Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16].[H-].[Na+].CCO>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C)c21
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 174.1 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (1.0 g) and 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.3 g) in DMF (10 mL) was added 60% NaH (0.23 g) at room temperature, and the mixture was stirred at 180° C. under microwave irradiation for 30 min. To the mixture was added EtOH (10 mL). The formed crystals were collected by filtration and washed with EtOH. This microwave reaction was repeated two additional times with the same amount of starting material. The combined crystals were recrystallized from EtOH containing 5% distilled water (270 mL) and dried under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (3.3 g) as white crystals (Form A).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6](F)[NH:5][C:4]=2[CH:3]=1.Cl.[CH3:15][C:16]1([NH2:20])[CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:20][C:16]3([CH3:15])[CH2:19][CH2:18][CH2:17]3)[NH:5][C:4]=2[CH:3]=1
Reactant: CC1(N)CCC1
Reactant: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A mixture of 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.3 g, 5.3 mmol), 1-methylcyclobutylamine hydrochloride (1.0 g, 8.1 mmol) and triethylamine (2.5 ml, 18.1 mmol) in ethanol (10 ml) was stirred for 16 h at 50° C. and then for 5 h at 70° C. in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was triturated with water (25 ml) followed by adjustment to pH <2 with 1M hydrochloric acid. The crude product was isolated by filtration, recrystallised from acetic acid and finally purified by chromatography (C18; 20-60% acetonitrile+0.01% TFA) to give 363 mg (22%) of the title compound; mp 294-296° C.; 1H-NMR (DMSO-d6): δ1.48 (s, 3H), 1.75-1.88 (m, 2H), 1.94-2.05 (m, 2H), 2.18-2.31 (m, 2H), 7.08 (s, 1H) 7.33 (br s, 1H), 10.67 (br s, 1H); LC-MS: m/e 306/308 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:24][C:23]2=[O:36])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17]C(O)(C)C)[N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1C=CC(N)=N1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:24][C:23]2=[O:36])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccc(N)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(C)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (prepared as in Example 28, 200 mg, 0.56 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (87 mg, 0.56 mmol) and 1-hydroxybenzotriazole (80 mg, 0.58 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-methyl-1H-pyrazol-3-amine (60 mg, 0.61 mmol). The reaction mixture was then stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (80 mg, 33%) as a light yellow solid: LR-ES-MS m/z calculated for C24H30N4O4 [M]+ 438, observed [M+H]+ 439; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-1.28 (m, 6H) 1.44-1.86 (m, 7H) 3.73 (s, 3H) 3.81 (s, 3H) 4.10 (d, J=18.2 Hz, 1H) 4.49 (d, J=18.2 Hz, 1H) 4.71 (s, 1H) 4.89 (dd, J=10.6, 5.1 Hz, 1H) 6.39 (d, J=2.1 Hz, 1H) 6.95-7.06 (m, 1H) 7.21 (d, J=7.5 Hz, 1H) 7.25-7.36 (m, 2H) 7.54 (d, J=2.1 Hz, 1H) 10.70 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.Br[C:13](Br)([CH2:24][CH3:25])[C:14]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][CH3:21])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:11][O:10][C:8]([C:6]1[CH:7]=[C:2]([O:1][CH:13]([CH2:24][CH3:25])[C:14]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][CH3:21])=[O:15])[CH:3]=[N:4][CH:5]=1)=[O:9]
Reactant: CCC#CC(C)(C)NC(=O)C(Br)(Br)CC
Reactant: COC(=O)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C(=O)OC)c1
Temperature: 70 °C

Procedure:
3-Hydroxy-5-methoxycarbonylpyridine (1.68 g, prepared using the method described in Bull. Acad. Sci. (Chem. Div.), (1976), 598) and 2-bromobromo-N-(5-methylhex-3-yn-5-yl)-butyramide (3.06 g) were dissolved in dry N,N-dimethylformamide (30 ml) containing anhydrous potassium carbonate (2.35 g). The mixture was heated to 70° C. for 3 hours with stirring, cooled to ambient temperature, diluted with water and extracted with diethyl ether (three times). The organic extracts were combined, washed with water (three times), dried over magnesium sulphate and evaporated under reduced pressure to give a brown gum. The gum was fractionated by chromatography (silica; diethyl ether) to give the required product, 2.38 g, as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:17])[C:14]=1[CH2:15][OH:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:17])[C:14]=1[CH2:15][O:16][S:26]([CH3:25])(=[O:28])=[O:27])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)c1cc(F)c(CO)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a stirred solution of tert-butyl 3,5-difluoro-4-(hydroxymethyl)benzoate (1.9 g, 7.78 mmol) in DCM was added Et3N (3.27 mL, 23.4 mmol, 3 eq) and methanesulfonylchloride (0.72 mL, 9.3 mmol, 1.2 eq) successively at 0° C. After the reaction was stirred for 30 min, it was extracted with CH2Cl2C and water. Organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (2.25 g, 89% yield) as a ivory solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=2)=[CH:29][CH:28]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: N#CCCNc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.10 g, 0.39 mmol), potassium carbonate (0.08 g, 0.58 mmol) and 4-chlorophenacyl bromide (0.11 g, 0.47 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 191-192° C.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]O)[CH2:4][CH3:5].P(Br)(Br)[Br:15]>C(Cl)Cl>[CH3:1][CH2:2][CH:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][Br:15])[CH2:4][CH3:5]
Reactant: BrP(Br)Br
Reactant: CCC(CC)c1cccc(CO)c1
Solvent: ClCCl
Product: CCC(CC)c1cccc(CBr)c1
Yield: 90 %

Procedure:
According to example 17, 1.84 g of 3-(3-pentyl)benzyl alcohol was treated with 0.34 mL of PBr3 in 25 mL of anhydrous CH2Cl2 to afford 2.23 g (90%) of 3-(3-Pentyl)benzyl bromide as a clear liquid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Al+3].[Cl-:8].[Cl-].[Cl-].[CH2:11]=[CH:12][CH3:13]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([CH2:11][CH:12]([CH3:13])[Cl:8])=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: [Cl-]
Reactant: C=CC
Agent: [Al+3]
Solvent: ClCCl
Product: CC(Cl)CC(=O)CCCl

Procedure:
At room temperature, 507.88 g of 3-chloropropionyl chloride are added dropwise over a period of 15 minutes to 758.08 g (5.6 mol) of AlCl3 in 560 ml of methylene chloride, and 189 g (4.5 mol) of propylene are introduced into this mixture at approximately 28 to 30° C. over a period of approximately 3 hours.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>C(O)C>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]=[C:22]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Temperature: 0 °C
Yield: 67.7 %

Procedure:
A stirred solution of 5-cyanoindole (10.0 g, 70.3 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (15.4 g, 77.3 mmol), and pyrrolidine (14.7 mL, 175.7 mmol) in ethanol (200 mL) was heated at reflux for 20 hours then cooled to 0° C. The resulting precipitate was collected by vacuum filtration and rinsed with cold ethanol and hexanes to afford the product as a white solid (15.4 g, 68%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]([CH3:21])([CH3:20])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][S:16]([CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:21])[CH3:20])(=[O:17])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN(CCS(C)(=O)=O)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCCN1CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 4-(2-methanesulfonylethyl)-3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (510 mg, 1.59 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white solid (320 mg, 91%). 1H NMR (CDCl3, 300 MHz): δ 3.49 (s, 1 H); 3.12-3.03 (m, 5 H); 2.92-2.84 (m, 4 H); 2.60 (s, 2 H); 2.53-2.47 (m, 2 H); 1.06 (s, 6 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.[H-].[Na+].O>CN(C=O)C>[CH:19]1([O:1][C:2]2[CH:3]=[C:4]([N:10]3[C:18]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=4[N:12]=[CH:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-n2cnc3cnccc32)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2cnc3cnccc32)cc1OC1CCCC1
Yield: 21.8 %

Procedure:
A solution of 2.05 g of 1-(3hydroxy-4-methoxyphenyl)-1H-imidazo[4,5-c]pyridine, 2.5 g of cyclopentylbromide and 665 mg of NaH in 20 ml of DMF was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate, dried to give 1.4 g of crude product. Recrystallization from CH2Cl2 gave 574 mg product. M.P.: 66°-88° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][O:16][C:17]1[C:21](OC)=[N:20][S:19](=[O:25])(=[O:24])[N:18]=1>CO>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:21]2[C:17]([O:16][CH3:15])=[N:18][S:19](=[O:25])(=[O:24])[N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.41 g; 11.2 mmoles) [prepared according to the procedure described in Belgian Pat. No. 857,388] in 20 ml of dry methanol was added all at once to a well stirred, cold (8°) suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200 ml of methanol. After stirring at 8°-10° for 15 minutes, a methanolic solution of the title compound is produced.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[I:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]>>[Cl:1][S:2]([C:14]1[CH:15]=[C:7]([I:6])[C:8]([CH3:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1c(I)cccc1C(=O)O
Product: Cc1c(I)cc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with chlorosulfonic acid (3.80 mL, 57.2 mmol), and 3-iodo-2-methylbenzoic acid (5.00 g, 19.1 mmol) was added in portions at 0° C. The reaction was heated at 95° C. for two hours and then stirred at room temperature overnight. The reaction mixture was poured onto ice and the solids formed were collected and dried to afford the desired product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([F:11])([F:10])[F:9])[C:4]([C:12]([OH:14])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=1>C(Cl)Cl.C(N(CC)CC)C>[C:26]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:12]([C:4]1[C:5]([C:8]([F:9])([F:10])[F:11])=[C:6]([CH3:7])[N:2]([CH3:1])[CH:3]=1)=[O:14]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: Cc1c(C(F)(F)F)c(C(=O)O)cn1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(F)(F)F)c(C(=O)Nc2ccccc2-c2ccccc2)cn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,5-dimethyl-4-trifluoromethylpyrrol-3-carboxylic acid (1.9 g) and oxalyl chloride (0.9 ml) in methylene chloride (20 ml) is stirred at room temperature in the presence of a catalytic amount of DMF. The solvent is evaporated under reduced pressure to give a crystalline solid. This solid is dissolved in methylene chloride (1 ml) and added to a solution of 2-biphenylamine (1.7 g) and triethylamine (4.2 ml) in methylene chloride (20 ml) at 0° C. The reaction mixture is stirred at room temperature for 2 hours. Evaporation of the solvent under reduced pressure, addition of water and filtering gives the N-(2-biphenylyl)-1,5-dimethyl-4-trifluoromethylpyrrol-3-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.CN(C1C=CC=CN=1)C.C(N=C=NC(C)C)(C)C>C1COCC1.CCOC(C)=O>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:24](=[O:26])[CH2:23][CH2:22][N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[CH2:20][CH2:21][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]2=3)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCC(=O)O)c3ccccc23)CC1
Reactant: COc1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)CCn2c3c(c4ccccc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 29 h
Yield: 83.5 %

Procedure:
3-(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanoic acid (0.105 g, 0.292 mmol), p-anisidine (0.0377 g, 0.306 mmol, 1.05 equiv.) and dimethylaminopyridine (0.0357 g, 0.292 mmol, 1.00 equiv.) were dissolved in THF at rt under N2. Diisopropylcarbodiimide (0.0503 mL, 0.0405 g, 0.321 mmol, 1.00 equiv.) was added, then the reaction mixture was stirred for 29 h. The reaction mixture was taken up in EtOAc and washed with 10% aq. citric acid (2×), saturated aq. NaHCO3 (2×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product (0.1686 g) was chromatographed (SiO2 25 g, eluted with 9:1 toluene: acetone) to give tert-butyl 6-[3-(4-methoxyanilino)-3-oxopropyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.113 g) in 84% yield. 1H NMR (300 MHz, CDCl3) δ 1.47, 2.68-2.76, 2.95-3.08, 3.56-3.70, 3.79, 4.53, 6.83, 7.12-7.54; MS (ESI+) for C27H33N3O4 m/z 464.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.C(N)CN.[N+:17]([CH3:20])([O-:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[C:7]([CH2:20][N+:17]([O-:19])=[O:18])[CH2:6][CH2:5]2)=[CH:10][CH:11]=1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: C[N+](=O)[O-]
Solvent: NCCN
Product: O=[N+]([O-])CC1=Cc2ccc(Br)cc2CC1
Temperature: 75 °C

Procedure:
Charged 900 g of 6-bromo-2-tetralone, 1.9 L of nitromethane and 37 g of ethylenediamine in 10 L flask. Heated the mixture liquid to 75° C. in a vessel under N2 for 24 hours to complete the reaction. When the reaction was complete, distilled out the excess nitromethane under reduce pressure. Introduced 200 g of silica gel to the residue with cooling. Hexane (10 L×3) was used to extracted, filtered and the hexane layer combined. On cooling, crystals were formed. About 500 g of 7-bromo-1,2-dihydro-3-(nitromethyl)naphthalene was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:19])[N:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>C(#N)C.CCO>[Cl:19][C:4]1[N:3]=[C:2]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1cnc2[nH]cc(-c3cc(Cl)nc(Cl)c3)c2c1
Solvent: CC#N
Solvent: CCO
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](O)CC4)c3)c2c1

Procedure:
A mixture of Example 149e (43.9 mg, 0.146 mmol) and trans-4-aminocyclohexanol (0.337 g, 2.92 mmol) in acetonitrile (1.5 mL) and EtOH (1.5 mL) was heated at 190° C. for 3 hours in a Biotage microwave reactor. The solvent was evaporated. The residue was treated with 5% citric acid and brine, and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc (5:95) to 100% EtOAc to give 22.0 mg of the title compound. 1H NMR (500 MHz, DMSO-d6) ppm 1.15-1.33 (m, 3H), 1.84 (d, J=10.98 Hz, 2H), 1.96 (d, J=11.29 Hz, 2H), 2.07 (m, 1H), 3.40 (m, 1H), 3.59 (m, 1H), 3.89 (s, 3H), 6.76-6.90 (m, 2H), 7.78 (d, J=2.75 Hz, 1H), 8.07 (dd, J=6.71, 2.75 Hz, 2H), 12.03 (s, 1H). MS (APCI+) m/z 373.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])C1C=C2C(C=CN2)=CC=1.C(O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([NH2:29])=[O:28])[CH:22]=[C:21]2[N:30]=[C:31]=[O:32])C=C>COCCOC>[F:1][C:2]([F:13])([F:12])[C:26]1[CH:25]=[C:24]2[C:20]([C:21]([N:30]=[C:31]=[O:32])=[CH:22][N:23]2[C:27]([NH2:29])=[O:28])=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Solvent: COCCOC
Product: NC(=O)n1cc(N=C=O)c2ccc(C(F)(F)F)cc21

Procedure:
was prepared from 6-trifluoromethylindole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide except that the acyl azide intermediate was prepared in 1,2 dimethoxyethane instead of toluene.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[S:35](=[O:39])(=[O:38])([OH:37])[OH:36]>>[S:35]([O-:39])([O-:38])(=[O:37])=[O:36].[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Reactant: O=S(=O)(O)O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Product: O=S(=O)([O-])[O-]

Procedure:
7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (4 g) was dissolved in 0.2 N sulfuric acid (40 ml). The mixture was lyophilized to give 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate hemisulfate (syn isomer) (4.1 g).
Reaction SMILES: C[CH:2]([C:6]1[CH:21]=[CH:20][C:9]2[O:10][CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4].[C:22]([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O>CN(C)C=O>[CH3:22][CH:11]1[O:10][C:9]2[CH:20]=[CH:21][C:6]([CH2:2][C:3]([O:5][CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[O:4])=[CH:7][C:8]=2[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=2
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Oc2ccc(CC(=O)OCC(=O)OCc3ccccc3)cc2C(=O)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 125.3 %

Procedure:
A mixture of 7.09 g (0.025 m) of 6,11-dihydro-α-methyl-11-oxodibenz[b,e]oxepin-2-acetic acid, and 2.59 g (0.0188 m) of anhydrous K2CO3 in 70 ml of dimethylformamide was warmed at 50° C. for one hour in an atmosphere of nitrogen. To this mixture 6.32 g (0.276 m) of benzyl bromoacetate was added dropwise and the mixture was held at 50° C. overnight (about 16 hours). The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5% NaHCO3, dried over Na2SO4, filtered and evaporated to give 10.11 g (94%) of an oil of (±)-2-phenylmethoxy-2-oxoethyl 6,11-dihydro-α-methyl-11-oxodibenz[b,e]oxepin-2-acetate.