Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH:10]([C:13]([CH3:15])=[O:14])[O:9][CH2:8][C:7]=2[C:6]([O:16][CH3:17])=[CH:5][CH:4]=1.C[Si](Cl)(C)C.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Br:43]NC(=O)CCC(N)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH:10]([C:13]([CH2:15][Br:43])=[O:14])[O:9][CH2:8][C:7]=2[C:6]([O:16][CH3:17])=[CH:5][CH:4]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: COc1ccc(OC)c2c1COC(C(C)=O)C2
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(OC)c2c1COC(C(=O)CBr)C2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of methyl (5,8-dimethoxy-3,4-dihydrobenzo [2,3-c] pyran-3-yl) ketone (1.905 g, 8.04 mmol) and trimethylsilyl chloride (1,530 μl, 12.0 mmol) in tetrahydrofuran (48 ml) under nitrogen, at -78° C., was slowly added lithium diisopropyl amide (diisopropyl amine 10.71 mmol, n-butyl lithium 4.26 ml of a 2.5M solution in tetrahydrofuran, and 6.0 ml of tetrahydrofuran). After stirring for 10 minutes the temperature was raised to 0° C., and stirring was continued for 10 more minutes. Solvent was removed and the crude product was dissolved in 48 ml of tetrahydrofuran, N-bromosuccinamide (1,716 mg, 9.66 mmol) was added slowly to the solution. After 10 minutes, the reaction system was worked up with saturated aqueous sodium bicarbonate and washed with brine. The titled compound was obtained following flash chromatography (hexanes:ethyl acetate, 9:1) of the crude product. 1H NMR (benzene-d6, 250 MHz) -- : 2.68 (dd, 1H,HCHa), 3.16 (dd,1H,HCHe), 3.28 (s,3H,OCH3), 3.32 (s,3H,OCH3), 3.73 (dd,1H,J=4.0,11.5 Hz,CH), 3.81 (dd,2H,CH2Br), 4.51 (d,1H, J=15.8 Hz, HCHaO), 5.05 (d,1H,J=15.8 Hz,HCHeO), 6.335 (dd,2H,ArH),
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:6][C@H:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)C[C@@H]1c1ccnn1C
Yield: 81.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (171 mg, 0.277 mmol) prepared in Example 133a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (106 mg, 82%) as a colorless solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([CH2:17][NH:18][CH3:19])[C:10]=1[O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[NH2:7].C(N(CC)C(C)C)(C)C.[CH2:29]([O:36][C:37]([O:39]N1C(=O)CCC1=O)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[NH2:7][C:6]1[CH:5]=[C:4]([F:3])[C:10]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])=[C:9]([CH:8]=1)[CH2:17][N:18]([CH3:19])[C:37](=[O:39])[O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNCc1cc(N)cc(F)c1O[C@@H](C)COC
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1c(F)cc(N)cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 37A (472 mg, 1.497 mmol) and N,N-diisopropylethylamine (1.043 ml, 5.99 mmol) in DMF (10 ml), was added N-(benzyloxycarbonyloxy) succinimide (411 mg, 1.647 mmol). The mixture was stirred rt for 1 h, then quenched with water, extracted with EtOAc (3×30 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexanes) to give 37B (520 mg, 1.381 mmol, 92% yield). MS (ESI) m/z: 377.3 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[C:19]1([C:25](=[N:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:44]=2)[C:38](N(OC)C)=[O:39])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:25](=[N:32][C:33]2[CH:44]=[C:37]([C:38]([C:2]3[C:10]4[CH:9]=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=3)=[O:39])[CH:36]=[N:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2cncnc21
Product: C[Si](C)(C)CCOCn1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (Preparation 101) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Preparation 23) to afford the title compound as a yellow oil in 32% yield, 460 mg.
Reaction SMILES: C(C1C=C2C(=CC=1)C(NC(=O)C1C=CC=CC=1)=NC=C2)=O.C([NH:29][C:30]1[C:39]2[C:34](=[CH:35][C:36]([CH:40]=[CH:41][C:42]([OH:44])=O)=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1)C1C=CC=CC=1.NC1C2C(=CC(C=CC(O)=O)=CC=2)C=CN=1.Cl.[CH3:62][O:63][C:64](=[O:76])[CH2:65][C:66]([N:68]1[CH2:73][CH2:72][CH:71]([NH:74][CH3:75])[CH2:70][CH2:69]1)=[O:67]>>[CH3:62][O:63][C:64](=[O:76])[CH2:65][C:66]([N:68]1[CH2:69][CH2:70][CH:71]([N:74]([C:42](=[O:44])[CH:41]=[CH:40][C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[C:30]([NH2:29])=[N:31][CH:32]=[CH:33]3)[CH3:75])[CH2:72][CH2:73]1)=[O:67]
Reactant: O=C(O)C=Cc1ccc2c(NCc3ccccc3)nccc2c1
Reactant: CNC1CCN(C(=O)CC(=O)OC)CC1
Agent: Cl
Agent: Nc1nccc2cc(C=CC(=O)O)ccc12
Agent: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Product: COC(=O)CC(=O)N1CCC(N(C)C(=O)C=Cc2ccc3c(N)nccc3c2)CC1

Procedure:
Using the method described in example 81a N-(6-formyl-1-isoquinolinyl)benzamide (1f) was transformed into 3-(1-(benzylamino)-6-isoquinolinyl)acrylic acid. This compound was used to prepare 3-(1-amino-6-isoquinolinyl)acrylic acid according to the procedure described in example 81b. Reaction of 3-(1-amino-6-isoquinolinyl)acrylic acid with 3-(4-(methylamino)piperidin-1-yl)-3-oxopropionic acid methyl ester hydrochloride according to the procedures described in example 81e yielded the title compound. NMR (CDCl3) δ:1.8 (4H, m), 2.7 (1H, m), 3.0 (3H, s), 3.2 (1H, m), 3.5 (2H, d), 3.7 (3H, s), 3.9 (1H, br d), 4.8 (2H, m), 4.9 (2H, br s), 7.0 (1H, d), 7.5 (1H, d), 7.65 (1H, d), 7.8 (3H, m), 8.0 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH2:13])[CH2:7][CH2:6]2.C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.O>ClCCl.C(OCC)(=O)C>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:13][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)CCC(N)C2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(c1)CCC(NC(=O)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine (0.57 g) in dichloromethane (5 ml) were added in turn triethylamine (0.46 ml) and 4-fluorobenzoyl chloride (0.30 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour, which was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give 4-fluoro-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-benzamide (0.59 g).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O.CC1O[N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[N:8]=1>CO>[C:1]([OH:4])(=[O:3])[CH3:2].[C:9]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])(=[NH:8])[NH2:10]
Reactant: COC(=O)c1cccc(-c2noc(C)n2)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(C(=N)N)c1
Reaction time: 18 h

Procedure:
150 ml of acetic acid, 150 ml of water and 50 g of water-moist Raney nickel are added to a solution of 327 g (1.47 mol) of methyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate in 3 l of methanol, and the mixture is hydrogenated at room temperature and atmospheric pressure for 18 hours. The catalyst is filtered off, and the filtrate is evaporated. The residue is taken up in tert-butyl methyl ether, heated to the boil and filtered off with suction. The residue is dried in vacuo: 3-methoxycarbonylbenzamidinium acetate as colourless crystals; m.p. 222° C.; ESI 179 (M+H); HPLC: Rt=1.40 min (method B).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5].C(N(CC)CC)C>C1COCC1>[CH:3]([S:4]([CH2:7][CH2:8][C:9]([F:27])([F:26])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])(=[O:6])=[O:5])=[CH2:2]
Reactant: O=S(=O)(CCCl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
2-(Perfluorohexyl)ethanyl 2-chloroethanyl sulfone (4.75 g, 10.0 mmole) was dissolved in 25 ml of THF at 30°, and triethylamine (1.52 g, 15.0 mmole) in 10 ml of THF was added in one minute. A white precipitate formed, and was filtered (1.37 g). The solvent was stripped carefully, as some foaming occurred.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([F:17])=[C:11]([F:18])[CH:10]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:25]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:17])=[C:11]([F:18])[CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7]1)[CH3:26]
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(F)c(F)cc2c1=O
Temperature: 90 °C

Procedure:
A 20 g portion of the above ester was suspended in 400 ml of dimethylformamide, 27.3 g of potassium carbonate was added and this mixture was stirred at 90° C. A 61.8 g portion of ethyl iodide was added and this mixture was stirred at 90° C. for 24 hours and then evaporated. The residue was dissolved in water and then extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated in vacuo. The residue was recrystallized from ethanol, giving 16.15 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[CH2:4]>[Pd].CO>[F:24][C:2]([F:1])([F:23])[CH:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH3:4]
Reactant: C=C(c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Reaction time: 12 h
Yield: 33.1 %

Procedure:
A mixture of tert-butyl 9-[1-(trifluoromethyl)ethenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.874 mmol) and 10% palladium on carbon (50.0 mg) in methanol (6 ml) was stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated. The residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (100 mg, 33.1%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([C:13]2([OH:16])[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: O=C1CCOCC1
Reactant: Fc1cc(F)cc(Br)c1
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (1.6 equiv.) in THF (0.26 M) under Ar was added Mg turnings (1.6 equiv.). A reflux condenser was attached and the solution was submerged in a 90° C. oil bath and refluxed for two hours. The dihydro-2H-pyran-4(3H)-one (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar for 5 hrs. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography (0-100% EtOAc/n-heptanes gradient) to yield 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol in 71% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.59-1.68 (m, 3H), 2.07-2.19 (m, 2H), 3.87-3.93 (m, 4H), 6.72 (tt, J=8.75, 2.20 Hz, 1H), 6.97-7.06 (m, 2H).
Reaction SMILES: [O:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[O:6]=O>O>[O:1]=[CH:2][C:3](=[CH2:4])[CH3:5].[C:2]([OH:6])(=[O:1])[C:3]([CH3:4])=[CH2:5]
Reactant: O=O
Agent: C=C(C)C=O
Solvent: O
Product: C=C(C)C(=O)O

Procedure:
41.2 mL of the coated catalysts obtained in Examples 1, 3 and 4 were filled in a stainless reaction tube with an internal diameter of 18.4 mm. A raw material gas (composition (molar ratio); methacrolein:oxygen:water vapor:nitrogen=1:2:4:18.6) was flowed into the reaction tube at 300 hr−1 of space velocity (SV), and methacrolein conversion rate, methacrylic acid selectivity and methacrylic acid yield were determined 24 hours after beginning of the reaction.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[S:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]2[N:30]=[CH:29][C:28]3[CH:27]=[CH:26][C:25]4[N:31]=[C:32]([C:34]([OH:36])=O)[S:33][C:24]=4[C:23]=3[N:22]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:13])(=[O:12])[NH2:11].[C:37]([O:41][C:42]([NH:44][CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:37]([O:41][C:42](=[O:43])[NH:44][CH:45]1[CH2:49][CH2:48][N:47]([C:34]([C:32]2[S:33][C:24]3[C:23]4[N:22]=[C:21]([NH:20][C:16]5[CH:17]=[CH:18][CH:19]=[C:14]([S:10](=[O:12])(=[O:13])[NH2:11])[CH:15]=5)[N:30]=[CH:29][C:28]=4[CH:27]=[CH:26][C:25]=3[N:31]=2)=[O:36])[CH2:46]1)([CH3:40])([CH3:38])[CH3:39]
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3ccc4nc(C(=O)O)sc4c3n2)c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2nc3ccc4cnc(Nc5cccc(S(N)(=O)=O)c5)nc4c3s2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
Diisopropylethylamine (68 μl, 0.39 mmol) was added to a mixture of 8-(3-Sulfamoyl-phenylamino)-thiazolo[4,5-h]quinazoline-2-carboxylic acid (78 mg, 0.19 mmol), 3-(tert-butoxycarbonylamino)pyrrolidine (36.2 mg, 0.19 mmol) and PyBrop (91 mg, 0.19 mmol) in dimethylformamide (1 ml). The reaction mixture was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure, redissolved in isopropanol (˜10 mL) and water was added (˜5 mL). The precipitate formed was isolated by filtration and washed with water (1×5 mL), dilute NaHSO4 (1×5 mL), water (1×5 mL), saturated Na2CO3 (1×5 mL), water (1×5 mL), isopropanol (1×5 mL), diethyl ether (4×5 mL) giving a yellow powder (87 mg, 80% yield). MS (ES+) 570, (ES−) 568.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][C:5]3=[O:12])[CH2:2]1)[CH2:9]2.C1(C)C=CC=CC=1.[OH-].[Na+].Br.Br.Br[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>O>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][N:4]2[C:5](=[O:12])[CH:6]3[CH2:11][CH:1]4[CH2:9][CH:8]([CH2:10][CH:3]2[CH2:2]4)[CH2:7]3)[CH2:29][CH2:30]1
Reactant: CN1CCN(CCCBr)CC1
Reactant: O=C1NC2CC3CC(C2)CC1C3
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN(CCCN2C(=O)C3CC4CC(C3)CC2C4)CC1
Reaction time: 0.08 h

Procedure:
To a well stirred solution of 2.4 gm. (0.02 mole) of 4-azatricyclo[4.3.1.13,8 ]undecan-5-one in 300 ml. of toluene, 3.2 gm. of powdered sodium hydroxide are added. After 5 minutes of vigorous stirring, 12 gm. of 1-(3-bromopropyl)-4-methylpiperazine dihydrobromide are added and the mixture heated for 20 minutes on a steam bath. The reaction mixture is cooled and stirred with 50 ml. of cold water. The toluene layer is separated, washed with 2 × 50 ml. of water and extracted with 3 × 100 ml. of 5 N HCl. The acid extracts are combined, washed with 100 ml. of ether, cooled and made basic with 2 N NaOH. The free base is extracted with 3 × 250 ml. of chloroform, dried (MgSO4) and evaporated in vacuo to give 4-[3-(4-methyl-1-piperazinyl)propyl]-4-azatricyclo[4.3.1.13,8 ]undecan-5-one.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15]C)=[CH:14][C:9]=2[O:8][C:7]1=[O:17])C.B(Br)(Br)Br>C(Cl)Cl>[OH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH2:5][C:4]([OH:18])=[O:3])[C:7](=[O:17])[O:8][C:9]=2[CH:14]=1
Reactant: CCOC(=O)Cn1c(=O)oc2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)Cn1c(=O)oc2cc(O)ccc21
Reaction time: 1 h

Procedure:
To a solution of (6-methoxy-2-oxo-benzooxazol-3-yl)-acetic acid ethyl ester (52) (251 mg, 1 mmol, 1 equiv) in 3 mL of DCM was added BBr3 (0.3 mL, 3 equiv) and the reaction solution was stirred for 1 h. The reaction mixture was quenched by slow addition of water, followed by the addition of EtOAc. The organic layer was isolated and dried over sodium sulfate, filtered, evaporated in vacuo to provide (6-hydroxy-2-oxo-benzooxazol-3-yl)-acetic acid (53).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:19]1[CH2:24][C@@H:23]([C:25]2[O:29][N:28]=[C:27]([CH3:30])[N:26]=2)[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.[ClH:48]>>[ClH:48].[ClH:48].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([C@H:19]1[CH2:24][C@@H:23]([C:25]2[O:29][N:28]=[C:27]([CH3:30])[N:26]=2)[CH2:22][NH:21][CH2:20]1)[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nc(C)no3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](c3nc(C)no3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (265 mg), N-hydroxy acetamidine (56 mg), 1H-benzotriazol-1-ol (95 mg) and N,N-diisopropylethylamine (259 μl)) were dissolved in DMF (10 ml), WSC.HCl (144 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in toluene (15 ml), and the mixture was refluxed under heating for 15 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (324 mg). The obtained tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue was dissolved in methanol (3 ml), 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (74 mg).
Reaction SMILES: [CH2:1]([SiH:7]([Cl:9])[Cl:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([Si:7]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([Cl:9])[Cl:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[SiH](Cl)Cl
Reactant: C1=CCCCC1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CCCCCC[Si](Cl)(Cl)C1CCCCC1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
This n-hexyldichlorosilane in an amount of 30.5 g (0.165 mol), 17.2 g of cyclohexene (0.21 mol) and 0.05 mol % of chloroplatinic acid (relative to hexyldichlorosilane) were subjected to reaction in a flask with stirring at a temperature of 40° C. for 20 hours. No hexylcyclohexyldichlorosilane was obtained.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.[CH3:11][N:12]([CH2:14][C:15]1[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[N:17][CH:18]=[C:19]([CH:23]=1)[C:20]([OH:22])=O)[CH3:13]>C(Cl)Cl>[CH3:11][N:12]([CH2:14][C:15]1[C:16]([O:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=2)=[N:17][CH:18]=[C:19]([CH:23]=1)[C:20]([NH2:7])=[O:22])[CH3:13]
Reactant: CN(C)Cc1cc(C(=O)O)cnc1Oc1ccc(OC(F)(F)F)cc1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)Cc1cc(C(N)=O)cnc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
N-N-Diisopropylethylamine (44 μL, 0.25 mmol), HOBt (20 mg, 0.15 mmol) and WSCDI (23 mg, 0.12 mmol) were added to the acid from step (i) (35 mg, 0.10 mmol) in CH2Cl2 (2 mL) and stirred for 30 min. (NH4)2CO3 (19 mg, 0.20 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between water (10 mL) and CH2Cl2 (10 mL) and the organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography [SiO2; DCM/MeOH/880 NH3 (93:7:1)] and then triturated with Et2O to give the desired product (20 mg, 57%) as a white solid; δH (CDCl3, 400 MHz) 2.35 (6H, s), 3.62 (2H, s), 5.66 (1H, br), 6.00 (1H, br), 7.18 (2H, m), 7.26 (2H, m), 8.23 (1H, d), 8.50 (1H, d); MS m/z (TS+) 356 (MH+).