Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31](O)=[O:32])[CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1.CS([O-])(=O)=O.ClC1C=CC=C[N+:41]=1C.N>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([NH2:41])=[O:32])[CH:29]=3)[NH:24][CH:23]=2)[CH2:20][CH2:21]1
Reactant: COc1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(C(=O)O)cc45)CC3)c2c1
Reactant: C[n+]1ccccc1Cl
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: CN1CCCC1=O
Product: COc1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(C(N)=O)cc45)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.1 g of 3-[1-(4-(5-methoxyindol-3-yl)butyl)-4-piperidyl]indole-5-carboxylic acid are suspended in 100 ml of N-methylpyrrolidone. 3.2 g of 2-chloro-1-methylpyridinium methanesulfonate are then added and the mixture is stirred at room temperature for 12 hours. Dried NH3 gas is passed into the resulting solution until it is saturated and it is stirred again for 10 hours. Working-up in a conventional manner gives 3-[1-(4-(5-methoxyindol-3-yl)butyl)-4-piperidyl]indole-5-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[S:8][C:9]([CH:12]=O)=[CH:10][N:11]=2)[CH:6]=1.[C:14](=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[C:12]([C:9]1[S:8][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[N:11][CH:10]=1)#[CH:14]
Reactant: O=C([O-])[O-]
Reactant: Cc1cn(-c2ncc(C=O)s2)cn1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cnc(-n2cnc(C)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-bromo-1,3-thiazole-5-carbaldehyde (10 mg, 0.068 mmol), 4-methyl-1H-imidazole (7.23 mg, 0.088 mmol), potassium carbonate (28.1 mg, 0.203 mmol) and DMF (5 ml) were heated at 110° C. for 1 h. The mixture was purified on silica gel (EtOAc/hexane 8:2) to afford 2-(4-methyl-1H-imidazol-1-yl)-1,3-thiazole-5-carbaldehyde (38.4 mg, 0.199 mmol) as a yellow solid. This aldehyde (38.4 mg, 0.199 mmol) and anhydrous potassium carbonate (110 mg, 0.795 mmol) were placed in a 25-ml flask and placed on high vacuum for 10 min. Under N2, anhydrous MeOH (2 ml) was added. To the suspension was added dimethyl (1-diazo-2-oxopropyl) phosphonate (40 μl, 0.256 mmol). The reaction was stirred at rt for 22 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, concentrated to afford crude product, which was used in next step directly.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[N:6]1.Cl>C1COCC1>[N+:10]([C:8]1[CH:7]=[N:6][N:5]([CH2:4][CH:3]=[O:2])[CH:9]=1)([O-:12])=[O:11]
Reactant: COC(Cn1cc([N+](=O)[O-])cn1)OC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCn1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2,2-dimethoxyethyl)-4-nitro-1H-pyrazole (2.65 g, 13.2 mmol) in THF (34 mL), a 2N aq. HCl-solution (60 mL, 120 mmol) was added dropwise. After stirring at 80° C. for 2 h, the reaction mixture was allowed to reach rt and freeze-dried overnight to yield 2-(4-nitro-1H-pyrazol-1-yl)acetaldehyde which was used as an yellow oil in the next step without further purification. LC-MS conditions B: tR=0.24 min, [M+H]+=no ionization.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:8]3[CH2:15][CH2:16][CH:5]([CH2:6][CH2:7]3)[C:4]=2[C:3]1=[O:17].N1C=CC=CC=1.[C:24]12([CH2:34][C:35](Cl)=[O:36])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>C(Cl)Cl.CCOC(C)=O>[C:24]12([CH2:34][C:35]([NH:1][N:2]3[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]4[CH:8]5[CH2:15][CH2:16][CH:5]([CH2:6][CH2:7]5)[C:4]=4[C:3]3=[O:17])=[O:36])[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)c1nn(N)c(=O)c2c1C1CCC2CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)c1nn(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(=O)c2c1C1CCC2CC1
Yield: 54.8 %

Procedure:
A mixture of Example 8C (18.3 mg), pyridine (0.008 mL, 0.10 mmol), and (adamantan-1-yl)acetyl chloride (18.7 mg, 0.088 mmol) in CH2Cl2 (0.35 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (20% EtOAc/CH2Cl2) to give the title compound (17.6 mg, 0.043 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 3.40-3.35 (m, 1H), 3.21-3.07 (m, 2H), 1.99 (s, 2H), 1.93 (s, 3H), 1.83-1.72 (m, 4H), 1.72-1.54 (m, 12H), 1.33-1.17 (m, 4H), 1.14 (d, 6H); MS (ESI+) M/Z 410.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)=[CH:17][CH:18]=1
Reactant: CNC(=O)COc1ccc(O)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)COc1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
In analogy to the procedure described in Example 3 b), the alkylation of 2-(4-hydroxy-phenoxy)-N-methyl-acetamide [Example 3a)] with 1-bromomethyl-4-chloro-benzene in 2-butanone using potassium carbonate as the base yielded the 2-[4-(4-chloro-benzyloxy)-phenoxy]-N-methyl-acetamide as white crystals; MS: m/e=306 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:41]=[C:42](C)[CH2:43][O:44][C:45](=[O:47])[CH3:46]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][C:42]([CH2:43][O:44][C:45](=[O:47])[CH3:46])=[O:41])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)COC(C)=O
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.5 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.12 gms, 0.338 mmole), 1-hydroxybenzotriazole (0.07 g, 0.507 mmol) ethylcarbodiimide (0.10 g, 0.507 mmol), triethylamine (0.3 mL, 2.0 mmol) and acetic acid 2-oxo-propyl ester (0.05 g, 0.40 mmol) were dissolved in 10 mL methylene chloride. The reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with water, and the entire mixture was absorbed on to silica gel and medium pressure chromatography, and eluted with ethyl acetate//hexanes (3:1) to give 0.1 g of acetic acid {[(R)-6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl ester.
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12](/[CH:14]=[C:15]2\[CH2:16][N:17]([CH:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[CH2:18][CH2:19][CH:20]\2[SH:21])[N:11]=[N:10]1)([OH:4])=[O:3].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([S:21][CH:20]1[CH2:19][CH2:18][N:17]([CH:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:23]([CH:25]2[CH2:26][CH2:27]2)=[O:24])[CH2:16]/[C:15]/1=[CH:14]\[C:12]1[N:11]=[N:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:13]=1)(=[O:37])[CH3:36]
Reactant: O=C(O)CCCCn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)nn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cn(CCCCC(=O)O)nn1
Yield: 99 %

Procedure:
In a similar manner to that described in Example 183, (E)-3-{[1-(4-carboxybutyl)-1H-1,2,3-triazol-4-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanylpiperidine hydrochloride (190 mg) was treated with acetic anhydride. The crude product extracted using conventional procedures was purified by chromatography on silica gel using a mixture of methanol and dichloromethane (1:99 to 7:93) as the eluent to afford the title compound as a colourless oil (190 mg, yield: 99%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[CH:48]1([CH2:51][C:52]([C:55]2[N:59]=[C:58]([CH3:60])[O:57][N:56]=2)([NH2:54])[CH3:53])[CH2:50][CH2:49]1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:54][C:52]([C:55]3[N:59]=[C:58]([CH3:60])[O:57][N:56]=3)([CH3:53])[CH2:51][CH:48]3[CH2:49][CH2:50]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: CC(CF)Oc1cc(C(=O)O)ncc1C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OC(C)CF)c(C3CC3)cn2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer A) (example 287e, 0.08 g, 334 μmol) in dry DMF (2 ml) was added TBTU (113 mg, 351 μmol) and triethylamine (102 mg, 140 μl, 1.00 mmol). The reaction was stirred at room temperature for 30 minutes followed by addition of 1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (example 66e, 72.8 mg, 334 μmol). The reaction was then stirred at room temperature overnight. The reaction was diluted with ethyl acetate and extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to give the a mixture of epimers. The epimers were then separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the second epimer collected (23 mg, 17%); MS (ESI, m/z): 403.4 (M+H+).
Reaction SMILES: Br[C:2]1([CH2:15][N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:4][C:3]1([CH2:10][O:11]C(=O)C)[CH2:5][O:6]C(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>CN(C)C=O>[OH:6][CH2:5][C:3]1([CH2:10][OH:11])[CH2:4]/[C:2]/1=[CH:15]/[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: CC(=O)OCC1(COC(C)=O)CC1(Br)Cn1cc(C)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cn(/C=C2/CC2(CO)CO)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
A mixture of compound 18 (0.60 g, 1.49 mmol) from Example 17 and flame-dried potassium carbonate (616 mg, 4.47 mmol) in N,N-dimethylformamide (50 mL) was stirred at 100° C. under nitrogen for 3 h. After cooling, methanol-water (9:1, 10 mL) was added with stirring which was continued at room temperature for 1 h. The insoluble portion was filtered off and it was washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residue was chromatographed on a silica gel column which was first eluted with ethyl acetate and then dichloromethane-methanol (20:1) to give the Z-isomer 1f (70 mg, 38%) and E-isomer 2f (65 mg, 36%) as white solids.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:12][C:11]([C:8]1[C:9]2[CH:10]=[C:2]([CH3:1])[NH:3][C:4]=2[CH:5]=[CH:6][CH:7]=1)=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc2c(C(=O)O)cccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(C(=O)OCc3ccccc3)cccc2[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methylindole-4-carboxylic acid (690 mg; prepared in Reference Example 10) in N,N-dimethylformamide (10 ml) was added anhydrous potassium carbonate (815 mg) and benzyl bromide (0.7 ml) at room temperature, and the mixture was stirred at 80° C. for 2 hours. To the reaction solution was added water and ethyl acetate, and then extracted. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give the title compound (610 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[CH2:18][CH2:19][CH2:20][S:21]2(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCCN1Cc1ccc(Br)cc1
Yield: 93.7 %

Procedure:
A solution of 4-bromobenzylamine (1.85 g, 10 mmol) and triethylamine (2 g, 20 mmol) in dimethylformamide (30 ml) was treated with 3-chloropropanesulfonyl chloride (1.78 g, 10 mmol) by dropwise addition over 10 minutes with stirring under argon. This mix was stirred for 30 minutes before being treated with a 60% suspension of sodium hydride in mineral oil (1.2 g, 30 mmol of NaH) portionwise and the whole mix stirred at room temperature for 3 days. The reaction mixture was partitioned between water (50 ml) and dichloromethane (30 ml). The organic layer was dried over sodium sulphate and reduced to minimum volume by rotary evaporation. The residue was added to a 20 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.72 g, 94%).
Reaction SMILES: [CH3:1][C@:2]1([CH2:17][OH:18])[O:6][C@@H:5]([N:7]2[CH:14]=[CH:13][C:11](=S)[NH:10][C:8]2=[O:9])[C@H:4]([OH:15])[C@@H:3]1[OH:16].[NH3:19]>>[CH3:1][C@:2]1([CH2:17][OH:18])[O:6][C@@H:5]([N:7]2[CH:14]=[CH:13][C:11]([NH2:19])=[N:10][C:8]2=[O:9])[C@H:4]([OH:15])[C@@H:3]1[OH:16]
Reactant: N
Reactant: C[C@]1(CO)O[C@@H](n2ccc(=S)[nH]c2=O)[C@H](O)[C@@H]1O
Product: C[C@]1(CO)O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
Compound 11 (890 mg, 1.93 mmol) was treated with methanolic ammonia (previously saturated at −10° C.), (12 mL) at 100° C. in a stainless-steel bomb for 3 hours, then cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride (40 mL) and water (40 mL). The aqueous layer was washed with methylene chloride (2×40 mL), concentrated under reduced pressure. The crude material was purified by silica gel column chromatography [eluent: methylene chloride/methanol/ammonium hydroxide 65:30:5]. The collected fractions were evaporated under reduced pressure and in absolute ethanol (6.3 mL). To the solution was added a 2N hydrochloric acid solution (1.5 mL) and the mixture was stirred before being concentrated under reduced pressure. The procedure was repeated twice and 12 was precipitated from absolute ethanol. Mp: 213–214 (dec.); UV (methanol): λmax=280 nm (ε=9800), λmin=245 nm (ε=3600); 1H-NMR (DMSO-d6): δ 9.82 (s, 1H, NH2), 8.72 (s, 1H, NH2), 8.34 (d, 1H, H-6, J6-5=7.8 Hz), 6.21 (d, 1H, H-5, J5-6=7.8 Hz), 5.83 (d, 1H, H-1′, J1′-2′=5.8 Hz), 4.22 (d, 1H, OH-2′, JOH-2′=6.5 Hz), 5.6–4.7 (m, 3H, OH-2′, OH-3′ and OH-5′), 4.28 (t, 1H, H-2′, J=5.6 Hz), 3.99 (d, 1H, H-3′, J=5.3 Hz), 3.43 (m, 2H, H-5′ and H-5″), 1.14 (s, 3H, CH3); MS (matrix GT): FAB>0 m/z 515 (2M+H)+, 258 (M+H)+, 147 (S)+, 112 (BH2)+ FAB<0 m/z 256 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:36](=[O:35])[CH2:37][OH:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OCC(=O)Cl
Product: C[C@H](NC(=O)CO)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 5 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and 2-chloro-2-oxoethyl acetate (21 mg, 150 μmol). Yield 18 mg (76%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:33])[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH:16]2[CH2:29][N:30]([CH3:32])[CH3:31])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.Cl.C[Si](C)(C)[Cl:37].O>>[ClH:37].[CH3:31][N:30]([CH2:29][CH:16]1[CH2:17][CH:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:20][C:15]1([C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)[OH:33])[CH3:32]
Reactant: C[Si](C)(C)Cl
Reactant: CN(C)CC1CC(CCc2ccccc2)CCC1(O)c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: O
Product: CN(C)CC1CC(CCc2ccccc2)CCC1(O)c1cccc(O)c1
Yield: 63 %

Procedure:
Compound (50) was hydrogenated corresponding to the conditions described in Example 23, step 2. The base obtained was converted into the hydrochloride with trimethylchlorosilane/water. Compound (49) was obtained in a yield of 63% theoretical.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:35])([CH3:34])NC(=O)C(Cl)(Cl)Cl.[Br:36]N1C(C)(C)C(=O)N(Br)C1=O>ClCCCl>[Br:36][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:35])([CH3:34])[CH3:25])=[O:9]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: C[Si](C)(C)NC(=O)C(Cl)(Cl)Cl
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: ClCCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reaction time: 0.25 h
Yield: 48 %

Procedure:
420 mg (1.21 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide were silylated by stirring at 30° C. for 1.5 hours in 60 ml of 1,2-dichloroethane with 1.0 g (4.3 mmoles) of N-trimethylsilyltrichloroacetamide. The slightly yellow, substantially clear solution obtained was cooled in an ice-bath and bromination was carried out in 15 minutes using 250 mg (0.87 mmole) of 1,3-dibromo-5,5-dimethylhydantoin as the brominating agent. During the bromination reaction, the mixture was irradiated with a 520 W fluorescent lamp to obtain a 48% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:13]([I:14])=[CH:12][C:11]([C:15](=[O:27])[C:16]([C:18]2[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=2)=[O:17])=[CH:10][C:9]=1[I:28].Br[CH2:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].Cl>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][O:7][C:8]1[C:9]([I:28])=[CH:10][C:11]([C:15](=[O:27])[C:16]([C:18]2[CH:19]=[C:20]([I:26])[C:21]([OH:25])=[C:22]([I:24])[CH:23]=2)=[O:17])=[CH:12][C:13]=1[I:14])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(C(=O)c1cc(I)c(O)c(I)c1)c1cc(I)c(O)c(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(COc1c(I)cc(C(=O)C(=O)c2cc(I)c(O)c(I)c2)cc1I)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.4 %

Procedure:
Cesium carbonate (1.30 g, 4.0 mmol) was suspended in a solution of 1,2-bis-(4-hydroxy-3,5-diiodophenyl)-ethane-1,2-dione (as prepared in Example 15, 1.49 g, 2.0 mmol) and benzyl 2-bromoacetate (0.46 g, 2.0 mmol) in 8 mL DMF. The mixture was stirred at RT for 16 hours and was poured into 1 M HCl. The resulting precipitate was isolated by filtration, then was dissolved in hot chloroform and filtered through Celite. The solvent was removed by rotary evaporation, and the crude material was purified by silica gel column chromatography (5% MeOH in CH2Cl2), yielding the title compound as a yellow powder (258 mg, 14%). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 8.23 (s, 2H), 7.45-7.34 (m, 5H), 5.27 (s, 2H), 4.73 (s, 2H). HPLC (50-90), 15.74 min. LRMS (EI−) calc'd for [C23H14I4O6—H] 893.0, found 892.6.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:31]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)=[O:32])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CN1CCN(C(=O)Cl)CC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCN(C)CC4)nc3cc21

Procedure:
4-Methyl-piperazine-1-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and 4-methyl-1-piperazinecarbonyl chloride. The title compound was obtained as light yellow powder (50 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:14]([S:15]CC3C=CC=CC=3)=[N:13][N:12]=[N:11]2)[CH2:4][CH2:3]1.C(O)(=O)C.[BrH:27]>O>[BrH:27].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]2[C:14]([SH:15])=[N:13][N:12]=[N:11]2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCn2nnnc2SCc2ccccc2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(CCn2nnnc2S)CC1

Procedure:
A mixture of 1-[2-(4-methyl-1-piperazinyl)ethyl]-5 benzylthio-1H-tetrazole (5.4 g), acetic acid (40 ml) and conc. hydrobromic acid (40 ml) was heated at 70° to 80° C. for 8 hours. After the concentration of the reaction mixture, the concentrate was diluted with water. The mixture was washed with diethyl ether twice and evaporated under reduced pressure. The residue was recrystallized from methanol. A solution of the obtained crystals in a little amounted of water was adjusted to pH 6.0 with 1 N aqueous solution of potassium hydroxide., washed with ethyl acetate and then evaporated under reduced pressure. To the residue was added hot ethanol and insoluble materials were filtered out. The filtrate was cooled and the precipitated crystals were collected by filtration to give 1-[2-(4-methyl-1-piperazinyl)ethyl]-1H-tetrazole-5-thiol hydrobromide (1.1 g), mp 216° to 222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]([C:12]2[C:17]([O:18][C:19]([C:21]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH3:29][C:28]([O:27][C:26]1[C:21]([C:19]([O:18][C:17]2[C:12]([C:10]([O:9][C:8]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:11])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:30]
Reactant: COc1ccccc1OC(=O)c1ccccc1OC(=O)c1ccccc1O
Reactant: CC(=O)OC(C)=O
Product: COc1ccccc1OC(=O)c1ccccc1OC(=O)c1ccccc1OC(C)=O

Procedure:
treating the guaiacol salsalate (II) with acetic anhydride to obtain guaiacol acetylsalsalate (III) in accordance with the reaction: ##STR4## In stage (a) the 2-hydroxybenzoylchloride is dissolved in an organic solvent, preferably 1,2-dichloroethane, the solution is cooled to a temperature of between -2° and +2° C., and N,N-dimethylaniline and guaiacol salsalate are added under energetic agitation.