Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[OH-].[K+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>C1(C)C=CC=CC=1.O.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: BrCc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2ccc3ccccc3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (125 mg, 536 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.30 mL, 0.60 mmol) at RT followed by 2-(bromomethyl)naphthalene (123 mg, 556 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with CH2Cl2 (80 mL). The organic phase was isolated and washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) gave 41 mg of 1-ethyl-6,7-dimethoxy-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.42 M HCl solution in MeOH (4.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol hydrochloride 19 as a yellow solid (44 mg, 20% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[N:11]=[C:10]([CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)[CH:9]=2)=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[N:11]=[C:10]([CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3[N+](=O)[O-])n2)CC(C)(C)O1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N)n2)CC(C)(C)O1
Temperature: 90 °C
Yield: 97.6 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1-(2-nitrophenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazole (Example 61) (1.10 g, 2.50 mmol) in 20 mL of ethanol and 20 mL of acetic acid was added iron powder (1.12 g, 20.0 mmol) and the mixture heated to 90° C. for 1 hr. The mixture was filtered through Celite and concentrated and the residue purified by silica gel chromatography (40-g cartridge, 10-25% EtOAc/heptane) to give 1.0 g (98%) the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][C:17](=[CH2:21])[C:18](Cl)=[O:19]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:21])=[CH2:16])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using 2-methyl-acryloyl chloride (53 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2-methylacrylamide (0.037 g).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:21])[NH:17][CH:18]([CH3:20])[CH3:19])=[O:10])C1C=CC=CC=1.O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[CH:18]([NH:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:21])([CH3:20])[CH3:19]
Reactant: CC(C)NC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)N1CCC[C@H]1C(=O)O
Yield: 40.7 %

Procedure:
(2S)-1-(Isopropylcarbamoyl)pyrrolidine-2-carboxylic acid benzyl ester (528 mg, 1.82 mmol) was dissolved in THF/H2O (9:1, 10 ml). Lithium hydroxide monohydrate (229 mg, 5.46 mmol) was added. After 18 h at room temperature the reaction mixture was diluted with ethyl acetate (50 ml). This solution was washed with 1M KHSO4, water and brine, dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as the title compound (148 mg, 0.74 mmol, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[CH:17]3[CH:12]([CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16]3)[NH:11][C:10](=[O:22])[C:9]=2[SH:23])[CH:7]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Br.[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[CH:17]3[CH:12]([CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16]3)[NH:11][C:10](=[O:22])[C:9]=2[S:23][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1=C(S)C(=O)NC2C=CC(C(F)(F)F)=CC12
Reactant: BrCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cl)cc1C1=C(SCC2CO2)C(=O)NC2C=CC(C(F)(F)F)=CC12
Yield: 70 %

Procedure:
4-(5-Chloro-2-methoxy-phenyl)-3-oxiranylmethylsulfanyl-6-trifluoromethyl-4a,8a-dihydro-1H-quinolin-2-one (VIII) was prepared by alkylation of 4-(5-Chloro-2-methoxy-phenyl)-3-mercapto-6-trifluoromethyl-4a,8a-dihydro-1H-quinolin-2-one (Ie) with epibromohydrin. To a warm solution of Ie (2.6 mmol) and epibromohydrin (3.9 mmol) in abs. EtOH was added dropwise NaOH solution (1 Molar, 3.9 mL) forming a yellow solution. The alkylation was allowed to proceed at room temperature for an hour. The mixture was evaporated to dryness, redissolved into methylene chloride, washed with water and the organic layer dried over MgSO4. The desired product was purified by a silica-gel column eluted with mixtures of hexanes and ethyl acetate. The desired product (5) was obtained as an off-white solid in 70% yield, mp 211–212° C. Calcd. for C20H15Cl1F3N1O3S1: C, 54.34; H, 3.42; N, 3.17. Found: C, 54.35; H, 3.43, N, 3.01. 1H NMR (300 MHz, DMSO-d6) δ 7.94–7.83 (m, 2H), 7.64 (dt, J=9.0, 2.4 Hz, 1H), 7.39–7.32 (m, 3H), 5.27–5.21 (m, 1H), 4.53–4.51 (m, 1H), 3.99–3.66 (m, 4H), 3.26–3.24 (m, 1H), 3.12–3.02 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][C:33]#[CH:34])([CH3:28])([CH3:27])[CH3:26].C(NC(C)C)(C)C>C1COCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][C:33]#[C:34][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)=[O:12])[CH:14]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C(c1cccc(I)c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(Cl)c23)c1
Yield: 85.8 %

Procedure:
A solution of (4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-iodo-phenyl)-methanone (500 mg, 1.1 mmol), Prop-2-ynyl-carbamic acid tert-butyl ester (341 mg, 2.2 mmol), Copper Iodide (21 mg, 0.11 mmol), PdCl2(PPh3)2 (77 mg, 0.11 mmol), and diisopropylamine (111 mg, 1.1 mmol) in THF (25 mL) was stirred at room temperature under N2. After 24 h the reaction was quenched with saturated aqueous NH4Cl and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash column chromatography (hexanes/ethyl acetate 7:3) afforded the title compound as a yellow solid (452 mg, 86%). %). MS: 479.2/481.2 (MH+); HPLC Rf: 7.26 min. (HPLC method 4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].[Cl-].[Li+].[Cu]C#N.C(Br)C=C>C1COCC1>[CH2:12]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[CH:10]=[CH2:11]
Reactant: Cc1cc(Br)ccc1I
Reactant: CC(C)[Mg]Cl
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1ccc(Br)cc1C
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a solution of 4-bromo-1-iodo-2-methylbenzene (8.41 mL, 58.9 mmol) in THF (200 mL) in a 1.0 L flask under Ar at −20° C., was added isopropylmagnesium chloride (2M, THF) (52.5 mL, 105 mmol) though a dropping funnel. The reaction was stirred for 20 min at −20° C. A solution of lithium chloride (6.00 g, 141 mmol) and copper(I) cyanide (6.33 g, 70.7 mmol) in THF (140 mL) (stirred 15 min at rt to dissolve the LiCl) was cannulated to the above solution. The pale green solution was stirred for 10 min at −10° C., then allyl bromide (15.30 mL, 177 mmol) was added. The mixture was stirred at −10° C. for 30 min. The reaction was quenched with 0.5 N HCl and the solvent was evaporated. The residue was redissolved in diethyl ether/ethylacetate and organic phase was washed with 1N HCl, H2O, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was purified by flash chromatography (0% to 15% EtOAc in hexanes). The desired fractions were combined and concentrated to give 16A (12.10 g, 97% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.15-7.25 (m, 2H) 6.92 (d, J=8.24 Hz, 1H) 5.83 (dddd, J=16.97, 10.37, 6.18, 6.05 Hz, 1H) 5.00 (d, J=9.89 Hz, 1H) 4.85-4.94 (m, 1H) 3.23 (d, J=6.60 Hz, 2H) 2.18 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:47]=[C:48]([C@@H:51]3[CH2:55][C@H:54]([S:56][CH3:57])[CH2:53][NH:52]3)[NH:49][CH:50]=2)=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7]([N:52]1[CH2:53][C@@H:54]([S:56][CH3:57])[CH2:55][C@H:51]1[C:48]1[NH:49][CH:50]=[C:46]([C:43]2[CH:44]=[CH:45][C:40]([Br:39])=[CH:41][CH:42]=2)[N:47]=1)=[O:8])[CH:10]([CH3:12])[CH3:11]
Reactant: CS[C@@H]1CN[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of (S)-2-methoxycarbonylamino-3-methyl-butyric acid (156 mg, 0.89 mmol) and HATU (407 mg, 1.07 mmol) was stirred in DMA (3.0 mL) for 10 min, then 4-(4-bromo-phenyl)-2-((2S,4S)-4-methylsulfanyl-pyrrolidin-2-yl)-1H-imidazole di-HCl (367 mg, 0.89 mmol; Preparation 18) and N,N-diisopropylethylamine (777.3 μL, 4.46 mmol) were added. The resulting mixture was stirred at RT overnight, concentrated, and purified by silica gel chromatography (0 to 90% EtOAc/hexane). Fractions with desired product were combined and concentrated to give the title intermediate (366 mg, 82% yield). (m/z): [M+H]+ calcd for C21H27BrN4O3S 495.10; 497.10. found 495.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([F:32])[C:10]=2[F:33])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:41](Cl)(=O)[O:42]C1C=CC=CC=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C1COCC1>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:42])[CH:7]=3)=[C:10]([F:33])[C:11]=2[F:32])=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2F)c(=O)n(-c2ccccc2)n1C
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)N4CCOCC4)c3)c(F)c2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (224 mg, 0.50 mmol) in THF (3 mL) was added Et3N (0.138 mL, 0.99 mmol), followed by adding phenyl carbonochloridate (0.125 mL, 1.00 mmol) dropwise. The reaction mixture was stirred at rt for 2 hours, then morpholine (0.4 mL, 5.00 mmol) was added. The mixture was stirred at rt for 36 hours, then quenched with saturated NH4Cl aqueous solution (20 mL) and CH2Cl2 (20 mL). The resulted mixture was stirred at rt for 10 minutes and extracted with CH2Cl2 (20 mL×3). The combined organic phases were washed with brine (20 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=20/1) to give the title compound as an orange solid (148 mg, 52.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1.[Cl:29]N1C(=O)CCC1=O>C(O)(C)C.ClC(Cl)C(O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:29])=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)cc2=O)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Cl)c2=O)c1
Temperature: 60 °C

Procedure:
To a solution of 4-methyl-3-[2-methyl-4-(6-methyl-pyridin-2-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-benzoic acid methyl ester from Step A, of Example 13 (100 mg, 0.26 mmol) in isopropanol (1 mL) was added N-chlorosuccinimide (39 mg, 0.29 mmol) and 1 drops of dichloroacetic acid. The solution was heated at 60° C. for two hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the chlorinated product as colorless oil (120 mg, quantitative yield). MS (M+H): 414
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.B(F)(F)F.CC[O:15][CH2:16][CH3:17].N(OC(C)(C)C)=[O:19].CCCCC>COCCOC>[C:16]([O:19][C:2]1[CH:3]=[N:4][C:5]([F:8])=[CH:6][CH:7]=1)(=[O:15])[CH3:17]
Reactant: CC(C)(C)ON=O
Reactant: CCOCC
Reactant: Nc1ccc(F)nc1
Agent: FB(F)F
Solvent: CCCCC
Solvent: COCCOC
Product: CC(=O)Oc1ccc(F)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
A solution of 3-amino-6-fluoropyridine (5.0 g, 45 mmol, from Step 8c above) dissolved in DME (30 mL) was added to a cooled solution (−15° C.) of boron trifluoride etherate (12.2 mL, 99 mmol). tert-Butyl nitrite (6.3 mL, 54 mmol) was then added at a rate which maintained the temperature below 0° C. After 10 minutes at −10° C. the reaction was warmed to 5° C. and stirred for 30 min. Pentane (150 mL) was then added to the reaction mixture, and the resultant solid was collected by suction filtration, washed with cold ether, air dried, and dissolved in acetic anhydride (75 mL). The solution was heated to 105° C. until nitrogen evolution ceased. The solvent was removed in vacuo, and the residue was suspended in saturated aqueous Na2CO3 (200 mL) and extracted with ethyl ether (2×150 mL). The combined organic extracts were dried (MgSO4) and concentrated. Purification by chromatography (silica gel; hexane/EtOAc, 9:1 to 7:3) afforded the title compound (2.25 g, 33%): 1H NMR (CDCl3 300 MHz) δ2.32 (s, 3H), 6.96 (d, J=3, 9 Hz, 1H), 7.59 (m, 1H), 8.03 (dd, J=0.5, 1 Hz, 1H); MS (CI/NH3) m/z 156 (M+H)+, 171 (M+NH4)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])=[S:22])[CH2:17][CH2:18][CH3:19]>>[ClH:1].[CH2:24]([N:23]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:22][C:21]1=[N:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:25][CH2:26][CH3:27]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: CCCCNC(=S)NCCCC
Product: CCCCN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1CCCC
Product: Cl

Procedure:
5.2 g of 2,4'-dichloro-3'-sulfamoylacetophenone were reacted with 3.8 g of 1,3-di-n-butylthiourea according to the prescription given in Example 12 and the end product was precipitated with diisopropyl ether. Colorless crystalline solid body: melting point: 164° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25].N1C=CC=C[CH:29]=1>>[CH3:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([N:1]([CH3:29])[S:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)(=[O:26])=[O:25])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: c1ccncc1
Reactant: CCOC(=O)c1cc2cc(OC)cc(N)c2[nH]1
Product: CCOC(=O)c1cc2cc(OC)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of ethyl 7-amino-5-methoxy-1H-indole-2-carboxylate (2.5 g) in pyridine (20 mL) was added 2-pyridinesulfonyl chloride (2.1 g) under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was dissolved in N,N-dimethylformamide (20 mL), methyl iodide (1.5 g) and potassium carbonate (2 g) were added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried (MgSO4), and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.7 g, yield 68%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (50:50, volume ratio). MS: 390(MH+).
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH2:9][C:8]=1[CH2:20][S:21][C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[Br:28][CH:9]1[C:8]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)=[C:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10]1(=[O:19])=[O:18]
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)CS(=O)(=O)[C@H]12
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(Br)S(=O)(=O)[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-tert-butylcarbonyl-7α-methoxy-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem 1,1 dioxide (350 mg) in dichloromethane (30 ml), N-bromosuccinimide (200 mg) and triethylamine (0.13 ml) were added sequentially. The mixture was stirred for 15 min at room temperature. Following dilution with dichloromethane, the organic phase was sequentially washed with 4% aqueous NaHSO3, saturated NaHCO3 and water. After drying over Na2SO4 and removal of the solvent, the residue was purified by flash chromatography (eluting with hexane-EtOAc mixtures) affording 2-bromo-4-tert-butylcarbonyl-7α-methoxy-3-(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl-3-cephem 1,1-dioxide as a waxy solid (200 mg), IR (KBr) νmax 1800, 1700 cm-1. A portion of this material (180 mg) was dissolved in acetonitrile (10 ml) and treated with silver benzoate (95 mg). The mixture was stirred for 30 min at room temperature, then filtered and rotoevaporated. Following flash chromatography (eluting with gradient of EtOAc in hexane) the title product was obtained as a light yellow solid (80 mg).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Brc1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)nc1
Temperature: 125 °C

Procedure:
To the solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (4.38 g, 15.0 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-bromopyrimidine (2.90 g, 15.0 mmol) (prepared as in Example 51) in dry degassed DMF (30 ml) was added N,N-diisopropylethylamine (4.2 ml, 30 mmol). The mixture was heated at 120-130° C. overnight. The mixture was then cooled and diluted with ethyl acetate. The solution was washed with 0.5 N citric acid, water and brine, then dried over Na2SO4 and concentrated in vacuo. Purification by flash column (silical gel, hexane:ethyl acetate=6:1, v/v, followed by hexane:ethyl acetate=4:1, v/v) yielded the product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:27]([O:30][C:31]1[C:36](NC)=[CH:35][CH:34]=[CH:33][N:32]=1)([CH3:29])[CH3:28].C[CH2:40][N:41](C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:41][CH2:40][C:36]3[C:31]([O:30][CH:27]([CH3:28])[CH3:29])=[N:32][CH:33]=[CH:34][CH:35]=3)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1cccnc1OC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ncccc1CNc1ncc([N+](=O)[O-])c(NCC2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (150 mg, 0.39 mmol) in DMF (1 mL) were added a solution of (2-isopropoxy-pyridin-3-yl)-methylamine (180 mg, 1.1 mmol) obtained above in DMF (1 mL) followed by DIPEA (135 μL, 0.78 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 and water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford [4-({2-[(2-isopropoxy-pyridin-3-ylmethyl)-amino]-5-nitro-pyrimidin-4-ylamino}-methyl)-cyclohexyl]-carbamic acid tert-butyl ester which was dissolved in CH2Cl2 and TFA was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was then treated with 1M Na2CO3 and extracted with CH2Cl2. MeOH was added to the mixture during the extraction to solublize the product into the organic phase. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 10:1:0.2 CH2Cl2:MeOH:NH4OH as an eluent to afford 75 mg of the title compound as a pale yellow solid (46%); m/z 416.4 [M+1]+.