Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:71])[CH:25]([C:46]3[N:47]=[C:48]([NH:51][C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:49][CH:50]=3)[O:26][CH:27]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:28][F:29])[C:21](=[O:72])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].[I-:73].[Na+]>CC(C)=O>[I:73][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:71])[CH:25]([C:46]3[N:47]=[C:48]([NH:51][C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:49][CH:50]=3)[O:26][CH:27]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:28][F:29])[C:21](=[O:72])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10]
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)C(OC(CF)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3C(NC(=O)C(OC(CF)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1

Procedure:
130 mg (0.125 mmol) of p-methoxybenzyl 3-chloromethyl-7-{2-(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-2-fluoroethoxy) acetamido}-ceph-3-em-4-carboxylate-syn isomer was dissolved in 1 l ml of acetone, and 0.5 ml of acetone solution containing 28 mg (0.19 mmol) of sodium iodide was added to the resulting solution at room temperature and reacted for 40 minutes. After the reaction, the solvent was distilled out, methylene chloride was added to the resulting residue, the insoluble materials were filtrated out, and the remaining filtrate was concentrated under reduced pressure to obtain p-methoxybenzyl 3-iodomethyl-7-{2-(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-2-fluoroethoxy)acetamido}-ceph-3-em-4-carboxylate-syn isomer. To this was added 23 mg (0.15 mmol) of 1-(2-fluoroethyl)-4-pyridothione, and the resulting mixture was dissolved in 1 ml of chloroform and reacted for 1 hour at room temperature. After the reaction, the chloroform was distilled out under reduced pressure, and the residue was purified by silicagel-chromatography (chloroform/methanol=10/1) and dissolved in 0.15 ml of anisole, and then, 1.5 ml of trifluoroacetic acid was added thereto, while cooled with ice, and reacted for 1 hour. After the reaction, isopropylether was added to the reaction solution to form a precipitate therein. After dried, 70 mg of a powder was obtained. To this was added 1 ml of water and the pH value of the resulting solution was adjusted to 7.8 with sodium hydrogencarbonate, and the solution was purified with HP-b 20 resin (methanol/H2O=1/4) to obtain 32 mg of the above entitled compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[C@@H:21]12[CH2:27][C@@H:24]([CH:25]=[CH:26]1)[CH2:23][C@H:22]2[CH2:28][C:29](O)=[O:30]>>[C@@H:21]12[CH2:27][C@@H:24]([CH:25]=[CH:26]1)[CH2:23][C@H:22]2[CH2:28][C:29]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20])=[O:30]
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)c(C)c1
Product: Cc1ccc(-c2nn(NC(=O)C[C@@H]3C[C@@H]4C=C[C@H]3C4)c(=O)c3ccccc23)c(C)c1

Procedure:
The product of Example 159A and 2-[(1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl]acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.26 (s, 1H), 8.37-8.40 (m, 1H), 7.85-7.97 (m, 2H), 7.26-7.32 (m, 1H), 7.20-7.25 (m, 2H), 7.16-7.20 (m, 1H), 6.21 (dd, J=5.7, 2.9 Hz, 1H), 6.05 (dd, J=5.7, 2.9 Hz, 1H), 2.86-2.91 (m, 1H), 2.76-2.81 (m, 1H), 2.41-2.49 (m, 1H), 2.38 (s, 3H), 2.01-2.12 (m, 2H), 2.06 (s, 3H), 1.86-1.93 (m, 1H), 1.33 (dd, J=7.9, 2.5 Hz, 1H), 1.26 (d, J=8.1 Hz, 1H), 0.59 (ddd, J=11.5, 4.3, 2.5 Hz, 1H); MS (APCI+) M/Z 400 (M+H)+.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11].N1C=CC=CC=1.[O:30](S(C(F)(F)F)(=O)=O)[S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32]>C(Cl)Cl>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[O:11][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:30]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(/C=C/c2cc(OC)c(O)c(OC)c2)cc1
Agent: N#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(/C=C/c2cc(OC)c(OS(=O)(=O)C(F)(F)F)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask (50 mL) equipped with magnetic stir bar and N2 bubbler was charged 6 (600 mg, 2 mmol), pyridine (332 mg, 4 mmol, 2 equiv) and CH2Cl2 (20 mL) The mixture was cooled in an ice bath before Tf2O (888 mg, 3 mmol, 1.5 equiv) was added dropwise over 20 min, during which the color changed from deep red to pale orange. Afterwards, the ice bath was removed and the reaction mixture was stirred at rt overnight. A work-up similar to that used in the preparation of 1a and 2a gave an oil that slowly crystallized in vacuo (790 mg, 90%). Recrystallization from heptanes/EtOAc gave compound 7 as clear, tan needles, mp. 104-106° C. (dec.). 1H NMR (CDCl3): δ 7.46 (d, J=8.7 Hz, 2H), 7.03 (d, Jab=16.1 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 6.89 (d, Jab=16.3 Hz, 1H), 6.72 (s, 2H), 3.93 (s, 6H), 3.84 (s, 3H); 13C NMR (CDCl3): δ 160.00, 152.69, 138.64, 130.35, 129.59, 128.21, 125.75, 118.92 (q, 1JCF=321.3 Hz), 114.49, 102.94, 56.49, 55.58; 19F {13C} NMR (CDCl3): δ −74.11. Anal. Calcd for C18H17F3O6S: C, 51.67; H, 4.10. Found: C, 51.84; H, 3.97.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.[CH:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH2:24].O>O1CCCC1>[Cl:3][C:4]1[C:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH2:17][C:18]([CH3:19])([O:20][CH2:24][CH2:23][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:21])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.04 mmol) was added to a stirred solution of 1-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (prepared as described in U.S. Pat. No. 5,266,575 Comparative Example C1, 3.00 g, 10.4 mmol) and methyl vinyl sulfone (2.20 g, 20.7 mmol) in tetrahydrofuran (41 mL). The reaction mixture was stirred at room temperature for 17 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with ethyl acetate) to yield 1.8 g of 4-chloro-2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].Cl>O.CCOCC>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([OH:14])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1ccccc1Cl

Procedure:
To 12.7 g. (0.52 moles) of magnesium turnings in 200 ml. of anhydrous ether is added 10.0 g. (0.052 moles) of p-bromochlorobenzene, and the mixture is warmed to reflux. When the Grignard reaction begins, the heat is removed and 80.0 g. (0.47 moles) of additional p-bromochlorobenzene in 80 ml. of ether is added dropwise as the refluxing continues. When the addition is completed, the reaction is heated at reflux for 2 hours, cooled, and 73.4 g. (0.52 moles) of o-chlorobenzaldehyde are slowly added. The reaction is refluxed for 2 hours, cooled and poured into iced water. The resulting mixture is made acidic with hydrochloric acid, and the organic phase is separated. The aqueous layer is extracted with ether, and the extract is added to the organic phase. This solution is washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oily solid. The material is crystallized from petroleum ether to give 109.4 g. (83%) of the product, mp 68°-70°.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15](C3CCCCO3)[N:14]=[C:13]4[C:25]3[N:30]=[C:29]([NH:31][C@@H:32]4[CH2:37][CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]4)[CH:28]=[N:27][CH:26]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]4[C:25]3[N:30]=[C:29]([NH:31][C@@H:32]4[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]4)[CH:28]=[N:27][CH:26]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cncc(C6CC6)n5)cc34)n2)C1
Agent: Cl
Solvent: CO
Product: c1cc2[nH]nc(-c3cncc(N[C@@H]4CCCNC4)n3)c2cc1-c1cncc(C2CC2)n1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A solution of (3R)-tert-butyl 3-(6-(5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (179 mg, 0.30 mmol) and HCl (5-6 M in IPA, 6.00 mL, 30.0 mmol) in 4 mL of MeOH was heated at 80° C. for 90 min. The crude reaction was cooled to RT and concentrated to a yellow solid that was slurried with a 1\1 mixture of DCM\MeOH (12 mL) and applied to a pre-washed (45 mL MeOH) of Si-propylsulfonic acid (12 g, Silicycle, Cat# R51230B). The column was washed with MeOH (35 mL). The compound was released with 35 mL of 2 M NH3 in MeOH to afford 120 mg of crude material, which was purified by HPLC (5-100% MeCN in H2O with 0.1% TFA over 15 min) to afford the title compound (56 mg, 0.14 mmol, 45% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 413.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (s, 2H), 8.55 (s, 1H), 8.47 (s, 1H), 8.16 (dd, J=8.80, 1.76 Hz, 1H), 7.95 (s, 1H), 7.75 (d, J=8.80 Hz, 1H), 7.13 (d, J=7.63 Hz, 1H), 4.03-4.16 (m, 1H), 3.14-3.25 (m, 1H), 2.78-2.87 (m, 1H), 2.53-2.62 (m, 2H), 2.30 (quin, J=6.41 Hz, 1H), 2.00-2.08 (m, 1H), 1.66-1.77 (m, 1H), 1.46-1.63 (m, 2H), 1.05-1.16 (m, 4H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:32]1([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][C:27](=[O:29])[N:42]2[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[CH2:44][CH2:43]2)=[O:24])=[CH:21][CH:20]=1)(=[O:17])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Reactant: C1CCN(CCN2CCNCC2)C1
Product: O=C(NCC(=O)N1CCN(CCN2CCCC2)CC1)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from [4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid and 1-(2-pyrrolidin-1-yl-ethyl)-piperazine (EMKA-Chemie) according to the method described in Example 1.1/f. MS (EI) 604.2 (MH+).
Reaction SMILES: [CH:1]([C:4]([OH:10])([CH:7]([CH3:9])[CH3:8])[C:5]#[CH:6])([CH3:3])[CH3:2].Br[C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:16][CH:17]=1>>[F:24][C:23]([F:25])([F:26])[C:22]([NH:21][CH2:20][CH2:19][CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:6]#[C:5][C:4]([OH:10])([CH:7]([CH3:9])[CH3:8])[CH:1]([CH3:3])[CH3:2])[CH:13]=1)=[O:27]
Reactant: C#CC(O)(C(C)C)C(C)C
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Product: CC(C)C(O)(C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1)C(C)C

Procedure:
Coupling of 3-isopropyl-4-methylpent-1-yn-3-ol with bromide 10 following the method used in Example 13 gave 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-isopropyl-4-methylpent-1-ynyl)phenyl)propyl)acetamide as a pale yellow oil. Yield (1.375 g, 66%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (br s, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.17-7.22 (m, 3H), 4.81 (s, 1H), 3.17 (q, J=6.8 Hz, 2H), 2.56 (t, J=8.0 Hz, 2H), 1.86 (quint, J=6.8 Hz, 2H), 1.76 (quint, J=7.6 Hz, 2H), 0.99 (d, J=6.8 Hz, 6H), 0.94 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:23])CC)C>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][F:23])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CF)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A solution of (6-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (prepared as illustrated in example 135) (0.20 g, 0.90 mmol) in dichloromethane (20.00 ml) was cooled under argon to 0° C. and (diethylamino)sulfur trifluoride (DAST) (0.20 g, 1.25 mmol) was added dropwise. The resulting solution was stirred at room temperature for 30 min, then quenched by pouring the reaction mixture onto saturated sodium bicarbonate. The organic phase was separated, dried over sodium sulphate and evaporated to a orange oil, which was purified by flash chromatography (dichloromethane/ether) to yield (6-fluoromethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.10 g, 51%) as a colorless oil, MS (ISP): m/e=211.3 (M+H+).
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH:15]([OH:30])[CH2:16][S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OCC(O)CSCCCCCCCCCCCC)CCCCCCCCCCCCCCC.[CH3:65][C:66]1[C:71]([CH3:72])=[C:70]([OH:73])[C:69]([C:74]([CH3:77])([CH3:76])[CH3:75])=[CH:68][C:67]=1[CH2:78][CH2:79][C:80](OC)=[O:81].CC1C=C(CCC(OC)=O)C=C(C(C)(C)C)C=1O>>[CH3:65][C:66]1[C:71]([CH3:72])=[C:70]([OH:73])[C:69]([C:74]([CH3:76])([CH3:77])[CH3:75])=[CH:68][C:67]=1[CH2:78][CH2:79][C:80]([O:30][CH:15]([CH2:16][S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:81]
Reactant: CCCCCCCCCCCCSCC(O)CSCCCCCCCCCCCC
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Agent: CCCCCCCCCCCCCCCCOCC(O)CSCCCCCCCCCCCC
Agent: COC(=O)CCc1cc(C)c(O)c(C(C)(C)C)c1
Product: CCCCCCCCCCCCSCC(CSCCCCCCCCCCCC)OC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C

Procedure:
When an equivalent amount of 1,3-bis(n-dodecylthio)-2-propanol was substituted for 1-n-hexadecyloxy-3-n-dodecylthio-2-propanol and an equivalent amount of methyl 3-(2,3-dimethyl-5-tert-butyl-4-hydroxyphenyl)propionate substituted for methyl 3-(3-methyl-5-tert-butyl-4-hydroxyphenyl)propionate in Example 1, the above-named ester was obtained as a viscous oil. (Compound 4)
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[H][H]>[Pd].C(O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[N:4][CH:5]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ccc(N)cn1
Yield: 49 %

Procedure:
2-Dimethylamino-5-nitropyridine (D34) (1.64 g, 9.8 mM) was stirred with 10% palladium on charcoal (0.16 g) in ethanol (200 ml) under 1 atmos. of hydrogen. After 6 h the catalyst was filtered off onto Kieselguhr and the filtrate was evaporated. The residue was dissolved in diethyl ether, filtered again, and chromatographed on silica gel (50 g) using ether as eluant. The eluted product was purified further by extraction with petrol (bp 60°-80° C.) to give the title compound as a reddish oil (0.66 g; 49%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:15]([N:17](CC)CC)[CH3:16].C(N)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:17][CH2:15][CH3:16])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: CCN
Solvent: C1CCOC1
Product: CCNc1nc(SC)ncc1C(=O)OCC
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a room temperature solution of 4-chloro-2-methylthio-5-pyrimidinecarboxylate ethyl ester (10.00 g, 43.10 mmol) in 150 mL of tetrahydrofuran was added triethylamine (18.5 mL, 133 mmol) followed by 9 mL of a 70% aqueous solution of ethylamine. The solution was stirred for 30 minutes, then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to provide 9.32 g (90%) of 4-ethylamino-2-methylthio-5-pyrimidinecarboxylate ethyl ester as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][NH:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C(O[C:41]1(O[Si](C)(C)C)[CH2:43][CH2:42]1)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][N:29]4[CH:41]4[CH2:43][CH2:42]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(CC3COCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncnn2c(CC3COCCN3C3CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 43.5 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(morpholin-3-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.23 mmol) in MeOH (2.0 mL) containing 3 Å molecular sieves was added AcOH (130 μL, 2.28 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (238 mg, 1.37 mmol) and sodium cyanoborohydride (64 mg, 1.02 mmol). The reaction was stirred at 60° C. for 17 h. Aqueous NaOH (1N, 15 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 48 mg (44%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.91 (s, 1 H), 7.79 (d, 1 H), 7.59 (s, 1 H), 7.26-7.41 (m, 5 H), 7.14 (d, 1 H), 6.63 (s, 1 H), 5.65 (s, 2 H), 3.55-3.65 (m, 2 H), 3.44-3.52 (m, 1 H), 3.30-3.41 (m, 1 H), 3.19-3.28 (m, 1 H), 2.80-2.96 (m, 3 H), 2.34-2.44 (m, 1 H), 1.77-1.86 (m, 1 H), 0.23-0.64 (m, 4 H); ES-MS m/z 480.13 [M+H]+, HPLC RT (min) 2.19.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>CN(C=O)C>[F:18][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:24]=[C:23]([Si:20]([CH3:22])([CH3:21])[CH3:19])[N:3]=[N:2]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[I:17]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)c1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Temperature: 95 °C
Yield: 99.9 %

Procedure:
A solution of (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023, 11.60 g, 32.0 mmol) in anhydrous DMF (50 mL) was treated with trimethylsilylacetylene (4.70 g, 6.77 mL, 48.0 mmol, 1.5 equiv) at room temperature, and the resulting reaction mixture was warmed up to 90-100° C. for 20 h. When TLC and HPLC/MS showed that the cycloaddition reaction was complete, the reaction mixture was cooled down to room temperature before being concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5R)-3-(3-fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one (1024, 14.72 g, 14.72 g theoretical, 100%) as brown oil, which was directly used in the subsequent reaction without further purification. For 1024: 1H NMR (300 MHz, DMSO-d6) δ 0.01. (s, 9H, SiCH3), 3.67 (dd, 1H, J=6.4, 9.2 Hz), 4.01 (t, 1H, J=5.4 Hz), 4.59 (d, 2H, J=4.9 Hz), 4.91-4.94 (m, 1H), 6.88 (dd, 1H, J=2.4, 8.7 Hz), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.58 (dd, 1H, J=7.5, 8.7 Hz), 7.73 (s, 1H, triazole-H); C15H18FIN4O2Si, LCMS (EI); m/e 461 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][CH2:52][C@H:51]([NH:55][C:56](=[O:65])[O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][CH2:52][C@H:51]([NH:55][C:56](=[O:65])[O:57][CH2:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[CH2:50]3)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)N1CCC[C@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
A solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.408 g) in DCM (21 ml) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.394 g), HOBT (0.278 g) and triethylamine (0.286 ml) and stirred at room temperature for 1 h. A solution of benzyl (3S)-piperidin-3-ylcarbamate (0.361 g) in DCM (1 ml) was then added and stirring continued for 72 h. The mixture was partitioned between DCM and water. The separated organic extracts were washed with water and brine, dried (over magnesium sulphate), and concentrated under reduced pressure. The residue was purified using Biotage™ chromatography (eluting with hexane:ethyl acetate 1:7→1:10) to give the title compound (0.268 g) as an oil.
Reaction SMILES: C(N(C)C[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16][CH2:15]2)C=C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH2:17]([N:18]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:30]([C:27]1[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=1)(=[O:32])=[O:31])[CH2:17][CH2:16][CH2:15]2)[CH3:19])[CH:16]=[CH2:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2
Product: C=CCN(C)CCCCCOc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
In analogy to example 3.6, Allyl-methyl-[6-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-hexyl]-amine and 4-chlorobenzene sulfonylchloride were converted to yield Allyl-{5-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-pentyl}-methyl-amine (70%) as light yellow oil, MS: 462 (M, 1Cl).