Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1[CH:3]=[C:4]([CH:7]=[CH:8]C=1F)[CH2:5]N.C(C1C=C(C=CC=1)[C:16]([OH:18])=[O:17])=O.CC(C)N=C=NC(C)C.ClCCCl.CN(C=[O:39])C>>[CH3:8][CH:7]([OH:39])[C:4]([C:16]([OH:18])=[O:17])([CH3:5])[CH3:3]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CN(C)C=O
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCCl
Product: CC(O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of above resin-bound 3-bromo-4-fluoro-benzylamine (200 mg, 1.15 mmol/g (theoretical loading), 0.23 mmol) in DCE/DMF (1:1, 8 mL) was added 3-formylbenzoic acid (350 mg, 2.3 mmol) and DIC (0.36 mL, 2.3 mmol). The mixture was shaken at rt for overnight and was then washed with DMF (20 mL×2), DCM (20 mL×2), MeOH (20 mL×2) and DCM (20 mL×2). The resulting resin was dried in vacuum oven at 20° C. for overnight to yield DMHB resin-bound N-[(3-bromo-4-fluorophenyl)methyl]-3-formylbenzamide (0.23 mmol). An analytical amount of the resin was cleaved with 50% of TFA in DCE for 10 min. The resulting solution was concentrated in vacuo and dissolved in 0.5 mL of CH3CN. MS (ESI): 336 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CC(C)CCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-{hydroxy-[4-(3-methyl-butoxy)-phenyl]-methyl}-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 25 mg of the title compound. 1H NMR (DMSO) 0.93 (s, 3H), 0.95 (s, 3H), 1.64-1.82 (m, 3H), 4.13 (t, 2H, J=6.41 Hz), 7.12 (d, 2H, J=8.67 Hz), 7.75-7.91 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 380 (M−1). CHN Calc C, 56.62; H, 5.28; N, 3.67. Found C, 56.54; H, 5.04; N, 3.73.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH3:5].BrBr.[NH2:9][C:10]([NH2:12])=[S:11]>CO>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:10]([NH2:12])[S:11][CH:5]=1
Reactant: COCC(C)=O
Reactant: NC(N)=S
Agent: BrBr
Solvent: CO
Product: COCc1csc(N)n1
Reaction time: 0.33 h

Procedure:
1-Methoxypropan-2-one (40 g, 454 mmol) was dissolved in 300 mL of anhydrous MeOH in a 1 L round bottom flask. The flask was cooled in an ice-water bath. Br2 (73 g, 454 mmol) was added to the flask dropwise through an addition funnel. After the addition, an additional 50 mL MeOH was added to the mixture. After stirring for 20 minutes, the ice water bath was removed and the reaction was stirred until the brown color disappeared. Thiourea (34.6 g, 454 mmol) was then added into the flask. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture was then cooled and the solvent was evaporated. Saturated sodium bicarbonate was then added into the reaction flask. The resulting mixture was extracted twice with EtOAc, and the combined organic layers were washed with brine and dried over sodium sulfate. After removing the solvent, the crude 4-(methoxymethyl)thiazol-2-amine was obtained. LCMS (API-ES) m/z (%) 145.2 (100%, M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (R)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.19 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[O:6][C@H:7]([CH2:10]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C=O)C>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[O:6][C@@H:7]([CH2:10][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3cc(Cl)c(Cl)cc3O2)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1COc2cc(Cl)c(Cl)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (8.0 g, 20.5 mmol) was combined with potassium phthalimide (6.1 g, 33 mmol) in DMF (75 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (0.5 L) and then stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and then let air dry to yield (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%) as a white powdery solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:28]([OH:30])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:28]([OH:30])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(O)[C@H](CCCCNS(=O)(=O)c1ccc(Br)cc1)NS(=O)(=O)c1ccc(Br)cc1
Product: O=C(O)[C@H](CCCCN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cc1)NS(=O)(=O)c1ccc(Br)cc1
Yield: 85 %

Procedure:
Nα,Nε-di-(4-bromobenzenesulfonyl)-L-lysine was reacted with 4-fluorobenzyl bromide under the conditions described in example 127 to yield 85% of the desired product.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][SH:9])[NH2:7])[CH3:3].[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][S:9][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:7])[CH3:3]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 87.9 %

Procedure:
L-Cysteine ethyl ester hydrochloride (5.0 g, 27.03 mmol, 1 eq.) and trityl chloride (11.3 g, 40.55 mmol, 1.5 eq) were stirred in 20 mL of DMF for 2 days at room temperature. The reaction was purified by direct injection into RP-HPLC using 50-100% water/acetonirile gradient (no TFA added) over 20 min. After drying in vacuo, 9.3 g (88%) of 203 was obtained as a white powder. 1H NMR (500 MHz, CD3OD): δ=7.23-7.41 (m, 15H), 4.18 (q, 2H, J=7.5 Hz), 3.17 (m, 1H), 2.58 (dd, 1H, J=8.5 Hz, 12 Hz), 2.48 (dd, 1H, J=5 Hz, 12 Hz), 1.35 (t, 3H, J=7.5 Hz). 13C NMR (125 MHz, CD3OD) δ 171.9, 145.9, 130.7, 129.0, 127.9, 68.1, 62.5, 53.3, 30.8, 14.3. EI-MS (m/z): [M+1] calculated for C24H27NO2S 392.2. found 393.2.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH:21]1[CH:25]=[CH:24][N:23]=[N:22]1.[CH3:26][O:27][C:28](=[O:31])[CH2:29]Br>>[CH3:26][O:27][C:28](=[O:31])[CH2:29][N:21]1[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: c1c[nH]nn1
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Li+]
Product: COC(=O)Cn1ccnn1

Procedure:
Nitriles were reacted with LiHMDS or KHMDS to benzamidines which were converted to triazole by melting with hydrazides. The triazoles were coupled with 2-bromoacetic acid methyl ester under basic conditions to give the desired triazole-1-yl-acetic acid methyl ester together with different quantities of the isomeric systhem. The triazole-1-yl-acetic acid methyl ester was hydrolyzed with LiOH to the coresponding acid. The isomeres were either seperated before ore after hydrolysis of the ester. Finally, the triazole-1-yl-acetic acides were coupled with aryl substituted piperazines to the desired products.
Reaction SMILES: [CH:1]1([C:7]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:15][C:12]1[CH:13]=[CH:14][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc(CO)ccc1C1CCCCC1
Reactant: O=S(Cl)Cl
Product: N#Cc1cc(CCl)ccc1C1CCCCC1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To 2-cyclohexyl-5-(hydroxymethyl)benzonitrile (190.5 mg, 0.885 mmol) was added thionyl chloride (5.0 mL, 68.1 mmol). The mixture was heated at 50° C. for 2 h and then room temperature overnight. The mixture was poured into an ice and stirred for 5 min. The mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the title compound as a white solid (184.9 mg). LCMS m/z=234.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.31 (m, 1H), 1.40-1.52 (m, 4H), 1.76-1.82 (m, 1H), 1.83-1.92 (m, 4H), 2.93-3.03 (m, 1H), 4.55 (s, 2H), 7.37 (d, J=8.08 Hz, 1H), 7.55 (dd, J=8.02, 1.83 Hz, 1H), 7.62 (d, J=1.64 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:17].C1C[O:21][CH2:20]C1>CO>[ClH:17].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13](=[NH:14])[O:21][CH3:20])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CO
Product: COC(=N)c1ccc(OCc2ccccc2)cc1
Reaction time: 16 h

Procedure:
A solution of 560 mg of 4-benzyloxybenzonitrile in 16 ml of THF and 0.2 ml of methanol, cooled to 0° C., was saturated with hydrogen chloride and kept at 4° C. for 16 hours. The precipitate was filtered off, washed with diethyl ether and dried to give 357 mg of methyl 4-benzyloxybenzimidate hydrochloride, m.p. 179°-180° C.
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[C:24]([F:26])[C:21]([C:22]#[N:23])=[C:20]([Cl:27])[CH:19]=2)=[N:14]1.CN(C=O)C.C(Cl)Cl>O>[Br:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[C:24]([F:26])[C:21]([C:22]#[N:23])=[C:20]([Cl:27])[CH:19]=3)=[N:14]2)=[O:9])[N:6]=1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1c[nH]c(Br)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]c(Br)n1
Yield: 1.9 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 2-bromo-1H-imidazole-4-carboxylic acid (4.31 mmol, 0.822 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (3.59 mmol, 1 g) using DMF (10 ml) as the solvent. DCM and water was added to the mixture, the layers were separated and the water phase was extracted with DCM. The combined organics were washed three times with water. The DCM phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 30.5 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.10 (d, 3H), 4.24-4.49 (m, 3H), 7.00 (d, 1H), 7.62 (s, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 7.96 (s, 1H), 8.11 (d, 1H), 13.23 (bs, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)#[N:14].C(=O)(O)[O-:25].[Na+]>CN(C=O)C.O>[Cl:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([NH2:14])=[O:25])[CH:11]=1
Reactant: Clc1cc(Cl)c2cccnc2n1
Reactant: N#Cc1ccccc1B(O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccccc1-c1cc(Cl)c2cccnc2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 1.99 g (10.0 mmol) 2,4-dichloro-[1,8]naphthyridine, 1.47 g (10.0 mmol) 2-cyanobenzeneboronic acid and 1.01 g (120.0 mmol) sodium bicarbonate in 100 ml DMF and 50 ml water was heated to 80° C. under nitrogen. 140 mg (0.20 mmol) bis-(triphenyl-phosphine)-palladium(II)-chloride were added and the mixture was stirred for 16 hrs at 80° C. Water was added to the reaction mixture and the resulting precipitate was filtered off and washed well with water. The residue was dried in vacuum yielding 2-(4-chloro-[1,8]naphthyridin-2-yl)-benzamide as yellow crystals; HPLC-MS: 1.55 min, [M+H] 284.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO.I[C:14]1[C:15]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][CH:17]=[CH:18][CH:19]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][CH:33]=[C:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:26]=1>C(O)CCC.CCOC(C)=O.[Cu]I>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[C:32][CH:33]=[C:34]2[CH2:35][CH2:36][N:37]([C:14]3[C:15]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:38][CH2:39]2)[N:26]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: CCCOc1ncccc1I
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: OCCO
Product: CCCOc1ncccc1N1CCC(=CC#Cc2cccc(C)n2)CC1
Temperature: 100 °C
Yield: 9.2 %

Procedure:
Into a flamed flask flushed with nitrogen a mixture of CuI (19.4 mg. 0.1 mmol)), K3PO4 (425 mg, 2 mmol), ethylene glycol (112 μL), 3-iodo-2-propoxypyridine (263 mg, 1 mmol) in 1 mL of n-Butanol were added 255 mg of the compound of Example 3 dissolved in 1 mL of n-Butanol. The suspension was heated at 100° C. for 5 h. The reaction mixture was then cooled to r.t., diluted with EtOAc, washed with aq., NaHCO3 and water, dried over Na2SO4 and evaporated to dryness in vacuo. After the work-up the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc 8:2. affording the title product (32 mg, 10%).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:7]=2)[CH2:3][CH2:2]1.[C:20]([O:24][C:25]([N:27]1[CH2:34][CH:33]2[CH2:35][CH:29](C(=O)[O:31][C:32]2=O)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CC#[N:40]>>[C:20]([O:24][C:25]([N:27]1[CH2:34][C@H:33]([C:32](=[O:31])[N:4]([CH:1]2[CH2:2][CH2:3]2)[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:7]=2)[CH2:35][C@H:29]([NH2:40])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: COCCCn1cc(CNC2CC2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)C(=O)OC2=O
Reactant: CC#N
Product: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example 152A using cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-amine and 2,4-Dioxo-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester. MS: 485 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.09 min.
Reaction SMILES: [NH2:1][N:2]1[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:29])([CH3:28])[CH2:3]1.Cl[C:31]([O:33][CH3:34])=[O:32].Cl>N1C=CC=CC=1>[CH3:28][C:4]1([CH3:29])[CH2:3][N:2]([NH:1][C:31]([O:33][CH3:34])=[O:32])[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:27])([F:26])[C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: CC1(C)CN(N)c2cc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc2O1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)NN1CC(C)(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc21
Yield: 70 %

Procedure:
3,4-Dihydro-4-amino-2,2-dimethyl-6-(nonafluorobutyl)sulfonyl-2H-1,4-benzoxazine (0.46 g) was dissolved in 5 ml of pyridine, followed by the dropwise addition of 0.12 ml of methyl chloroformate under ice cooling and stirring. After the reaction mixture was stirred for 15 hours at room temperature, the reaction mixture was added with 10% hydrochloric acid and then extracted twice with chloroform. The combined chloroform layer was washed with water and with saturated brine and was then dried over magnesium sulfate. The solvent was distilled off and the residue was purified by chromatography on a silica gel column, whereby 0.77 g of Compound No. 53 was obtained (yield: 70 %).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:34]([OH:35])=[CH:33][CH:32]=[CH:31][C:8]=1[O:9][CH2:10][CH:11]([OH:30])[CH2:12][O:13][C:14]1[C:19]2[C:20](=[O:29])[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:6].C(O)C.Cl.O>C(Cl)(Cl)Cl>[O:6]=[C:5]1[C:7]2[C:8]([O:9][CH2:10][CH:11]([OH:30])[CH2:12][O:13][C:14]3[C:19]4[C:20](=[O:29])[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:23][C:18]=4[CH:17]=[CH:16][CH:15]=3)=[CH:31][CH:32]=[CH:33][C:34]=2[O:35][CH:3]=[CH:4]1
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(O)c3C(=O)C=CN(C)C)cccc2o1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc4occc(=O)c34)cccc2o1

Procedure:
0.200 parts of ethyl 5-(3-[2-{3-dimethylaminoacryloyl}-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate were refluxed for 16 hours in 15.8 parts of ethanol containing 1 part of concentrated hydrochloric acid. The solution was poured into a stirred mixture of 10 parts of water and 73 parts of chloroform and the organic extract separated, and washed with 5% sodium bicarbonate solution and water. Evaporation of the chloroform gave a residue which was chromatographed on silica gel, eluting with 1:1 chloroform/ethyl acetate. The product obtained from chromatography was crystallised from ethanol to give 0.027 parts of ethyl 5-(3-[4-oxo-4H-1-benzopyran-5-yloxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate, m.pt. 154°-158°.
Reaction SMILES: C1C[O:4]CC1.[OH2:6].Cl[Si:8]1(Cl)[C:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]1[Si:29]([CH3:32])([CH3:31])[CH3:30]>CCOCC>[OH:6][Si:8]1([OH:4])[C:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]1[Si:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: C[Si](C)(C)C1=C(c2ccccc2)C(c2ccccc2)=C([Si](C)(C)C)[Si]1(Cl)Cl
Reactant: O
Reactant: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)C1=C(c2ccccc2)C(c2ccccc2)=C([Si](C)(C)C)[Si]1(O)O
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixed solution 2.5 ml of THF and water (4:1) was added to 100 mg of 1,1-dichloro-3,4-diphenyl-2,5-bis(trimethylsilyl)silole, and stirring was continued at room temperatures for one hour. Ether was added to the reaction mixture thus obtained to extract the product. The extract was washed with water and dried on sodium sulfate. Sodium sulfate was removed by filtering, and then the filtrate was concentrated to obtain 92 mg of 1,1-dihydroxy-3,4-diphenyl-2,5-bis(trimethylsilyl)silole. The yield was 100%.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][CH2:8][P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11])=[O:6])[CH3:4].[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:28]([NH:2][C@H:3]([C:5]([NH:7][CH2:8][P:9](=[O:14])([O:10][CH3:11])[O:12][CH3:13])=[O:6])[CH3:4])=[O:29])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COP(=O)(CNC(=O)[C@H](C)N)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COP(=O)(CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1)OC
Reaction time: 8 h

Procedure:
24.65 g of dimethyl (L-alanylamino)-methylphosphonate hydrochloride and 32.0 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine were stirred in 200 ml of dry dimethylformamide while 14 ml of dry triethylamine were added dropwise at 20° C. The mixture was stirred overnight and then the triethylamine hydrochloride filtered off and washed with a small amount of dimethylformamide. The filtrate was evaporated under an oil-pump vacuum, the residue treated with 150 ml of water and then extracted with four 125 ml portions of chloroform. The combined chloroform layers were washed with a 20 % potassium carbonate solution, separated and dried over sodium sulphate. The sodium sulphate was filtered off, the filtrate evaporated firstly under a water-pump vacuum and then under an oil-pump vacuum and the residue taken up in 100 ml of ethyl acetate. About 100 ml of ether were added to faint turbidity when crystallization began. After refrigeration overnight, the solid was filtered off, washed successively with ethyl acetate/ether (1:1) and ether and then dried in vacuo. Recrystallization from 200 ml of boiling ethyl acetate by the addition of 200 ml of ether gave 27.8 g of dimethyl [(N-benzyloxycarbonyl-L-alanyl-L-alanyl)amino] -methylphosphonate of melting point 106°-108° C; [α]D20 =- 37.4° (c =1% in glacial acetic acid).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.[C:10]1([S:16]([OH:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Ca+2].[Cl-]>C(Cl)Cl>[C:10]1([S:16]([CH:5]2[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[O:4]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1CCC(OC)O1
Reactant: O=S(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COC1CCC(S(=O)(=O)c2ccccc2)O1
Reaction time: 4 h
Yield: 55 %

Procedure:
2,5-Dimethoxytetrahydrofuran (17.1 ml, 0.13M) was added dropwise to a stirred solution of benzenesulphinic acid (17.0 g, 0.12M) in dry DCM (100 ml) containing a suspension of powdered calcium chloride (1.0 g) at room temperature under argon. After 4 h, the solution was washed with water (2×50 ml), dried over anhydrous sodium sulphate, filtered and evaporated. The product was crystalised (diethyl ether/hexane) to give 2-benzenesulphonyl-5-methoxytetrahydro-furan as a white crystalline solid (15.9 g, 55%).