as brown liquid, nD26.5 =1.5810.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH:16]([OH:18])[CH3:17])([CH2:13][O:14]2)[C@@H:11]([OH:19])[C@H:10]([OH:20])[C@H:9]3[OH:21])=[CH:4][C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1.C(N(CC)CC)C>CO.[Pd]>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:3]2[CH:4]=[C:5]([C@@:8]34[O:15][C@@:12]([CH:16]([OH:18])[CH3:17])([CH2:13][O:14]3)[C@@H:11]([OH:19])[C@H:10]([OH:20])[C@H:9]4[OH:21])[CH:6]=[CH:7][CH:2]=2)=[CH:28][CH:27]=1)[CH3:31]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOc1ccc(Cc2cccc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.3 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 1 (10.0 g, 21.6 mmol, HPLC: 97.5%) in methanol (80 mL) were added Pd/C (1.5 g, 0.705 mmol, 5%) and triethylamine (5 mL, 32.4 mmol) at room temperature in turn. The mixture was stirred at room temperature under H2 for 20 hours and filtered. The filtrate was concentrated in vacuo. To the residue were added ethyl acetate (80 mL) and water (50 mL) and the resulting mixture was stirred at room temperature for 5 min, then stood for a few minutes and partitioned. The organic layer was washed with saturated aqueous sodium chloride (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 30 as a white solid (9.2 g, 99.6%, HPLC: 97.1%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CD3OD) δ (ppm): 7.43 (s, 1H), 7.38 (d, 1H), 7.26 (t, 1H), 7.15 (d, 1H), 7.11 (d, 2H), 6.82 (d, 2H), 4.18 (d, 1H), 4.01 (m, 3H), 3.95-3.91 (m, 3H), 3.80 (dd, 1H), 3.68 (t, 1H), 3.60 (d, 1H), 1.37 (t, 3H), 1.33 (d, 3H); and MS (ESI, pos. ion) m/z: 417.1[M+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH:26][CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:44]([Cl:46])[Cl:45]>C(O)(=O)C>[NH3:1].[CH2:44]([Cl:46])[Cl:45].[CH2:19]([N:26]([CH3:27])[CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNCc1ccccc1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)Cc1ccc(OCCCN2CCCCC2)cc1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (218 mg), benzyl methylamine (108 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (300 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (269 mg). 1H NMR (400 MHz, CDCl3): 7.37-7.28 (m, 4H), 7.27-7.22 (m, 5H), 6.85 (d, J=8.6 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.49 (s, 2H), 3.45 (s, 2H), 2.50-2.31 (m, 6H), 2.16 (s, 3H), 1.97 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.40 (m, 2H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[Cl:20][C:21]1[CH:26]=[C:25]([N:27]=C=O)[CH:24]=[C:23]([Cl:30])[CH:22]=1.[CH2:31]([N:33]1[C:45]2[CH:44]=[CH:43][C:42]([NH2:46])=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH3:32]>>[Cl:20][C:21]1[CH:26]=[C:25]([NH:27][C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]2[C:17]([NH:46][C:42]2[CH:43]=[CH:44][C:45]3[N:33]([CH2:31][CH3:32])[C:34]4[C:39]([C:40]=3[CH:41]=2)=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:19])=[O:7])[CH:24]=[C:23]([Cl:30])[CH:22]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)Nc2cc(Cl)cc(Cl)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, 1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=552.6.
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].NC1C=CC=CC=1>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(CBr)c1
Reactant: Nc1ccccc1N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: COc1cccc(CNc2ccccc2N2CCCCC2)c1
Yield: 87 %

Procedure:
To 1 g of 2-piperidinoaniline in 10 mL of DMF are added 795 μL of 3-methoxybenzyl bromide (1 equivalent) and 1.57 g of potassium carbonate (2 equivalents). The whole is heated to 100° C. for 2-3 hrs, until disappearance of the starting aniline. The medium is poured onto ice and then extracted with ethyl acetate. The organic phase washed with water is dried on magnesium sulfate, filtered and evaporated under reduced pressure. By silica gel chromatography of the residue (cyclohexane/ethyl acetate: 99/1) 1.46 g of the desired product may be isolated.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]=3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1>C(Cl)Cl>[CH3:31][C@H:11]1[C:12]2[C:17]([C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH:19]=3)=[N:16][CH:15]=[N:14][C:13]=2[C@H:9]([OH:8])[CH2:10]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(C3=CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C[C@@H](O)c2ncnc(C3=CCNCC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (193 μL, 2.5 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (33 mg, 0.10 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour, and concentrated to give (5R,7R)-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol as an oil, which was used further without purification.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:43]C1C=CC(C2C=NC(C3CCNCC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:43])=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cnc(C3CCNCC3)nc2)cc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 100 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 5-(4-chlorophenyl)-2-piperidin-4-ylpyrimidine (0.123 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)-oxazolidin-2-one (0.269 g), to yield the title compound as a cream foam (0.275 g, 100%).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](C2C=CC=CC=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:2]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1cccc(C(N)=O)c1Br
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Product: Cc1cccc(C(N)=O)c1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
Prepared from 2-bromo-3-methylbenzamide by the procedure of Example 135 using Intermediate 2 in Step 2. m/z (ES+) 397 [(M−NH2)+].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C([O-])(=O)C.[NH4+:23]>C(O)C>[NH2:23]/[C:4](/[CH2:3][C:2]([F:18])([F:17])[F:1])=[CH:5]/[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: [NH4+]
Reactant: O=C(CC(=O)OCc1ccccc1)CC(F)(F)F
Agent: CC(=O)[O-]
Solvent: CCO
Product: N/C(=C/C(=O)OCc1ccccc1)CC(F)(F)F
Temperature: 80 °C
Yield: 33.9 %

Procedure:
Benzyl 5,5,5-trifluoro-3-oxopentanoate (2.1 g) in ethanol (15 mL) was treated with ammonium acetate (2 g). The mixture was heated at 80° C. for 18 h and was then concentrated in vacuo. Water and DCM were added. The organic phase was separated and washed with sodium bicarbonate solution and water and then dried over sodium sulphate and filtered. The solvent was concentrated in vacuo to yield the title compound as a colourless oil (0.71 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([CH3:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([CH3:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N+:23]=[N-:24]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCN=[N+]=[N-]

Procedure:
3-(2-azidoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole was prepared according to method D Step IV with 3-(2-bromoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole (0.725 g; 1.87 mmol) and sodium azide (0.365 g; 5.62 mmol) in DMF (8 mL); the yield was quantitative as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=S)[NH:6][C:7]=1[CH3:8].ClCC(O)=[O:14]>O>[CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:14])[NH:6][C:7]=1[CH3:8]
Reactant: O=C(O)CCl
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1C
Solvent: O
Product: Cc1[nH]c(=O)[nH]c(=O)c1C
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of 5,6-dimethyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (14.4 g, 0.09 mol, Step A) and chloroacetic acid (100.0 g, 1.06 mol) in water (43 mL) was refluxed overnight, cooled down to ambient temperature and quenched with water (500 mL). The formed precipitate was collected by filtration and dried to yield 10.3 g (79.7%) of the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.70 (s, 3H) 2.02 (s, 3H) 10.56 (s, 1H) 10.86 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH3:12]>CO>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([NH2:12])=[O:5]
Reactant: N
Reactant: O=C(Cl)c1cc(I)ccc1F
Solvent: CO
Product: NC(=O)c1cc(I)ccc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
Add slowly 2-fluoro-5-iodobenzoyl chloride (4.0 g, 14.1 mmol) to a 7 N solution of ammonia in methanol (20 mL, 141 mmol) cooled to 0° C. Stir at 0° C. for 45 min then warm to room temperature and stir 5 h. Add an additional amount of the 7 N solution of ammonia in methanol (20 mL) to the reaction mixture and stir for 15 h. Concentrate, dilute with ethyl acetate (300 mL) and wash twice with water (30 mL) and twice with an aqueous saturated solution of sodium chloride (30 mL). Dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 60:40 to 40:60 hexanes:ethyl acetate, to give the title compound as a white solid (3.45 g, 92%).
Reaction SMILES: [Si]([O:18][CH:19]([C:21]1[CH:25]=[N:24][N:23]([CH2:26][C@@H:27]2[C@H:30]([NH:31][C:32](=[O:34])[O-:33])[C:29](=[O:35])[NH:28]2)[N:22]=1)[CH3:20])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:36][CH2:37][CH2:38]C[N+](CCCC)(CCCC)CCCC.[F-].[CH2:54]1[CH2:58]O[CH2:56][CH2:55]1>>[OH:18][CH:19]([C:21]1[CH:25]=[N:24][N:23]([CH2:26][C@@H:27]2[C@H:30]([NH:31][C:32](=[O:34])[O:33][CH2:56][C:55]3[CH:38]=[CH:37][CH:36]=[CH:58][CH:54]=3)[C:29](=[O:35])[NH:28]2)[N:22]=1)[CH3:20]
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)[O-])n1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Agent: [F-]
Product: CC(O)c1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of ((2R,3S)-2-((4-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (1.35 g, 2.31 mmol) and TBAF (1 M in THF, 4.63 ml, 4.63 mmol) in THF (23 ml) was stirred at room temperature 3 h. The solvent was removed and the residue was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (450 mg, 56%) as a light yellow solid. LCMS: Rt=0.53 min, m/z=346.1 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[O:15]1.C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared by adding 2,3-dichloro-benzenesulfonyl chloride (11.2 g) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine (10.0 g) to a reaction vessel containing a magnetic stirring bar, followed by 200 ml dry DCM and 4.1 ml pyridine. The reaction mixture was stirred at RT for 20 h before being cooled on an ice-bath and quenched with 1M aqueous sodium hydroxide solution. The organic phase was separated and the aqueous phase acidified with 2M aqueous hydrochloric acid and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate and evaporated to afford the crude product. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded 2,3-dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide as a colorless solid after evaporation of the solvents under reduced pressure. Yield: 15.11 g (77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:11])(=[O:14])[CH3:13]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)Cc2cc(F)ccc21
Temperature: 25 °C

Procedure:
At 170° C. 3.0 g (20 mmol) 5-fluoroindolinone were stirred in 10 mL (98 mmol) acetic anhydride for 3 h. After cooling to RT the mixture was poured onto 200 mL ice water, the precipitated substance was suction filtered and washed with 100 mL water. The solid was recrystallised from water and ethanol. The precipitated product was suction filtered, washed with water and dried i. vac.