Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:14]=4)[N:10]=[C:9]3[C:23]([NH2:25])=[O:24])=[C:4]2[CH:3]=1.[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32].C(O)C(N)(CO)CO>N1C=CC=CC=1>[NH2:22][S:19]([C:15]1[CH:14]=[C:13]([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]4[CH:26]=[CH:27][C:2]([NH:1][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=5[Cl:28])=[CH:3][C:4]4=3)[C:9]([C:23]([NH2:25])=[O:24])=[N:10]2)[CH:18]=[CH:17][CH:16]=1)(=[O:21])=[O:20]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1ccc1ccc(N)cc12
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Product: NC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1ccc1ccc(NC(=O)c3ccccc3Cl)cc12
Reaction time: 14 h

Procedure:
To a stirred solution of 8-amino-1-[3-(aminosulfonyl)phenyl]-1H-benzo[g]indazole-3-carboxamide from step 2 (76.2 mg, 0.20 mmol) in pyridine (25 mL) at RT was added 2-chlorobenzoic chloride (53 mg, 0.3 mmol). After 14 h, trisamine was added and the mixture was stirred for 2 h. The mixture was filtered through a silica gel pad with EtOAc and concentrated. The resulting title product was a solid (42 mg, 40%). Its structure was confirmed by 1H NMR and MS (521, M+1). C25H18ClN5O4S, Calc.: C: 57.75, H: 3.49; N: 13.47; Found, C: 57.06, H: 3.65, N: 13.51.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=O)[O:16]CC)=[C:4]([F:20])[CH:3]=1.[OH:21][CH:22]([C:27](OC)([CH3:29])[CH3:28])[C:23]([O:25]C)=O>CCCCCC>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:23](=[O:25])[C:22](=[C:27]([CH3:28])[CH3:29])[O:21][C:15]2=[O:16])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: COC(=O)C(O)C(C)(C)OC
Solvent: CCCCCC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 195 °C
Yield: 21.3 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (2.00 g, 6.63 mmol), methyl 2-hydroxy-3-methoxy-3-methylbutanoate (2.69 g, 16.6 mmol) and stannous acetate (0.20 g) were introduced into a two-necked eggplant type flask (50 cc) equipped with a Dean Stark and heated at 195° C. for 3 hours with stirring. After completion of the reaction, hexane (10 mL) was added, and the insolubles were filtered off. The filtrate was concentrated under reduced pressure, and the resulting oily substance was purified through a silica gel column (benzene/hexane=1/3) to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione as white crystals (0.50 g, yield 21.3%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH2:35]([C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:26][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:19]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1)[CH3:36]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1cnc(N2CCC3(CC2)CC2(Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O2)C3)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(4-methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 50 mg), 2-chloro-5-ethyl-pyrimidine (18 mg), potassium carbonate (35 mg), and N-methyl-pyrrolidinone (2 ml) is stirred at 80° C. for 4 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→1:9) to give the title compound. LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[CH:9][C:8]=2[N:15]=1)([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([N+:34]#[C-:35])S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CCO>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:34]=[CH:35][O:14][C:13]=1[C:11]1[N:10]=[CH:9][C:8]2[N:15]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[S:6][C:7]=2[CH:12]=1
Reactant: [C-]#[N+]C(c1ccccc1F)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)Nc1nc2cnc(C=O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)Nc1nc2cnc(-c3ocnc3-c3ccccc3F)cc2s1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A solution of 2-(isopropylamino)thiazolo[4,5-c]pyridine-6-carbaldehyde (presumed 0.234 mmol, 1.0 eq.), 1-fluoro-2-(isocyano(tosyl)methyl)benzene (0.079 g, 0.273 mmol, 1.2 eq.), and K2CO3 (0.0654 g, 0.473 mmol, 2.0 eq.) in EtOH (2.4 mL) was refluxed for 4.75 hr. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was taken up in EtOAc and water. After separation of the layers, the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 6-(4-(2-fluorophenyl)oxazol-5-yl)-N-isopropylthiazolo[4,5-c]pyridin-2-amine as a light yellow solid (0.0243 g, 29% yield). LC/MS (MH)=355.16.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1]
Reactant: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 65 h
Yield: 25.9 %

Procedure:
8.56 g (42.99 mmol) of 2-methyl-5-fluoro-3-nitrobenzoic acid is added in 76 ml of N,N-dimethylformamide and mixed with 9.15 g (64.48 mmol) of methyl iodide and 8.91 g (64.48 mmol) of potassium carbonate. After 65 hours of stirring at room temperature, the reaction mixture is added to ice water and extracted several times with ethyl acetate. The combined organic extracts are washed with water and brine. After drying (sodium sulfate), desiccant is suctioned out, and the solvent is spun off. Repeated chromatography on silica gel (mobile solvent:ethyl acetate/hexane) yields the desired compound, specifically in a yield of 25.9% (2.37 g).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[CH:10]=[C:11]([F:13])[CH:12]=1.[C:16](=[O:18])=[O:17].CCOCC>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[CH:10]=[C:11]([F:13])[C:12]=1[C:16]([OH:18])=[O:17]
Reactant: COc1cc(F)cc(F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C(=O)O)c(F)c1

Procedure:
A solution of n-butyllithium (10.0M in hexane; 25.0 ml, 0.25 mol) was added dropwise to a stirred, cooled (-78° C.) solution of 3,5-difluoroanisole (35.9 g, 0.25 mol) in dry THF (200 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and then poured into a slurry of solid carbon dioxide and dry ether. The product was extracted into 10% sodium hydroxide (twice), the combined basic extracts were acidified with 36% hydrochloric acid, and the product was extracted into ether (twice), the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a colourless solid.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH2:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36]>CC#N.C([O-])(O)=O.[Na+]>[CH2:35]([O:34][C:33](=[O:37])[NH:11][C@@H:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:22])([F:2])[F:23])=[CH:9][CH:8]=1)[C:12]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methanamine (Intermediate 1) (0.0610 g, 0.190 mmol) and DIPEA (0.066 mL, 0.381 mmol) in MeCN (1 mL) was added ethyl carbonochloridate (0.027 mL, 0.286 mmol). The mixture was then stirred at rt overnight. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting product was purified by silica gel chromatography: 5-50% EtOAc-hexanes to give the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (d, J=4.30 Hz, 1H), 7.99 (d, J=7.24 Hz, 1H), 7.46-7.60 (m, 4H), 7.40 (dd, J=7.73, 4.79 Hz, 1H), 6.54 (d, J=7.43 Hz, 1H), 6.41 (d, J=8.22 Hz, 1H), 4.11 (q, J=7.17 Hz, 2H), 1.17-1.30 (m, 3H). MS (ESI pos. ion) m/z: 393.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[O-]CC.[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1ccc(C)c(O)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)c(OCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,5-dimethylphenol (24.5 g, 0.2 mol) was dissolved in 125 ml of anhydrous ethanol. To the solution was added 75 ml of 21 wt % sodium ethoxide solution in ethanol (0.2 mol). The mixture solution was stirred at room temperature for 10 min. Ethyl 4-bromobutyrate (40 g, 0.205 mol) was then added to the solution. The reaction mixture was refluxed at 80° C. for 24 h. The precipitate was filtered off. The filtrate was then mixed with a solution of sodium hydroxide (10 g, 0.25 mol) in 150 ml of water. The mixture was stirred at 70° C. for about 2 hours, monitored with HPLC. It was diluted with 150 ml of water and acidified to pH 1. Oily precipitate formed immediately. It was collected by decanting the supernatant and washed with water twice (100 ml×2). The oily precipitate solidified after kept in water at room temperature overnight.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=[O:9])[N:6]=1.C1C(=O)N([Cl:21])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:21])=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)O)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.2 %

Procedure:
To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (15.0 g) in anhydrous DMF (150 mL) was added NCS (11.95 g) and the mixture was stirred at rt for 2-3 hrs. The reaction mixture was concentrated to remove most of the DMF. The resulting oil was added dropwise to DCM (˜600 mL) at 0° C. with stirring. Solid precipitation was collected by filtration, rinsed with DCM and dried under high vacuum to provide a brownish solid (11.8 g, 67%). ESI-MS (EI+, m/z): 236.0. 1H NMR (300 MHz, DMSO-d6) δ 7.60 (br s, 2H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:26])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: C1CCNC1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), pyrrolidine (228 μl, 2.76 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 3 hours at 70° C. The mixture is diluted with ethyl acetate and washed with sat. aqueous sodium hydrogencarbonate solution and brine. The organic layer is separated, dried with magnesium sulfate and the solvent is evaporated. The residue (65 mg white solid) is triturated with diethylether affording 2-methyl-4-(pyrrolidine-1-carbonyl)-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (24 mg, 20.9%) as a white solid. mp.: 210-215° C. MS: m/z=416.2 (M+H+).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1.[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1F)[C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:7][CH:5]1[CH2:6][O:3][CH2:4]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2COC2)c(F)c1
Temperature: 80 °C

Procedure:
NaH (80 mg, 2.0 mmol) was added to a mixture of oxetan-3-ol (150 mg, 2.0 mmol) and DMF (2 mL) at 0° C. The reaction was allowed to stir for 10 minutes before methyl 3,4-difluorobenzoate (170 mg, 1.0 mmol) was added. The reaction was then heated at 80° C. overnight. The reaction was quenched with brine and was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate and the solvent was removed to give methyl 3-fluoro-4-(oxetan-3-yloxy)benzoate. ESI-MS m/z calc. 226.1, found 227.2 (M); Retention time: 2.36 minutes (4 min run).
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]([C:14](OC)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C([NH2:31])=O.C[O-].[Na+].CO.Cl>CN(C=O)C>[CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]([C:14]([NH2:31])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: NC=O
Reactant: CCCN(CCC)C1Cc2cc(OCc3ccccc3)c(C(=O)OC)cc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc(OCc3ccccc3)c(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(dipropylamino)-2,3-dihydro-6-(phenylmethoxy)-1H-indene-5-carboxylate (74, 0.95 g, 2.5 mmol) and formamide (1.1 g, 25 mmol) in DMF (10 mL) at 100° C. was added 25% sodium methoxide in methanol (2.5 mmol, 0.57 mL) dropwise. The mixture stirred for 2 h. The reaction was cooled to rt and quenched with water (100 mL). The resulting precipitate was stirred for 0.5 h and the solvent was removed via filtration. This solid was crystallized from EtOAc/MeOH to give a white solid that was converted into the HCl salt and crystallized from EtOAc/MeOH to give the title compound 78 as a white solid (m.p. 247-248° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1.C(O)(=O)C(O)=[O:16].O1CCOCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:16])([OH:12])[CH3:13]
Reactant: Clc1ccc(CCC2CO2)c(Cl)c1
Reactant: O=C(O)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(O)(O)CCc1ccc(Cl)cc1Cl

Procedure:
A mixture of 50 parts of [2-(2,4-dichlorophenyl)ethyl]-oxirane, 7 parts of ethanedioic acid, 300 parts of 1,4-dioxane and 150 parts of water is stirred and refluxed for 36 hours. The reaction mixture is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried at the air, yielding 1-[2-(2,4-dichlorophenyl)ethyl]ethanediol; mp. 83.2° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8]1([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[CH3:1][C:2]1[N:6]=[C:5]2[N:7]=[C:20]([OH:21])[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:15]([OH:16])[N:4]2[CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Cc1cnc(N)[nH]1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn2c(O)c(-c3ccccc3)c(O)nc2n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
18 g (135 mmol) 5-Methyl-1H-imidazol-2-ylamine are dissolved in 155 mL DMF and 31.8 g (135 mmol) diethyl phenylmalonate are added. After dropwise addition of 61.5 g (404 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene the reaction mixture is stirred at 100° C. for 16 h. The DMF has been removed and the darkbrown oily residue treated with 150 mL water (complete dissolution). 2M HCl (250 mL) is added at room temperature until a pH of 1. After stirring for 1 h at ice bath cooling the formed crystals are collected by filtration to yield the product (10.2 g=31%), which is used without further purification.
Reaction SMILES: [C:1]([NH:4][N:5]=[C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:10]([O:9][C:7]([C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[N:5][N:4]=[C:1]([Cl:18])[CH3:2])=[O:8])[CH3:11]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=NNC(C)=O)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=NN=C(C)Cl)c1cccs1
Temperature: 0 °C
Yield: 92 %

Procedure:
240 g (1 mol) of thien-2-yl-glyoxylic acid ethyl ester 2-acetylhydrazone were dissolved in 1,000 ml of methylene chloride and 208 g (1 mol) of phosphorus pentachloride were added at -10° to 0° C. Stirring was continued for half an hour, ice-water was added to the reaction mixture and the batch was neutralised with sodium bicarbonate solution. The organic phase was separated off, dried over sodium sulphate and concentrated by distilling off the solvent. 234 g (0.92 mol) of crude 1-ethoxycarbonyl-4-chloro-4-methyl-1-thien-2-yl-2,3-diazabutadiene were obtained as an oil which would be directly reacted further. ##STR11##
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:33]=[N-:34]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(C(F)(F)F)cc4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2O1

Procedure:
Treatment of (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (3.3 g, 7.34 mmol) with sodium azide (1.91 g, 29.38 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.205 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.82 g (75%) of (±)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 57.47; H, 4.82; N, 3.65.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].C(N(CC)CC)C.S>O1CCCC1>[NH2:1][C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)=[O:10]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N=[N+]=[N-])C[C@H]12
Agent: S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N)C[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (37 mg, 0.1 mmol) and triethylamine (14 μl, 0.1 mmol) in anhydrous tetrahydrofuran (2 ml) is cooled in an ice-bath while hydrogen sulfide is gently bubbled in over 15 minutes. After an additional 15 minutes at 0°, the solution is evaporated under vacuum and the residue is purified by preparative layer chromatography on silica gel to afford p-nitrobenzyl (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]1=O.[CH3:15][CH:16](C)[C:17](=O)C.N>CO>[CH:16]([C:7]1[CH:6]=[CH:5][C:4]([N+:11]([O-:13])=[O:12])=[CH:3][N:2]=1)([CH3:17])[CH3:15]
Reactant: CC(=O)C(C)C
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: CC(C)c1ccc([N+](=O)[O-])cn1
Temperature: 70 °C
Yield: 28.3 %

Procedure:
To a solution of 1-methyl-3,5-dinitro-2-pyridone (8.0 g, 40 mmol) in methyl alcohol (20 mL) was added dropwise 3-methyl-2-butanone (5.1 mL, 48 mmol), followed by ammonia solution in methyl alcohol (10.0 g, 17%, 100 mmol). The reaction mixture was heated at 70° C. for 2.5 h under atmospheric pressure. The solvent was removed under vacuum and the residual oil was dissolved in CH2Cl2, and then filtered. The filtrate was dried over Na2SO4 and concentrated to afford 2-isopropyl-5-nitro-pyridine (1.88 g, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1nccs1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1nccs1
Yield: 87.8 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.60 mmol) to give 185 mg of the title compound (88%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.20 (s, 1H), 12.07 (s, 1H), 7.47 (d, 2H, J=3.6 Hz), 7.23 (d, 1H, J=3.6 Hz), 7.22 (bs, 1H), 7.17 (bs, 1H), 5.17~5.28 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.64~2.89 (m, 3H), 2.06 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:24]([O:23][C:21]([CH2:20][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21

Procedure:
A mixture of 4.00 g (14.9 mmol) of tert-butyl 5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIa), 3.19 g (16.4 mmol) of tert-butyl bromoacetate and 7.28 g (22.3 mmol) of cesium carbonate in acetonitrile (80 ml) was heated under reflux for 3 h. The solvent was removed in vacuo, the residue was mixed with water, and the aqueous mixture was extracted four times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% ethyl acetate in dichloromethane).