Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O.ClCCl>[O:8]([CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
4-Pyridylcarbinol (8.5 g, 0.08 mol) was dissolved in a 9:1 mixture of N,N-dimethylformamide and dichloromethane (150 mL). t-Butyldimethylsilylchloride (13 g, 0.09 mol) and imidazole (6.4 g, 0.09 mol) were added and the solution was stirred for 12 hours at room temperature. The reaction mixture was concentrated at reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure to give the title compound (17.4 g, 92%) as a colorless oil; MS(ES) m/e 244 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([Cl:17])=[O:14])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=C(O)c1cc(Cl)cc2c1OCCO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)cc2c1OCCO2
Yield: 100 %

Procedure:
32.2 g of 7-chloro-1,4-benzodioxane-5-carboxylic acid and 64 ml of thionyl chloride were introduced into a balloon flask provided with an agitator, a thermometer and a condenser. The mixture was heated under reflux and then the thionyl chloride in excess was distilled off under vacuum. 35 g of 7-chloro-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 140° C.; yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:10]([O-])([OH:12])=[O:11]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To stirred 3,4-dichloro-toluene 4 (10.0 g, 62.2 mmol) at 0° C. was slowly added fuming nitric acid (20.0 mL). The mixture was stirred for 2 hrs at RT, then water added (200 mL) and the reaction mixture filtered. The filtrate was purified by silica gel chromatography using 5% ethyl acetate in hexanes to give the title compound 11.7 g (92%). 1H NMR (400 MHz, CDCl3) δ8.14 (s, 1 H, Ar), 7.47 (s , 1 H, Ar), 2.59 (s, 3 H, CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)C(NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1C(=O)C(NC(=O)OC(C)(C)C)CN(S(=O)(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 0.087 g (1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 1 ml of dichloromethane, 0.064 g of benzene sulfonyl chloride and 0.052 g of pyridine were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched by addition of 1 M HCl (1 ml) and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3, dried (MgSO4) and evaporated on the rotary evaporator to yield 0.113 g (95%) of the product as a light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH2:7][C@H:8](O)[CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C@H:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=2)=[C:4]([C:31]#[N:32])[CH:3]=1.C(N(S(F)(F)[F:39])CC)C.O.[Cl-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH2:7][C@@H:8]([F:39])[CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C@H:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=2)=[C:4]([C:31]#[N:32])[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)[C@H](Cc1cccc(OC[C@@H](O)COc2ccc(Cl)cc2C#N)c1)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cccc(OC[C@H](F)COc2ccc(Cl)cc2C#N)c1)OC(C)C
Temperature: -68 °C
Reaction time: 96 h

Procedure:
65.3 g of ethyl (2S)-3-{3-[(2R)-3-(4-chloro-2-cyanophenoxy)-2-hydroxypropoxy]phenyl}-2-isopropoxypropionate was dissolved in 1.3L of dichloromethane, which was then cooled to −68° C. Then 54 mL of diethylaminosulfur trifluoride was added, followed by stirring at room temperature for 4 days. The reaction mixture was cooled with ice, to which water (1 L) and a saturated sodium chloride solution (1 L) were then added, followed by extraction with ethyl acetate (4 L). The organic layer was washed with the saturated sodium chloride solution (2 L) and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under a reduced pressure. The residue was purified using silica gel column chromatography to obtain 33 g of ethyl (2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionate from a hexane-ethyl acetate (7:1→5:1)-eluted fraction. This compound was dissolved in 400 mL of ethanol, to which 107 mL of 2N sodium hydroxide aqueous solution was then added, followed by stirring the reaction mixture at room temperature for 2 hours. The reaction mixture was cooled with ice, to which water (500 mL) and a 5N hydrochloric acid aqueous solution (50 mL) were then added before further adding water (1 L), followed by extraction with ethyl acetate (2.5 L). The organic layer was washed with the saturated sodium chloride solution (1 L) and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under a reduced pressure. The residue was purified using silica gel column chromatography to obtain 27.6 g of the title compound in the form of colorless oily matter from a hexane-ethyl acetate (3:1→1:1)-eluted fraction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N+:6]([O-:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N+]([O-])=O.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>ClCCl>[Cl:15][C:3]1[CH:4]=[C:5]([CH3:9])[N+:6]([O-:8])=[CH:7][C:2]=1[Br:1]
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(Cl)c(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-bromo-4-nitro-2-picoline-N-oxide (30.0 g) in dichloromethane (250 ml) was cooled at 10°, and a solution of phosphoryl chloride (35.5 ml) in dichloromethane (200 ml) added over 15 minutes. The mixture was heated under reflux for 5 hours, allowed to cool to ambient temperature, and allowed to stand for 16 hours. After pouring onto ice (300 ml) and stirring for 15 minutes, the mixture was basified to pH 10 using concentrated aqueous sodium hydroxide. The organic phase was separated off, and the aqueous phase further extracted with chloroform (2×100 ml). The combined organic phases were dried (K2CO3) and stripped to a solid, which was triturated with petroleum ether (40-60), filtered, washed and dried to yield 4-chloro-5-bromo-2-picoline-N-oxide, 24.08 g, m.p. 121°-4° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:25])[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC.CCOC(C)=O>C1(C)C=CC=CC=1.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>[Cl:25][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([CH:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[N:3]2
Reactant: CC(c1cc2c(Cl)cccc2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(c1cc2c(Cl)cccc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 0.01 h

Procedure:
Transferred 2-(1-(2,5-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (197 mg, 531 μmol) from 100 mL flask to 10 mL flask by dissolving/slurrying in toluene and concentrating. Added Pd(Ph3P)4 (61 mg, 53 μmol) and 2-tri-n-butylstannylpyridine (955 μl, 2653 μmol). Bubbled argon through mixture for 30 sec. Equipped with condensor and nitrogen inlet. Heated at 110° C. for ˜16 h. The reaction mixture was concentrated and chromatographed on 12 g silica gel column with 0-60% EtOAc. The desired fractions were combined and concentrated to yield an oil. NMR indicates residual EtOAc. LC. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.98 (d, J=7.04 Hz, 3 H) 6.38 (q, J=7.04 Hz, 1 H) 7.24-7.37 (m, 1 H) 7.62-7.76 (m, 8 H) 8.01 (dd, J=8.61, 1.96 Hz, 1 H) 8.56-8.66 (m, 1 H) 9.02 (s, 1 H).−MS (+esi, M+H+=414.1)
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([F:12])[C:6]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)(=O)C.[OH-].[K+].O.[OH-].[K+].O>O1CCOCC1>[Br:11][C:9]1[CH:8]=[C:7]([F:12])[C:6]2[O:13][CH2:14][CH:15]([CH2:17][OH:16])[O:4][C:5]=2[CH:10]=1
Reactant: CC(=O)Oc1cc(Br)cc(F)c1OCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: OCC1COc2c(F)cc(Br)cc2O1
Yield: 35 %

Procedure:
5-bromo-3-fluoro-2-(oxiran-2-ylmethoxy)phenyl acetate (2.6 g, 8.7 mmol) was stirred in dioxane at RT. Aqueous KOH (10%) was added until basic pH was reached (1:1 water/KOH (10%)). Water was added and the solution was extracted with EtOAc: The combined organic phases were washed with brine, dried and evaporated to dryness to give the title compound (0.8 g). MS m/z (rel. intensity, 70 eV) 263 (M+, 97), 262 (M+, bp), 218 (39), 207 (50), 206 (51).
Reaction SMILES: [NH2:1][C:2]1[C:3](C#CCCCCC(O)=O)=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>>[NH2:1][C:2]1[C:3]([C:34]#[C:33][CH2:32][CH2:31][OH:35])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: C#CCCO
Reactant: Cc1ccc(-c2nc(N)c(C#CCCCCC(=O)O)nc2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(N)c(C#CCCO)nc2-c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared analogously to 7-(3-amino-5,6-di-p-tolylpyrazin-2-yl)hept-6-ynoic acid (Ex 7 step 1) by replacing hept-6-ynoic acid with but-3-yn-1-ol;
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][C:12](=[O:14])[C:11]([C:15](O)=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][C:12](=[O:14])[C:11]([C:15]([Cl:25])=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)sc2cc1OC(C)=O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)sc2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-2-oxo-2H-1-benzothiopyran-3-carboxylic acid (60 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 2 hours in benzene (15 mL), and then the solvent was distilled off. Benzene (15 mL) was added to the residue, and the benzene was distilled off again, followed by vacuum drying to yield 6,7-diacetoxy-2-oxo-2H-1-benzothiopyran-3-carbonyl chloride.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4,4-diphenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 60% overall yield. mp 198°-199°. FDMS m/e=426 (M+ of free base). α[D]589 =-17.80 (c=0.66, methanol).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[NH2:24]OC(C1C=CC(OC)=CC=1)=O.COC1C=CC(C(ON)=O)=CC=1>CN1CCCC1=O.CCOC(C)=O>[NH2:24][N:10]1[C:8]2[N:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:12]=[N:11]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Reactant: COc1ccc(C(=O)ON)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2N
Reaction time: 0.33 h

Procedure:
Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865 mmol) was dissolved in N-Methyl-2-pyrrolidone (NMP) (8 mL), followed by addition of potassium tert-butoxide (116 mg, 1.038 mmol). After 20 minutes stirring, O-{[4-(methyloxy)phenyl]carbonyl}hydroxylamine 1-[(aminooxy)carbonyl]-4-(methyloxy)benzene (289 mg, 1.730 mmol) was added and the mixture stirred at room temperature for 16 h. The contents were diluted with EtOAc, and then washed with brine, and saturated NaHCO3. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography (eluent: 0 to 50% EtOAc). The final product as collected as 106 mg (50%). LCMS E-S (M+H)=274.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.14 (m, 4 H), 1.41 (t, J=7.07 Hz, 3 H), 2.34-2.47 (m, 1 H), 4.44 (q, J=7.07 Hz, 2 H), 6.39 (s, 2 H), 7.64 (s, 1 H), 8.09 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:36](=[O:38])[CH3:37])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: CC(=O)Cl
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol) and triethylamine (0.035 ml, 0.25 mmol) in dichloromethane (0.6 ml) was added acetyl chloride (0.18 ml, 0.251 mmol) at room temperature. Stirring for 20 h was followed by partitioning between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5 ml-portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (7 mg, 12%) as off-white solid. MS m/e: 440 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[C:24]4[N:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:18][CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccnc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ncccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: ClC1C=CC=CC=1C([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:23]([Cl:26])(Cl)Cl>>[Cl:26][C:23]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:7]([C:12]1[CH:11]=[C:10]([F:13])[CH:9]=[CH:8][C:7]=1[OH:6])=[O:6]
Reactant: ClC(Cl)Cl
Reactant: O=C(Oc1ccc(F)cc1)c1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1cc(F)ccc1O)c1ccccc1Cl
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a stirred solution of 2.5 g of compound A was added in small portions 1.47 g of powdered aluminum chloride at 130° C. and stirring was continued for another 1 hour. After cooling 1N HCl and chloroform was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with chloroform. The combined organic layer was dried over magnesium sulfate and distilled to remove the solvent. The crude product thus obtained was crystallized from hexane to obtain 1.41 g of compound B. Yield: 56.3%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][C@H:15]4[C@H:14]([N:27]1[C:31](=[O:32])[CH:30]=[CH:29][C:28]1=[O:33])[CH2:13][CH2:12][C@@:11]35[OH:34])(=[O:3])[CH3:2].[N+]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O-])=O.C1CCN2C(=NCCC2)CC1.C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH2:23][CH:24]4[CH2:25][CH2:26]4)[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][C@H:15]4[C@H:14]([N:27]1[C:31](=[O:32])[CH2:30][C:29](=[CH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:28]1=[O:33])[CH2:13][CH2:12][C@@:11]35[OH:34])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])Cc1ccccc1
Reactant: CC(=O)Oc1ccc2c3c1O[C@H]1[C@H](N4C(=O)C=CC4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@H](N4C(=O)CC(=Cc5ccccc5)C4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
In 5 mL of THF, 200 mg (0.43 mmol) of N-(3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl)-maleimide obtained in Example 21-1 was dissolved, and 85 mg (0.62 mmol) of nitromethylbenzene and 66 mg (0.43 mmol) of DBU were added, followed by stirring the mixture at room temperature for 1 hour. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 196 mg (yield: 82%) of the captioned compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:47].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:47])[NH2:41])=[CH:36][CH:35]=1)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CCCn1c(COc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCCn1c(COc2ccc(C(=N)N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 1e from 1-(3-ethoxycarbonylpropyl)-2-[(4-cyanophenyl)-oxymethyl]-5-(quinoline-8-sulphonylamino)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][NH:3][C:2]1=[O:6].[CH2:7]([SH:9])[CH3:8].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:7]([S:9][CH:5]1[O:1][C:2](=[O:6])[NH:3][CH2:4]1)[CH3:8]
Reactant: CCS
Reactant: O=c1[nH]cco1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCSC1CNC(=O)O1

Procedure:
A solution mixture comprising 3 g of 2-oxazolone, 25 ml of ethyl mercaptan and 600 mg of azobisisobutyronitrile, was reacted at 100° C. for 8 hours in an autoclave. After the completion of the reaction, excess ethyl mercaptan was distilled off, and the residue was purified by silica gel chromatography to obtain 1.6 g of 5-ethylthiooxazolidin-2-one having a melting point of from 82° to 86° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])(=[O:15])=[O:14].[OH-].[Li+]>O.CO>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=1[S:13]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][CH2:5][CH2:4][C:3]([OH:24])=[O:2])(=[O:14])=[O:15]
Reactant: COC(=O)CCCC1CCCCN1S(=O)(=O)c1c(C)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CCCC(=O)O

Procedure:
4-(1-(2-Chloro-6-methylphenylsulfonyl)piperidin-2-yl)butanoic acid methyl ester (2.7 g, 7.3 mmol, 1 eq.) was dissolved in water (20 ml) and methanol (30 ml). Lithium hydroxide (0.87 g, 36.5 mmol, 5 eq.) was added, while stirring. The mixture was stirred at room temperature for 24 h.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12](=[O:15])[NH:13][CH3:14])=[C:7](B(O)O)[O:8][C:4]=2[CH:3]=1.Br[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12]([NH:13][CH3:14])=[O:15])=[C:7]([C:20]3[CH:25]=[N:24][C:23]([F:26])=[CH:22][CH:21]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CNC(=O)c1c(B(O)O)oc2cc(N)c(Br)cc12
Reactant: Fc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)nc2)oc2cc(N)c(Br)cc12
Temperature: 50 °C
Reaction time: 10 h
Yield: 51.2 %

Procedure:
To a solution of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (500 mg, 1.61 mmol) in dioxane/H2O (5 mL/0.5 mL) was added 5-bromo-2-fluoropyridine (420 mg, 2.42 mmol), Pd(dppf)Cl2(10 mg) and K3PO4.3H2O (855 mg, 3.21 mmol). The mixture was stirred at 50° C. for 10 h. The mixture was evaporated and washed with MeOH to obtain the yellow solid as the product of 6-amino-5-bromo-2-(6-fluoropyridin-3-yl)-N-methylbenzofuran-3-carboxamide (300 mg, yield: 51%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.76 (s, 1H), 8.44˜8.51 (m, 2H), 7.75 (s, 1H), 7.39˜7.42 (m, 1H), 7.09 (s, 1H), 5.71 (s, 2H), 2.88 (d, J=8.4 Hz, 3H). (M+H)+: 364/366.