Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17]>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:20][CH:16]([CH2:18][CH3:19])[CH3:17]
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: CCC(C)N
Solvent: CCO
Product: CCC(C)NCCOc1cc(F)cc(S(C)(=O)=O)c1
Yield: 70.4 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and sec-butylamine 1.37 ml, 13.46 mmol) in ethanol (5 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (342 mg, 70%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 166.5° C. MS m/z (relative intensity, 70 eV) 289 (M+, 1), 261 (25), 260 (bp), 86 (49), 70 (12).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[O:27][CH3:28])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[NH2:25][C@@H:24]1[C:23](=[O:26])[N:22]2[C:17]([C:15]([OH:16])=[O:14])=[C:18]([O:27][CH3:28])[CH2:19][S:20][C@H:21]12
Reactant: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A suspension of 1.65 g of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 2 ml of anisole is mixed with 20 ml of pre-cooled trifluoroacetic acid and stirred for 15 minutes in an ice bath. It is diluted with 100 ml of cold toluene and the reaction mixture is evaporated under reduced pressure. The dark brown residue is dried under a high vacuum and stirred with diethyl ether; the precipitate is filtered off, washed with acetone and diethyl ether and dried. The salt, thus obtainable, of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid and of trifluoroacetic acid is dissolved in 10 ml of water; the aqueous solution is twice washed with 10 ml of ethyl acetate at a time and brought to a pH of 4.5 by adding a 10% strength solution of triethylamine in methanol. The mixture is diluted with 10 ml of acetone and stirred for one hour at 0° C. The precipitate is filtered off, washed with a 1:2 mixture of acetone and diethyl ether and dried in a high vacuum and yields 7β-amino-3-methoxy-3-cephem-4-carboxylic acid in the form of the internal salt, thin layer chromatogram (silica gel): Rf~0.16 (system: n-butanol/acetic acid/water, 67:10:23); ultraviolet absorption spectrum (in 0.1 N hydrochloric acid): λmax =261 mμ (ε=5,400).
Reaction SMILES: [Li]CCCC.[CH3:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[C:16](=[C:19]1[CH:28]=[C:27]2[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:20]1)([CH3:18])[CH3:17]>CCCCCC.C(OCC)C.O>[CH3:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([C:19]2[CH2:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[CH:20]=2)([CH3:18])[CH3:17])[CH:8]=1
Reactant: CC1C=Cc2ccccc21
Reactant: CC(C)=C1C=C2CCCCCC2=C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C2=CC3=C(CCCCC3)C2)c2ccccc21
Reaction time: 3 h
Yield: 67.3 %

Procedure:
12.4 ml of LiBu 2.5 M in hexane are added, at room temperature, to an ether solution of 4.2 g (0.032 moles) of 1-methylindene in 100 ml of ethyl ether. The mixture is left under stirring for 3 hours, then 3.8 g (0.022 moles) of 2-isopropylidene-2,4,5,6,7,8-hexahydroazulene are added at -70° C. The temperature is left to rise and the mixture is left under stirring for 48 hours. The reaction mixture is hydrolyzed in water and extracted with ethyl ether which after evaporation provides a solid which is purified on a silica gel column using petroleum ether as eluant. 4.5 g (0.0148 moles) of 2-[1-(3-methyl-1H-Inden-1-yl) -1-methyl-ethyl]-1,4,5,6,7,8-hexahydroazulene are obtained which are dissolved in 200 ml of ethyl ether, to which 18.8 ml of LiMe 1.6 M in ether ethyl are added and the mixture is left under stirring for a night. A slightly yellow precipitate is formed. The mixture is cooled to -70° C. and 3.51 g (0.015 moles) of zirconium tetrachloride are added. The temperature is brought to room temperature and the mass tends to take on a dark brownish-yellow coloring. The mixture is filtered, washed with ethyl ether which tends to become yellow, and is then extracted with methylene chloride (2×100 ml). The solution is brought to a small volume and 20 ml of ethyl ether are then added. A solid precipitates which is filtered, washed with ether and hexane and then dried. 1.0 g of complex are obtained. After two days large orange crystals separate from the yellow ether mother liquor, which when filtered and washed with hexane give 2.1 g of pure complex for a total of 3.1 g (45% yield calculated on the ligand used). 1H NMR (CDCl3, δ ppm rel. TMS): 7.55 (d, 2H); 7.25 (m, 1H); 6.95 (m, 1H); 5.65 (s, 1H); 5.43 (d, 1H); 2.8-2.5 (m, 4H); 2.45 (s, 3H); 1.9-1.6 (m, 7H); 1.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14](OC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C(OCC)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCO
Yield: 96.5 %

Procedure:
A solution of methyl 5-methyl-2-phenyl-4-oxazoleacetate (54 g) in dry ethyl ether (150 ml) was added dropwise to a stirred, ice-cooled suspension of lithium aluminum hydride (8.8 g) in dry ethyl ether (700 ml) during 1.5 hours. Ethyl acetate (20 ml) was added dropwise thereto with ice-cooling and then water (50 ml) was added cautiously thereto. The resulting white precipitate was filtered off and the filtrate was concentrated to give 2-(5-methyl-2-phenyl-4-oxazolyl) ethanol as crystals (45.8 g, 96.2%). Recrystallization from ethyl acetate-hexane gave colorless rods, m.p. 73°-74° C.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH3:6][Si:7]([C:10]#[C:11][C:12]([CH2:14][CH2:15][CH2:16][Cl:17])=[O:13])([CH3:9])[CH3:8]>CCOCC>[Cl:17][CH2:16][CH2:15][CH2:14][C:12]([OH:13])([C:11]#[C:10][Si:7]([CH3:8])([CH3:9])[CH3:6])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: C[Si](C)(C)C#CC(=O)CCCCl
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(C#C[Si](C)(C)C)CCCCl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 1.29 grams of magnesium and 10 mg. of mercuric chloride in 12 ml. of ether is added 0.4 ml. of propargyl bromide. The reaction is initiated after stirring at room temperature for a few minutes. The solution of 11.2 grams of 3-chloropropyl trimethylsilylethynyl ketone and 3.51 ml. of propargyl bromide in 13 ml. of ether is added dropwise so that the mixture is very gently boiled during a period of about 40 minutes. After addition is complete, the cooling bath is removed and the mixture is stirred at room temperature for about 1.5 hours. The mixture is recooled in an ice bath and 10 ml. of saturated ammonium chloride solution is added. The resulting white mixture is filtered through diatomaceous earth. The clear mother liquor is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated to dryness giving a red liquid. The liquid is Kugelrohr-distilled to afford the pale yellow liquid distillate which is the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:48]=[CH:49][C:50]=1[F:51])[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH:45]3C)=[O:43])[N:40]=2)[N:37]=1>CN(C)C(=O)C.O1CCCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([NH:27][C:28]2[CH:29]=[C:30]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]5[CH2:46][CH2:45]5)=[O:43])[N:40]=4)[N:37]=3)[CH:48]=[CH:49][C:50]=2[F:51])=[O:15])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Reactant: O=C(O)c1ccn(Cc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F)c1ccn(Cc2ccccc2)c1
Yield: 24.3 %

Procedure:
Using 1-benzyl-1H-pyrrole-3-carboxylic acid (276 mg, 1.37 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (120 μL, 1.37 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide (300 mg, 0.92 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (114 mg, 24%) was obtained as a white powder.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[Cl:9][C:10]1[CH:38]=[CH:37][C:13]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([NH:25][C@H:26]([CH:34]([CH3:36])[CH3:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:25]([S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:38][CH:37]=2)[CH2:17][CH2:18]1)(=[O:23])=[O:24])[C@H:26]([CH:34]([CH3:35])[CH3:36])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28]
Reactant: O=C([O-])[O-]
Reactant: CC(C)[C@@H](NS(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)[C@H](C(=O)OC(C)(C)C)N(C)S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reaction time: 3 h
Yield: 63 %

Procedure:
Anhydrous potassium carbonate (152 mg, 1.1 mmol) and iodomethane (0.034 ml, 0.5 mmol) were added to a solution of tert-butyl 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate (100 mg, 0.22 mmol) in DMF (1.5 ml) at RT. After 3 h, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed with 0.1M HCl and brine, and dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed (]PTLC, SiO2, 25% ethyl acetate/hexane) to give tert-butyl 2-(R)-{methyl-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate as a colorless oil (63%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[F-].[K+].[S:43]1[C:47](B(O)O)=[CH:46][C:45]2[CH:51]=[CH:52][CH:53]=[CH:54][C:44]1=2>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:43]1[C:47]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[NH:4][N:3]=2)=[CH:46][C:45]2[CH:51]=[CH:52][CH:53]=[CH:54][C:44]1=2
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc(C#N)ccc21
Reactant: OB(O)c1cc2ccccc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
To a solution of 600 mg of tert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate produced in Production Example I-14-b in 9 ml tetrahydrofuran were added 21 mg of palladium(II) acetate, 57. mg of 2-(di-tert-butylphosphino)biphenyl, 357 mg of potassium fluoride and 498 mg of 2-benzo[b]thiopheneboronic acid, and the mixture was stirred at 50° C. for 1 hour. After removing the solvent by distillation, the residue was dissolved in 2 ml of methylene chloride. 4 ml of trifluoroacetic acid was added and the mixture was stirred at room temperature for one day. After removing the solvent by distillation, the residue was diluted with 50 ml of ethyl acetate. The mixture was sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:19), to give 294 mg of the title compound as bright yellow crystals.
Reaction SMILES: C(NCCCCCC(N1C[C@@H](S)[C@H](N[S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])C1)=O)(=O)C.[C:34]([N:41]1[CH2:45][C@@H:44]([OH:46])[C@H:43]([N:47]=[N+]=[N-])[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.C1(C2C=CC(S(Cl)(=O)=O)=CC=2)C=CC=CC=1>C1COCC1.O.CCCCCC.C1COCC1.C(OCC)(=O)C>[C:34]([N:41]1[CH2:45][C@@H:44]([OH:46])[C@H:43]([NH:47][S:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Reactant: CC(=O)NCCCCCC(=O)N1C[C@@H](S)[C@H](NS(=O)(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NS(=O)(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 65 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
(±)-N-(6-Acetamidohexanoyl)-trans-3-(4-phenylbenzene-sulfonamido)-4-mercaptopyrrolidine. To a solution of (±)-N-Boc-trans-3-azido-4-hydroxypyrrolidine (228 mg, 1.0 mmol) in THF—H2O (10:1, 5 mL) was added Ph3P (275 mg, 1.05 mmol), and the mixture was stirred at room temperature for 2 hr and at 65° C. until no starting material was detected on TLC (25% ethyl acetate in hexane). The solution was cooled with stirring to 0° C., and triethylamine (167 μL, 1.2 mmol) was added, then a solution of 4-phenylbenzenesulfonyl chloride (256 mg, 1.1 mmol) in THF (2 mL) was added dropwise. The reaction mixture was warmed to room temperature and was stirred for 3 hr. The mixture was concentrated under reduced pressure, ethyl acetate was added to the residue and the organic layer was washed with 10% aq citric acid and sat. aq NaHCO3, then it was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (50% ethyl acetate in hexane) to give (±)-N-Boc-trans-3-(4-phenylbenzenesulfonamido)-4-hydroxypyrrolidine (337 mg, 73.5%): 1H NMR (300 MHz, CDCl3+CD3OD) δ 7.88 (d, J=8, 2H), 7.69 (d, J=8, 2H), 7.56 (d, J=8, 2H), 7.41 (m, 3H), 4.06 & 4.20 (br m, 1H), 3.52 (br m, 3H), 3.12 (m, 2H), 1.36 & 1.38 (s, 9H); HRMS (ESI) calculated for C21H26N2O5SNa+441.1460. found 441.1469.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrBr
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2sc3ccccc3c2Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of 5.0 g (20.8 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) in 400 mL of CHCl3 at 0° C. was treated slowly with 1.6 mL of Br2, resulting in a yellow solution. The reaction was stirred at 0° C. for 1 h and then washed sequentially with 200 mL of 1.0 N aq Na2S2O3, 200 mL of 1.0 N aq NaHCO3, and 200 mL of H2O. After drying over Na2SO4, evaporation of the solvent in vacuo gave 6.24 g (19.5 mmol; 94%) of an off-white solid which was clean by thin layer chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20]1(C)[CH:25]=[CH:24]C(S(O)(=O)=O)=[CH:22][CH:21]=1>CN(C=O)C>[CH2:21]([C:22]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1)[CH2:20][CH2:25][CH3:24]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(C)c2c(=O)n1C1CCC(=O)NC1=O
Yield: 30.1 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (0.65 g, 2.5 mmol) and trimethyl orthopentionate (0.66 mL, 3.8 mmol) and p-toluenesulfonic acid (140 mg) in DMF (7 mL) was heated at 150° C. in a microwave oven for 20 minutes. The mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers was washed with water (50 mL), HCl (1N, 50 mL) and brine (50 mL). The solvent was removed in vacuo to give an oil, which was purified with column chromatography (Silica Gel, methanol/methylene chloride 0% gradient to 5% 15 min), and followed by reversed layer column chromatography (C-18, acetonitrile/water 0% gradient to 100% 15 min) to give 3-(2-butyl-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (80 mg, 10% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 grad 90/10 in 5 min CH3CN/0.1% H3PO4, 6.59 min (95.4%); mp: 190-192° C.; 1H NMR (DMSO-d6) δ 0.95 (t, J=8 Hz, 3H, CH3), 1.40-1.49 (m, 2H, CH2), 1.67-1.75 (m, 2H, CH2), 2.05-2.09 (m, 1H, CHH), 2.51-2.67 (m, 3H, CH2, CHH), 2.69 (s, 3H, CH3), 2.81-2.90 (m, 3H, CH2, CHH), 5.20 (dd, J=5, 11 Hz, 1H, NC H, 7.25 (d, J=7 Hz, 1H, Ar), 7.44 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.80, 21.11, 21.72, 22.48, 28.60, 30.50, 34.42, 55.41, 118.63, 124.98, 128.83, 133.70, 139.81, 148.25, 156.95, 161.17, 169.75, 172.65; LCMS: MH=328; Anal Calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.87; H, 6.61; N, 12.89.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[N:10][C:11]([Cl:24])=[CH:12][CH:13]=2)[CH:8]=1)C.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O.O>[Cl:24][C:11]1[N:10]=[C:9]2[CH:8]=[C:7]([CH2:6][C:5]([CH3:26])([CH3:25])[C:4]([OH:27])=[O:3])[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[C:14]2=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(C)(C)Cc1cc2nc(Cl)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(Cc1cc2nc(Cl)ccc2n1Cc1ccc(Cl)cc1)C(=O)O
Temperature: 60 °C

Procedure:
3-[5-Chloro-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionic acid ethyl ester (0.025 g, 0.062 mmol) was dissolved in THF (0.1 mL), MeOH (0.1 mL), and H2O (0.1 mL). LiOH (0.01 g, 0.238 mmol) was added and the reaction was heated to 60° C. for 2 hours. Once no starting material was seen by LCMS, the reaction was cooled to room temperature and diluted with EtOAc and water. The mixture was neutralized with solid citric acid to ˜pH 5, the aqueous layer was extracted three times with EtOAc, the combined organics were washed twice with water, once with brine, dried over MgSO4, filtered and concentrated to give the desired acid. LCMS (ESI) M+H 379.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([NH2:46])=[NH:45])[CH2:40][CH2:39]1.CS(C)=O>CN(C=O)C>[C:44]([N:41]1[CH2:42][CH2:43][CH:38]([CH2:37][NH:36][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH2:39][CH2:40]1)(=[NH:45])[NH2:46]
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: N=C(N)N1CCC(CN)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCC2CCN(C(=N)N)CC2)cc1OCCc1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 21.4 %

Procedure:
A solution of 100 mg 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid in 2 ml DMF was activated by the addition of 53 mg carbonyldiimidazole. After stirring for 2 h at RT 90 mg of 4-Aminomethyl-piperidine-1-carboxamidine hydrochloride and 2 ml DMSO were added and the mixture was stirred overnight. Subsequent dilution with 3 ml water and filtration through a chem elut® cartridge, eluting with ethyl acetate yielded after concentration under reduced pressure a white solid. Purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) and lyophilisation afforded 30 mg (20%) of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:33](=[O:42])[NH:34][C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:28][CH2:27]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[C:33](=[O:42])[NH:34][C:35]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:30][CH2:31]3)[CH2:15][C:4]=2[CH:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Yield: 32 %

Procedure:
((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-acetic acid (90 mg, 0.23 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (80 mg, 0.30 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 32% yield. High resolution MS m/e (M+H)+=602.1776.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH2:16].COCCOCCN(CCOCCOC)CCOCCOC.C(=O)([O-])[O-].[K+].[K+]>[Pd](Cl)Cl.O.CN1C(=O)CCC1>[F:12][C:11]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH:16]=[CH:15][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(C=Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)cc1
Yield: 51 %

Procedure:
In a 250 mL round bottom flask equipped with stirbar, reflux condenser and nitrogen inlet was placed 2-bromo-5-nitrobenzotrifluoride (5.40g, 20 mmol), 4-vinylanisole (2.95 g, 22 retool), NMP (20 mL), tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) (0.65 g, 2.0 mmol), potassium carbonate (4.2 g, 30 mmol) and palladium chloride (0.035 g, 0.20 retool). The resulting slurry was gradually warmed up to 140° and maintained at that temperature for 4 hr. The mixture was then cooled and water (200 mL) was added dropwise with stirring. The oily aqueous layer was decanted and replaced by more water (200 mL) and the resulting suspension was stirred and the black solid isolated by suction filtration, washed well with water and then air dried. The crude product was transferred to an Erlenmeyer flask containing Bentonite clay (5 g), silica gel (5 g) and methylcyclohexane (150 mL). The slurry was boiled with stirring, hot filtered and upon cooling the product was isolated from the filtrate as light yellow crystals, (3.30 g, 51%): mp 120.4-122.7°; 1H NMR (CDCl3)δ8.52 (s, 1H), 8.35 (d, J=9Hz, 1H), 7.94 (d, J=9 Hz), 7.51 (d, J=9 Hz, 2H), 7.28 (q, J=16 Hz, 2H), 6.95 (d, J=9 Hz), 3.86 (s, 3H); 13C NMR (CDCl3)ppm 160.669, 145.561,143.022, 136.361,128.812, 128.438, 128.005, 127.502, 127.251,126.439, 129.315, 121.961,121.864, 120.953. 119.581, 114.318, 55.278.