Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]([CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)([CH3:5])[O:3]C1.Cl>C1COCC1>[CH:15]([N:12]1[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][C:4](=[O:3])[CH3:5])[CH2:14][CH2:13]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 5-(4-benzhydrylpiperazin-1-yl)-2-pentanone ethylene ketal (1.10 g, 2.9 mmol) in THF (25 ml) was treated with concentrated hydrochloric acid (2 ml) and stirred at room temperature overnight. The reaction mixture was evaporated to dryness before partitioning between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated to yield 5-(4-benzhydrylpiperazin-1-yl)-2-pentanone as a colourless oil (716 mg, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16]1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:15]([CH2:14][C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:16]1
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccccc2)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Temperature: 120 °C
Yield: 88.7 %

Procedure:
5-bromo-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxamide (40 mg, 0.108 mmol), phenylboronic acid (19.71 mg, 0.162 mmol, 1.5 eq), PdCl2(dppf) (7.88 mg, 10.77 μmol, 0.1 eq), potassium carbonate (44.7 mg, 0.323 mmol, 3 eq) were diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL), in a 2-5 mL biotage microwave reaction tube. The mixture was degassed by bubbling nitrogen through for 5 minutes and was then heated in a microwave at high absorption for 15 minutes at 120° C. The reaction was filtered through a thiol SPE cartridge (polymer labs) and was concentrated and purified by Gilson HPLC with trifluoroacetic acid buffer. The desired product fractions were combined and concentrated in an EZ2 Genevac evaporator, giving 35.3 mg (84%) of the title compound.
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:3]2([CH2:8][CH2:7][C:6](O)([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[O:2]1>C1(C)C=CC=CC=1>[CH2:20]1[CH2:1][O:2][C:3]2([CH2:4][CH:5]=[C:6]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH3:17])=[CH:13][CH:14]=3)[CH2:7][CH2:8]2)[O:19]1
Reactant: CCCc1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Solvent: Cc1ccccc1
Product: CCCc1ccc(C2=CCC3(CC2)OCCO3)cc1
Yield: 98.2 %

Procedure:
To 500 ml of toluene was dissolved 98 g of the 1,1-ethylenedioxy-4-hydroxy-4-(4-n-propylphenyl)cyclohexane mentioned above, 5 g of Amberlist 15E was added as catalyst thereto, and stirred under a reflux for 2 hours. After the reaction solution was cooled, the catalyst was filtered off. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 90 g of 1,1-ethylenedioxy-4-(4-n-propylphenyl)-4-cyclohexene.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[C:19](Cl)=[N:18][S:17][N:16]=1.Cl>CN(C=O)C.O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:19]2[C:15]([Cl:14])=[N:16][S:17][N:18]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Clc1nsnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
1-Boc-piperazine (30.2 g, 165 mmol) was dissolved in DMF (30.0 mL) and heated to 100° C. 3,4-Dichloro-1,2,5-thiadiazole (7.5 mL, 80 mmol) was added dropwise with stirring and the mixture heated at 100° C. for 5.5 h. The reaction mixture was diluted with H2O and the pH adjusted to 2.0 with 1N HCl. The resulting solids were filtered, washed with H2O and dried under vacuum to give 20.1 g (83%) of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester as a tan solid. 1H NMR (DMSO-d6) 3.48 (m, 4H), 3.36 (m, 4H), 1.42 (s, 9H) ppm. LC-MS (MH+)=205 (-Boc).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][CH2:18][C:10]=3[C:9]=2[CH:8]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][CH2:18][C:10]=3[C:9]=2[CH:8]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OC)cc21
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Temperature: -2.5 °C
Yield: 20.4 %

Procedure:
DCM (305 mL) was transferred to a 1 L 3-necked round-bottomed flask and cooled to −11° C. (internal) (ice acetone bath). BBr3 (72.0 mL, 761 mmol) was added to the DCM with stirring. A solution of ethyl 2-(7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (41.62 g, 152 mmol) in DCM (145 mL) was added in drops maintaining the internal temperature at between −5 to 0° C. After the addition the reaction was stirred for 1 h below 0° C. The reaction mixture was slowly poured into mixture of ice (400 mL) and saturated K2CO3 (400 mL) and stirred well (pH maintained at 9-7). The organic layer was separated, washed with brine (1×100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residual brown oil was purified by a pad of silica gel to give the title compound (8.03 g). LCMS m/z=260.2.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].O.[NH2:32][NH2:33]>CN(C=O)C>[N+:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:33][N:32]=1)([O-:29])=[O:28]
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 85.1 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (643 mg, 1.60 mmol, prepared in Synthetic Example 20) in DMF (16 ml) was added hydrazine monohydrate (80%, 230 μl, 5.74 mmol, 3.6 eq.), and the mixture was treated in the same manner as in Example 24 to give 3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (541 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:22]2[CH:26]=[C:25]([C:27]3([CH2:32][CH3:33])OCC[O:28]3)[S:24][CH:23]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[N:3]=1.[OH-].[Na+]>C(OCC)C.Cl.C(Cl)Cl>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)([C:22]2[CH:26]=[C:25]([C:27](=[O:28])[CH2:32][CH3:33])[S:24][CH:23]=2)[N:3]=1
Reactant: CCC1(c2cc(C3(c4cccc(-c5cccnc5F)c4)N=C(N)N(C)C3=O)cs2)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(=O)c1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cs1
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 2-amino-5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-3,5-dihydro-imidazol-4-one (0.11 g, 0.23 mmol) in diethyl ether and 1 N HCl was heated at reflux temperature for 1 h, cooled to room temperature, diluted with methylene chloride and basified to pH 9 using 2 N sodium hydroxide. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resultant concentrate was freeze dried from 1:1 acetonitrile/water (4 mL) to afford the title compound as a white solid, 0.069 g (71% yield), mp 98-112° C.; 1H NMR (500 MHz, CDCl3) δ 8.19 (dt, J=4.7, 1.4 Hz, 1H), 7.85-7.81 (m, 1H), 7.78-7.69 (m, 3H), 7.61-7.55 (m, 1H), 7.52-7.48 (m, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.29-7.23 (m, 1H), 3.12 (s, 3H), 2.88 (q, J=7.3 Hz, 2H), 1.17 (t, J=7.3 Hz, 3H); ESI MS m/z 423 [C22H19FN4O2S+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.Cl>C(#N)C>[Cl:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:5][C:4]3[CH:6]=[C:7]([CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:8]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:23][CH:24]=[N:25]2)=[CH:30][CH:29]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1cc(N)cc(CN2CCCC2)c1N1CCOCC1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(Nc2ccnc3cc(Cl)ccc23)cc(CN2CCCC2)c1N1CCOCC1
Yield: 71.3 %

Procedure:
3-Methyl-4-(morpholin-4-yl)-5-(pyrrolidin-1-ylmethyl)aniline (46 mg, 0.17 mmol) and 4,7-dichloroquinoline (40 mg, 0.20 mmol) were refluxed overnight in 5 mL of acetonitrile with 0.51 mL of HCl 1M. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//95/5/0 to 90/10/1) to yield expected compound as a white solid (53 mg, 71% yield); m/z (ESI) 437.3 [M+H]+;
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:4]([N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)[C:3](=[O:10])[C:2]([CH3:12])([CH3:11])[CH3:1])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cn1cncn1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Yield: 12.1 %

Procedure:
167 g (1 mol) of 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one and 140.5 g (1 mol) of 4-chlorobenzaldehyde were dissolved in 700 ml of toluene and 1.2 g (0.02 mol) of glacial acetic acid and 1.8 ml (0.02 mol) of piperidine were added. The reaction mixture was heated for 40 hours to 120° C., while continuously separating off the water of reaction. Thereafter the reaction mixture was concentrated in vacuo and the oil which remained was distilled (boiling range 130°-160° C./0.04 mm Hg). The distillate was stirred with ethanol, whereupon crystals separated out. These were filtered off and dried. 35 g (12% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one (E isomer) of melting point 110° C. were thus obtained.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1.CC(C)([O-])C.[K+].Cl.[OH-].[Na+]>C(O)(C)(C)C>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[OH:11])[CH:13]=1
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1cccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Oc1c(Cc2cccnc2)ccc2ccccc12
Temperature: 25 °C

Procedure:
A solution of 1-tetralone (5.85 g, 0.040 mole) and pyridine-3-carboxaldehyde (4.28 g, 0.40 mol) in t-butanol (400 mL) was treated with potassium t-butoxide (8.98 g, 0.080 mol) and the resulting mixture heated at reflux for 16 hours. After cooling to room temperature, the solution was poured into stirred 1.0N hydrochloric acid, and the pH of the resulting mixture was adjusted to 7.0 with 10% aqueous sodium hydroxide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]2[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:36]=[CH:35][C:24]3[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:30])([CH3:31])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc21
Yield: 26.2 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (82 mg, 0.276 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (61 mg, 0.263 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 3.5 hours. Filtered off solid, then purified the solid with normal phase chromatography eluting with 9/1 methylene chloride/methanol. Washed product with saturated sodium bicarbonate solution and extracted into methylene chloride. Washed organic phase with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield an off-white solid, 2-[5-Chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (34 mg, 25%). LCMS: m/z=493.37 (M+H+), 1H NMR (400 MHz, CDCl3) δ 11.11 (s, 1H), 8.60 (d, 1H, J=8.3 Hz), 8.09 (s, 1H), 7.68 (dd, 1H, J=8.3, 2.3 Hz), 7.52 (d, 1H, J=7.3 Hz), 7.39 (m, 1H), 7.33 (d, 1H, J=2.3 Hz), 7.16 (d, 1H, J=8.8 Hz), 7.08 (m, 1H), 6.70 (br s, 1H), 3.79 (m, 2H), 3.40 (s, 1H), 3.01 (d, 3H, J=4.5 Hz), 2.38 (s, 2H), 2.27 (m, 2H), 1.29 (m, 9H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[O:22])=[CH:17][CH:16]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: O=C(c1ccc(Cl)cc1)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)N2CCC[C@H]2C(=O)c2ccc(Cl)cc2)c(C(F)F)n1
Reaction time: 3 h
Yield: 97.3 %

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (1.94 g; 10.0 mmol) in dichloromethane (5 ml) was added dropwise to a stirred suspension of (4-chloro-phenyl)-(S)-pyrrolidin-2-yl-methanone hydrochloride (2.46 g; 10.0 mmol), which was prepared as described in example P16, and triethylamine (3.0 g; 30.0 mmol) in dichloromethane (25 ml). Dichloromethane (40 ml) was added to the mixture. The ice bath was removed and reaction mixture was allowed stirring for 3 hours. The reaction mixture was washed with 1M NaOH (20 ml), 1M HCl (20 ml) and saturated NaCl (20 ml) and then dried over Na2SO4. After removal of the solvent, the residue was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:19). 3.58 g (97.3% of theory) of (4-chloro-phenyl)-[(S)-1-(3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-2-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.91-1.98 (m, 1H), 2.02-2.16 (m, 2H), 2.33-2.42 (m, 1H), 3.75-3.85 (m, 2H), 3.97 (s, 3H, NCH3), 5.61-5.65 (m, 1H), 6.99-7.28 (t, 1H, CHF2), 7.45-7.47 (d, 2H, Ar—H), 7.73 (s, 1H) 7.96-7.98 (d, 2H, Ar—H). MS [M+H]+ 368/370.
Reaction SMILES: ClCCl.C[C:5]([O:7][CH2:8][C:9]1[CH2:18][S:17][C@@H:12]2[C@H:13]([NH2:16])[C:14](=[O:15])[N:11]2[C:10]=1[C:19]([OH:21])=[O:20])=O.CS(O)(=O)=O.[OH-].[Na+]>CO>[NH2:16][CH:13]1[C:14](=[O:15])[N:11]2[C:10]([C:19]([OH:21])=[O:20])=[C:9]([CH2:8][O:7][CH3:5])[CH2:18][S:17][C@H:12]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To 10 ml of dichloromethane were added 1.41 g of 7-ACA, 5.1 ml of methanesulfonic acid and 1.23 ml of methanol. The reaction was conducted at 0° C. for 6 hours. After completion of the reaction, the reaction mixture was poured into ice water. Then, the resultant mixture was adjusted to pH 3.5 with 10% aqueous sodium hydroxide to form a precipitate. The precipitate was collected by filtration, and then washed with water and dried to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.14 g. The yield of the desired product was 65%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccco2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccco2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
To a mixed solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(2-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (243 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 160 mg, 77%).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:24]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH2:27][N:21]3[CH:20]=[CH:19][CH:18]=[C:22]3[CH2:23]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A mixture of 2.16 g of 4-(benzoyl)benzoyl chloride (Reference Example 36) and 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 30 ml of methylene chloride containing 7 ml of triethylamine is stirred under nitrogen atmosphere for 16 hours. The reaction mixture is diluted with 50 ml of chloroform and washed with 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.8 g of the desired product as a solid. M+H 393.2; M+Na 415.2.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19]C)=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:2]3[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([OH:19])=[O:18])[CH:8]=4)[N:3]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (60 mg, 0.20 mmol, 1.00 equiv), 1H-indol-5-ylboronic acid (100 mg, 0.62 mmol, 3.05 equiv), Pd(PPh3)4 (23.6 mg, 0.02 mmol, 0.10 equiv), K3PO4 (174 mg, 0.82 mmol, 4.01 equiv), 1,4-dioxane/H2O (4/1 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 55% in 8 min, hold 55% in 3 min, up to 100% in 0.1 min, hold 100% in 0.9 min); Detector, UV 220&254 nm. This resulted in 25 mg (33%) of 2-(1H-indol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a red solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)C.Cl>CC(C)=O.C(Cl)Cl>[CH:4]([C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)=[O:3]
Reactant: CCOC(OCC)c1nc(C(=O)OC)cs1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)c1csc(C=O)n1
Reaction time: 2 h
Yield: 67.2 %

Procedure:
Thiazole-4-carboxylate 3 (30 g, 122 mmol) was dissolved in 300 mL of acetone, to which was added aqueous HCl (21 mL, 2M). After keeping the reaction mixture at RT for overnight, the reaction mixture was heated up and kept at 60° C. for 2 h. The reaction mixture was then cooled and evaporated under vacuum to give a residue which was taken up in 200 mL of DCM. DCM solution was then washed with saturated NaHCO3 solution and then brine and dried over anhydrous Na2SO4. DCM solution was filtered and concentrated under vacuum to give the concentrated solution which was triturated by ether to give methyl 2-formylthiazole-4-carboxylate 4 (14 g, 82 mmol, 54% for two steps) as a white solid. 1HNMR (400 MHz, CDCl3) δ 133-8-p110.16 (d, J=1.3 Hz, 1H), 8.53 (d, J=1.3 Hz, 1H), 4.01 (s, 3H).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])[C:4]=2[CH2:3][O:2]1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:14]([NH:13][S:10]([C:9]2[C:4]3[CH2:3][O:2][CH2:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])=[O:15])[N:19]=1
Reactant: O=C=NS(=O)(=O)c1cccc2c1COC2
Reactant: COc1cc(C)nc(N)n1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2COC3)n1
Reaction time: 1.75 h

Procedure:
A 7.0 ml portion of the methylene chloride solution of 1,3-dihydrobenzo[c]furan-4-sulfonyl isocyanate prepared in Example 4 was added to a stirred suspension of 0.78 g of 4-methoxy-6-methylpyrimidin-2-amine in 20 ml of methylene chloride. After several minutes the amine dissolved, followed by formation of a precipitate. After stirring for 1.75 hours, the solid was collected, washed with methylene chloride and 1-chlorobutane, then dried to give 1.4 g of 1,3-dihydro-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzo[c]furan-4-sulfonamide, m.p. 190°-194° (d).