Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[CH3:43])[NH2:39]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:39][C:38]2[CH:40]=[CH:41][C:42]([CH3:43])=[C:36]([CH3:35])[CH:37]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-amino-3-nitro-benzoic acid (546 mg). EDCI (576 mg) and HOBt (405 mg) in DMF (8 mL) was added 3,4-dimethylaniline (363 mg) and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and exreacted with EtOAc. The organic phase was washed with water (2×) and was dried over sodium sulfate. The solvent was concentrated to approximately 10 mL and the resulting precipitate was filtered, washed with EtOAc and dried under reduced pressure to give 4-amino-N-(3,4-dimethyl-phenyl)-3-nitro-benzamide as a yellow solid, mp=192-195° C.; MS (m/z) 284 (M−1).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.[C:26](O)(C(F)(F)F)=O.C=O>C(Cl)Cl.O>[CH3:26][N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)[CH:13]=[CH:12][N:11]=1)[CH3:6]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccc(-c2ccnc(CNC(=O)OC(C)(C)C)c2)cc1
Agent: C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccnc(CN(C)C)c2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of Methyl 4-(2-[t-butyloxycarbonylamino-methyl]-pyridin-4-yl)-benzoate (reference example 56) (520 mg, 1.5 mmol) in CH2Cl2 (5 mL) is added TFA (1.5 mL) and 2 drops of water (approx. 100 mL). The resulting solution is stirred for 90 minutes, then concentrated under reduced pressure. The residue is dissolved in THF (4 mL) then NaBH4 added (222 mg, 6 mmol) followed by paraformaldehyde (360 mg, 12 mmol). To this mixture is added TFA (4 mL) dropwise. The resulting mixture is stirred for 6 hours then concentrated. The residue is brought to pH 8 with aqueous NaOH (1M) and sat NaHCO3. The mixture is then extracted with ethyl acetate then ethyl acetate methanol (9/1). The combined organic extracts are washed with brine dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% methanol in CH2Cl2) to give 329 mg of the title compound. 1H NMR (CD3OD) δ 3.00 (s, 6H), 3.94 (s, 3H), 4.56 (s, 2H), 7.74 (d, J=5 Hz, 1H), 7.83 (s, 1H), 7.88 (d, J=8 Hz, 2H), 8.17 (d, J=8 Hz, 2H), 8.76 (d, J=5 Hz, 1H). MS (ion spray) m/z 271 (M+H).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:10])[CH2:6][CH:7]([Cl:9])[CH3:8].[CH3:11][N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:23])[C:14]2=[CH:24][S:25][CH:26]=[C:13]12.Cl>C(O)C.CCOCC.CN(C)C=O>[ClH:9].[CH3:4][N:5]([CH3:10])[CH2:6][CH:7]([N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:12]([CH3:11])[C:13]2=[CH:26][S:25][CH:24]=[C:14]2[C:15]1=[O:23])[CH3:8]
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: CC(Cl)CN(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOCC
Product: CC(CN(C)C)N1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.47 g. of 55% sodium hydride-mineral oil dispersion and 0.83 g. of 2-dimethylamino-1-methylethylchloride hydrochloride in 30 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.6 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an oil which is chromatographed on silica gel preparative thin layer chromatographic (tlc) plates using 10:1 benzene:methanol to give a yellow oil. The oil is dissolved in ethanol and treated with anhydrous hydrogen chloride followed by dilution with ether to give a solid, which is recrystallized from ethanol to give white crystals, m.p. 280°-282°C. (dec.).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][N:17]=[C:11]3[CH:10]=2)O1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.CS(C)=O>[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][N:17]=[C:11]3[CH:10]=2)=[CH:25][N:24]=1)=[O:22]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccn3ccnc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccn3ccnc3c2)cn1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a stirred mixture of 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridine (732 mg, 3 mmol), 5-bromopyridine-2-carboxylic acid methyl ester (650 mg, 3 mmol) and cesium carbonate (2.0 g, 6 mmol) in dry DME (15 ml) was added PdCl2dppf (220 mg, 0.3 mmol) and H2O (55 μl, 3 mmol). The reaction mixture was deoxygenated and then heated at 80° C. for 3 h. The mixture was allowed to cool, then partitioned between CH2Cl2/H2O and stirred for 20 min. The solid material was filtered off and washed with MeOH (100 ml). The CH2Cl2 layer was separated, combined with the MeOH washings and the solvent removed in vacuo. The residue was purified by silica column chromatography (0-3% 2M NH3. MeOH/CH2Cl2) to afford a dark yellow solid, which was used directly in the next reaction (492 mg). MS: [M+H]+=254. 1H NMR d6 DMSO: 9.21 (1H, d), 8.71 (1H, d), 8.44 (1H, dd), 8.20-8.10 (2H, m), 8.04 (1H, s), 7.69 (1H, s), 7.43 (1H, dd), 3.92 (3H, s).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[C:20](=[O:42])[NH:21][C:22](=[O:41])[C:23]=2[C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][CH2:34][CH2:35]OS(C)(=O)=O)[CH:25]=2)=[CH:11]1>CN(C=O)C>[NH:5]1[CH:6]=[CH:7][N:8]=[C:4]1[S:3][CH2:35][CH2:34][CH2:33][N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:23]2[C:22](=[O:41])[NH:21][C:20](=[O:42])[C:19]=2[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH3:9])[CH:11]=2)=[CH:25]1
Reactant: Sc1ncc[nH]1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(CCCSc4ncc[nH]4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
7 mg of a 80% dispersion of sodium hydride in mineral oil was added to a cooled solution of 23 mg of 2-mercaptoimidazole in 10 ml of DMF. The mixture was stirred for 0.5 hour while cooling. 100 mg of the product of Example 58 were added and the mixture was stirred for 2 hours while cooling. The mixture was then allowed to warm to room temperature and was stirred overnight. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 20 mg of 3-[1-[3-(2-imidazolylthio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 130°-132° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[CH:10][CH2:11]Cl)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:39][NH:40][CH:41]1[C:50]2[N:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:44][CH2:43][CH2:42]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(#N)C.[I-].[K+]>[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:39][N:40]([CH2:11]/[CH:10]=[CH:9]\[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:13])[C@@H:41]1[C:50]2[N:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:44][CH2:43][CH2:42]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC=CCCl
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC/C=C\CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)[C@H]1CCCc2cccnc21
Temperature: 60 °C
Reaction time: 17 h
Yield: 161.1 %

Procedure:
(4-Chloro-but-2-enyl)-carbamic acid tert-butyl ester (1.81 g, 7.47 mmol), potassium iodide (59 mg, 0.36 mmol) and diisopropylethylamine (1.80 mL, 10.3 mmol) were added to a solution of 2-[(5,6,7,8-tetrahydroquinolin-8-ylamino)-methyl]-benzimidazole-1-carboxylic acid tert-butyl ester (2.57 g, 6.79 mmol)) in acetonitrile (70 mL) and warmed to 60° C. and stirred for 17 h under nitrogen. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (100 mL) and washed with brine (100 mL). The aqueous layer was extracted with methylene chloride (2×150 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude mixture was purified by column chromatography on silica gel (150 g) to afford 2-{[(S)-((Z)-4-tert-butoxycarbonylamino-but-2-enyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (5.99 g, 88%) as a white foamy solid. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.72 (s, 9H), 1.95-2.08 (m, 4H), 2.09-2.20 (m, 1H), 2.61 (d, 1H, J=16.2 Hz), 3.28 (dd, 1H, J=14.1, 5.4 Hz), 3.62 (dd, 1H, J=13.7, 7.2 Hz), 3.69-3.85 (m, 2H), 4.29 (dd, 1H, J=9.2, 6.6 Hz), 4.42 (d, 1H, J=14.9 Hz), 4.48 (d, 1H, J=14.9 Hz), 5.43-5.63 (m, 2H), 6.19 (s, 1H), 6.87 (dd, 1H, J=7.5, 4.8 Hz), 7.17 (d, 1H, J=7.7 Hz), 7.23-7.28 (m, 1H), 7.65-7.71 (m, 1H), 7.75-7.80 (m, 1H), 8.34 (d, 1H, J=4.4 Hz).
Reaction SMILES: [C:1]([CH2:6][CH2:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:13][OH:14].[C:15](=[O:18])([O-])[O-].[Na+].[Na+].BrBr>[Cl-].[Na+].O>[CH3:13][O:14][C:8]1([CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:12]=[CH:11][CH:10]([O:18][CH3:15])[O:9]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCc1ccco1
Reactant: CO
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCC1(OC)C=CC(OC)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(2'-carbethoxyethyl)furan (42.5 g.) in 750 ml. of methanol containing 53 g. of sodium carbonate at -25° C. is added a solution of 40.5 g. of bromine in 250 ml. of methanol during the course of 2.5 hours. The solution is stirred at room temperature for 30 minutes, diluted with brine, and extracted with diethyl ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is distilled to provide a light yellow liquid, b.p. 78°-84° C. (0.2 mm.), ν max 1740 (ester carbonyl group) and 1015 cm-1 (dimethoxydihydrofuran group).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:37]1[S:38][C:39]2[C:44]([Cl:45])=[N:43][C:42]([CH:46]3[CH2:48][CH2:47]3)=[N:41][C:40]=2[N:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:37]3[S:38][C:39]4[C:44]([Cl:45])=[N:43][C:42]([CH:46]5[CH2:47][CH2:48]5)=[N:41][C:40]=4[N:49]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:32][CH:33]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a mixed solution of the compound (0.94 g) obtained in Example 783, the compound (0.48 g) obtained in Step 5 and chloroform (2.8 ml) was added N,N-diisopropylethylamine (0.30 ml) at room temperature. The mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound (1.3 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C=C2N=NN(O)C2=CC=1.N.C(N(CC)CC)C.[NH2:39][CH2:40][C:41]1[C:42]([OH:49])=[N:43][C:44]([CH3:48])=[CH:45][C:46]=1[CH3:47]>ClCCl>[CH3:47][C:46]1[CH:45]=[C:44]([CH3:48])[NH:43][C:42](=[O:49])[C:41]=1[CH2:40][NH:39][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:14][C:15]2[CH:20]=[N:19][CH:18]=[N:17][CH:16]=2)[C:2]=1[CH3:1])=[O:13]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1cncnc1
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(Cc3cncnc3)c3ccccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A mixture of 2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxylic acid (60 mg, 0.22 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (65 mg, 0.34 mmol), N-hydroxybenzotrizole (180 mg, 1.33 mmol) and triethylamine (46 mg, 0.34 mmol) in dichloromethane (30 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethyl pyridin-2-ol (33.44 mg, 0.22 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (20 mL×3). The organic layer was concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxamide (17 mg, 19%). LRMS (M+H+) m/z: calcd 401.19. found 401. HPLC purity (214 nm): 92%. 1H.NMR (300 MHz, CD3OD): δ 9.03 (s, 1H), 8.43 (s, 2H), 7.80-7.78 (m, 1H), 7.39-7.36 (m, 1H), 7.19-7.16 (m, 2H), 5.56 (s, 2H), 4.55 (s, 2H), 2.62 (s, 3H), 2.42 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])/[C:7](=[N:11]\[OH:12])/[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[C:1]([O:5][C:6](=[O:13])/[C:7](=[N:11]\[O:12][CH3:14])/[C:8](=[O:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: CO/N=C(/C(C)=O)C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 4 h

Procedure:
626.65 g of (Z)-2-hydroxyimino-3-oxo-butyric acid tert.butyl ester are dissolved in 2.86 l of acetone. The solution is cooled to 5° C. and treated portionwise with 703.5 g of potassium carbonate. 322 ml of dimethyl sulphate are then added dropwise to the yellow suspension without cooling during 1 hour, whereby the temperature of the mixture should not rise above 25° C. The light beige suspension is stirred at 20°-25° C. for about 4 hours until starting material can no longer be detected by thin-layer chromatography. Thereafter, the mixture is poured into 7 l of water and extracted three times with 1 l of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 l of water each time, dried over sodium sulphate and evaporated in vacuo at 40° C. The residual yellow oil is dried for a further 6 hours in a high vacuum at 40° C. and subsequently distilled. There is obtained (Z)-2-methoxyimino-3-oxo-butyric acid tert.butyl ester as a yellow oil with a boiling point of 57° C. at 0.02 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:11][C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1sc2ccccc2c1Cl
Solvent: O
Solvent: CCOCC
Product: Clc1c(CBr)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3-chloro-1-benzothiophen-2-yl)methanol (480 mg, 2.4 mmol) in anhydrous diethyl ether (8 mL) was added dropwise a solution of phosphorus tribromide (230 μL, 2.4 mmol) in anhydrous diethyl ether (2 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 2-(bromomethyl)-3-chloro-1-benzothiophene was obtained as a pink pale solid (537 mg, 85% yield) and used for the next step without further purification; 1H NMR (400 MHz, CDCl3): δ 4.81 (s, 2H), 7.40-7.48 (m, 2H), 7.76-7.82 (m, 2H).
Reaction SMILES: C1(CO[C:6]([S:8][CH:9]2[N:12]([C:13](=C(N3CCOCC3)CBr)[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:36])[CH:10]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:52][OH:53].Cl>C(Cl)Cl>[OH:53][C:52]1[CH2:6][S:8][C@@H:9]2[CH:10]([NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:11](=[O:36])[N:12]2[C:13]=1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: CO
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(CBr)N2CCOCC2)C1SC(=O)OCC1CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 63 %

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate (151 mg) in methylene chloride is added aluminum chloride mg), and the mixture is stirred for 50 minutes under ice cooling. The mixture is diluted with ice water (2 ml), stirred for 5 minutes, and stirred with a mixture (15 ml) of methanol and methylene chloride (5:1) after addition of 10% hydrochloric acid (3 ml) at room temperature for 80 minutes. The reaction mixture is diluted with ice water, and is extracted with chloroform. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (63 mg). Yield: 63%. This product is identical with the product of Example 4.-III (3) produced by hydrolysis of the 4-morpholino group to be replaced with the corresponding hydroxy group.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[N:12]=[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:30]4[CH:29]=[N:28][C:27]([NH2:26])=[CH:32][CH:31]=4)[CH:20]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.38) (0.20 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light brown solid (0.15 g, 63%). MS (ISP) 462.1 [(M+H)+]; mp 224.5° C.
Reaction SMILES: [N:1]1C=CC=CC=1.Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[NH2:16][C:17]1[CH:24]=[C:23]([Br:25])[C:22]([F:26])=[CH:21][C:18]=1[CH:19]=O.N1CCCC1>CCO>[NH2:1][C:8]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:16][C:17]2[C:18]([CH:19]=1)=[CH:21][C:22]([F:26])=[C:23]([Br:25])[CH:24]=2
Reactant: Nc1cc(Br)c(F)cc1C=O
Reactant: c1ccncc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCNC1
Solvent: CCO
Product: CCOC(=O)c1nc2cc(Br)c(F)cc2cc1N
Temperature: 65 °C
Yield: 77.2 %

Procedure:
To a solution of pyridine (310.6 mg, 3.927 mmol) in EtOH (8.0 mL), a solution of ethyl bromopyruvate (752.1 mg, 3.857 mmol) in EtOH (8.0 mL) was added dropwise over a period of 20 min. The mixture was heated to 65° C. for 1 h, and then cooled to room temperature. 2-Amino-4-bromo-5-fluorobenzaldehyde (796.1 mg, 3.651 mmol) was added, followed by pyridine (690.6 mg, 8.731 mmol). The mixture was heated at 85° C. for 5 h. Pyrrolidine (640.1 mg, 9.000 mmol) was then added. After heating for an additional 3 h, the reaction mixture was allowed to cool and was then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow solid (882.5 mg, 77%). LCMS calc. for C12H11BrFN2O2(M+H)+: m/z=313.0. found 313.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a mixture of (7-hydroxy-naphthalen-1-yl)-carbamic acid tert-butyl ester (5.11 g, 19.7 mmol) and potassium carbonate (3.26 g, 23.6 mmol) in N,N-dimethylformamide is added benzyl bromide (3 mL, 4.31 g, 25.2 mmol) slowly. The mixture is then stirred at room temperature over night and poured into ice-water (150 mL). The resulting mixture is extracted with ethyl acetate (4×100 mL) and the organic portions are combined, washed with water and brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography (Hexanes/EtOAc=15/1) to give (7-benzyloxy-naphthalen-1-yl)-carbamic acid tert-butyl ester (5.93 g, 86.3%); 1H NMR 400 Hz (CDCl3) δ1.60 (s, 9H), 5.22 (s, 2H), 6.63 (br, 1H), 7.27 (m, 2H), 7.38 (m, 2H), 7.45 (m, 2H), 7.44 (d, J=7.44 Hz, 2H), 7.61 (d, J=8.11 Hz, 1H), 7.80 (m, 2H); MS m/z (M+Na+) 372.10.
Reaction SMILES: ClC1N=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2N=1.[S:20]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21]1.CCOC(C)=O.[CH:32](O)([CH3:34])[CH3:33]>>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([N:10]2[CH2:9][CH2:8][C:6]3[C:5](=[CH:4][CH:33]=[C:32]([NH:25][C:22]4[CH:23]=[CH:24][S:20][CH:21]=4)[CH:34]=3)[CH2:11]2)=[O:13])[CH:15]=1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: Nc1ccsc1
Reactant: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(c1cccnc1)N1CCc2cc(Nc3ccsc3)ccc2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with thiophen-3-amine (0.0099 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 39.1% yield (0.012 g, 0.035 mmol).