Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH2:8]([NH2:11])[CH2:9][CH3:10]>C(O)C>[CH2:8]([NH:11][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[CH2:9][CH3:10]
Reactant: CCCN
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (640 mg) in ethanol (6 mL) was added propan-1-amine (0.397 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg).
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]([CH2:7][CH:8]([NH:16][C:17](=[O:40])[CH2:18][CH:19]([NH:26][S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:29])=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9](=[O:15])[N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1)#N.C(O)=[O:44]>[Al].[Ni]>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([NH:16][C:17](=[O:40])[CH2:18][CH:19]([NH:26][S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:28])=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9](=[O:15])[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:41][CH:42]=1)=[O:44]
Reactant: O=CO
Reactant: N#Cc1ccc(CC(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)C(=O)N2CCCC2)cc1
Agent: [Ni]
Agent: [Al]
Product: O=Cc1ccc(CC(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)C(=O)N2CCCC2)cc1

Procedure:
3 g of aluminium/nickel alloy are added to a mixture of 3 g of the compound obtained in step A of Example 1 and 40 ml of 75% formic acid, and the mixture is refluxed for 2 hours. The insoluble material is filtered off by suction while hot and washed with MeOH, and the filtrate is concentrated under vacuum. The residue is taken up in chloroform, the insoluble material is filtered off by suction and washed with an MeOH/chloroform mixture, and the filtrate is concentrated under vacuum. The residue is taken up in chloroform and filtered, the filtrate is washed with saturated NaHCO3 solution and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 2.4 g of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O.[OH-].[Na+]>>[OH:8][C:7]1[C:2]2=[N:1][C:18]([CH3:20])=[CH:17][C:16](=[O:21])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ncccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)n2cccc(O)c2n1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a suspension of 2-amino-3-benzyloxypyridine (5.01 g) in polyphosphoricacid (40 ml) was dropwise added ethyl acetoacetate (6.51 g) at 60° C., and the mixture was warmed at 100° C. for 3 hours. The mixture was poured into ice water, neutralized with sodium hydroxide and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (methanol-chloroform) to give 9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (880 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:17]([OH:19])=O)=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C.[O:37]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:1]([O:8][C:9]1[C:10]([C:17]([NH:48][C:47]2[CH:46]=[CH:45][C:44]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:50][CH:49]=2)=[O:19])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccnc(C(=O)O)c1OCc1ccccc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1OCc1ccccc1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
3-Benzyloxy-4-methoxypicolinic acid (0.65 g, 2.5 mmol) and 0.50 g (3.0 mmol) of carbonyldiimidazole were mixed into anhydrous DMF to prepare a suspension (8 ml). An anhydrous DMF solution (2 ml) of 0.56 g (3.0 mmol) of 4-phenoxyaniline was added dropwise to this suspension, and a reaction was allowed to proceed at room temperature overnight. Water (10 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the dried organic layer was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 0.76 g (yield 71%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: Nc1cc(F)ccc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1cc(F)ccc1F)c1ccccc1
Temperature: 40 °C

Procedure:
0.194 mole (25 g) of 2,5-difluoroaniline is added to 125 ml of pyridine. 0.2 mole (25.5 ml) of benzenesulphonyl chloride is added, while the temperature is between 35° C. and 45° C. The temperature is maintained at 40° C. for 1 hour after the addition is completed, and then the reaction mixture is poured onto 1 kg of ice and water to which 100 ml of concentrated hydrochloric acid have been added. The expected product precipitates. After filtration and washing, it is treated with a normal sodium hydroxide solution in order to remove insoluble material. The soda-containing filtrate is neutralized with concentrated hydrochloric acid. The expected product, which has precipitated, is filtered off, washed to neutrality and recrystallized from acetic acid. It melts at 115° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:34])([F:33])[F:32])[O:15][N:14]=[C:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]4[CH:27]=[N:28][NH:29][CH:30]=4)=[CH:18][CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.I[CH2:36][C:37]([F:40])([F:39])[F:38].O>CN(C=O)C>[Cl:10][C:8]1[CH:7]=[C:6]([C:11]2([C:31]([F:32])([F:34])[F:33])[O:15][N:14]=[C:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]4[CH:30]=[N:29][N:28]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH:27]=4)=[CH:18][CH:17]=3)[CH2:12]2)[CH:5]=[C:4]([Cl:3])[CH:9]=1
Reactant: FC(F)(F)CI
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(-c3cn[nH]c3)c3ccccc23)=NO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Cn1cc(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (2 mg) is added to a solution of 5-(3,5-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-naphthalen-1-yl]-5-trifluoromethyl-4,5-dihydro-isoxazole (3 mg, Example 2) in DMF (0.4 ml) at 0° C. After 1 hour at room temperature 2-iodo-1,1,1,-trifluoroethane (16 mg) is added and the reaction mixture is further stirred for 16 hours at room temperature. Water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-(3,5-dichloro-phenyl)-3-{4-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-naphthalen-1-yl}-5-trifluoromethyl-4,5-dihydro-isoxazole (compound 1.18, Table 1) as a colorless wax.
Reaction SMILES: C([O:4][CH:5]([CH3:29])[CH2:6][C:7]([CH2:18][P:19]([O:25]C(C)C)([O:21]C(C)C)=[O:20])=[CH:8][CH:9]([NH:15]C=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)C.C(Cl)Cl.C[Si](C)(C)Br>C(O)C>[NH2:15][CH:9]([CH:8]=[C:7]([CH2:18][P:19]([OH:25])([OH:21])=[O:20])[CH2:6][CH:5]([OH:4])[CH3:29])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C=C(CC(C)OC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CC(C)O)CP(=O)(O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
11.5 g (26.4 mmol) of ethyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate are dissolved in 70 ml of abs. CH2Cl2 and to this solution are added 13.7 ml (105.6 mmol) of trimethylbromosilane. The reaction mixture is allowed to stand for 24 hours at room temperature and, after addition of 70 ml of abs. ethanol, allowed to stand again for 24 hours. The reaction mixture is concentrated by evaporation and the residue is dissolved in 70 ml of ethanol. A mixture of 70 ml of propylene oxide and 70 ml of ethanol is then added dropwise. The white suspension so obtained is stirred for 30 minutes at room temperature and for 30 minutes at 0° C. and then filtered with suction. The filter product is dried giving white crystals of ethyl 2-amino-6-hydroxy-4-phosphonomethyl-hept-3-enoate with a melting point of 211°-212° C. (decomp.).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]([Cl:13])=[C:6]([NH2:14])[CH:5]=1.[CH:16]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])=[CH2:17].O>P(=O)(O)(O)O>[Cl:13][C:7]1[C:8]([O:10][CH2:11][CH3:12])=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[CH:5][C:6]=1[N:14]1[CH2:22][CH2:21][S:18](=[O:20])(=[O:19])[CH2:16][CH2:17]1
Reactant: C=CS(=O)(=O)C=C
Reactant: CCOc1cc(C(=O)OC)cc(N)c1Cl
Agent: O=P(O)(O)O
Solvent: O
Product: CCOc1cc(C(=O)O)cc(N2CCS(=O)(=O)CC2)c1Cl
Temperature: 140 °C
Yield: 12.4 %

Procedure:
A mixture of 3-amino-4-chloro-5-ethoxy-benzoic acid methyl ester (1.0 g, 4.35 mmol, 1.0 equiv) and divinylsulfone (0.44 mL, 0.51 g, 4.35 mmol, 1.0 equiv) in phosphoric acid 85% (25 mL) was heated to 140° C. overnight. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1+1% acetic acid) yielding 0.18 g (12%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.0 Hz, 3H), 3.25-3.29 (m, 4H), 3.57-3.60 (m, 4H), 4.19 (q, J=7.0 Hz, 2H), 7.44 (d, J=1.7 Hz, 1H), 7.47 (d, J=1.7 Hz, 1H). MS (ISN): 332.1 [M−H]−.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[Cl:24])[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Ni]>[Cl:24][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH2:23][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15](=[O:25])[NH:16]2
Reactant: O=C1Nc2cccc(Cl)c2CN1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Product: O=C1Nc2cccc(Cl)c2CN1C1CCNCC1

Procedure:
100 mg (3-(1-benzyl-piperidin-4-yl)-5-chloro-3,4-dihydro-1H-quinazolin-2-one and 15 mg Raney nickel were stirred for 12 h at RT in a hydrogen atmosphere (30 psi). The reaction was filtered and the filtrate was evaporated to give 67 mg of the desired product. (M+H)+: 266
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[CH2:9]([O:11][C:12]#[CH:13])[CH3:10].C(N(CC)CC)C>CCOCC>[CH2:12]([O:11][C:9]1[C:2]([CH3:1])([CH2:6][CH2:7][CH3:8])[C:3](=[O:4])[CH:10]=1)[CH3:13]
Reactant: C#COCC
Reactant: CCCC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCC1(C)C(=O)C=C1OCC
Yield: 77 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al [J. Org. Chem, 38, 1451-1455, (1973)]; to a solution of 2-methyl pentanoyl chloride (3.91 ml) and ethyl ethynylether (5 g, 40% solution in hexanes, 28.6 mmol) in Et2O (35 ml) at room temperature was added triethylamine (9.9 ml), with stirring. The reaction was warmed to 50° and stirred for 72 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a colourless oil (3.71 g, 17.9 mmol, 77%). δH (CDCl3, 300K), 4.84 (1H, s), 4.24-3.98 (2H, m), 2.04 (3H, s), 1.56-1.43 (4H, m), 1.30-1.26 (3H, m), 0.91 (3H, t, J 7.3 Hz). m/z (ES+, 70V) 178.1 (MH+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH3:19][C@H:20]([C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[C:21](Cl)=[O:22]>C1COCC1>[CH2:17]([O:16][C:13](=[O:15])[CH2:14][C:21](=[O:22])[C@H:20]([CH3:19])[C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[CH3:18]
Reactant: CCOC(C)=O
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)OCC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution containing 2.0 g (13.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was added 2.1 g (16.6 mmol) of chloromethylene dimethyl-ammonium chloride. After stirring the resulting solution under nitrogen for 1.5 hours, the solvent was evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml, 52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5 mmol) in dry THF (20 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. and 4.3 g (48.5 mmol) of ethyl acetate was added. The solution was stirred at that temperature for 45 minutes. (2R,3R)-2,3-Dimethyl-hexanoyl chloride in dry THF (20 mL) was slowly added to the ethyl acetate enolate at −78° C. and the resulting reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and was cooled to 0° C. The reaction was quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 2.7 g (89.2% yield) of the titled compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1
Reactant: O=C1CCCc2[nH]c3c(Cl)cccc3c21
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccc(F)cc1
Reaction time: 0.37 h
Yield: 70.8 %

Procedure:
8-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1973 g, 0.90 mmol) is added to a slurry of pentane-washed NaH (0.0286 g, 0.72 mmol) in DMF (1 mL) and, after stirring for 22 min, p-fluorobenzyl bromide (0.14 mL, 0.0011 mol) is added. Starting material remained after 30 min, so additional NaH (0.0166 g, 0.42 mmol) and DMF (1.8 mL) are added. The mixture is stirred for 1 h, at which time the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from 30% ethyl acetate/hexane and dichloromethane to give 0.2088 g (71%) of the title compound; mp 166-166.5° C.; MS (ESI+) for C19H15ClFNO m/z 328.1 (M+H)+; IR (drift) 1639, 1607, 1510, 1485, 1449, 1426, 1413, 1226, 1189, 1157, 1108, 1095, 830, 790, 734 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.84, 5.78, 6.97, 7.19, 8.27. Anal. Calcd for C19H15ClFNO: C, 69.62; H, 4.61; N, 4.27. Found: C, 69.44; H, 4.55; N, 4.34.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])=[O:3].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27]Br>>[C:2]([C:4]1[C:9]([O:10][CH2:27][CH2:26][CH2:25][Br:24])=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])(=[O:3])[CH3:1]
Reactant: BrCCCBr
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1c(C(C)=O)c(OCCCBr)c(OC)c2occc12
Yield: 88 %

Procedure:
Khellinone (400 mg, 1.7 mmol, 0.3 M), K2CO3 (3 eqs) and 1,3-dibromopropane (3 eqs) were reacted according to General Procedure A. The crude product was purified by flash chromatography, eluting with ethyl acetate:petroleum ether (15:85) to afford the title compound as a clear oil (530 mg, 88%). 1H NMR (300 MHz, CDCl3): δ 2.24 (quintet, J=6.2 Hz, 2H), 2.51 (s, 3H), 3.57 (t, J=6.6 Hz, 2H), 3.97 (s, 3H), 4.07 (s, 3H), 4.19 (t, J=6.4 Hz, 2H), 6.86 (d, J=2.2 Hz, 1H), 7.56 (d, J=2.2 Hz, 1H). MS (ES+) m/z 356.8/358.8 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26]C3CCCCO3)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:33](=[O:36])[CH2:34][CH3:35])=[C:5]2[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH2:23][CH2:24][CH2:25][OH:26])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:33](=[O:36])[CH2:34][CH3:35])=[C:5]2[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-propionyl-2-[4-[3-(tetrahydropyran-2-yloxy)propan-1-sulfonyl]benzyl]-2H-isoquinolin-1-one (110 mg) in methanol (10 ml) was added p-toluenesulfonic acid monohydrate (49 mg), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2-+1/9) to give the title compound (95 mg, 98%).
Reaction SMILES: O[CH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:45]=[N+:46]=[N-:47].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[N:45]([CH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1)=[N+:46]=[N-:47]
Reactant: [N-]=[N+]=N
Reactant: O=[N+]([O-])c1ccc(C2=NN=C(CO)Cc3cc4c(cc32)OCO4)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 3.06 g (9.0 mmol) of 8-hydroxymethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine (starting compound III.) and 2.58 g (9.9 mmol) of triphenylphosphine in 100 ml of dry tetrahydrofuran is mixed with 13.5 ml of a 1.2N hydrazoic acid solution in toluene, then a solution of 1.74 ml (9.9 mmol) of azodicarboxylic acid-diethyl ester is added, and the mixture is stirred for another 2 hours. The precipitated product is suctioned off and washed with tetrahydrofuran and n-hexane. 2.23 g (68%) of the title compound with a melting point of 198-200° C. is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=1[O:5][CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:19]([C:23]1[N:24]=[C:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34](O)=[CH:33][C:31]=3[CH:32]=2)[S:26][CH:27]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:19]([C:23]1[N:24]=[C:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([O:1][CH2:2][C:3]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=4[O:5][CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:33][C:31]=3[CH:32]=2)[S:26][CH:27]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Reactant: CCOC(=O)C(C)Oc1c(CO)cccc1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1c(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)cccc1OC
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a solution of ethyl 2-(2-hydroxymethyl-6-methoxyphenoxy)propionate (1.97 g), 2-(4-tert-butylthiazol-2-yl)-5-hydroxybenzofuran (1.83 g), and triphenylphosphine (2.83 g) in tetrahydrofuran (20 ml) was added a solution of diethyl azodicarboxylate (1.67 g) in tetrahydrofuran (2 ml) under ice-cooling. The mixture was stirred at the same temperature for an hour and at room temperature for an hour. The mixture was concentrated under reduced pressure and the residue was subjected to a column of silica gel (250 ml) eluting with a mixed solvent of n-hexane and ethyl acetate (7:1) to give ethyl 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-6-methoxyphenoxy}propionate (2.31 g).
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CO>[CH2:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:9]([OH:10])=[O:8])[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)C1CCCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution 3.0 g (9.7 mmol) of 1-benzylpiperidine-3-carboxylic acid benzyl ester (Example A21) in methanol (20 mL) was added 1N sodium hydroxide (20 mL), and the reaction is stirred at room temperature for 18 hours. The methanol is removed in vacuo and the basic aqueous solution is acidified to pH 4 with 1.0 M hydrochloric acid. After washing with ethyl acetate, the aqueous acid layer is lyophilized. The solid is suspended in methanol (10 mL), stirred for 10 minutes and filtered. The filtrate is evaporated in vacuo to afford the title compound (2.0 g). 1H NMR (200 MHz, DMSO-d6): δ 7.38-7.23 (m, 5H), 3.58 (s, 2H), 2.98-2.40 (m, 3H), 2.30-1.25 (m, 6H).
Reaction SMILES: CCN(CC)CC.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[CH2:8]([NH:15][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of Et3N (13.55 g, 133.9 mmol) and benzylamine (11.96 g, 111.6 mmol) in THF (25 ml) was added 2-bromo-1-(4-methoxy-phenyl)-ethanone (25.56 g, 111.6 mmol). The reaction was stirred at RT for 60 minutes, then filtered and the filtrate concentrated in vacuo. The residue was purified via flash chromatography (SiO2, gradient column 35% to 80% EtOAc/hexanes) to give the title product (17.12 g, 67.0 mmol, 60% yield).