Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:36][S:37][C:38]2[N:39]=[N:40][NH:41][CH:42]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:28]1([CH2:27][C:26]([NH:25][C@@H:24]2[C:23](=[O:35])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:36][S:37][C:38]4[N:39]=[N:40][NH:41][CH:42]=4)[CH2:19][S:20][C@H:21]23)=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CSc3c[nH]nn3)CS[C@H]12
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(O)=S)=C(CSc3c[nH]nn3)CS[C@H]12
Reaction time: 0.67 h
Yield: 50.6 %

Procedure:
To a suspension of 7β-phenylacetylamino-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (186 mg: 0.296 mMol.) in dichloromethane (3 ml) under ice cooling is added anisole (0.45 ml) and trifluoroacetic acid (0.45 ml), and the mixture is stirred for 1 hour 40 minutes. The reaction mixture is concentrated, triturated with hexane, and washed with ethyl acetate to give 7β-phenylacetylamino-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid as white solid (67 mg). Yield: 49%.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CN(C)C(=N)N(C)C>ClCCl>[C:1]1([CH:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-phenyl-2-aminoethanol (5.323 g, 38.80 mmole) in 50 mL dichloromethane was added tert-butyldimethylsilyl chloride (7.030 g, 46.63 mmole) followed, after 15 minutes by tetramethylguanidine (2.430 g, 21.09 mmole). The reaction mixture was stirred at room temperature for 15 minutes and quenched by addition of water (40 mL). Layers were separated. The aqueous phase was extracted with dichloromethane (40 mL). Combined organic phases were washed with brine (2×50 mL), dried over magnesium sulfate and concentrated in vacuo to give crude 2-phenyl-2-tert-butyl dimethylsiloxy-1-ethylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2Cl)([O-:3])=[O:2].CN1C(=O)CCC1.[N-:29]=[N+:30]=[N-:31].[Na+].O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2[N:29]=[N+:30]=[N-:31])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(Cl)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1cc(-c2cccc(F)c2)nc2ccc([N+](=O)[O-])cc12
Temperature: 60 °C

Procedure:
6-Nitro-4-chloro-2-(3-fluorophenyl)-quinoline 3.2 g (9.50 mmoles) was placed in a 250 mL three neck round bottom flask equipped with a condenser, magnetic stirrer, silicone oil heating bath, nitrogen inlet and gas outlet. To this was added 75 mL of N-methyl pyrrolidinone then 6.0 g (95 mmoles, 10 equiv.) of sodium azide. The mixture was stirred and warmed to 60° C. for 18 hr. After this time the mixture was cooled, poured into a 1 L separatory funnel containing 500 mL water and 250 mL of ethyl acetate. The pH was adjusted to 9.0 and the layers separated. The aqueous layer was extracted twice with 100 mL of ethyl acetate, the organic layers combined, dried over Na2SO4, filtered and concentrated to yield a product, which was carried to the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:40])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:34][CH2:35][CH2:36][CH2:37][N:38]=2)=[CH:25][CH:24]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:40])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:38][CH2:37][CH2:36][CH2:35][N:34]=2)=[CH:25][CH:24]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
190 mg (0.34 mmol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(2-(1,4,5,6tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionate (step d) were dissolved in 5 ml of 95% trifluoroacetic acid and the mixture was stirred at room temperature for 1 h. The trifluoroacetic acid was distilled off in vacuo and the mixture was co-evaporated with toluene. The residue was dissolved in glacial acetic acid, and the solution was diluted with water and freeze-dried.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([N+:22]([O-])=O)[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[K+].[H][H]>CO.O.[Pd]>[C:1]1([S:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([NH2:22])[CH:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Yield: 57.8 %

Procedure:
N-benzenesulfonyl-4-acetylamino-3-nitrobenzamide (12.67 g) was dissolved in 200 ml of methanol and 30 ml of water, and 7.59 g of potassium hydrogencarbonate were further added thereto. The mixture was hydrogenated in a hydrogen atmosphere using 2.53 g of 5% palladium on carbon as catalyst at 40° C. for 24 hours. The solid material was separated through filtration, and the filtrate was concentrated. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 4:1) to give 6.72 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][CH:33]=1>>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:38])=[CH:39][CH:40]=1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: COc1ccc(C(=O)O)cc1
Agent: Cl
Product: COc1ccc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 4-methoxybenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(4-methoxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 500 (M+H)+.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.CC(C)([O-])C.[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[CH2:26]([N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cccc3nc4c(c(c23)N1Cc1ccccc1)CCCC4
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.30 g) in dry dimethylformamide (50 ml) was added potassium tert-butoxide (2.1 g). To the solution was added benzyl bromide (2.22 ml), and stirring was continued for five mins. The reaction mixture was diluted with water (150 ml) and extracted with diethyl ether. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Trituration of the residue with pentane followed by recrystallization from methanol gave 2.42 g (41%) of product, mp 166°-167.5° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1>C(O)(=O)C.O>[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: Cn1ccc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
Sodium cyanoborohydride (63 mg, 1.004 mmol) was added to an ice-cold solution of the N-methyl indole (110 mg, 0.335 mmol) in glacial acetic acid (6 mL). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, cooled in an ice bath, and diluted with H2O (10 mL). Ice-cold concentrated aq. ammonium hydroxide (30 mL) was added until the solution reached pH 12. After extraction (2×) with CH2Cl2, the organic layer was dried over MgSO4/Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (SiO2, 10 g, 10% EtOAc/hexanes) gave the desired N-methyl indoline product (15 mg, 15%) as brown oil. The material is air-sensitive and requires storage under nitrogen: 1H NMR (500 MHz, CDCl3) δ 7.28-7.25 (m, 1H), 7.01 (dd, J=10.4, 2.0 Hz, 1H), 6.95 (dd, J=8.2, 1.9 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 6.28 (d, J=8.1 Hz, 1H), 4.11 (t, J=5.9 Hz, 1H), 3.50 (dd, J =13, 2.0 Hz, 2H), 3.36-3.32 (m, 2H), 2.88 (dd, J=11.3, 5.2 Hz, 1H), 2.82 (t, J=8.2 Hz, 2H), 2.73 (s, 3H), 2.56 (dd, J=11.4, 7.0 Hz, 1H), 2.41 (S, 3H); IR (KBr) 3052, 2925, 2850, 2786, 1609, 1422, 1265, 739 cm−1; ESI MS m/z=331 [C19H20ClFN2+H]+.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([F:15])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].Cl>[Cl-].[Cl-].[Zn+2]>[F:15][C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: COc1cc(F)cc(OC)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Product: CCC(=O)c1c(F)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50306.3 %

Procedure:
Under nitrogen atmosphere, 5 ml solution of dichloroethane with 2 g of 3,5-dimethoxy-1-fluorobenzene, and 5 ml solution of dichloroethane with 1.3 mg of propionyl chloride were dropped sequentiallly at −10° C. to 40 ml solution of dichloroethane with 2.4 g of alumimium trichloride and 240 mg of zinc dichloride, and the mixture was stirred at room temperature for 2 hours. 20% hydrochloric acid aqueous solution was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure and the residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=5/1), to obtain 1.5 g of the above compound as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].N[C:14]1[CH:22]=[CH:21]C(CN(C=O)C)=C[C:15]=1[C:16]([OH:18])=[O:17]>CN(C)C=O>[C:15]12[C:12](=[CH:11][CH:21]=[CH:22][CH:14]=1)[NH:8][C:1](=[O:2])[O:18][C:16]2=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C=O)Cc1ccc(N)c(C(=O)O)c1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2c(=O)o1

Procedure:
There was suspended, in 7.6 mL of N,N-dimethylformamide, 1.67 g of 1,1′-carbonyl-diimidazole (CDI) and the suspension was cooled to 5° C. To this slurry, there was added 2.0 g of 2-amino-5-(N-formyl-N-methylamino-methyl)-benzoic acid to thus carry out a reaction for forming an isatoic anhydride derivative at 5° C. After the confirmation of the completion of the reaction by HPLC, 3.80 g of 4-amino-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine isopropyl ester was added to the reaction system to thus carry out amidation at 60° C. overnight. After the confirmation of the completion of the reaction by HPLC, the reaction system was cooled to a temperature ranging from 25 to 50° C. followed by the addition of 3 mL of water. This solution was slowly dropwise added to another egg plant-shaped flask to which 29 mL of water had previously been added to thus form a solid material and then the separated solid was isolated through filtration under reduced pressure. After washing the solid with 20 mL of water, it was dried under reduced pressure to thus give 5.50 g of a crude product of the intended compound. To this crude product, there was added 5.5 mL of acetonitrile to obtain a uniform dispersion, 137.5 mL of 2-propanol and seed crystals were added thereto to precipitate a solid material and the slurry was stirred at 20° C. for 2 hours. The solid thus separated was isolated through filtration under reduced pressure, washed with 20 mL of 2-propanol and then dried under reduced pressure to thus give 2.60 g of the intended product as a white crystalline solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34](OCC)=[O:35]>>[CH:34]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35]
Reactant: O=C(NCC1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCOC(=O)Cl
Product: O=CN1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (pyrrolidin-3-ylmethyl)-amide (example A146) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Mg].BrCC.C(NCC)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:18])[CH3:17].Br[C:20]([CH3:30])([CH3:29])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].OS(O)(=O)=O.CCN(CC)CC>C1(C)C=CC=CC=1.CCOCC>[CH3:29][C:20]([CH3:30])([CH2:17][C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)=[O:18])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: CC(C)(Br)C(=O)c1ccccc1
Reactant: CC(=O)c1ccccn1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCBr
Product: CC(C)(CC(=O)c1ccccn1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
In a dried 3 neck flask fitted with magnetic stirrer and condensor was placed metal magnesium (12 mmol) and ether (1.8 mL). Neat bromoethane (2.5 mmol) was added via syringe and the reaction was started immediately. A solution of bromoethane (10.5 mmol) in toluene (30 mL) was added to the solution slowly. After completion of the addition, the solution was stirred at room temperature for 30 min under nitrogen before adding neat diethylamine (24 mmol). The solution was further stirred at room temperature for 15 min. The solution was cooled to 0° C. and a mixture of 1-(pyridin-2-yl)ethanone (XVIII) (12 mmol) and 2-bromoisobutyrophenone (XVII) (13 mmol) was added to the solution. The solution was further stirred for 3 h at 0° C. under nitrogen. Aqueous 5% H2SO4 (20 mL) was added to the solution and the solution was warmed to room temperatue. The organic layer was separated, dried over MgSO4 and filtered. The organic layer was then treated with Et3N (10 mmol) and allowed to stir overnight at room temperature. The solution was then washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography eluting with 1-5% EtOAc in hexane gradient to give 2,2-dimethyl-1-phenyl-4-(pyridin-2-yl)butane-1,4-dione 9 as a colorless viscous oil (11% yield). 1H NMR (CDCl3, 400 MHz): δ ppm 1.47 (s, 6H), 3.80 (s, 2H), 7.34-7.50 (m, 4H), 7.65-7.75 (m, 2H), 7.80 (m, 1H), 7.94 (m, 1H), 8.67 (m, 1H); ESIMS found C17H17NO2 m/z 268 (M+H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[OH:18][CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[OH:18][CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)NCCO)cc2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)cc1
Yield: 20.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (500 mg, 1.5 mmol) was reacted with N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (450 mg, 1.5 mmol) to afford the desired product (130 mg, 20%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.78-7.74 (m, 2H), 7.58-7.42 (m, 4H), 5.74 (d, J=5.4 Hz, 1H), 4.78 (t, J=5.6 Hz, 1H), 3.71 (s, 3H), 3.45 (q, J=6.1 Hz, 2H), 2.93 (q, J=6.2 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1Br
Reactant: CCCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Br)c(C#N)c1
Temperature: -8 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A round bottom flask was charged with the 2-bromo-5-iodobenzonitrile (2.00 g, 6.49 mmol) and THF (9 mL). Solution cooled down to −8° C. (ice/brine bath). Turbo Grignard 1.3M in THF (5.50 mL, 7.14 mmol) is then added in one portion and the reaction stirred for 15 minutes at −8° C. Butyraldehyde (0.698 μL, 7.79 mmol) is then charged in another flask and the preformed anion is added over the aldehyde/THF (4 mL) via canula and then, reaction allowed to warmed at room temperature overnight under magnetic stirring. Ammonium chloride (sat. aq.) added to the mixture. Extracted 3× with Ethyl Acetate. Combined organic layers washed with water (1×), with brine (1×), dried over sodium sulfate, filtered and concentrated to afford the crude material. Purification by silica gel flash chromatography (Ethyl Acetate/Heptane) provide the title compound as a yellow oil (1.33 g, 80.6%). 1H NMR (400 MHz, DMSO-d6) δ 0.83 (t, J=7.41 Hz, 3 H) 1.18-1.34 (m, 2 H) 1.46-1.57 (m, 2 H) 4.52-4.58 (m, 1 H) 5.37 (d, J=4.88 Hz, 1 H) 7.56 (dd, J=8.58, 1.95 Hz, 1 H) 7.79 (d, J=8.39 Hz, 1 H) 7.81 (d, J=2.15 Hz, 1 H); MS (M): 255.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=3)[C:10]3[CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[N:26]([Si](C)(C)C)=[N+:27]=[N-:28].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]4[NH:28][N:27]=[N:26][N:25]=4)=[CH:21][CH:22]=3)[C:10]3[CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Nc2nc(-c3ccc(Cl)s3)nc3c2CCC3)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(-c2nc3c(c(Nc4ccc(Cc5nnn[nH]5)cc4)n2)CCC3)s1
Temperature: 110 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
In an 4-mL was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetonitrile (20 mg, 0.055 mmol), azidotrimethylsilane (80 mg, 1.44 mmol) and tetrabutylammonium fluoride trihydrate (25 mg, 0.07 mmol). The mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was dissolved in dichloromethane (2 ml) and 2N HCl (aq.) (1 ml) was added. The precipitate was collected by filtration and washed with water (5 ml) followed dichloromethane (5 ml). The solid thus obtained was further triturated with dichloromethane (4 ml) to give the title compound (11 mg, 45% yield, HCl salt, it is regioisomers). MW/HCl=446.36. 1H NMR (DMSO-D6, 360 MHz) δ 7.76 (m, 3H), 7.30 (d, J=7.9 Hz, 2H), 7.23 (d, J=3.6 Hz, 1H), 4.29 (s, 2H), 2.92 (t, J=6.8 Hz, 2H), 2.86 (t, J=6.8 Hz, 2H), 2.11 (t, J=6.8 Hz, 2H). MS: ESI+, m/z 410 [M+H]+. LCMS: 97%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[CH3:22])=[O:16])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])C.O.[OH-].[K+].Cl>CO>[CH3:22][C@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[C:15]([C:8]1[N:9]2[C:10]([CH2:11][O:12][CH2:13][CH2:14]2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=1)=[O:16]
Reactant: CCOC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 6c) (762 mg, 2.49 mmol) in methanol (10 ml) was added water (4 ml) and 2 N aqueous potassium hydroxide (6 ml, 12 mmol). The mixture was stirred for 3 h at 80° C., then cooled down to 25° C. and acidified with excess 10 M aqueous hydrochloric acid. After extraction (3 times with dichloromethane), the combined organic layers were dried over sodium sulfate and the solvents evaporated to give 595 mg (86%) 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid as a white solid. LC/MS (method 2): Rt=0.98 min; m/z=279.06 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:24]=[CH:23][S:22][CH:21]=1>CN(C)C=O>[S:22]1[CH:23]=[CH:24][C:20]([CH2:19][O:1][C:2]2[CH:11]=[CH:10][C:5]3[S:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)=[CH:21]1
Reactant: ClCc1ccsc1
Reactant: O=c1oc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1oc2cc(OCc3ccsc3)ccc2s1
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
A mixture of 6-hydroxy-1,3-benzoxathiol-2-one (15 g) and potassium carbonate (13.8 g) in dimethylformamide (200 mL) is stirred for 20 minutes, and is then treated, dropwise, with 3-chloromethylthiophene (11.8 g). The mixture is stirred at 60° C. for 16 hours. The reaction mixture is then concentrated in vacuo, and partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous layer is extracted with ethyl acetate (100 mL) and with diethyl ether (100 mL), and the combined aqueous layers are washed with brine, dried over magnesium sulphate, and evaporated to give a yellow solid, which is recrystallised from ethanol (200 mL) to give 6-(3-thienylmethoxy)-1,3-benzoxathiol-2-one (8.9 g), in the form of pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](\[NH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])/[CH3:7])[CH3:2].[C:19](#[N:26])[C:20]1C=CC=C[CH:21]=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]([C:5]1[C:19]([CH2:20][CH3:21])=[N:26][N:8]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:6]=1[CH3:7])=[O:18])[CH3:2]
Reactant: N#Cc1ccccc1
Reactant: CCOC(=O)/C=C(/C)Nc1c(C)cc(C)cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)c1c(CC)nn(-c2c(C)cc(C)cc2C)c1C
Yield: 83 %

Procedure:
According to AVV A, (Z-3-(2,4,6-trimethylphenylamino)-but-2-enoic acid ethylester (247.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into benzonitrile (3.0 ml, 29.4 mmol, 29.4 equiv.) for 14 hours at 120° C. The brown oil obtained as raw product (524.3 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→0:100). The product was obtained in the form of a white solid (289.4 mg, 0.83 mmol, 83%).