Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22](C)=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].ClC1C2C=CC([F:39])=CC=2SC=1C(O)=O>>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([F:39])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: Cc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Reactant: O=C(O)c1sc2cc(F)ccc2c1Cl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(F)ccc2c1Cl

Procedure:
Following the 2a synthetic method, using 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylic acid (115.32 mg, 0.5 mmol) instead of 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid gave 4a as a white powder; (177.01 mg, 93.7%). [α]D25: −21.9 (c=0.37, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.95-7.76 (m, 3H), 7.44-7.22 (m, 6H), 5.04-4.97 (m, 1H), 3.45-3.26 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.48, 163.90, 160.62, 159.50, 139.15, 136.67, 133.50, 129.50, 128.40, 126.89, 124.94, 118.57, 115.15, 114.82, 109.30, 108.95, 53.95, 36.78; HRMS (ESI): calcd for: C18H13ClFNO3S [M+H]+=378.0361, obsd [M+H]+=378.0347.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]1[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19][CH2:18][CH2:17][C@@H:16]([CH3:24])[CH2:15][C@@H:14]([C@@H:25]([OH:36])[CH2:26][C@H:27]([C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])[NH:13][C:12](=[O:37])[C@H:11]([CH3:38])[NH:10][C:9]1=[O:39])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CCO.[Pd]>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:24])[CH2:15][C@@H:14]([C@@H:25]([OH:36])[CH2:26][C@H:27]([C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])[NH:13][C:12](=[O:37])[C@H:11]([CH3:38])[NH:10][C:9]1=[O:39])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCC=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1

Procedure:
A solution of 199 mg (0.35 mmol) [(3S,6S,14R,16S)-16-((1S,3R)-3-butylcarbamoyl-1-hydroxy-butyl)-3,14-dimethyl-2,5-dioxo-1,4-diaza-cyclohexadec-10-en-6-yl]-carbamic acid tert-butyl ester in 10 ml THF and 10 ml EtOH is stirred in the presence of 20 mg 10% Pd-C under an hydrogen atmosphere for 1 h. The mixture is filtered over a pad of celite and the solvent evaporated. This yields the title compound as a white powder.
Reaction SMILES: [C:1]1(=[O:10])[O:9][C@H:6]([CH2:7][OH:8])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12]1([CH3:14])[O:3][CH:2]2[CH:4]([CH:6]([CH2:7][OH:8])[O:9][C:1]2=[O:10])[O:5]1
Reactant: CC(C)=O
Reactant: O=C1O[C@H](CO)[C@H](O)[C@@H]1O
Product: CC1(C)OC2C(=O)OC(CO)C2O1

Procedure:
The multi-step synthesis from D-galactose comprises oxidizing the D-galactose in KOH solution to open the pyranose ring and form potassium D-lyxonate, subjecting the latter compound to alcoholic solution under acid conditions to provide furanose ring closure and form the D-lyxono-1,4-lactone, and then introducing a protecting group at C-2 and C-3 by reaction with ketone in the presence of a dehydrating agent. Use of acetone as the ketone in the latter step gives the compound 2,3-0-isopropylidene-D-lyxono-1,4-lactone. From that point on the multi-step system includes the general reaction steps of the above short synthesis.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution containing ethyl 6-methyl-3-pyridyloxyacetate (0.026 g, 0.13 mmol) in a mixture of THF (0.5 mL) and water (0.5 mL) was treated with lithium hydroxide monohydrate (0.008 g, 0.19 mmol), stirred at 25° C. for 18 hours, aid concentrated to give the crude product, which was used without purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[C:13]([CH2:26][OH:27])=[N:14][C:15]2[C:16]([CH3:25])([CH3:24])[CH2:17][CH2:18][C:19]([CH3:23])([CH3:22])[C:20]=2[N:21]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.CCCCCC.O>[CH3:11][C:12]1[C:13]([CH:26]=[O:27])=[N:14][C:15]2[C:16]([CH3:25])([CH3:24])[CH2:17][CH2:18][C:19]([CH3:23])([CH3:22])[C:20]=2[N:21]=1
Reactant: Cc1nc2c(nc1CO)C(C)(C)CCC2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2c(nc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
A solution of 923 μl of dimethylsulfoxide in 2 ml of dichloromethane was added dropwise to a solution of 797 μl of oxalyl chloride in 6 ml of dichloromethane at −60° C. under a nitrogen gas stream, followed by stirring for 5 minutes. To the reaction mixture, a solution of 1 g of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylquinoxaline-2-methanol in 6 ml of dichloromethane was added dropwise and the resulting mixture was stirred for 15 minutes. Triethylamine (4.8 ml) was then added dropwise to the reaction mixture, followed by stirring for 5 minutes. After the reaction mixture was raised to room temperature and stirred for 15 minutes, water was added thereto. The resulting mixture was extracted with dichloromethane. The organic layer was successively washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 10% ethyl acetate/n-hexane), whereby 940 mg of the title compound were obtained in the form of a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:1][CH2:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:7][CH2:8]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate (0.50 g, 2.2 mmol) (Supplier: Chem-Impex) in methylene chloride (15 mL) was added triethylamine (1.29 mL, 9.27 mmol), 4-dimethylaminopyridine (53 mg, 0.44 mmol), and p-toluenesulfonyl chloride (0.89 g, 4.7 mmol). The resulting mixture was stirred at room temperature for 2 h before adding more p-toluenesulfonyl chloride (0.42 g, 2.2 mmol). The mixture was stirred overnight. Water and dichloromethane were added and the layers separated. The aqueous was extracted with dichloromethane. The combined organics were washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue was purified on Biotage Isolera (40 g Agela cartridge, eluted with 5-50% EtOAc/hexanes over 15 min) to give the desired product (0.72 g, 86%) as a white crystalline solid. LCMS calculated for C19H29NO5SNa (M+Na)+: m/z=406.2. Found: 406.0.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH2:20][O:21][C:22]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=4[CH:24]=3)(=[O:18])=[O:17])[CH2:12][C:11]2=[O:30])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[C:33]([O:36][CH:37]([O:39][C:40](OC1C=CC([N+]([O-])=O)=CC=1)=[O:41])[CH3:38])(=[O:35])[CH3:34].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:33]([O:36][CH:37]([O:39][C:40]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH2:20][O:21][C:22]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=4[CH:24]=3)(=[O:18])=[O:17])[CH2:12][C:11]2=[O:30])=[CH:31][CH:32]=1)=[NH:3])=[O:41])[CH3:38])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(C)OC(=O)NC(=N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Yield: 41.7 %

Procedure:
A solution of 1-(4-amidinobenzyl)-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone hydrochloride (99 mg), O-(1-acetoxyethoxycarbonyl)-4-nitrophenol (54 mg), diisopropylethylamine (39 mg) in DMF (5 ml) was stirred at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated. Precipitated crystals were washed with ether to give colorless crystals of the title compound (49 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:24]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][N:33]=[CH:32]2)([O-:26])=[O:25]>CN(C=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:34]3[C:35]4[C:31](=[CH:30][CH:29]=[CH:28][C:27]=4[N+:24]([O-:26])=[O:25])[CH:32]=[N:33]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=[N+]([O-])c1cccc2cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1ncc2cccc([N+](=O)[O-])c21)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (0.834 g, 3.3 mmol) was taken in dry DMF (15 mL) and dry potassium carbonate (1.6 g, 11.6 mmol) was added to it and the reaction mixture stirred at room temperature for 1 h under nitrogen. 7-Nitro-1H-indazole (0.5 g, 2.9 mmol) in DMF (2 mL) was then added to the mixture through a syringe. The reaction was then heated at 70° C. for 14 h, cooled and then quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded material that was purified on neutral alumina column (pet ether/ethyl acetate). The resulting solid was recrystallized from DCM/pet ether to obtain pure product as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1.[OH-].[Na+]>O1CCCC1.O>[N:1]1([CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:26])[CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCc1ccccc1)N1CCC(CCCl)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCc1ccccc1)N1CCC(CCn2ccnc2)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of imidazole (1.4 g) in dry tetrahydrofuran (20 ml) was added dropwise with stirring to a mixture of sodium hydride (0.8 g, 60% dispersion in mineral oil) in tetrahydrofuran (20 ml) under nitrogen. The mixture was stirred at 20° C. for 3 hours and then a solution of the product from Example 42 (5.6 g) in dry tetrahydrofuran (50 ml) was added dropwise with stirring. The mixture was heated under reflux for 9 hours and then cooled to 20° C. Water (50 ml) was added and the solution stirred for 10 minutes. The mixture was basified with dilute sodium hydroxide solution and extracted with dichloromethane. The combined dichloromethane extracts were washed (water), dried and filtered before evaporation to give 4-[2-(imidazol-1-yl)ethyl]-1-(3-phenylpropionyl)piperidine as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([N:21]=[N+]=[N-])[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[CH:17][N:16]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(N=[N+]=[N-])ncn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(N)ncn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of [4-(6-azido-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (870 mg, 2.66 mmol) and 10% Pd/C (174 mg) in MeOH (35 mL) is stirred for 1.5 h at rt and a hydrogen atmosphere. The reaction mixture is filtered through a plug of celite (washing the filter cake with copious amounts of MeOH). The filtrate is concentrated in vacuo to afford the title compound as a beige solid: ES-MS: 301.1 [M+H]+; single peak at tR=6.25 min (System 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[C@H:10]([CH2:23][C:24]([OH:26])=[O:25])[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=O)C(Cl)=O.CO>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[C@H:10]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetic acid (100 mg, 0.27 mmol) and N,N-dimethylformamide (1 drop) in dichloromethane (10 mL) was added oxalyl chloride (56 mg, 0.40 mmol) dropwise at 0° C. The mixture was stirred for 0.5 hour at room temperature. The solution was cooled to 0° C. and methanol (100 mL) was added. The mixture was stirred for 0.5 hour at room temperature. The mixture was concentrated in vacuo, and the residue was diluted with water (5 mL), and extracted with ethyl acetate (10 mL×3). The combined organic layers were dried by sodium sulfate, concentrated in vacuo and the residue was purified by column chromatography (silica-gel, petroleum:ethyl acetate=2:1) to give methyl 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (80 mg, 77%) as a light yellow solid. LC/MS m/z 380 [M+H]+.
Reaction SMILES: [C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18](Br)=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2].[C:39](N(CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C=C(C)C(C)=CC1=2)(=O)C>>[C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18]([CH3:39])=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cc(C)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(C)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(C)cc(C)cc21

Procedure:
This compound prepared utilizing the same methodology described in Example 56 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl 5-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-9-bromo-7-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylate following the procedure of Example 56 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7,8-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. ESI MS 545 (M+H).
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)[OH:4].C(N)(=O)C1CC=CNC=1.[C:23]([OH:32])(=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:26]>>[OH:26][C:25]1[C:27]([OH:4])=[CH:28][CH:29]=[CH:30][C:24]=1[C:23]([OH:32])=[O:31]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: NC(=O)C1=CNC=CC1
Product: O=C(O)c1cccc(O)c1O

Procedure:
The process is conducted in a manner similar to that described in Example 1 hereinbefore, except that 1 ml of the citrate buffer, 1 mg of cellulose modified with 1,4-dihydronicotinamide and 0.03 mg of 9-methyl-phenazium methyl sulfate and 0.3 mg. of salicylic acid are used. As a result, 0.28 mg. of 2,3-dihydroxybenzoic acid is obtained (95% as calculated for the starting compound) having m.p. 203°-204° C. The composition, in %, is as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:13][CH:14]=[C:7]1[C:6](=[O:21])[NH:5]2.[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cu](I)I.O>[CH:15]1([C:12]2[N:8]3[C:9]4[C:4]([NH:5][C:6](=[O:21])[C:7]3=[CH:14][N:13]=2)=[CH:3][C:2]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[CH:11][CH:10]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=c1[nH]c2cc(Br)ccc2n2c(C3CCCCC3)ncc12
Reactant: c1cn[nH]c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(-n3cccn3)ccc2n2c(C3CCCCC3)ncc12
Temperature: 160 °C
Reaction time: 22 h

Procedure:
7-Bromo-1-cyclohexylimidazo[1,5-a]quinoxalin-4(5H)-one as synthesized in above Example 145, 200 mg, pyrazole 59 mg, potassium carbonate 120 mg, copper iodide 28 mg and N,N-dimethylformamide 4 mL were mixed and stirred for 22 hours at 160° C. The reaction liquid was poured into water, and the precipitated matter was recovered by filtration. The precipitate was mixed with 25% aqueous ammonia and methanol, and heated under stirring. The insoluble matter was recovered by filtration, washed with water and dried by heating under reduced pressure to provide 30 mg of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:35](=[O:36])[C:34]([C:29]3[NH:28][C:27]4[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=4[S:31](=[O:33])(=[O:32])[N:30]=3)=[C:4]([OH:5])[C:6]3([CH2:7][CH2:8]3)[CH2:9]2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1(CNCc2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)C3(CC3)CN(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
A solution of 1-[(4-fluoro-benzylamino)-methyl]-cyclopropanecarboxylic acid ethyl ester (72 mg, 0.29 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (105 mg, 0.32 mmol) in anhydrous N,N-dimethylformamide (4 mL) was treated sequentially with N-methylmorpholine (70 μL, 0.64 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol). The reaction mixture was stirred at 25° C. for 1 h, diluted with a 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethanol (5 mL), treated with a 21 wt % solution of sodium ethoxide in ethanol (0.5 mL, 1.37 mmol). The reaction was stirred and heated at 60° C. for 1.5 h, allowed to cool to 25° C., and quenched with a 0.5 M aqueous hydrochloric acid solution (10 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by prep-HPLC {Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30-100% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to give N-{3-[5-(4-fluoro-benzyl)-8-hydroxy-6-oxo-5-aza-spiro[2.5]oct-7-en-7-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (58 mg, 39%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.97 (br s, 2H), 1.34 (br s, 2H), 3.06 (s, 3H), 3.41 (s, 2H), 4.65 (s, 2H), 7.17 (t, J=8.8 Hz, 2H), 7.36 (dd, J1=8.8 Hz, J2=5.4 Hz, 2H), 7.51 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.57-7.60 (m, 2H), 10.16 (s, 1H), 13.86 (br s, 1H). LC-MS (ESI) calculated for C22H21FN4O6S2: 520.1, found 521.3 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[O:27][CH3:28])=[CH:21][C:20]=2[NH:30][C:31](=[O:36])[C@H:32]([CH3:35])[CH:33]=[CH2:34])[CH:16]=[CH:15][N:14]=1)[CH2:10]C=C)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:13]2[CH:18]=[C:17]([CH:16]=[CH:15][N:14]=2)[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[O:27][CH3:28])=[CH:21][C:20]=2[NH:30][C:31](=[O:36])[C@H:32]([CH3:35])[CH:33]=[CH:34][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2NC(=O)[C@H](C)C=C)ccn1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)/C=C/C[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)C=CC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Temperature: 25 °C

Procedure:
To a RBF was added 1G (0.5 g, 1.011 mmol), pTsOH monohydrate (0.212 g, 1.112 mmol), and dichloromethane (84 ml). The flask was equipped with a reflux condensor and the clear yellow solution was degassed with argon for 30 min. The reaction was then warmed to reflux for 1 h. Then a solution of Grubbs II (0.172 g, 0.202 mmol) in DCM (2 mL) was added dropwise to the reaction mixture. After 4 h at reflux, the reaction was cooled to rt, washed with sat. Na2CO3, brine, dried over MgSO4, filtered, and concentrated to give a brown solid. The crude product was then purified using silica gel chromatography to give 1H (0.336 g, 71.2% yield) as a yellow solid. 1H NMR (500 MHz, METHANOL-d4) δ 8.52 (d, J=5.2 Hz, 1H), 7.54 (d, J=1.4 Hz, 1H), 7.48-7.43 (m, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.24 (dd, J=5.1, 1.5 Hz, 1H), 6.89 (s, 1H), 5.75-5.65 (m, 1H), 4.60 (dd, J=11.3, 3.6 Hz, 1H), 4.39 (dd, J=15.1, 9.6 Hz, 1H), 3.75 (s, 3H), 3.14-3.06 (m, 1H), 2.75-2.68 (m, 1H), 2.04-1.94 (m, 1H), 1.44 (s, 9H), 1.30 (br. s., 1H), 1.04 (d, J=6.6 Hz, 3H). MS (ESI) m/z: 467.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](O)=O)=[CH:14][CH:15]=1.[OH-].[Na+]>O>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
125 g (1 mol) of o-aminothiophenol, 136 g (1 mol) of p-toluic acid and 600 g of polyphosphoric acid were admixed and stirred into nitrogen gas at 170°-200° C. for 4 hours. After the reaction mixture was cooled to 100° C., it was poured in 5 l of water. The mixture was adjusted to pH 5 with NaOH and the resulting crystals were filtered off, whereupon 220 g of 4-(benzothiazol-2-yl) toluene was obtained as crude crystals. Recrystallization from n-hexane gave 172 g of pure product as colorless prisms melting at 84°-85° C.