Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17](=O)[C:16]2[C:15]([C:19](OCC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][CH:9]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH3:2].O.[NH2:32][NH2:33]>CO>[CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17]2=[N:32][NH:33][C:19](=[O:20])[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=32)[NH:10][CH:9]1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1CC)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CCn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
A mixture of ethyl 3-(1-ethyl-1H-imidazol-2-yl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (90 mg, 0.22 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (10 mL) was stirred for 4 h at room temperature. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give the crude product. The crude product was purified by prep-HPLC to give the title compound (38.5 mg, yield: 47%). 1H-NMR (400 MHz, CD3O) δ(ppm): 1.06-1.09 (t, J=7.2 Hz, 3H), 3.74-3.78 (m, 2H), 4.60-4.62 (d, J=11.6 Hz, 1H), 4.98-5.01 (d, J=11.6 Hz, 1H), 6.91-7.02 (m, 4H), 7.19-7.21 (m, 1H), 7.39-7.43 (m, 2H), 7.56-7.64 (m, 2H); LC-MS (ESI) m/z: 376 (M+1)+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH:15]([C:22]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:27][C:23]=1[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClC1C=CC=CC=1NC1C=C(C(O)=O)C(NC2C=CC=CC=2Cl)=CC=1C(O)=O>>[CH:38]1[CH:39]=[C:40]2[C:31]([C:29]3[C:28]([NH:34][C:35]2=[CH:36][CH:37]=1)=[CH:27][C:23]1[C:24]([C:21]2[C:16]([NH:15][C:22]=1[CH:30]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:25])=[O:32]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=C(O)c1cc(Nc2ccccc2Cl)c(C(=O)O)cc1Nc1ccccc1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C

Procedure:
380 parts of polyphosphoric acid, containing 85.0% P2O5, are introduced into a pressure vessel. Then 68.5 parts of 2,5-dianilinoterephthalic acid and 7.6 parts of 2,5-di(2-chloro-anilino)terephthalic acid are introduced with stirring at from 80 to 90° C. and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is then introduced into a second pressure vessel where it is hydrolyzed under pressure and with stirring with a mixture of 1711 parts of 30% phosphoric acid at 140° C. During this hydrolysis the temperature rises to 155° C. The mixture is stirred at 155° C. for 0.5 hour. Then it is cooled to 60° C. and the mixed crystal pigment is filtered off with suction, washed to neutrality with water and dried at 80° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)=[CH:21][CH:20]=3)[N:16]=2)=[CH:6][CH:5]=1.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>CCO>[C:36]1([CH3:46])[CH:37]=[CH:38][C:39]([S:42]([O-:45])(=[O:43])=[O:44])=[CH:40][CH:41]=1.[F:34][C:2]([F:1])([F:35])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH+:29]4[CH:33]=[CH:32][N:31]=[N:30]4)=[CH:21][CH:20]=3)[N:16]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ccc(CCCC[NH+]4C=CN=N4)cc3)co2)cc1
Temperature: 60 °C

Procedure:
To a solution of 0.124 g (0.26 mmol) 1-[4-(4-{2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole in 20 ml EtOH 0.973 μl (50 mg/ml in EtOH) of p-toluenesulfonic acid was added and heated to 60° C. for complete dissolution. After evaporation of the solvent the oily residue crystallized slowly to yield 1-[4-(4-{2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazolium p-toluenesulfonate.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:19][C:20](=[O:33])[CH:21]=[CH:22][C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.Cl.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([NH:1][CH2:2][C@@H:3]([NH:19][C:20](=[O:33])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C#N)cc1C=CC(=O)N[C@H](CN)CN1CCC(Oc2ccc(F)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CNC(C)=O)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of E)-N-{(R)-1-aminomethyl-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide.HCl salt (0.35 g, 0.66 mmol) and triethylamine (0.27 ml, 1.99 mmol) in DCM (5 ml) is treated with acetyl chloride (0.042 ml, 0.6 mmol) at 5° C. The reaction mixture is stirred at ambient temperature for 1 hour then washed with water, saturated aqueous NaHCO3 and brine. The organic phase is dried over MgSO4 and the solvent evaporated. The crude product is purified by flash chromatography (elution methanol:DCM; 4:96) to afford (E)-N-{(R)-1-(acetylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide. [MH]+ 495.0.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C([Cl:18])=O)CCCCC1.[C:19]1([CH3:46])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:27]=[CH:28][C:29]([CH:37](O)[CH:38]([NH:41][CH:42]([CH3:44])[CH3:43])[CH2:39][CH3:40])=[C:30]2[C:35]=1[NH:34][C:33](=[O:36])[CH:32]=[CH:31]2.CO>Cl.C(OCC)C>[ClH:18].[C:19]1([CH3:46])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:27]=[CH:28][C:29]([CH:37]([O:8][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])[CH:38]([NH:41][CH:42]([CH3:44])[CH3:43])[CH2:39][CH3:40])=[C:30]2[C:35]=1[NH:34][C:33](=[O:36])[CH:32]=[CH:31]2
Reactant: CCC(NC(C)C)C(O)c1ccc(Oc2ccccc2C)c2[nH]c(=O)ccc12
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C(O)C1CCCCC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCC(NC(C)C)C(OC(=O)C1CCCCC1)c1ccc(Oc2ccccc2C)c2[nH]c(=O)ccc12
Temperature: 0 °C

Procedure:
2 ml of cyclohexanecarboxylic acid and 2 ml of cyclohexanecarbonyl chloride were added to 1 g of 8-toluyloxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril and the mixture was allowed to react for 1 hour at a temperature of 80° C. After completion of the reaction, 2 to 3 drops of concentrated hydrochloric acid and 10 ml of methanol were added to the reaction mixture while cooling with ice-water followed by addition of diethyl ether to crystallize the product. The crystals thus obtained were separated by filtration, washed with diethyl ether and recrystallized from a mixture of methanol and diethyl ether to obtain 1.3 g of 8-toluyloxy-5-(1-cyclohexylcarbonyloxy-2-isopropylaminobutyl)carbostyril hydrochloride having a melting point of 231°-232.5° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([F:10])=[C:4]([Br:9])[CH:5]=[CH:6][C:7]=1[F:8].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:11][O:1][C:2]1[C:3]([F:10])=[C:4]([Br:9])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1c(F)ccc(Br)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)ccc(Br)c1F
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A quantity of 3.7 g of 3-hydroxy-2,4-difluoro-bromobenzene is dissolved in 25 ml of acetone and 2.5 g of potassium carbonate is added followed by 2.2 ml of methyl iodide. The mixture is stirred at 20° C. for 6 hours and the solvent evaporated. After addition of dichloromethane, the suspension is filtered. Evaporation of the solvent affords the desired product.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]3[C:15]([C:16](B4OC(C)(C)C(C)(C)O4)=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)O1.Br[C:34]1[CH:35]=[CH:36][C:37]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[N:38][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:59][CH2:58]OCC1>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.O>[N:38]1[CH:39]=[C:34]([C:16]2[C:17]3[C:18]([C:9]([C:34]4[CH:35]=[CH:36][C:37]([C:40]5[CH:41]=[N:42][CH:43]=[CH:58][CH:59]=5)=[N:38][CH:39]=4)=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:35]=[CH:36][C:37]=1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC1(C)OB(c2c3ccccc3c(B3OC(C)(C)C(C)(C)O3)c3ccccc23)OC1(C)C
Reactant: C1COCCO1
Reactant: Brc1ccc(-c2cccnc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1cncc(-c2ccc(-c3c4ccccc4c(-c4ccc(-c5cccnc5)nc4)c4ccccc34)cn2)c1
Temperature: 25 °C

Procedure:
Into a flask, 2.53 g of 9,10-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)anthracene, 2 g of 5-bromo-2,3′-bipyridine, 960 mg of Pd(PPh3)4, 3.81 g of tripotassium phosphate, 60 ml of dioxane, and 15 ml of pure water were put, and the solution was stirred at reflux temperature for 3 days under argon atmosphere. After heating, the reaction liquid was cooled to room temperature, pure water was added, and then the organic layer was extracted. The organic layer was concentrated in an evaporator, the concentrates were purified by column chromatography, yellow powders which were concentrated again and obtained were washed by toluene, and thus 800 mg of 9,10-bis(2,3′-bipyridine-5-yl)anthracene was obtained. 1H-NMR (CDCl3) δ 7.4-7.6 (m, 6H), 7.2-7.3 (m, 4H), 8.0 (d, 4H), 8.5 (s, 2H), 8.8 (d, 4H), 9.4 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9][C:10]1[C:15]([NH2:16])=[C:14]([S:17][CH3:18])[N:13]=[CH:12][N:11]=1.[Br:19][CH2:20][C:21](Br)=[O:22]>C1COCC1.O>[CH3:18][S:17][C:14]1[C:15]([NH:16][C:21](=[O:22])[CH2:20][Br:19])=[C:10]([S:9][CH3:8])[N:11]=[CH:12][N:13]=1
Reactant: O=C(Br)CBr
Reactant: CSc1ncnc(SC)c1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncnc(SC)c1NC(=O)CBr
Reaction time: 1 h
Yield: 36.2 %

Procedure:
Triethylamine (78 mg, 0.8 mmol) was added to a solution of 4,6-bis(methylthio)-5-aminopyrimidine (120 mg, 0.7 mmol) in THF (2 ml) at room temperature, then bromoacetyl bromide (141 mg, 0.7 mmol) was dropped thereinto and the mixture was stirred for 1 hour. Then the same amounts of triethylamine and bromoacetyl bromide were added followed by stirring for 1 hour. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (20 g of silica gel; developing solvent, hexane:acetone=5:1) to provide 78 mg (yield 40%) of N-[4,6-bis(methylthio)-5-pyrimidyl]-2-bromoacetamide as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[C:11]1([CH2:17][CH:18]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: O=CCc1ccccc1
Reactant: CCOC(CCN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(CCNCCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
3,3-Diethoxypropan-1-amine (0.20 g) dissolved in ethanol (10 mL) was treated with 2-phenylacetaldehyde (0.163 g) and acetic acid (0.02 mL). The resulting mixture was stirred at room temperature for 15 minutes and treated with sodium cyanoborohydride (0.051 g). After 14 hours the mixture was concentrated, taken up in ethyl acetate (30 mL) washed with saturated sodium bicarbonate (20 mL), brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give a crude sample of the sub-titled compound (0.33 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14].[CH3:16][CH:17]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH3:18]>C1COCC1.CCOC(C)=O.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:16])[CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)c1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a suspension of NaH (509 mg, 20.16 mmol) in THF (50 ml) was added 5-bromo-3-isopropyl-1H-indole (4.55 g, 19.20 mmol). The reaction mixture was stirred at r.t. for 30 min, and TIPSCl was then added at r.t. The reaction was stirred further for 1 hr, diluted with EtOAc, and water was added to quench the reaction. The organic layer was collected and the water layer was further extracted with EtOAC once. The combined organic layer was dried over MgSO4, filtrated and concentrated. The residue was purified by column chromatography on silica gel, eluting with hexane to afford 5-bromo-3-isopropyl-1-triisopropylsilyl-1H-indole (5.1 g, 67.6%): 1H NMR (200 MHz, CDCl3): δ 7.53 (d, J=1.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.99 (m, 1H), 6.76(s, 1H), 2.92 (m, 1H), 1.44 (m, 3H), 1.14 (d, J=6.6 Hz, 6H), 0.93 (d, J=7.4 Hz, 18H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=Hexane (1:9); Rf=0.65.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].C(NC1C=CC(C2C([C:50]([C:52]3[C:53]([C:58]4[CH:63]=[CH:62][C:61]([NH:64][C:65](=[O:67])[CH3:66])=[CH:60][CH:59]=4)=[N:54][CH:55]=[CH:56][CH:57]=3)=O)=CC=CN=2)=CC=1)(=O)C>O1CCCC1>[C:65]([NH:64][C:61]1[CH:60]=[CH:59][C:58]([C:53]([C:52]2[CH:50]=[N:54][CH:55]=[CH:56][CH:57]=2)=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:63][CH:62]=1)(=[O:67])[CH3:66]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1ccc(-c2ncccc2C(=O)c2cccnc2-c2ccc(NC(C)=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=CCCCC(=O)O)c2cccnc2)cc1
Temperature: 0 °C

Procedure:
To a suspension of 307 g of 4-carboxybutyltriphenylphosphonium bromide and 233 g of potassium tert.butoxide in 2.8 liters of tetrahydrofuran are added, at -40° C., 140 g of 4-acetylaminophenyl-3-pyridyl-ketone and this mixture is stirred for 2 hours. The reaction mixture is decomposed by the addition of ice water and evaporated down. The residue is taken up in water and washed with ethyl acetate. The aqueous phase is acidified to pH 5 to 6 and extracted with ethyl acetate. The organic phase is concentrated by evaporation and the residue is recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29](OCC)=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:37]1[N:42]([CH2:43][CH2:44][NH2:45])[CH2:41][CH2:40][O:39][CH2:38]1>>[F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29]([NH:45][CH2:44][CH2:43][N:42]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCN3CCOCC3)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(4-morpholino)ethylamine employing methods similar to those described in Example 5 and was obtained as a white solid; 1H NMR (CDCl3) δ 13.49 (1H, br), 10.45 (1H, t, J=6 Hz), 8.57 (1H, s), 7.84 (2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.3 Hz), 7.04 (1H, s), 7.00 (4H, m), 5.43 (2H, br), 4.31 (2H, m), 4.08 (2H, m), 4.02 (2H, s), 3.99 (2H, m), 3.58 (2H, m), 3.29 (2H, m), 3.03 (3H, s), 2.97 (2H, m); ES+ MS: 595 (M+H+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1.C1([O:17][S:18](=O)(=[O:20])[NH2:19])C=CC=CC=1>O1CCOCC1.C(O)(C)C.C(OC(C)C)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][O:10][S:18](=[O:20])(=[O:17])[NH2:19])[CH:2]=1
Reactant: OCCOc1cccnc1
Reactant: NS(=O)(=O)Oc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: CC(C)O
Product: NS(=O)(=O)OCCOc1cccnc1
Reaction time: 18 h

Procedure:
A mixture of 4.9 g (0.035 mole) of 2(3-pyridinyloxy)ethanol (Preparation 18) and 8 g (0.046 mole) of sulfamic acid phenyl ester (Example 33) in 100 ml of dioxane was heated at reflux temperatue for 20 min. and the solvent then evaporated. The residue was triturated with 250 ml of acetone, filtered, and the filtrate acidified with a solution of anhydrous hydrogen chloride in isopropyl alcohol and the sticky brown precipitate collected. The brown solid was redissolved in 125 ml of methanol and diluted with 125 ml of ethanol. The solution was stirred with charcoal, filtered, and the filtrate partially evaporated to give a suspension. The suspension was diluted with isopropyl alcohol-isopropyl ether and filtered. The solid was dried at 50° C. for 18 hr and then at 70° C. for 18 hr in a vacuum oven. The yield was 4.5 g of solid title compound as the monohydrochloride, mp 156°-157° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([Si:15]([C:44]2[CH:49]=[CH:48][C:47]([O:50]CC3C=CC=CC=3)=[CH:46][CH:45]=2)([C:30]2[CH:35]=[CH:34][C:33]([O:36]CC3C=CC=CC=3)=[CH:32][CH:31]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([Si:15]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:44]2[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=2)=[CH:21][CH:20]=1
Reactant: c1ccc(COc2ccc([Si](c3ccc(OCc4ccccc4)cc3)(c3ccc(OCc4ccccc4)cc3)c3ccc(OCc4ccccc4)cc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1ccc([Si](c2ccc(O)cc2)(c2ccc(O)cc2)c2ccc(O)cc2)cc1
Reaction time: 48 h
Yield: 91.1 %

Procedure:
A THF (200 mL) solution containing tetrakis(4-benzyloxyphenyl)silane 40 (10.00 g, 13.15 mmol) and 10 wt % palladium on carbon (400 mg) (e.g., catalyst), was placed in the 1000 mL pressure safe vessel equipped with viton seals and, in turn, connected to the hydrogenator, as provided above. The vessel was pressurized with hydrogen (35 psi) and the solution was allowed to react with stirring for 48 hr. The catalyst was removed by filtration through celite, and the solvent was removed under reduced pressure to afford 4.80 g (91% yield) of tetrakis(4-hydroxyphenyl)silane 42 (FIG. 8) as an off-white solid. For purification, tetrakis(4-hydroxyphenyl)silane 42 was dissolved in THF and precipitated out in hexane. The white product was filtered, washed with ether, and dried under dynamic vacuum. NMR assignments of the molecule shown in FIG. 8, include: 1H NMR (acetone-d6) δ: 8.63 (s, 4H), 7.38 (d, J=6 Hz, 8H), 6.81 (d, J=6 Hz, 8H). 13C NMR (acetone-d6) δ: 159.54 (C4), 138.59 (C2), 125.98 (C1), 115.92 (C3). 29Si NMR (acetone-d6) δ: −14.64 (s).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>CN(C)C=O>[C:40]([N:28]1[CH2:29][CH2:30][C:31]2[N:32]=[C:24]([C:22]([NH:21][C@@H:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:15]3[NH:14][C:12]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=4)=[O:13])=[O:23])[S:25][C:26]=2[CH2:27]1)(=[O:42])[CH3:41]
Reactant: O=C(N[C@@H]1CCCC[C@@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(±)-cis-N1-[(5-Chloroindol-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexanediamine hydrochloride (100 mg) was dissolved in N,N-dimethylformamide (3 ml), triethylamine (84 μl) and acetic anhydride (29 μl) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane and 1N hydrochloric acid were added to the residue to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain the title compound (86 mg) as a pale yellow foamy substance.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:3]([OH:18])[CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH2:26]([O:33][C:34]([N:36](C#N)[C@H:37]([C:39]([OH:41])=O)[CH3:38])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.OC1C2N=N[NH:51][C:50]=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C=O>[CH2:26]([O:33][C:34]([NH:36][C@H:37]([C:39]([NH:1][C@@H:2]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:3]([OH:18])[CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:41])[CH2:38][C:50]#[N:51])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: C[C@@H](C(=O)O)N(C#N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
A solution of 90mg (0.26 mmol) of 2(S)-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide in 4 ml of dichloromethane was added to a mixture of 65 mg (0.26 mmol) of N-benzyloxycarbonyl-cyano-L-alanine, 35 mg (0.23 mmol) of hydroxybenzotriazole hydrate and 54 mg (0.26 mmol) of dicyclohexylcarbodiimide in 2 ml of dimethylformamide. The mixture-was stirred under nitrogen at room temperature for 18 hours and then filtered. The filtrate was evaporated and the residue was partitioned between 25 ml of ethyl acetate and 10 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulphate and evaporated. The crude product was chromatographed on a column of silica gel using 3% methanol in dichloromethane for the elution and the product was purified further by crystallization from a mixture of 1 ml of dichloromethane and 10 ml of hexane. There were obtained 68 mg of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-3-cyano-L-alanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid; MS m/e 577 [M+H]+.