Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:2]([C:26]4[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=4)=[N:3][CH:4]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C

Procedure:
To a solution of 6-chloro-N-quinolin-7-yl-nicotinamide (D70) (40 mg, 0.14 mmol) in DME (0.9 ml) under an argon atmosphere was added 4-trifluoromethylphenylboronic acid (33 mg, 0.17 mmol), 2M sodium carbonate solution (0.17 ml) and tetrakis(triphenylphosphine)palladium (0) (8 mg, 0.007 mmol). The reaction was heated at reflux until complete by tlc, then cooled to room temperature and diluted with EtOAc and dried over MgSO4. The solvent was removed in vacuo and the resultant crude product was purified by SPE column chromatography. Elution with 75% EtOAc in 40-60° C. petroleum ether gave the title compound as an off-white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.31 (dd, 1H), 8.83 (dd, 1H), 8.46 (dd, 1H), 8.39 (dd, 1H), 8.20 (m, 3H), 8.07 (d, 1H), 7.94 (dd, 1H), 7.89 (d, 1H), 7.79 (d, 2H), 7.40 (dd, 1H).
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[F:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]=[N+:16]=[N-:17].FC1C=CC=CC=1CN1C(C(N)=O)=C(C(N)=O)N=N1>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]1[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:1]([C:7]([O:9][CH3:10])=[O:8])[N:17]=[N:16]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: [N-]=[N+]=NCc1ccccc1F
Agent: NC(=O)c1nnn(Cc2ccccc2F)c1C(N)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1nnn(Cc2ccccc2F)c1C(=O)OC
Temperature: 90 °C
Reaction time: 5 h

Procedure:
The starting material may also be prepared as follows: A solution of 40 g (0.282 mole) of dimethyl acetylenedicarboxylate in 500 ml of toluene is added dropwise to a solution of 41.5 g (0.255 mole) of o-fluorobenzyl azide in 50 ml of toluene, which solution has been heated to 90° C. After a further 5 hours at 90° C., the toluene is stripped off, the reaction mixture is cooled and the crystalline product is filtered with suction. Recrystallisation from a 1:1 mixture of diethyl ether/petroleum ether yields dimethyl 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylate with a melting point of 49°-51° C.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[C:3]([O:5]CC)=[O:4].Cl>O1CCOCC1.[OH-].[Na+].C(OCC)(=O)C>[CH3:1][C:2]([CH3:19])([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Cc1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(Cc1ccc2ccccc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
The crude ester (915 mg) was taken up in dioxane (4 mL) and 20% aqueous sodium hydroxide (8 mL). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate. The aqueous fraction was acidified to pH=2 with concentrated hydrochloric acid and was then extracted with ethyl acetate. The combined organic fractions were dried over sodium sulfate and concentrated to yield 2,2-dimethyl-3-(naphthalene-2-yl)propanoic acid (211 mg, 40% yield for two steps) as a white solid, which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[S:4].[F:17][C:18]([F:34])([F:33])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)=[N:23][CH:24]=1>CN(C)C=O>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:34])([F:17])[F:33])=[CH:24][N:23]=3)=[CH:27][CH:28]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[S:4]
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCOC(=O)C1C(=O)N(C)C(=S)N(C)C1=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)N(C)C1=S

Procedure:
2.5 g (10 mmol) of 1,3-dimethyl-5-ethoxycarbonyl-2-thiobarbituric acid, 2,55 g (10 mmol) of 4-(5-trifluoromethylpyrid-2-yloxy)aniline and 5 ml of dimethylformamide are stirred for 6 hours at 118° C. The reaction mixture is then cooled, triturated with water and the crystalline precipitate is isolated by filtration. The crude product is recrystallised from ethanol. Melting point 156°-158° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccccc2n1
Temperature: 25 °C
Yield: 12608 %

Procedure:
To a solution of chinaldine (14.3 g, 0.1 mmol) and N-bromosuccinimide (17.8g, 0.1 mmol)in CCl4 (150 mL) was added benzoylperoxide (2.6 g, 0.025 mol) and the mixture was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature and evaporated in vacuum. The residue was treated with 5% HBr solution, the precipitate was filtered offand the filtrate was treated with celite and then basified with NaHCO3solution. The product was extracted with ether and crystallized from petrolether to yield 2-(bromomethyl)-quinoline (2.8 g, 12.6%) as light tancrystals.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[NH2:20][C:21]1[C:29]2[NH:28][CH:27]=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[NH:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:20][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[C:29]=2[N:28]=[CH:27]1
Reactant: Nc1cccc2nc[nH]c12
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2[nH]cnc12
Yield: 63.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 130 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 113 mg of 4-aminobenzimidazole hydrochloride and 127 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 80 μl of pyridine and 2.0 ml of N,N-dimethylformamide. 112 mg of N-(1H-benzimidazol-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.Cl.[NH2:18][OH:19].C(N(CC)CC)C>C(O)C>[OH:19][N:18]=[C:13]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:16][CH:15]=1)[NH2:14]
Reactant: N#Cc1ccc(COC2CCOCC2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1ccc(COC2CCOCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-[(tetrahydro-2H-pyran-4-yloxy)methyl]benzonitrile (Step 1, 780 mg, 3.59 mmol), hydroxylamine hydrochloride (549 mg, 7.90 mmol) and triethylamine (1.10 mL, 7.90 mmol) in ethanol (20 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate, and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was stirred in hexane and filtered. After evaporation of the solvent, the title compound was obtained (857 mg, 95%): 1H NMR (400 MHz, CDCl3) δ 7.55 (d, 2H), 7.40 (d, 2H), 4.81 (s, 2H), 4.06-3.99 (dd, 2H), 3.81 (d, 2H), 3.48-3.40 (m, 2H), 2.15-2.02 (m, 1H), 1.78-1.72 (dd, 2H), 1.52-1.40 (m, 2H); ES-MS m/z 251, HPLC RT (Method E) 0.56 min.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:40])[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH:10]=1)[CH3:6]>>[CH2:5]([O:7][C:8](=[O:40])[C:9]1[C:14]([NH:15][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH:10]=1)[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)ccc1N
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)ccc1NC(C)=O

Procedure:
Prepared by general procedure E but using acetyl chloride instead of propionyl chloride and 3-{2[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic acid ethyl ester instead of 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acid methyl ester.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:2][C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccco1
Product: CN(C)C=CC(=O)c1ccco1
Temperature: 100 °C
Reaction time: 9 h
Yield: 97 %

Procedure:
A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100° C. for 9 hours. After cooling as it was, the reaction solution was concentrated. Diethyl ether and hexane were added to the residue, and the resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97%) as a brown solid.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CCO>[C:27]([O:26][C:25](=[O:31])[NH:24][CH2:23][CH2:22][N:21]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethyl-1H-pyrimidine-2,4-dione (step 3) (1 g, 2.97 mmol) in EtOH (12 mL) was treated with TEA (0.41 mL, 2.97 mmol) and tert-butyl 2-aminoethylcarbamate (commercial) (0.465 mL, 2.97 mmol). The mixture was heated to 100° C. for 1 h using microwave irradiation. After this time, a white precipitate had formed. The solid was collected via reduced pressure filtration and was washed with diethyl ether. The title compound was obtained as white needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:17]=[CH:18][C:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2)CC1
Temperature: 120 °C
Yield: 77.3 %

Procedure:
A solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (427 mg; 2.13 mmol), bis(4-fluorophenyl) sulfone (493 mg; 1.94 mmol) and potassium carbonate (1.01 g; 7.76 mmol) in dimethylsulfoxide (5 mL) is heated over night at 100° C. The temperature is then increased to 120° C. and the mixture is reacted at this temperature for 24 hours. The reaction is then diluted with dichloromethane (100 mL), filtered and the filtrate is washed with aq. 1N hydrochloric acid (2×20 mL), and water (2×20 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is finally purified by column chromatography on silica gel (dichloromethane:methanol 100:0 (200 mL) and then 98:2 (150 mL)) to afford the desired product (653 mg; 1.50 mmol).
Reaction SMILES: [Na].[Br-].[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:5])=[O:4].[C:29]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>CS(C)=O>[C:29]1(=[CH:9][CH2:8][CH2:7][CH2:6][C:3]([OH:5])=[O:4])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCCC=C1CCCCCCCCCCC1
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
Dry dimethylsulfoxide (50 ml, distilled from calcium hydride) and 24.1 ml (0.06 mole) of the sodium salt of dimethylsulfoxide (2.49 M in dimethylsulfoxide, Fieser and Fieser, "Reagents for Organic Synthesis", 1:310 [1967]) were mixed together and cooled in an ice-water bath. Then 13.29 g (0.03 mole) of (4-carboxybutyl) triphenylphosphonium bromide (Aldrich Chemical Co.) was added thereto and the mixture was stirred for 30 min. Cyclododecanone (3.64 g, 0.02 mole; Aldrich Chemical Co.: Beilstein 7[2],36) was dissolved in 10 ml of dry dimethylsulfoxide and added to the above mixture and the mixture was stirred for 15 hr at room temperature. The resulting mixture was then poured into 500 ml of water. This aqueous mixture was extracted with 900 ml (3×300 ml) of ether-ethyl acetate (1:1 V/V). The aqueous phase was acidified (pH 1 to 2) with 30 ml of concentrated hydrochloric acid. The aqueous phase was then extracted with 900 ml (3×300 ml) of ether-hexane (1:1 V/V). The ether-hexane extract was then dried over anhydrous magnesium sulfate, filtered, and the solvent removed in vacuo. The resultant product was recrystallized from ethanol-water to yield 2.0 g (36.2%) of 5-cyclododecylidenepentanoic acid (mp 70°-72° C.) having the following physical characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH:10]2[O:14][CH2:15][C:16]([O:19][CH3:20])([O:17][CH3:18])[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C[O:33][CH2:32]C1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:32][OH:33])[CH:10]2[O:14][CH2:15][C:16]([O:17][CH3:18])([O:19][CH3:20])[CH:9]12)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: COC1(OC)COC2C(=O)CN(C(=O)OC(C)(C)C)C21
Agent: B1C2CCCC1CCC2
Product: COC1(OC)COC2C(CO)CN(C(=O)OC(C)(C)C)C21
Yield: 86 %

Procedure:
The olefin 1e (524 mg, 1.84 mmol) was dissolved in dry THF (70 mL), 9-BBN-H (0.5 M in THF) (7.34 mL, 3.67 mmol) was added and the solution was stirred over night. The solvent was removed by rotary evaporation and redissolved in THF (20 mL). MeOH (10 mL) was slowly added to the solution and when the gas evolution had ceased, H2O (20 mL) was added to the solution followed by NaBO3. The solution was filtered after it had been stirred for 18 hrs and the filtrate was diluted with EtOAc (70 mL) and washed with brine (2*50 mL). The organic phase was dried with Na2SO4, filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (heptane: ethyl acetate 2:1) which gave the title compound (477 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15](NC[C@@H]2C[C@H](S)CN2C(OCC=C)=O)=[O:16])=[N:13][CH:14]=1)=[O:8].[CH3:35][O:36]C(C1C=CC(C(Cl)=O)=CN=1)=O.ClC1C=C(C=CC=1Cl)CN.C(OC(C1SC(C(=O)NCC2C=CC(Cl)=C(Cl)C=2)=CC=1)=O)C>>[CH3:35][O:36][C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][C:4]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:2]([Cl:1])[CH:3]=2)=[CH:14][N:13]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)Cl)cn1
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cn1
Agent: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Agent: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cn1
Yield: 61 %

Procedure:
Starting material (13(e)) was prepared as follows, 5-chlorocarbonyl-pyridine-2-carboxylic acid methyl ester was reacted with 3,4-dichlorobenzylamine analogously with preparation of compound (12(a)) in Example 12 to obtain 5(3,4-dichlorobenzylcarbamoyl)-pyridine-2-carboxylic acid methyl-ester (13(a)) as a cream solid (61%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28](B(O)O)[CH:29]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:26]4[CH:25]=[C:24]([Cl:23])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Product: COc1ccc(Cl)cc1-c1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 66 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (5-chloro-2-methoxyphenyl)boronic acid (0.365 g, 1.96 mmol generally according to the procedure described for Intermediate 184 provided 0.382 g (66%) of (±)-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C@H:7]([C:17]([OH:19])=O)[O:8][C@@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[NH2:26][CH:27]([CH3:29])[CH3:28]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C@H:7]([C:17]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:19])[O:8][C@@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:4]=2[CH:3]=1
Reactant: O=C(O)[C@H]1Oc2ccc(Cl)cc2[C@H](c2ccccc2F)O1
Reactant: CC(C)N
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)[C@H]1Oc2ccc(Cl)cc2[C@H](c2ccccc2F)O1
Reaction time: 16 h

Procedure:
A solution of 3.38 g (10.9 mmoles) of trans-6-chloro-4-(2-fluorophenyl)-1,3-benzodioxan-2-carboxylic acid, 10.0 ml (16.4 g, 137 mmoles) of thionyl chloride, and 5 drops of anhydrous DMF in 200 ml of anhydrous Ch2Cl2 was refluxed for 2 hours; the solvent and excess SOCl2 were removed under reduced pressure and the residue was flashed down with 3 portions of anhydrous benzene to remove traces of SOCl2. The acid chloride was redissolved in 100 ml of anhydrous CH2Cl2 and 5.57 ml (3.86 g, 65.4 mmoles) of 2-aminopropane was added all at once; heat was evolved. The reaction mixture stood in a stoppered flask for 16 hours.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[C:16](O)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([NH:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:24]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)NCCSSCCN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCSSCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
tert-Butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 1.98 mmol) was taken up in CH2Cl2 (20 mL) along with salicylic acid (273 mg, 1.98 mmol) and EDCI (693 mmol, 2.2 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (40% EtOAc, 60% pentane) afforded tert-butyl 2-(2-(2-(2-hydroxybenzamido)ethyl)disulfanyl)ethylcarbamate (400 mg, 54%). Mass calculated for C16H24N2O4S2: 372.12; found: [M+H]+=373.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][NH:36][CH3:37].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:36]([CH3:37])[CH3:35])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CNC
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 12.2 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, Dimethyl-amine (98 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 339 (61.4 mg, yield: 12%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.91-7.87 (m, 1H), 7.73-7.71 (m, 2H), 7.42-7.40 (m, 2H), 7.19 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.16-3.11 (m, 8H). ESI-MS: m/z=503 [M+H+]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[F:20])[N:29]=1
Reactant: NNc1ccc(F)cc1F
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(-c2ccc(F)cc2F)n1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 3.9 g of 2,4-difluorophenylhydrazine hydrochloride and 3 ml of triethylamine are boiled under reflux for 2 h in 25 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 144-146 C.