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][C:7]([CH3:12])=[C:6]2[CH2:13][CH2:14][C:15]([OH:17])=[O:16].[Li]CCCC.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.Cl>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:7]2[CH3:12])=[CH:26][CH:25]=1
Reactant: COc1ccc2[nH]c(C)c(CCC(=O)O)c2c1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc2c(c1)c(CCC(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
To a cold (-78° C.) solution of the indole from Step 1 (877 mg, 4.04 mmol) in 40 mL of THF and 2.5 mL of HMPA was added n-BuLi (1.45M solution in hexanes, 5.6 mL, 8.12 mmol), giving a thick slurry. The mixture was warmed to 0° C., then cooled to -78° C. A solution of p-bromobenzyl bromide (1.18 g, 4.72 mmol) in 8 mL of THF was then added, and the mixture was warmed to room temperature. After 30 min, the reaction was poured into 1M HCl and extracted with ether. The organic layer was washed thrice with water, then with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to give 529 mg of the title compound as a crystaline solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[S:13][C:6]=12.[BH4-].[Na+]>C1COCC1.CO.Cl[Ni]Cl>[F:1][C:2]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=3)[S:13][C:6]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 5.6 %

Procedure:
Nitro compound 48 (97 mg, 2 mmol) was dissolved in a mixture of THF (7 mL) and MeOH (15 mL); NiCl2×6H2O (130 mg, 0.5 mmol) was added and the solution was cooled to 0° C. To the cooled mixture NaBH4 (42 mg, 1.1 mmol) was added portion wise. The reaction was stirred for 20 min and quenched with 2 M HCl. The solvents were removed under reduced pressure and the residue was treated with concentrated ammonium hydroxide solution (pH 10) and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (eluent EtOAc) to afford the title compound 49 (46.7 mg, 51% yield) as a white solid 1H NMR (DMSO) δ (ppm): 8.52 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.63-7.58 (m, 2H), 7.56-7.52 (m, 2H), 7.13 (t, J=8.6 Hz, 1H), 6.61 (d, J=2.2 Hz, 1H), 6.56 (dd, J=10 Hz, 1H), 6.46 (dd, J=5.7 Hz, 1H), 5.57 (s, 2H), 3.29 (s, 3H), MS (m/z): 414.8 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([O:25][CH3:26])[CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([CH3:24])[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCOC(C)=O.CCCCCC>CO.[Pd]>[CH3:26][O:25][C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=1)[N:22]=[C:21]([CH3:24])[CH:20]=[CH:19]2
Reactant: COc1cc(N2CCN(Cc3ccccc3)CC2)c2nc(C)ccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(N2CCNCC2)c2nc(C)ccc2c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A mixture of 1-benzyl-4-(6-methoxy-2-methylquinolin-8-yl)piperazine (0.527 g, 1.52 mmol), 10% Pd/C (0.20 g), and ammonium formate (0.96 g, 15.2 mmol) in methanol (10 mL) were heated at reflux under N2 for 3 hours. TLC analysis (35% EtOAc/hexane) indicated only a trace of starting material remained. After cooling to room temperature, the reaction was filtered through celite, washing with excess methanol. The filtrate was concentrated, diluted with CH2Cl2 (50 mL), and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 0.37 g (95%) of the title compound as a yellow oil, which was used in the subsequent reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C@H:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13].[BH4-].[Na+]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:10][C@@H:11]([CH:12]([CH3:14])[CH3:13])[C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)[C@H](NCc1ccc(Br)cc1)C(=O)O

Procedure:
EP 1777224 describes the condensation of p-Bromobenzaldehyde with L-valine followed by reduction with sodium borohydride to give (S)-2-(4-bromobenzyl)amino-3-methylbutyric acid. (S)-2-(4-bromobenzyl)amino-3-methyl butyric acid is treated with valerylchloride to give (S)-2-(4-bromobenzyl)-pentanoyl-amino-3-methyl butyric acid. (S)-2-(4-bromobenzyl)-pentanoyl-amino-3-methyl butyric acid is treated with 2-(2H-tetrazol-5-yl)benzene-boronic acid in tetrahydrofuran, triphenylphosphine and palladiumacetate yield valsartan.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.BrC1C=CC(OC2C=CC=CC=2)=C(Cl)C=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Clc1cc(Br)ccc1Oc1ccccc1
Solvent: CC#N
Product: Fc1cc(Br)ccc1Oc1ccccc1
Yield: 33 %

Procedure:
The title compound was prepared in a 33% yield from 4-bromo-2-fluorophenol and phenyl boronic acid in a manner similar to that described for the preparation of 4-bromo-2-chloro-1-phenoxybenzene: 1H NMR (DMSO-d6, 400 MHz) δ 7.75(dd, 1H), 7.40(m, 3H), 7.15(m, 2H), 7.01(dd, 2H); MS MH+267.2; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 13.57 min.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.C(N(C(C)C)C(C)C)C.Cl.Cl[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>CC(O)C.C(OCC)(=O)C>[N:32]1[CH:33]=[CH:34][C:29]([N:2]2[CH2:3][CH2:4][C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:1]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccncc1)C2
Temperature: 90 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (10.402 mmol, 1.0 eq.), N-ethyl-diisopropylamine (4.0 eq.) and 4-chloropyridine hydrochloride (3.0 eq.) in 2-propanol (20 ml) was stirred at 90° C. overnight. Ethyl acetate and sat. NaHCO3 solution were added and the aqueous phase was extracted with ethyl acetate a further 4×. The combined organic phases were washed 1× with sat. NaCl solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, ethyl acetate/ethanol/ammonia (25% aq) 500:100:2). Yield: 45%
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([OH:17])=O)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:6]=[CH:5][C:4]=1[C:15]([NH:33][CH:30]1[CH2:32][CH2:31]1)=[O:17])#[N:2]
Reactant: NC1CC1
Reactant: N#Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: N#Cc1c(C(=O)NC2CC2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.47 g of 5-cyano-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid and 2.03 g of carbonyldiimidazole dissolved in 25 ml of DMF was stirred at room temperature for approximately 15 minutes. Seven milliliters of cyclopropylamine was next added to the reaction mixture which was allowed to stir for approximately 16 hours. The mixture was poured into 150 ml of ice water and the precipitated solid was collected by filtration. This solid was recrystallized from ethanol and dried to afford 1.86 g of 5-cyano-1-(4-chlorophenyl)-N-cyclopropyl-1H-pyrazole-4-carboxamide. MP=204°-206° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]([O:13][CH3:14])=[O:12].Br[CH2:25][CH2:26][CH2:27][CH2:28]Br>C(O)(C)(C)C>[C:20]([O:19][C:17]([NH:16][CH2:15][C@H:10]([N:9]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:11]([O:13][CH3:14])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: BrCCCCBr
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCCC1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
10 ml (65 mmol) of triethylamine are added to a solution of 5 g (20 mmol) of commercial methyl(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride in 150 ml of tert-butanol. The reaction medium is stirred for 20 min at 40° C. and then filtered in order to remove the triethylammonium salts. 3.8 ml (32 mmol) of 1,4-dibromobutane are added to the filtrate thus obtained, and the reaction medium is heated at 80° C. for 3 days. After the insoluble material has been filtered off, the filtrate is concentrated under vacuum. The residue obtained is purified by chromatography on a silica column, elution being carried out with a 98/2 dichloromethane/methanol mixture. 2.9 g (55%) of methyl(S)-3-tert-butoxycarbonylamino-2-pyrrolidin-1-ylpropanoate are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:17]([O:18][CH3:19])[CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[CH3:13])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccccc1C
Product: CON(Cc1ccccc1C)C(=O)C=C1OC(C)(C)OC1=O
Yield: 100 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-methylbenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (100% yield): mp 96-97° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.78 (6H, s, CH3), 2.4 (3H, s, CH3), 3.59 (3H, s, OCH3), 4.89 (2H, s, NCH2), 6.44 (1H, s, CH), 7.2-7.28 (4H, m, aromatics). Anal. calcd. for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C, 62.90; H, 6.21; N, 4.52.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10])#[N:2].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:11])=[O:10])#[N:2]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of 3-(2-cyanophenylsulfonyloxy)-5-methylphenol (580 mg, 2.0 mmol), as prepared in preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in tetrahydrofuran (20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (10% ethyl acetate in dichloromethane) to give the title compound as a colorless oil (560 mg, 80%). 1H-NMR (300 MHz, CDCl3) δ8.11 (m, 1H), 7.94 (m, 1H), 7.77-7.82 (m, 2H), 6.65 (s, 1H, 6.59 (s, 1H), 6.57 (s, 1H), 4.05 (t, J=6.0 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 2.26 (s, 3H), 2.00 (m, 2H), 1.76 (br s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][O:20][CH3:21])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:22]([OH:29])[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][O:20][CH3:21])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:22](=[O:29])[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCc1cnc2c(c1)cc(C(O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCc1cnc2c(c1)cc(C(=O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanol (710 mg, 1.71 mmol) in dichloromethane (50 mL) was added Dess-Martin periodinane (1.8 g, 4.2 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 1-(1-benzenesulfonyl-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanone (704 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C22H24N2O4S [M+H]+ 413.51, observed 413.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)=[CH:4][C:5]([NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CN(C)Cc1ccc(C(=O)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cc2[N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1ccc(C(=O)Nc2cc(N3CCNCC3)c(Cl)cc2[N+](=O)[O-])cc1

Procedure:
tert-butyl 4-(2-chloro-5-(4-((dimethylamino)methyl)benzamido)-4-nitrophenyl)piperazine-1-carboxylate was stirred in TFA/DCM (50%) for 1 h. After solvent was removed, the residue was dried in vacuo overnight.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:31])[C:10]2[O:16][C:15]3[C:17]([Cl:27])=[CH:18][C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:20][C:14]=3[CH2:13][S:12](=[O:29])(=[O:28])[C:11]=2[CH:30]=1)=[O:6]>O.O1CCCC1>[Cl:27][C:17]1[C:15]2[O:16][C:10]3[C:9]([CH3:31])=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:30][C:11]=3[S:12](=[O:28])(=[O:29])[CH2:13][C:14]=2[CH:20]=[C:19]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH:18]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of sodium hydroxide (0.22 g, 5.49 mmol) in water (15 mL) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.88 g, 1.83 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at 40° C. for 4 h, the solvent was removed under vacuum. The reaction mixture was acidified to pH 4-5 using 10% aqueous hydrochloric acid. The precipitate was filtered, washed with water and dried to obtain the title compound. Yield: 0.84 g, (98%); 1H NMR (DMSO-d6, 300 MHz): δ 2.65 (s, 3H, CH3), 3.26 (s, 4H, 2CH2), 3.43 (s, 4H, 2CH2), 5.16 (s, 2H, CH2), 7.20 (s, 2H, Ar), 8.08 (s, 1H, Ar), 8.18 (s, 1H, Ar); MS: m/e (ES−) 421 (M−1); analysis: C19H19ClN2O5S.2H2O requires C, 49.73, H, 5.05, N, 6.10; Cl, 7.73; S, 6.99; found: C, 50.27, H, 5.12, N, 6.12, Cl, 7.47, S, 6.92%.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:11][C:12]1[C:19]([F:20])=[C:18]([CH3:21])[C:17]([F:22])=[C:16]([F:23])[C:13]=1[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>>[F:11][C:12]1[C:19]([F:20])=[C:18]([CH3:21])[C:17]([F:22])=[C:16]([F:23])[C:13]=1[CH2:14][NH:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: Cc1c(F)c(F)c(CBr)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(F)c(F)c(CNc2ccc3[nH]cnc3c2)c(F)c1F

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 2,3,5,6-tetrafluoro-4-methylbenzylbromide (566 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5. Yield: 0.034 g (11.0%); MS m/z: 310.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 2.20 (t, 3H, 3J(H,F)=1.9 Hz); 4.35 (d, 2H); 5.85 (br s, 1H); 6.60 (dd, 1H, 4J=1.8 Hz, 3J=8.5 Hz); 6.69 (br s, 1H); 7.28 (d, 1H, 3J=8.5 Hz); 7.87 (s, 1H); 11.95 (br s, 1H); HPLC (METHOD [A]): rt 13.04 min (100%)
Reaction SMILES: [N+](C1C=C[C:7]([C:8](Cl)=[O:9])=CC=1)([O-])=O.CC(CC)CN.[CH3:19][CH:20]([CH2:34][CH3:35])[CH2:21][NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1>>[CH3:19][CH:20]([CH2:34][CH3:35])[CH2:21][NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:8](=[O:9])[CH3:7])=[CH:26][CH:25]=1
Reactant: CCC(C)CNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CCC(C)CN
Product: CCC(C)CNC(=O)c1ccc(NC(C)=O)cc1

Procedure:
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and 2-methylbutyl amine in the amidation step. This yields N-2-methylbutyl-4-nitrobenzamide (CPI1146).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:18])=[C:6]([Cl:17])[C:7]2[O:11][CH:10](/[C:12](=[N:14]\[OH:15])/[OH:13])[CH2:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2].O1CC[CH2:21][CH2:20]1.S(=O)(=O)(O)O>C(O)C>[C:1]([C:4]1[C:5]([OH:18])=[C:6]([Cl:17])[C:7]2[O:11][CH:10](/[C:12](=[N:14]\[OH:15])/[O:13][CH2:20][CH3:21])[CH2:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(c(Cl)c1O)OC(/C(O)=N\O)C2
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCO/C(=N/O)C1Cc2cc(C(C)=O)c(O)c(Cl)c2O1
Yield: 76.1 %

Procedure:
The acid 4a was esterified by stirring in a solution of tetrahydrofuran, ethanol, and concentrated sulfuric acid (39:60:1) for 16 hours at room temperature. The resulting solution was evaporated and the residue dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. Recrystallization from ethyl acetate/hexane furnished 76.1% of white crystals, m.p. 154°-155° C. Anal. (C13H14ClNO5) C,H,N.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][NH:24][C@H:25]([C:30]([NH:32][CH:33]([C:39]([O-:41])=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)CCC1=O.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[CH2:55][NH2:56]>O1CCOCC1>[CH2:16]([O:23][NH:24][C@H:25]([C:30]([NH:32][CH:33]([C:39](=[O:41])[NH:56][CH2:55][C:54]1[CH:57]=[CH:58][CH:59]=[C:52]([O:51][CH3:50])[CH:53]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:31])[CH2:26][CH:27]([CH3:28])[CH3:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(NC(=O)[C@H](CC(C)C)NOCc1ccccc1)C(=O)[O-]
Reactant: COc1cccc(CN)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)[C@H](CC(C)C)NOCc1ccccc1)C(=O)NCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.03 g of dicyclohexylcarbodiimide was added to 30 ml of a solution of 1.83 g of ethyl N-(N-benzyloxyleucyl)aminomalonate, 0.58 g of N-hydroxysuccinimide and 1.3 ml of (3-methoxybenzyl)amine in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove-the insoluble materials. The filtrate was diluted with 100 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride in this order, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. 1.49 g of the resulting yellow oily substance was purified by silica gel column chromatography (eluant: ethyl acetate/n-hexane=1/2)to obtain 0.96 g of ethyl N-(N-benzyloxyleucyl)-α-[N-(3-methoxybenzyl)carbamoyl]glycinate as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[Cl:7][C:8]1[C:9](S(C)(=O)=O)=[N:10][CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:9]2[C:8]([Cl:7])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=1
Reactant: CS(=O)(=O)c1ncccc1Cl
Reactant: Brc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccnc1-n1cnc(Br)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 96.9 %

Procedure:
A mixture of 1.0 g of 4-bromoimidazole, 1.3 g of 3-chloro-2-(methanesulfonyl)pyridine, 2.7 g of cesium carbonate and 10 ml of N,N-dimethylformamide was stirred at 100° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and water was poured into the mixture. A deposited precipitate was collected by filtration to obtain 1.7 g of 2-(4-bromo-1H-imidazol-1-yl)-3-chloropyridine of the formula:
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:12][C:13](=[O:29])[C@@H:14]([CH2:19][NH:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)=[O:5].[CH:32](CC(OC(=O)CC=O)=O)=[O:33]>ClCCl>[CH3:31][C:2]([CH3:30])([CH3:1])[C@H:3]([NH:12][C:13](=[O:29])[C@@H:14]([CH2:19][N:20]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:32]=[O:33])[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)=[O:5]
Reactant: O=CCC(=O)OC(=O)CC=O
Reactant: CCCC[C@H](CNOCc1ccccc1)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Solvent: ClCCl
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 2(R)-[(N-benzyloxyamino)-methyl]-hexanoic acid-[2,2-dimethyl-1(S)-(1-methyl-1H-imidazole-2-carbonyl)-propyl]-amide (77 mg, 0.18 mmol) in dichloromethane (2 mL) at 0° C. was added formylacetic anhydride (50 μL, 0.54 mmol, 3 eqv) and the reaction allowed to stir at room temperature. After 2 hours the solvents were removed in vacuo and the residue azeotroped with toluene (2×30 mL). The product was placed under high vacuum for several hours to give the title compound as an off white waxy solid (76 mg, 93%).