Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4](=[O:9])[C:3]=1[OH:10].[CH3:11][O-:12].[Na+].[Na]>CO>[OH:10][C:3]1[C:4](=[O:9])[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[O:12][CH3:11]
Reactant: C[O-]
Reactant: O=c1ccccc(Br)c1O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ccccc(=O)c1O
Temperature: 80 °C

Procedure:
A solution of 3-bromo-2-hydroxy-2,4,6-cycloheptatrien-1-one [27.5 g, described by T. Toda et al., Nippon Kagaku Zasshi, 88, 1234-5 (1967), (CA 68 101342)] and sodium methoxide (prepared from 12.6 g of sodium in methanol followed by evaporation of the methanol) in dimethyl sulfoxide (300 ml) is heated at 80° C. for one hour. The solution is cooled poured on ice, acidified with 2N sulfuric acid and extracted with ethyl acetate. The organic extract is washed with brine, dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate-hexane to give 2-hydroxy-3-methoxy-2,4,6-cycloheptatrien-1-one. Evaporation of the mother liquors gives 2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:22](=[O:24])[CH2:21][NH:20][C:17]2[S:18][CH:19]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)[N:16]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)Nc1ccc(F)cc1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 200 mg (0.55 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 121.3 mg (1.1 mmol) of 4-fluoroaniline. Yield: 13 mg.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([Cl:15])=[N:10]2.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>CCOCC>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[CH2:4][CH2:3][OH:2])[N:10]=1
Reactant: COC(=O)Cc1cccc2nc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCc1cccc2nc(Cl)ccc12
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A mixture of 0.35 g (1.46 mmol) (2-chloro-quinolin-5-yl)-acetic acid methyl ester and 10 mL anhydrous THF was cooled to −20° C. in a dry ice/acetone bath. 1.4 mL (1.4 mmol) IM LiAlH4 solution in ether was added dropwise. After 10 min, TLC analysis (ethyl acetate, silica, Rf prod 0.3) showed starting material consumed. The reaction was quenched with 1 mL of 1M aqueous potassium sodium tartrate solution. The product was partitioned between ethyl acetate and 10 ml brine and the product extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were washed with 25 mL of brine, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield 0.29 g (1.37 mmol 99.9%) of 2-(2-chloro-quinolin-5-yl)-ethanol as a white solid. MS(APCI) m/z 208 (M, 100% abundance), 210 (M+2, 32% abundance). 1H NMR (400 MHz) CDCl3 8.38 (d, J=8.9 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.70 (m, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.41 (d, J=8.9 Hz), 3.97 (m, 2H), 3.32 (t, J=6.5 Hz, 2H), 1.45 (m, 1H).
Reaction SMILES: C(OC(C)(C)C)(=O)C=C.[C:10]([O:14][C:15](=[O:33])[CH:16]=[CH:17][C:18]1[CH:31]=[CH:30][C:29]2[C:20](=[C:21]([NH2:32])[C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=1)([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([O:14][C:15](=[O:33])[CH2:16][CH2:17][C:18]1[CH:31]=[CH:30][C:29]2[C:20](=[C:21]([NH2:32])[C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc2nc3ccccc3c(N)c2c1
Agent: C=CC(=O)OC(C)(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc2nc3ccccc3c(N)c2c1

Procedure:
Heck reaction with tert-butyl acrylate (Step 4) worked well to successfully synthesise 3-(9-amino-acridin-2-yl)-acrylic acid tert-butyl ester (Compound 6). The best condition to reduce the double bond was a catalytic hydrogenation at 3 bars in ethanol. The expected 3-(9-amino-acridin-2-yl)-propionic acid tert-butyl ester (Compound 7) was isolated by column chromatography as the major product. Another isomer and a by-product resulting in the reduction of the aromatic ring were also isolated.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:12])[NH:9][N:10]=[CH:11][C:6]=2[N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(O)C.C1(C)C=CC=CC=1.O.CC(=O)OCC.C(Cl)Cl.CO>[N:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:7]3[C:8](=[O:12])[NH:9][N:10]=[CH:11][C:6]=3[N:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=c1[nH]ncc2nccc(Cl)c12
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]ncc2nccc(-c3ccncc3)c12
Temperature: 130 °C

Procedure:
A reaction tube was charged with a solution of 4-chloropyrido[3,2-d]pyridazin-5(6H)-one (0.354 mmol) in 1 mL of ethanol and 1 mL of toluene under argon. To this suspension, a 2M solution of Na2CO3 (0.531 mmol) and pyridin-4-ylboronic acid (0.354 mmol) were added. Then, tetrakis(triphenylphoshine)palladium (0.035 mmol) was added. The reaction mixture was heated in a CEM microwave at about 130° C. for about 20 min. The reaction was monitored by TLC (DCM/methanol=9:1). After completion of the reaction, EA was added followed by the addition of water. The organic layer was basified with NaHCO3. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (25.2%).
Reaction SMILES: Br[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:16][O:17][C:18](=[O:32])[C:19]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[CH2:20].CC(N=NC(C#N)(C)C)(C#N)C.[SnH](CCCC)(CCCC)CCCC>C1C=CC=CC=1>[CH2:25]([O:24][C:22]([NH:21][CH:19]([CH2:20][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:18]([O:17][CH3:16])=[O:32])=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCC[C@H]1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: COC(=O)C(C[C@@H]1CCCC[C@H]1O[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 39.1 %

Procedure:
A benzene solution of ((1R*,2R*)-2-bromocyclohexyloxy)(tert-butyl)dimethylsilane (17.8 g, 0.061 mol), 2-benzyloxycarbonylamino-acrylic acid methyl ester (8 g, 0.037 mol), AIBN (1.22 g, 0.019 mol) was heated to reflux. After 5 minutes, n-Bu3SnH (19.8 mL, 0.074 mol) was added. The resulting mixture was then stirred at reflux for 14 hours. Solvent was removed under reduced pressure, the residue was purified by column chromatography to give methyl 2-(benzyloxycarbonylamino)-3-((1S*,2R*)-2-(tert-butyldimethylsilyloxy)cyclohexyl)propanoate (6.5 g, 24%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[C:10]([O:14][C:15](=[O:24])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22]Cl)[N:21]=1)([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:22][C:20]1[N:21]=[C:17]([NH:16][C:15](=[O:24])[O:14][C:10]([CH3:12])([CH3:11])[CH3:13])[S:18][CH:19]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2N)cs1
Yield: 100.7 %

Procedure:
Following General Procedure A, the title compound (588 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (376 mg, 2.36 mmol), tert-butyl[4-(chloromethyl)-1,3-thiazol-2-yl]carbamate (391 mg, 1.57 mmol) and K2CO3 (1.08 g, 3.45 mmol) in DMF (10 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[C:18]([C:26]([C:25]([Cl:30])([Cl:29])[Cl:24])=[O:27])[NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)C(Cl)(Cl)Cl)c2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3.4 g (11 mmole) of 8-chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine, 2.6 g (14 mmole) of trichloroacetyl chloride, and 100 ml of methylene chloride was stirred at room temperature for 12 hr. The resulting precipitate was collected by filtration, resuspended in methylene chloride, and basified with ammonium hydroxide. The methylene chloride solution was separated, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a (mp 222°-225°) colorless solid. A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 222°-223°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.[CH3:15][S:16][CH2:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1.CO.C[O-].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:17]([C:18]2[N:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[N:23]=2)[S:16][CH3:15])[C:3]=1[NH2:4]
Reactant: Nc1ccccc1Cl
Reactant: COc1cc(OC)nc(CSC)n1
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)nc(C(SC)c2cccc(Cl)c2N)n1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
2-Chloroaniline 5.2 g (26.0 mmol) was dissolved in dichloromethane (200 ml) and the solution was cooled to −70° C. To the cooled solution a dichloromethane (10 ml) solution of tert-butyl hypochlorite 2.82 g (26.0 mmol) was added dropwise and the solution was stirred at −70° C. for 10 minutes. To the obtained reaction solution a dichloromethane (20 ml) solution of 2-methylthiomethyl-4,6-dimethoxypyrimidine 3.38 g (26.0 mmol) was added dropwise and the solution was stirred at −70° C. for 40 minutes. To the obtained reaction solution 28% sodium methoxide methanol solution (9 ml) was added and the solution was stirred until it came to room temperature. Water was added to the reaction solution and the organic layer was separated. The water layer was further extracted twice with dichloromethane. After the organic layer had been washed with water and dried, dichloromethane was distilled off under reduced pressure and the objective 2-chloro-6-[1-(4,6-dimethoxypyrimidin-2-yl)-1-methylthiomethyl]aniline 7.00 g (yield 83%) was obtained as oily substance from the obtained oily substance by column chromatography using 1:8 mixed solvent of ethyl acetate and hexane as eluent.
Reaction SMILES: [CH2:1]([C:5]1[S:20][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3].CS(O[CH:26]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])[CH3:27])(=O)=O>>[F:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([F:35])[C:28]=1[CH:26]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[C:7]3[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:20][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1)[CH3:27]
Reactant: CC(OS(C)(=O)=O)c1c(F)cccc1F
Reactant: CC(C)Cc1cc2c(NC3CCNCC3)ncnc2s1
Product: CC(C)Cc1cc2c(NC3CCN(C(C)c4c(F)cccc4F)CC3)ncnc2s1

Procedure:
The title compound was prepared (104 mg, 54%) from 6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (130 mg, 0.45 mmol) and 1-(2,6-difluorophenyl)ethyl methanesulfonate (211 mg, 0.9 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.10 (m, 1H), 6.90 (m, 2H), 6.75 (s, 1H), 4.90 (d, 1H), 4.25 (q, 1H), 4.05 (m, 1H), 3.05 (m, 2H), 2.70 (d, 2H), 2.15 (m, 1H), 2.10 (m, 3H), 1.95 (m, 1H), 1.40 (d, 3H), 1.45-1.65 (m, 2H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 430.56; Observed: 431.2 (M++1).
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)#[CH:11].[N+:19]([CH2:22][CH3:23])([O-])=[O:20].C(N(CC)CC)C>C1C=CC=CC=1.O>[CH3:23][C:22]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[O:20][N:19]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: CC[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: O=C=Nc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(C)no2)cc1

Procedure:
6.23 ml (57.39 mmol) of phenyl isocyanate are added dropwise at room temperature to a solution of 5 g (43.04 mmol) of 1-ethynyl-4-methylbenzene, 1 ml (14.34 mmol) of nitroethane and 0.4 ml (2.87 mmol) of triethylamine in 100 ml of benzene. The reaction mixture is then stirred under reflux for 12 h. After cooling, the suspension is mixed with water (50 ml) and stirred at room temperature for a further 4 h. The precipitate is filtered off with suction and washed with benzene (10 ml). The organic phase of the filtrate is separated off, dried with magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 6:1). 1.13 g (46% of theory) of the title compound are obtained as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][N:31]1[CH2:35][CH2:34][N:33]=[C:32]1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([CH2:36][C:32]4[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=4)[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: CN1CCN=C1C=O
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cccc2cc(C3=NCC4(CCN(Cc5nccn5C)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg) and 1-methyl-4H-imidazole-2-carbaldehyde (33 mg) in tetrahydrofuran (3 ml) was added sodium triacetoxyborohydride (125 mg), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (14 mg, yield 12%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 103° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([C:30]([NH2:32])=[O:31])[O:27][C:26]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][O:16]CC2C=CC=CC=2)[CH2:10][CH2:9]1.[H][H]>CO.CCO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([C:30]([NH2:32])=[O:31])[O:27][C:26]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][OH:16])[CH2:12][CH2:13]1
Reactant: NC(=O)[C@H]1CN(c2ccc(N3CCN(C(=O)COCc4ccccc4)CC3)c(F)c2)C(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: NC(=O)[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1

Procedure:
A mixture of (5R)-3-[3-fluoro-4-[4-[(phenylmethoxy)acetyl]-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinecarboxamide (Step 2, 260 mg, 0.570 mmol) and 10% palladium-on-carbon (61 mg, 0.0570 mmol) in a mixture of methanol (5 mL) and EtOH (23 mL) was shaken under a 40 psi hydrogen atmosphere on a Parr apparatus for 22 hours. The catalyst was then removed by filtration through a pad of Celite, rinsing with tetrahydrofuran (200 mL), and the filtrate was concentrated under reduced pressure and triturated with methanol/diethyl ether. Filtration then provided the title compound, mp 232-235° C. (dec.); MS (ESI+) for C16H19FN4O5 m/z 367 (M+H)+; [α]25D=−20 (c 0.98, DMSO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([O:21][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:19]=[N:18][CH:17]=2)=[CH:23][CH:24]=1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Oc1ccncc1
Product: COc1cc(Nc2cncc(Oc3ccncc3)n2)cc(OC)c1OC
Yield: 50 %

Procedure:
Using Method X with 150 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine and 4-hydroxypyridine, the title compound was obtained (89 mg). Yield: 50%. 1H NMR (250 MHz, DMSO-d6) δ 3.64 (s, 3H), 3.79 (s, 6H), 6.29 (d, 2H, J=7.9 Hz), 7.07 (s, 2H), 8.19 (s, 1H), 8.32 (s, 1H), 8.43 (d, 2H, J=8.0 Hz), 9.91 (bs, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 55.61, 60.11, 96.50, 117.94, 121.98, 132.71, 132.79, 135.77, 136.52, 145.43, 150.31, 152.85, 178.22. m/z 355.1 [(M+H)+ calcd for C18H18N4O4 354.1].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:11][CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[CH:12]([N:11]([C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:13]
Reactant: Cc1cccc([N+](=O)[O-])c1NC=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C=O)c1c(C)cccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 63 %

Procedure:
To a mixture of (2-methyl-6-nitrophenyl)formamide (180 mg, 1.0 mmol), potassium carbonate (276 mg, 2.0 mmol), potassium iodide (5 mg) and N,N-dimethylformamide (1 mL) a solution of ethyl bromoacetate (184 mg, 1 mmol) in N,N-dimethylformamide (1 mL) was added at room temperature. The mixture was heated at 60° C. for 3 h, then cooled to room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine and dried over magnesium sulfate. The volatiles were removed in vacuo. The crude product was purified by column chromatography using heptane/ethyl acetate (70:30→50:50) as an eluent affording ethyl N-formyl-N-(2-methyl-6-nitrophenyl)glycinate, 167 mg (63% yield) as an oil. MS (1S) m/z 267 [M+H].
Reaction SMILES: C(OC([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][O:22][CH2:23][CH:24]=[CH2:25])[CH2:12]1)=O)C1C=CC=CC=1.CO>C(Cl)Cl>[CH2:23]([O:22][CH2:21][CH:13]1[CH2:12][NH:11][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14]1)[CH:24]=[CH2:25]
Reactant: C=CCOCC1CN(C(=O)OCc2ccccc2)c2ccccc2O1
Solvent: ClCCl
Solvent: CO
Product: C=CCOCC1CNc2ccccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.8 ml of iododtrimethylsilane is added to a solution of 1.37 g of N-benzyloxycarbonyl-2(R,S)allyloxymethyl-3,4-dihydro-2H-1,4-benzoxazine in 25 ml of methylene chloride under argon. The reaction mixture is stirred at room temperature for 2 h, 10 ml of methanol are then added and the mixture is concentrated. The residue is extracted twice with 50 ml of a 10:1 mixture of hexane and diethyl ether and then dissolved in ethyl acetate, and the solution is washed with a 1N sodium carbonate solution and saturated sodium chloride solution. The crude product is purified by means of FC (100 g of silica gel, mobile phase D). This gives the pure title compound: Rf (D)=0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26](F)[C:27](F)=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.[Br:38]C1C=C(Cl)C=CC=1C1NC2C=CC=CC=2N=1.BrCC1CCCCC1>>[Br:38][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=2[N:9]=1
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)c(Br)c1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCC1
Product: Clc1ccc(-c2nc3ccccc3n2CC2CCCCC2)c(Br)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(2-bromo-4-chloro-phenyl)-1H-benzoimidazole and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Colorless solid (95%). MS (Turbo Spray): m/z=404.2 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C:20](=[O:22])[NH:19][S:18]3(=[O:24])=[O:23])=[C:13]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:12]=2)[CH:5]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:26]([O:25][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[N:17]1[CH2:21][C:20](=[O:22])[NH:19][S:18]1(=[O:23])=[O:24])[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:33])=[O:2])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1cccc(Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(Cc3cccc(C(=O)O)c3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-benzoic acid methyl ester (intermediate from Example LBY596) (0.3 g, 0.643 mmol) in THF is added a solution of LiOH (0.081 g, 1.929 mmol) in H2O. The reaction is stirred at ambient temperature overnight. The mixture is poured into 1 M HCl and extracted with EtOAc. The organic layer is dried over MgSO4, filtered and concentrated to afford a brown oil. The oil is place under high vacuum to afford solid 3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-benzoic acid: MS (M−H)−=451.2.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][C:6]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])O[N:13]2[C:8]([C:9]([CH3:16])([CH3:15])[O:10][CH2:11][CH2:12]2)=[N:7]1)C.C(OCC)(=[O:25])C>CC1C=CC(C)=CC=1C.CCOCC>[OH:25][C:5]1[C:4](=[O:22])[N:13]2[C:8]([C:9]([CH3:15])([CH3:16])[O:10][CH2:11][CH2:12]2)=[N:7][C:6]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC1(C(=O)OCC)N=C2N(CCOC2(C)C)O1
Reactant: CCOC(C)=O
Agent: Cc1ccc(C)c(C)c1
Solvent: CCOCC
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Yield: 18 %

Procedure:
A solution of intermediate 24, ethyl 2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate (31.16 g) in 1,2,4-trimethylbenzene (200 mL) was heated at 180° C. for 5 h. The resulting dark reaction solution was cooled then concentrated to give a dark brown paste which was taken up into ethyl acetate (250 mL) and extracted with 0.5 M aq Na2CO3 (4×50 mL). The organic layer was discarded and the aqueous layer acidified by carefully adding conc. HCl (20 mL) before being extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give a dark paste which was dissolved in ether (100 mL) and allowed to stand at room temperature in a open flask. The brown/light yellow solid that formed was filtered to afford the title compound. The mother liquor that contained product was re-processed to afford additional material (combined yield ˜18-20% over two steps). 1H NMR (500 MHz, CDCl3) δ: 10.55 (1H, s), 4.45 (2H, q, J=7.0 Hz), 4.02 (4H, s), 1.61 (6H, s), 1.43 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C12H17N2O5: 269.1138; found: 269.1149. Anal calcd for C12H16N2O5: C, 53.72; H, 6.01; N, 10.44. Found: C, 53.71; H, 6.04; N, 10.30.