Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CCN(C(C)C)C(C)C.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([Si:24]([CH3:26])([CH3:25])[O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-chloro-2-hydroxy-benzaldehyde (9.3 g) in DMF (45 mL) was added DIPEA (20 mL) and tert-butyl-chloro-dimethyl-silane (19 g). The mixture was stirred at room temperature for 1.5 h. Then the mixture was poured into ice water (200 mL), extracted with ether (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4. The solvent was removed to give the title compound which was used directly for next step.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].CC(C)([O-])C.[K+].[CH2:33]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[CH2:33]([N:40]1[CH2:45][CH2:44][C:43](=[CH:7][CH2:6][CH2:5][CH2:4][C:2]#[N:3])[CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCCCC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a suspension of 4-cyanobutyltriphenylphosphonium bromide (21.80 g) in tetrahydrofuran (100 ml) was added potassium tert-butoxide (5.76 g) in tetrahydrofuran (50 ml) over 30 minutes at 0° C. After 1 hour, a solution of 1-benzyl-4-piperidone (8.84 g) was added to the mixture over 30 minutes at 0° C. The mixture was stirred at ambient temperature for 1 hour, poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on alumina eluting with chloroform/hexane (1:1) and the fractions containing the object compound were combined and evaporated to afford 1-benzyl-4-(4-cyanobutylidene)piperidine (9.8 g) as an oil.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[CH2:5].C([O-])([O-])=O.[Na+].[Na+]>O.C(OC(=O)C)(=O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:4][CH2:5][C:1]#[N:2]
Reactant: C=Cc1ccccn1
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#CCCc1ccccn1
Temperature: 105 °C

Procedure:
3-(2-Pyridinyl)propionitrile is prepared in this example using the procedure of V. Boekelheide, et al., J. Am. Chem. Soc., 75, 3243 (1953). A solution of potassium cyanide (83.74 g) in water (160 ml) is added to a solution of freshly distilled 2-vinylpyridine (67.59 g) in acetic anhydrid (131.30 g) with the rate of addition adjusted to maintain gentle refluxing. When the addition is complete, the resulting dark red mixture is heated for about 17 hours at 105° C. in an oil bath with vigorous stirring. The cooled reaction mixture is adjusted to pH 8 with a saturated Na2CO3 solution. The mixture is extracted with CHCl3 (4×150 ml), washed with water, dried with Na2SO4, and evaporated to a dark viscous oil. The oil is fractionally distilled in vacuo through a Vigreaux column. After a small forerun containing 2-vinylpyridine (0.35 g), the desired 3-(2-pyridinyl)propionitrile is collected as a clear, fluorescent yellow-green, viscous oil: yield 59.8 g; 70.4%; bp 86° C. at 1.0 mm Hg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[H-].[Na+].Cl[C:12]1[C:13]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:18][C:14]=2[N:15]=[CH:16][N:17]=1.O>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:12]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=[N:17][CH:16]=[N:15][C:14]=3[O:18][C:19]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: N#CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCCCC#N)c23)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Dissolve 850 mg (3.8 mmol) 6-hydroxyhexanenitrile [obtained according to Eur. J. Med. Chem. 36 (4), 303-311 (2001)] in 15 ml DMF, add, at 0° C., 180 mg 60% sodium hydride (dispersion in mineral oil; approx. 4.5 mmol) and stir the mixture for 1 h at room temperature. Next, add 1.26 g (3.8 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and stir the mixture overnight at 120° C. After cooling, add water to the mixture and extract with ethyl acetate. Dry the organic phase, and concentrate by evaporation. Purify the residue by flash chromatography on silica gel (solvent: cyclohexane/ethyl acetate 2:1→cyclohexane/ethyl acetate 1:2). 1.05 g (68% of theor.) of an orange-coloured oil is obtained, which is used as raw product in further reactions.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]([OH:20])[CH3:19])[CH2:14][CH2:13]1)C1C=CC=CC=1.C(OCC)(=O)C>[OH-].[OH-].[Pd+2].CO>[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]([OH:20])[CH3:19])[CH2:14][CH2:13]1
Reactant: CC(O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)[C@H]1CC[C@H](CN)CC1
Reaction time: 2 h

Procedure:
A 500 mL Parr bottle was charged with 400 mg Pd(OH)2, 7.0 g (24.1 mmol) trans-(−)-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]-carbamic acid benzyl ester, 125 mL ethyl acetate and 125 ml MeOH. The bottle was placed under 50 psi H2 and shaken for 2 hours. The suspension was then filtered through Celite and concentrated to give 3.6 g of a white solid.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C[Si](C)(C)N[Si](C)(C)C>O1CCOCC1>[N:16]1([C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: O=C1CONC(=O)N1
Reactant: C1CNCCN1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: O=C1N=C(N2CCNCC2)CON1
Yield: 42 %

Procedure:
A solution of 1.16 g (0.010 of 6H-1,2,4-oxadiazin-3,5-(2H,4H)-dione, 5 mg of ammonium sulfate, 2.49 g (0.029 mole) of piperazine and 20 ml of hexamethyldisilazane in 40 ml of dry freshly distilled dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 0.78 g (42 percent) of 5-(1-piperazinyl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][Si:15]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C([O-])(O)=O.[Na+].[C:30](Cl)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C1COCC1.[Pd]>[CH2:33]([O:32][C:30](=[O:31])[NH:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:12]2[CH2:17][CH2:16][Si:15]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[C:4]([F:11])[CH:5]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C[Si]1(c2ccccc2)CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si]1(c2ccccc2)CCN(c2c(F)cc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
To a solution of 9b (1.96 g, 7.59 mmol) in THF, Pd/C is added for hydrogenation under a pressure of 35 psi in a par hydrogenator. The reaction mixture was filtered through celite. To the filtrate, saturated NaHCO3 (1.90 g, 22.77 mmol) and CBzCl (1.3 mL, 9.10 mmol) were added and stirred at 25° C. for 5 h. The solvent is removed, 10 mL water is added and the aqueous layer is extracted with EtOAc. The crude mixture is then subjected to column chromatography on silica gel using hexane-DCM mixtures to afford the product 10b as a viscous liquid (1.80 g) in 71% yield.
Reaction SMILES: N1C=CC=C1[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[C:14]3[CH:21]=[C:20]([C:22]4[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=4)[NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:9]=[CH:10][CH:11]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][NH:46][CH:47]=2)O1>>[NH:45]1[CH:44]=[C:43]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]4[CH:21]=[C:20]([C:22]5[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:26][CH:27]=5)[NH:19][C:15]=4[N:16]=[CH:17][N:18]=3)[CH:9]=[CH:10][CH:11]=2)[CH:47]=[N:46]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ccc[nH]5)c4)ncnc3[nH]2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5cn[nH]c5)c4)ncnc3[nH]2)CC1

Procedure:
The title compound was prepared following the procedure for tert-butyl 4-{4-[3-(1H-pyrrol-2-yl)phenylamino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylate, but using 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole. 1H-NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.57 (m, 2H), 3.67 (m, 2H), 4.14 (m, 2H), 6.29 (s, br, 1H), 6.66 (s, 1H), 7.33-7.39 (m, 2H), 7.58 (dt, J=2.0, 7.2 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.93-8.00 (m, 2H), 8.23 (s, 1H). MS (ES+): m/z 458.03 [MH+]. HPLC: tR=2.70 min (ZQ2000, polar—5 min).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8]1([C:14]([O:16][CH2:17][CH2:18][O:19][C:20](ON2C(=O)CCC2=O)=[O:21])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([C:14]([O:16][CH2:17][CH2:18][O:19][C:20]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:21])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(OCCOC(=O)C1CCCCC1)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)C(=O)O
Product: O=C(N[C@H](CO)C(=O)O)OCCOC(=O)C1CCCCC1
Yield: 57.7 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl cyclohexanecarboxylate (626 mg, 2.0 mmol) were reacted to provide 350 mg (58% yield) of the title compound (27) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.79 (m, 1H), 6.05 (t, 1H), 5.45 (br s, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.92 (m, 1H), 2.30 (m, 1H), 1.09-1.95 (m, 13H). MS (ESI) m/z 321.13 (M+NH4)+; 326.09 (M+Na)+; 302.06 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(Cl)cc1
Yield: 81.7 %

Procedure:
0.3 g (0.0015 mol) of 1-benzyl-4-hydroxypiperidine and 0.216 ml (0.00155 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.21 ml (0.0016 mol) of 4-chloro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.404 g (82%) of 1-benzyl-piperidin-4-yl 4-chloro-benzoate was obtained as a colorless oil. MS: me/e (% basic peak)=329 (C19H20CINO2+, 7), 252 (7), 173 (32), 139 (15), 91 (91), 82 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].Cl[C:44]1C=CC(Cl)=CC=1S(Cl)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:44])[C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:39])=[O:40])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5c(C)cccc5Cl)c4)cc23)CC1
Yield: 30 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting 2-chloro-6-methylbenzenesulfonyl chloride (86 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 17.9 mg the title compound (30%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cnc(-c2ccc(F)cc2)s1
Temperature: 85 °C
Yield: 3.7 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (5.0 g, 26.04 mmol) in toluene (150 mL) and ethanol (75 mL) was added (4-fluorophenyl)boronic acid (7.29 g, 52.08 mmol), 2M sodium carbonate solution (73.58 mL), Pd(PPh3)4 (1.5 g, 1.3 mmol) under argon atmosphere. The resulting mixture was heated at 85° C. for 6 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (150 mL), and extracted with ethyl acetate (5×500 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressures to obtain crude product. The crude product was purified by Combiflash® chromatography (Mobile phase: 10% ethyl acetate in hexane) to give 2-(4-fluorophenyl)thiazole-5-carbaldehyde as off-white solid (200 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 8.74 (s, 1H), 8.14-8.11 (m, 2H), 7.39 (t, 2H); LC-MS m/z calculated for [M+H]+ 208.02, found 207.9.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][O:16][C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[Br:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC[C@H]1CN(Cc2ccccc2)CCN1
Reactant: COc1ccc(Br)c(O)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(OCC[C@H]2CN(Cc3ccccc3)CCN2)c1
Reaction time: 16 h

Procedure:
A round bottom flask was charged with (S)-2-(4-benzylpiperazin-2-yl)ethanol (1.0 g, 4.5 mmol), 2-bromo-5-methoxyphenol (1.0 g, 5.0 mmol), di-tert-butyl azodicarboxylate (1.57 g, 6.81 mmol), polymer-supported triphenylphosphine resin (4.354 g, 9.08 mmol) and tetrahydrofuran (30 mL). The reaction stirred for 16 hours. The resin was removed via filtration and the solution was concentrated. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Br:1][C:15]1[CH:14]=[C:13]([CH2:16][CH:17]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:11][C:10]=1[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(O)c(Br)c1)Oc1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
N-bromosuccinimide (1.12 g) was added to a solution of ethyl 3-(4-hydroxyphenyl)-2-phenoxypropionate (1.43 g), which is the product of reference example 4(c) in chloroform (20 ml) at ambient temperature. The mixture was stirred at 70° C. for 4 hour and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel column using hexane/ethyl acetate=4/1 as the eluant to afford the desired compound (1.41 g) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=3)[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: CC1NCCc2cc(O)c(O)cc21
Reactant: Cc1nc(Cl)nc(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)nc(N2CCc3cc(O)c(O)cc3C2C)c1C
Yield: 75.9 %

Procedure:
After 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(1.6 g, 4.98 mmol) and triethylamine(0.7 ml, 4.98 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(0.8 g, 4.53 mmol) in dimethylformamide, 1.1 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 76%)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][OH:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([O:15][CH2:14][CH2:13][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)(=[O:19])=[O:18]
Reactant: OCCCc1nc(-c2ccccc2)cs1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A solution of 3-(4-phenylthiazol-2-yl)propan-1-ol (0.4 g, 1.82 mmol) in dry pyridine (8 mL) was cooled to 0° C. and methanesulfonyl chloride (0.43 mL, 5.47 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature, stirred for 1 h, and quenched with ice water. The organic product was extracted with EtOAc and organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 3-(4-phenylthiazol-2-yl)propyl methanesulfonate (0.4 g, yield 74%) as a pale yellow liquid, which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.90-7.87 (m, 2H), 7.46-7.40 (m, 2H), 7.37-7.31 (m, 2H), 4.42-4.38 (t, J=6.1 Hz, 2H), 3.24-3.19 (t, J=7.2 Hz, 2H), 3.04 (s, 3H), 2.39-2.30 (m, 2H). MS (ESI) m/z: Calculated for C13H15NO3S2: 297.05. found: 298.0 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:22]([CH3:27])[CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH2:27][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(Br)CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCN(C)CCCCCN)cc1OC
Yield: 55 %

Procedure:
2.5 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in 25 ml of N,N-dimethylformamide, followed by the addition of 1.95 g of anhydrous potassium carbonate and 1.65 ml of 4-bromovaleronitrile. The obtained mixture was reacted at a room temperature for 16 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate and distilled to remove the solvent. 40 ml of ethanol, 3.2 ml of concentrated hydrochloric acid and 0.3 g of platinum oxide were added to the obtained residue to carry out hydrogenation at a room temperature under 3 kg/cm2 for 6 hours. The catalyst was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of concentrated aqueous ammonia. The obtained mixture was extracted with chloroform. The chloroform phase was dried over anhydrous potassium carbonate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol/concentrated aqueous ammonia (100:10:1)] to obtain 1.95 g of the title compound as a yellow oil (yield: 55%).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:65])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[CH:25]=[C:24]([CH3:38])[C:23]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([S:45]([C:48]3[CH:52]=[C:51]([C:53]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[NH:54])[S:50][C:49]=3[S:63][CH3:64])(=[O:47])=[O:46])[CH:40]=2)=[O:20])=[CH:8][CH:7]=1.O>O1CCOCC1>[C:59]([O:58][C:56]([NH:55][C:53](=[NH:54])[C:51]1[S:50][C:49]([S:63][CH3:64])=[C:48]([S:45]([C:41]2[CH:40]=[C:39]([C:23]3[C:24]([CH3:38])=[CH:25][C:26]([NH:28][C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])=[O:30])=[CH:27][C:22]=3[NH:21][C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:65])=[O:4])=[CH:7][CH:8]=3)[CH:44]=[CH:43][CH:42]=2)(=[O:46])=[O:47])[CH:52]=1)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: COC(=O)c1ccc(OCCCCCNC(=O)Nc2cc(NC(=O)OCC[Si](C)(C)C)cc(C)c2-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Yield: 100 %

Procedure:
Lithium hydroxide (45.8 mg, 2.08 mmol) was added to a solution of 4-(5-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid methyl ester (280 mg, 0.298 mmol, Example 283: step c) in 1,4-dioxane:water (10 mL, 2:1) over 2 days at rt. The solvents were removed in vacuo. The residue was diluted in water, acidified to pH˜5 with acetic acid, and extracted with EtOAc. The organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed in vacuo to afford the title compound as a yellow solid (276 mg, quantitative). 1H-NMR (CDCl3/CD3OD): δ 7.93–7.99 (m, 3H), 7.83–7.86 (m, 2H), 7.52–7.59 (m, 2H), 7.15–7.20 (m, 2H), 6.85–6.89 (m, 2H), 4.21–4.26 (m, 2H), 3.99 (t, 2H, J=6.43 Hz), 3.13–3.24 (m, 2H), 2.61 (s, 3H), 2.02 (s, 3H), 1.75–1.83 (m, 2H), 1.43–1.56 (m, 13H), 1.02–1.08 (m, 2H), 0.07 (s, 9H).