Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].C(=O)(O)[O-].[Na+].O1CCOCC1>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 120 °C

Procedure:
To a 25 mL pressure tube was charged 3-iodo-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70.9 mg, 0.234 mmol), 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (93 mg, 0.234 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9.55 mg, 0.012 mmol), and sodium bicarbonate (39.3 mg, 0.468 mmol) followed by dioxane (4 mL), and water (1 mL). The reaction was heated at 120° C. for 40 min in microwave reactor. LCMS showed incomplete conversion. The reaction was heated in microwave at 120° C. for another 1 hour. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL erlenmeyer flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 100 mL of EtOAc was added to the mixture). The EtOAc solution was evaporated to dryness, and re-dissolved in CH2Cl2/MeOH (8 mL/2 mL). It was purified by flash column 25-100% EtOAc/hexane, then 0-10% MeOH/EtOAc, Analogix Si SF15-24g, to afford a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound as a brown solid. LC/MS (ES) m/z=449.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (d, J=6.82 Hz, 6H), 3.27-3.33 (m, 2H), 3.97 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 5.06 (t, J=6.82 Hz, 1H), 7.18-7.21 (m, 1H), 7.22-7.27 (m, 2H), 7.44 (d, J=8.08 Hz, 1H), 7.54 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.23 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].[NH3:19].[C:20](Cl)(Cl)=[S:21]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:20]([NH2:19])=[S:21])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1CNC(=O)OC(C)(C)C
Reactant: S=C(Cl)Cl
Reactant: N
Solvent: ClCCl
Product: COc1ccc(NC(N)=S)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a mixture of the compound (52 mg) obtained in Example 119 and N,N-dimethylaminopyridine (53 mg) in methylene chloride (5 ml), thiophosgene (0.02 ml) was added dropwise and stirred at room temperature for 15 min. To the reaction mixture, 28% aqueous ammonia solution (5 ml) was added and stirred at room temperature for 1.5 h. After neutralization with 2 N HCl, the reaction mixture was extracted with methylene chloride and the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate) to give 58 mg of the titled compound (yield, 91%).
Reaction SMILES: C(N)C1C=CC=CC=1.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:27][O:28][C:29]1[C:34]([O:35][CH2:36][CH2:37][N:38]([CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]2[C:55]3[C:56]4[C:61]([NH:62][C:54]=3[CH:53]=[CH:52][CH:51]=2)=[CH:60][CH:59]=[CH:58][CH:57]=4)CC2C=CC=CC=2)=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cl-].[Cl-].[Zn+2].C(COC)OC>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][NH:38][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[NH:62][C:61]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:55]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Cl-]
Agent: [Zn+2]
Agent: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: COCCOC
Solvent: NCc1ccccc1
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Reaction time: 10 h

Procedure:
To 250 ml dimethoxyethane, 70 g (0.27 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 10.25 g (0.075 moles) of anhydrous ZnCl2 and 50 g (0.21 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 2.5 hrs (TLC control for checking conversion to N-benzyl carvedilol). Dimethoxyethane is distilled off from the reaction mixture and to the concentrated mass is added 400 ml ethylacetate, followed by 100 ml of ˜12-15% aqueous ammonia. The aqueous layer separated, and the product enriched organic layer is washed with water till neutral pH. The organic layer is charcoalised, filtered. To this solution of N-benzyl carvedilol in ethylacetate, (7 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 Kg/cm2 at temperature of 60-70° C. for a period of about 10 hours. The reaction mixture is filtered and filtrate concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (100 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (50 ml) and toluene (50 ml) to obtain carvedilol (50 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (45 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1/[CH:6]=[CH:7]/[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:50])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:37])=[CH:31][CH:30]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:50])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2/[CH:6]=[CH:7]/[C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: CCOC(=O)c1ccc(/C=C/C2CCCN2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(/C=C/C2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)cc1
Reaction time: 15 h
Yield: 100 %

Procedure:
A mixture of ethyl (E)-4-[2-(2-pyrrolidinyl)ethenyl]benzoate (434 mg, 1.77 mmol), pentafluorophenyl 4-[N′-(2-methylphenyl)ureido]phenylacetate (797 mg, 1.77 mmol), Et3N (0.37 mL, 2.66 mmol) in DMF (15 mL) was stirred for 15 hr. The mixture was diluted with EtOAc (300 mL). The solution was washed with brine (2×200 mL), dried over MgSO4, and evaporated off in vacuo. The residue was chromatographed on silica-gel with CHCl3-EtOAc (4:1) as eluent to give 906 mg (q.y.) ethyl (E)-4-[2-[1-[4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoate as a brown oil. 1H-NMR (CDCl3) δ1.39 (3 H, t, J=7.3 Hz), 1.83-2.20 (4 H, series of m), 2.24 (3 H, d, J=4.9 Hz), 3.63 (4 H, m), 4.36 (2 H, q, J=7.3 Hz), 4.62 and 4.84 (total 1 H, m), 6.18-6.47 (2 H, m), 7.03-8.02 (14 H, series of m).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:21]([OH:23])=O)[CH3:20].C(OC([N:31]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH-:40])=[CH:37][CH:36]=1)[C:32]([NH2:34])=[NH:33])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([S:8]([NH:11][C@@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH:31]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:21](=[O:23])[C@H:19]([CH3:20])[NH2:18])=[CH:37][CH:36]=1)[C:32]([NH2:34])=[NH:33]
Reactant: CC(C)(C)OC(=O)N(C(=N)N)c1ccc(C[NH-])cc1
Reactant: C[C@H](N)C(=O)O
Agent: O=C(O)[C@@H](CO)NS(=O)(=O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)NCc1ccc(NC(=N)N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution benzylsulfonyl-D-serine-L-alanine-(4-(N-tert-butoxycarbonylguanidino) benzylamide (7-5) (9.0 mg, 0.016 mmol), in a mixture of CH2Cl2/TFA (1:1, 600 μl) was stirred at room temperature for 90 minutes. The solvent was removed in vacuo to give a transparent oil. HPLC purification (CH3CN, H2O, 0.1% TFA) gave a fluffy white solid as the title compound (5.0 mg, 66%), MS (electrospray) 477 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C(#N)C>[Br-:10].[CH2:16]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:18]2([CH2:17][CH3:16])[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:11][CH3:12]
Reactant: CCBr
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1ccc2ccccc2c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].Cl>C(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Yield: 66.7 %

Procedure:
A mixture of 0.30 g (0.91 mmole) 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138) and 0.18 g (1.09 mmole) 4-amino-3-methoxy-benzoic acid in a 1:4 mixture of 5 mL of ethanol and 1 M hydrochloric acid was heated at 100 degrees for 18 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to give 0.28 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-156).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.CCO.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COC(=O)C1(c2ccccc2F)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(c2ccccc2F)CCOCC1
Temperature: 130 °C
Yield: 84.7 %

Procedure:
A solution of methyl 4-(2-fluorophenyl)-tetrahydro-2H-pyran-4-carboxylate (2.45 g, 10 mmol), water (10 mL, 555 mmol), EtOH (50 mL, 10 mmol) and KOH (2.3 g, 41 mmol) was placed in a sealed flask and then heated at 130° C. for 10 hours. After cooling to room temperature, the reaction was concentrated to afford a yellow oil. The residue was diluted with water (100 mL) and extracted with DCM (120 mL). The separated aqueous phase was then acidified to pH=1 and then extracted with EtOAc (3×10 mL). The organic later was dried (Na2SO4), filtered, and concentrated to afford a tan solid (1.9 g). MS m/e=223.1 (M−1)−.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[C:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C>ClCCl>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[C:24](=[CH:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
500 μl (4.6 mmol) of phenyl isocyanate are added dropwise to a solution of 1.2 g (2.3 mmol) of 5-(3′-aminobiphenyl-4-ylmethylene)thiazolidine-2,4-dione prepared as in Example 33(a) and 0.9 ml (6.4 mmol) of triethylamine in 12 ml of dichloromethane. The reaction medium is stirred at room temperature for 2 hours. It is extracted with dichloromethane and washed with water, and the organic phase is separated out after settling of the phases has taken place. The organic phase is evaporated and the residue obtained is washed with dichloromethane and dried. 950 mg (50%) of the expected product are collected.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.[CH:12](=O)[CH3:13].C(O)(=O)C.[BH3-]C#N.[Na+]>C1COCC1.O>[CH2:12]([NH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1)[CH3:13]
Reactant: Nc1ccc2nc(S)sc2c1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCNc1ccc2nc(S)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Into a 100 mL two-necked flask are added 6-amino-1,3-benzothiazole-2-thiol (1.92 g, 10.5 mmol) and THF (20 mL), followed by acetaldehyde (0.591 mL, 10.5 mmol), glacial acetic acid (1 mL) and water (1 mL) at 0° C. The suspension is stirred for 1.5 hrs before a solution of NaCNBH3 (0.723 g, 10.5 mmol) in THF (20 mL) is introduced slowly through a dropping funnel. The reaction mixture is stirred at room temperature for 2 hrs after the addition. The precipitates are collected by filtration, washed with water and ether, and dried under reduced pressure to give the intermediate of 6-ethylamino-benzothiazole-2-thiol as light yellow solid (1.8 g, 82%). 1H NMR (CD3OD) δ 1.21 (t, 3H), 3.08 (q, 2H), 6.68-6.72 (m, 2H), 7.04 (d, 2H); ESIMS: m/z 211.0(M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]=[C:57]=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:57]([NH:56][CH3:55])=[O:58])[CH2:49][CH2:48]1)=[O:53]
Reactant: CN=C=O
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and methyl isocyanate as the starting materials in 70% yield. LCMS for C25H28ClN8O3 (M+H)+: m/z=523.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[Cl-].[NH4+]>C(O)C.O.CCOCC.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(Cl)nc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: Nc1ccc(OCc2ccc(Cl)nc2)cc1

Procedure:
Two grams (7.6 mmol) of 2-chloro-5-(4-nitrophenoxy) methylpyridine and 4 grams (76.0 mmol) of ammonium chloride in 40 ml of ethanol and 20 ml of water are heated to 60°, after which 2.1 grams (38.0 mmol) of iron powder is added in small portions over 15 minutes. The mixture is heated under reflux for 2 hours. The reaction is cooled and stripped, and the residue is taken up in ether, washed with water, dried over sodium sulfate and stripped to yield 2-chloro-5-(4-aminophenoxy)methylpyridine.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][NH:40][CH3:41]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH3:41])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CNCCOC
Product: COCCN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (367 mg, 0.72 mmol) and 2-methoxyethylmethyl amine (130 mg, 1.45 mmol) as starting materials.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7](/[CH:9]=[N:10]/[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[N+:1]([C:4]1[O:8][C:7]([CH2:9][NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)o1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3)CC2)o1
Yield: 81.7 %

Procedure:
5-[1-(4-[(E)-1-(5-Nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9a, 0.38 g, 1 mmol) on reduction with sodiumcyano borohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 5-[1-(4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10a, 315 mg, 82%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]([C:24](O)=[O:25])[C:16](O)([CH:20]([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.C(OCC)(=O)C>C(OC(=O)C)(=O)C>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[C:24]([O:18][C:17](=[O:19])[C:16]=2[CH:20]([CH3:21])[CH3:22])=[O:25])[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)C(O)(C(=O)O)C(C(=O)O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)C1=C([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)C(=O)OC1=O
Temperature: 120 °C
Reaction time: 18 h

Procedure:
3-(Trans-4-t-butyldimethylsilyloxycyclohexyl)-2-hydroxy-2-isopropylsuccinic acid (510 mg, 1.31 mmol) was dissolved in acetic anhydride (5.5 mL), and the solution was stirred at 120° C. for 18 h. The acetic anhydride was evaporated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 50:1) to give 293 mg of 2-(trans-4-t-butyldimethylsilyloxycyclohexyl)-3-isopropylmaleic anhydride as oil (yield: 63%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:36])([F:35])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:33][CH2:32][C:30]3[N:31]=[C:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:36])([F:19])[F:35])=[CH:26][CH:25]=4)[S:28][CH:29]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1csc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(OCCc3csc(-c4ccc(C(F)(F)F)cc4)n3)cc21

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (6-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy]-indol-1-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([C:14](O)=[O:15])[N:13]=1.O.OC1C2N=N[NH:31]C=2C=CC=1.CN(C)CCCN=C=NCC.N.O1CCOCC1>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([C:14]([NH2:31])=[O:15])[N:13]=1
Reactant: O=C(O)c1nc(-c2c(F)cccc2F)oc1Nc1ccccc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylic acid (0.030 g, 0.095 mmol) in DCM (3 mL) was added hydroxybenzotriazole monohydrate (0.015 g, 0.098 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.020 g, 0.10 mmol) and 0.5M ammonia in dioxane (0.9 mL, 0.45 mmol). The reaction mixture was stirred at room temperature overnight. Further 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.007 g, 0.038 mmol) and ammonia in dioxane (0.57 mL, 0.29 mmol) were added and the reaction stirred for 3 hours at room temperature. The solvent was evaporated in vacuo and the residue purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxamide (0.006 g, 0.019 mmol, 20%) as a white solid. 1H NMR (DMSO) δ 7.03 (1H, dd), 7.35 (4H, m), 7.38 (2H, br. s), 7.43 (2H, m), 7.64 (1H, m), 9.34 (1H, br. s). LCMS (2) Rt 2.87 min; m/z (ES+) 338 (M+Na), 299 (M-NH2).