Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(OCc2ccc(F)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(OCc4ccc(F)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (53 mg, 0.30 mmol) was reacted with 4-[2-amino-4-(4-fluoro-benzyloxy)-phenylsulfanyl]-phenol (102 mg, 0.30 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (115 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3H) 5.11 (s, 2H) 6.26 (d, J=6.99 Hz, 1H) 6.65 (d, J=8.46 Hz, 2H) 7.10 (d, J=8.82 Hz, 2H) 7.15-7.27 (m, 4H) 7.49 (m, J=5.88 Hz, 2H) 7.81 (d, J=8.46 Hz, 1H) 8.40 (d, J=6.98 Hz, 1H) 8.98 (d, J=8.46 Hz, 1H) 9.78 (s, 1H) 11.03 (br s, 1H) 14.36 (br s, 1H); MS (ESI+) m/z, 484 (M+H−TFA)+; (ESI−) m/z, 482 (M−H−TFA)−.
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Br.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[C:18]([OH:24])=[N:19][CH:20]=[C:21]([CH3:23])[N:22]=1>CC(O)C.CCOCC>[CH3:23][C:21]1[N:22]2[CH:1]=[CH:2][N:16]=[C:17]2[C:18]([OH:24])=[N:19][CH:20]=1
Reactant: Cc1cnc(O)c(N)n1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1cnc(O)c2nccn12
Reaction time: 8 h
Yield: 35.4 %

Procedure:
Bromoacetaldehyde diethyl acetal (12.2 mL, 81.4 mmol) and a solution of 48% HBr (0.94 mL) are heated at reflux for 1.5 hours, then poured into a suspension of NaHCO3 (1.92 g) in propan-2-ol (31.3 mL). The resulting solid is filtered off and 3-amino-5-methyl-pyrazin-2-ol (3.13 g, 25.0 mmol) is added. The solution is refluxed for 2 hours then left to stand overnight and the solid formed washed with IPA and ether. The solid is added to a solution of DCM (60 mL) and NaHCO3 sat. (30 mL), the two layers are separated and the aqueous phase is extracted with DCM. The combined organic layers are dried with MgSO4 anh., filtered and evaporated to give a brown solid product. The aqueous phase is again extracted with a CHCl3/IPA 9/1, dried with MgSO4 anh., filtered and concentrated to give a brown solid product. The IPA and Ether used previously for washing the solid are combined, evaporated and submitted to the same process described previously to give a brown solid quite impurified from the DCM extraction and a brown solid with the CHCl3/IPA of similar purity to the one obtained beforehand. The products resulting from the first DCM extraction and the two CHCl3/IPA extraction are combined and washed with cold MeOH to give 5-Methyl-imidazo[1,2-a]pyrazin-8-ol as a pale yellow solid (1.32 g) that is submitted into the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.C([O:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH:23]1[CH:22]=[CH:21][C:20]2[N:19]=[C:18]([C:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=4[NH:9][C:8]=3[OH:11])[C:17](=[O:16])[C:25]=2[CH:24]=1
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: CC(=O)Oc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C(c2c(O)[nH]c3c(F)cccc23)=Nc2ccccc21
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
Methanol (25 mL) was vigorously stirred under nitrogen for 20 min and then 7-fluoroisatin (IIIa) (150 mg, 0.91 mmol) and 3-acetoxyindole (106 mg, 0.61 mmol) were added and stirring was Continued for 5 min. Anhydrous Na2CO3 (155 mg) was added and the stirring was continued for 3 h. The dark precipitate was filtered and washed with aqueous methanol (1:1, 20 mL) to give 7 (130 mg, 0.46 mmol, 77%) selectively in a Z form. 1H NMR (DMSO, 400 MHz, δ ppm, J in Hz) 11.37 (1H, s, N′—H), 11.12 (1H, s, N—H), 8.58 (1H, d, J=7.7 Hz, H-4), 7.64 (1H, d, J=7.5 Hz, H-4′), 7.57 (1H, t, J=7.5 Hz H-6′), 7.42 (1H, d, J=7.5 Hz, H-7′), 7.15 (1H, t, J=8.0 Hz, H-5), 7.02 (2H, m, H-5′, 6); CI-MS m/z 281 (M+H)+. Anal. (C16H9N2O2F) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+].Cl.C(OCC1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([O:21][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](OCc1ccccc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
(S)-3-t-butoxycarbonylamino-(R)-2-hydroxy-4-cyclohexylbutyric acid methyl ester (4.58 g., 14.52 mmol) was dissolved in anhydrous dimethylformamide (30 ml.) together with benzyl bromide (2.6 ml., 21.7 mmol) and cooled to 0° C. Sodium hydride (freed of oil by washing with hexane, 450 mg., 19.6 mmol) was added in one portion and the mixture was stirred under nitrogen and allowed to warm to 25° C. over a period of about 15 minutes. The mixture was poured slowly into a stirred ice-cooled mixture of ether (500 ml.) and excess aqueous 1N hydrochloric acid, and was then combined with two previous reaction mixtures where a total of 4.27 mmol (1.34 g.) of this hydroxy methyl ester had been etherified and worked up in an identical fashion. The ether layer was separated and the aqueous layer was extracted thoroughly with ether. The ether layers were combined and washed with 1M lithium chloride solution (2×30 ml.), and dried over magnesium sulfate. The concentrate was chromatographed on silica (0.032-0.064 mm) in 1:6 ether-hexane. Several impure fractions were combined, concentrated, and rechromatographed on 50 g. silica, eluting with 1:10 ether-hexane. The pure fractions combined and concentrated gave 6.45 g. (85%) of the benzyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:20])C(Cl)(Cl)Cl)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)N2CCCC2)n2c1COCC2
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 4a) (1.2 g, 3.52 mmol) in anhydrous tetrahydrofuran (7 ml) was added pyrrolidine (0.376 g, 5.28 mmol). The resulting mixture was stirred at 55° C. for 1.5 h, and then evaporated to dryness. To the residue was added 15 ml water and 30 ml ethyl acetate and the layers were separated. The aqueous layer was extracted once with 15 ml ethyl acetate. The organic layers were combined and evaporated to dryness. The product was purified by flash chromatography to give 0.95 g (92%) of 6-(pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. LC/MS (method 4): Rt=1.14 min; m/z=293.22 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[N:3]=[CH:4][N:5]=1
Reactant: c1cn[nH]c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2cccn2)ncn1
Yield: 66.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), 1H-pyrazole (2.72 g, 40.0 mmol), and cesium carbonate (13.03 g, 40.0 mmol) was stirred in DMF (25 mL) at room temperature for 18 h. The reaction was diluted into 100 mL water and extracted with EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 240 g silica gel cartridge with 0 to 20% ethyl acetate in hexane to yield 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (4.80 g, 66% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (1H, d, J=0.76 Hz), 8.55 (1H, d, J=2.77 Hz), 7.96 (1H, d, J=1.01 Hz), 7.80 (1H, d, J=1.01 Hz), 6.51 (1H, dd, J=2.64, 1.64 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3](=[O:23])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][O:21][CH3:22])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:35]1[C:36]2[C:43]([CH3:44])=[CH:42][NH:41][C:37]=2[N:38]=[CH:39][N:40]=1>C(O)(C)C>[CH3:24][N:2]([CH3:1])[C:3](=[O:23])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][O:21][CH3:22])[CH2:15][CH2:16][N:17]([C:35]3[C:36]4[C:43]([CH3:44])=[CH:42][NH:41][C:37]=4[N:38]=[CH:39][N:40]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: COCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(c2ncnc3[nH]cc(C)c23)CC1
Temperature: 110 °C
Yield: 42 %

Procedure:
To a solution of 3-(4-(methoxymethyl)piperidine-4-carboxamido)phenyl dimethylcarbamate, from step D, and N,N-diisopropylethylamine (2 mL, 11.9 mmol) in isopropanol (5 mL) was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (397 mg, 2.37 mmol). The reaction mixture was heated to 110° C. in a sealed high-pressure vial for 17 hours, during which time the mixture became homogenous. The reaction was concentrated under vacuum and purified by silica gel chromatography (3-5% methanol:CH2Cl2). The product was washed with cold methanol to provide the title compound as an off-white solid (462 mg, 42% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:3])[CH3:2].[C:15](=O)([O-])[O-:16].[K+].[K+].CO[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[CH2:31][C:32](Cl)=[O:33].Cl>O.CC(C)=O>[CH3:15][O:16][CH:31]([C:24]1[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][CH:23]=1)[C:32]([NH:14][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])=[O:33]
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1ccc(N)c(C(=O)O)c1
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(C(OC)C(=O)Nc2ccc(OC(C)C)cc2C(=O)O)c1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a suspension of 9.8 g (50 mmol) of 5-isopropoxy-2-aminobenzoic acid and 11.0 g (80 mmol) of potassium carbonate in a mixed solvent of acetone (40 ml) and water (40 ml), 10.5 g (50 mmol) of 2,5-dimethoxyphenylacetic acid chloride were added dropwise at 10° C. After the resulting reaction mixture was stirred under ice cooling for 1 hour, stirring was continued for further 2 hours at room temperature. The thus obtained solution was made acidic with conc. hydrochloric acid and extracted with dichloromethane. After the extract was dried over magnesium sulfate, the solvent was distilled off to obtain 14.0 g (75%) of 2-(2,5-dimethoxyphenylacetylamino)-5-isopropoxybenzoic acid (m.p. 132°-135° C.). Then the thus obtained acid was heated under reflux for 2 hours in acetic anhydride (100 ml), followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 6.8 g of 2 -(2,5-dimethoxyphenylmethyl)-6-isopropoxy-4H-3,1-benzoxazine-4-one (yield from 5-isopropoxy-2-aminobenzoic acid: 36%)
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[OH:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CCOC(C)=O>[CH3:20][O:19][C:17]([C:16]1[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=1[O:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])=[O:18]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccccc1Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (5.0 g, 27.0 mmol), methyl 2-hydroxybenzoate (4.11 g, 27.0 mmol) and Cs2CO3 (18.49 g, 56.7 mmol) were dissolved in acetonitrile (100 mL) and stirred at 80° C. for 3 h. The reaction mixture was diluted with AcOEt and washed with 1M HCl and water. The organic layer was separated, dried with Na2SO4, filtered and concentrated via rotary evaporation to afford the title compound 545 (7.55 g, 88%) as a light yellow foam.
Reaction SMILES: C[N:2]1CCOCC1.CC(C)(OC([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([OH:19])=O)=O)C.N[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:14][C:15]1[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([NH2:2])=[O:19]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reactant: Cc1ccc(N)cc1
Reactant: CN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C)c(C(N)=O)c2N)cc1
Temperature: 18 °C
Reaction time: 16 h

Procedure:
Firstly N-methylmorpholine (6.15 mL, 5.64 g, 55.8 mmol) and then O-(benzotriazol1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (10.15 g, 26.8 mmol) are added to a stirred mixture of 2-{[(1,1-dimethylethoxy)carbonyl]amino}-6-methylbenzoic acid (5.60 g, 22.3 mmol) and p-toluidine 4.78 g, 44.6 mmol) in dry dimethylformamide (110 mL) under an argon atmosphere, and stirred at 18° C. for 16 hours. The solvent is evaporated off under reduced pressure to give a residue which is treated with aqueous sodium hydrogen carbonate solution (200 mL of 10%) and extracted with dichloromethane (3×100 mL). The combined extracts are washed with aqueous citric acid solution (100 mL of 10%), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 20% ethyl acetate in hexane, and recrystallised from tert-butyl-methyl-ether-hexane to give the title compound as a colourless crystalline solid, m.p. 250° C.
Reaction SMILES: [CH2:1]([CH:8]([C:12](=[O:19])C1CNCCO1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(=O)C(CC1C=CC=CC=1)C(O)=O.[CH2:35]([O:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>O.CO>[CH2:35]([O:42][NH:43][C:12]([CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([OH:11])=[O:10])=[O:19])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C(Cc1ccccc1)C(=O)C1CNCCO1
Agent: COC(=O)C(Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1ccccc1)C(=O)NOCc1ccccc1

Procedure:
In a manner analogous to that described for α-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, benzylmalonic acid monomethyl ester was amidated with O-benzylhydroxylamine and the resulting product [MS: 314 (M+H)+ ] was saponified with 1N sodium hydroxide solution in a 9:1 mixture of methanol and water to the corresponding acid. Recrystallization of the crude product from methanol/methylene chloride/ether yielded α-[(benzyloxy)carbamoyl]hydrocinnamic acid of melting point 147°.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[C:13]=3[C:28]=2[CH3:29])=O)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]3[O:16][C:15]([CH3:17])([CH3:18])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][CH:20]=4)[C:13]=3[C:28]=2[CH3:29])=[CH:32][CH:33]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(Cl)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NCc1ccc(Cl)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 37 %

Procedure:
By using 4-chloro-N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 37%. Melting point: 93-94° C. (Methanol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([CH2:28][O:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:26]3[CH2:27][C@@H:23]([F:22])[CH2:24][C@H:25]3[CH2:28][O:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=C(O)Cc1ccc2nc(Nc3ccccc3Cl)oc2c1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2C(=O)Cc2ccc3nc(Nc4ccccc4Cl)oc3c2)cc1
Temperature: 0 °C
Yield: 66.9 %

Procedure:
In DMF (5 ml), 2-(2-chlorophenylamino)-6-benzoxazolylacetic acid (303 mg, 1.0 mmol), methyl 4-((2S,4S)-4-fluoro-2-pyrrolidinylmethoxy)benzoate (253 mg, 1.0 mmol), EDC•HCl (288 mg, 1.5 mmol), HOBt (203 mg, 1.5 mmol) and triethylamine (0.70 ml, 5.0 mmol) were stirred at room temperature for 14 hours. The reaction mixture was poured in ice water (30 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (360 mg, 67%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12]Cl)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:19]([NH:21][CH2:22][C:23]#[N:24])=[O:20].ClC1C=CC=CC=1Cl.[Sn](Cl)(Cl)(Cl)Cl>O=[Pt]=O.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:27]=1[O:28][CH3:29])[C:19]([NH:21][CH2:22][CH:23]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=2)[CH2:11][CH2:12][NH:24]1)=[O:20]
Reactant: COc1cc(C(=O)NCC#N)cc(OC)c1OC
Reactant: COc1ccc(CCCl)cc1OC
Agent: O=[Pt]=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(cc1OC)C(CNC(=O)c1cc(OC)c(OC)c(OC)c1)NCC2
Reaction time: 8 h

Procedure:
A mixture of 2.0 g. of 1-(3,4-dimethoxyphenyl)-2-chloroethane and 2.5 g of 3,4,5-trimethoxybenzamidoacetonitrile (obtainable from aminoacetonitrile and 3,4,5-trimethoxybenzoyl chloride) is allowed to stand overnight at 20° in 100 ml. of o-dichlorobenzene and with 2.6 g. of tin tetrachloride; the mixture is thereafter heated for 3 hours to 110°. The solution is concentrated by evaporation, and the residue is shaken with chloroform and sodium hydroxide solution. The chloroform solution is evaporated, and the thus-obtained crude 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline is dissolved in 30 ml. of methanol and hydrogenated with 200 mg. of PtO2 at 20° and under normal pressure. After filtration, evaporation, and purification by chromatography on silica gel, 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is obtained; hydrochloride, m.p. 234°-236°.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[C:15](=C)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)=[O:35]>C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])=[C:15]([OH:35])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
Following the ozonization procedures described in Example 9, a solution of 350 mg. of p-nitrobenzyl 7-phenylacetamido-3-methylenecepham-4-carboxylate in 250 ml. of methylene chloride was cooled to -78°C. and was ozonized. The intermediate ozonide was decomposed in situ with sulfur dioxide and the reaction product was recovered and obtained crystalline by extraction with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[S:23]1[CH:27]=[C:26]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[N:25]=[N:24]1>>[S:23]1[CH:27]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=4[CH3:21])[CH:5]=[CH:6][C:7]=3[Cl:8])=[O:33])=[CH:35][CH:36]=2)[N:25]=[N:24]1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: O=C(O)c1ccc(-c2csnn2)cc1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(-c3csnn3)cc2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 4-(1,2,3-thiadiazol-4-yl)benzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(3-(4-(1,2,3-thiadiazol-4-yl)benzamido)-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 518.1 (M)+
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][C:8]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][C:8]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(C)(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(C)(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 35.6 %

Procedure:
Pd(PPh3)2Cl2 (14 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′,2-dimethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 0.113 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.45 mL) and 4-cyanophenylboronic acid (33 mg, 0.226 mmol). The mixture was refluxed under Ar in a microwave reactor for 2 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative HPLC twice to give pure 3-(2′-amino-1′,2-dimethyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (17 mg, 36%). 1H-NMR (CDCl3): 1.78 (s, 3H), 1.97 (s, 3H), 2.60 (d, 1H), 2.85 (d, 1H), 6.84&6.93 (s, 1H), 7.23 (m, 2H), 7.31 (m, 4H), 7.48 (m, 2H), 7.52 (m, 2H), 7.62 (m, 1H), 7.67 (m, 1H), 11.51 (brs, 1H).