Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)CC)C>C(Cl)Cl>[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:4](=[O:6])[CH2:3][C:2]([CH3:1])([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:7])[CH2:50][CH2:49]1
Reactant: OCCN1CCNCC1
Reactant: CC(C)(CC(=O)O)SCc1ccccc1
Agent: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC(=O)N1CCN(CCO)CC1)SCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-methyl-3-(phenylmethylthio)butanoic acid (1 g, 4.6 mmol) and hexachloroacetone were dissolved in CH2Cl2 (20 mL) and cooled to −78° C. Triphenyl phosphine was added and the mixture was stirred for 30 minutes. Hydroxyethyl piperazine (550 μL, 4.5 mmol) was added in CH2Cl2 (10 mL) dropwise. Triethylamine (630 μL, 4.5 mmol) was added in CH2Cl2 (10 mL) dropwise. The cold bath was removed and the solution was stirred for 24 hours. The solvent was evaporated. The crude mixture was poured into 1N HCl (100 mL) and washed with Et2O (2×50 mL). The aqueous layer was made basic with 10% K2CO3 in a brine solution. The product was extracted with EtOAc (3×100 mL), dried over Na2SO4, and concentrated. This gave the title compound which was used immediately in the next reaction. 1H NMR (300 MHz, CDCl3) δ 7.18-7.37 (mult, 5H), 3.8 (s, 2H), 3.6 (t, J=5 Hz, 4H), 3.4 (t, J=5 Hz, 2H), 2.45-2.65 (mult, 8H), 1.5 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(benzyloxy)-1-methoxy-4-nitrobenzene (35.35 g, 136 mmol) in 1:1 ethyl acetate: ethanol (640 mL) at 80° C. is added tin(II) chloride hydrate in portions over 25 minutes. The mixture is heated at this temperature for 5 h. The mixture is allowed to cool to room temperature and stirred for 2 days. The mixture is poured into water (1 L) and neutralized with solid sodium bicarbonate. The mixture is extracted three times with ethyl acetate. The combined organic extracts are washed with water and brine, dried (sodium sulfate), filtered and evaporated to yield the title compound as a dark brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[N:12][OH:13])[NH2:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(Cc1ccc(Cl)cc1)=NO
Temperature: 80 °C
Yield: 83.3 %

Procedure:
To a stirred solution of 2-(4-chlorophenyl)acetonitrile (1 g, 6.5 mmol) in ethanol (20 mL) at room temperature, hydroxylamine hydrochloride (4.5 g, 65.6 mmol) and potassium carbonate (12.5 g, 91 mmol) were added and heated at 80° C. overnight. Solvent was removed under vacuum. The residue was dissolved in ethyl acetate (50 mL) and the solution was washed with water and brine, and dried over sodium sulfate. Solvent was removed under vacuum to afford 2-(4-chlorophenyl)-N′-hydroxyacetimidamide (1 g, 83%) as an off-white solid. 1H NMR: 400 MHZ, DMSO-d6: δ 3.26 (s, 2H), 5.43 (s, 2H), 7.29-7.30 (m, 2H), 7.34-7.34 (m, 2H), 8.91 (s, 1H). LCMS: RT 0.89 min. LCMS (ES-API), m/z 186.0 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.S([CH2:31][N+:32]#[C-:33])(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO>[CH3:14][N:10]([CH2:11][CH2:12][CH3:13])[C:8](=[O:9])[C:7]1[CH:6]=[C:5]([CH:17]=[C:16]([C:18]2[O:19][CH:33]=[N:32][CH:31]=2)[CH:15]=1)[C:4]([OH:3])=[O:20]
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2cnco2)c1
Yield: 65.2 %

Procedure:
Heat a solution of 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (300 mg, 1.08 mmol), tosylmethyl isocyanide (254 mg, 1.3 mmol), and sodium methoxide (193 mg, 3.57 mmol) in methanol (3.1 mL) at 40° C. for 1 h. Add water to the hot solution and extract with dichloromethane and ethyl acetate. Acidify the aqueous with 5 N HCl, extract with dichloromethane, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 4:96 methanol:dichloromethane) to give the title compound (203 mg, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:16])([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][N:54]2[C:50](=[O:60])[C:51]3[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:53]2=[O:55])([F:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
After dissolving 4-fluoro-4-(hydroxymethyl)piperidinecarboxylic acid tert-butyl ester (4.26 g, 18.3 mmol) in THF (183 mL), the solution was cooled to 0° C. Triphenylphosphine (7.19 g, 27.4 mmol) and DIAD (diisopropyl azodicarboxylate) (5.39 mL, 27.4 mmol) were then added to the solution. After stirring for 20 minutes, phthalimide (4.03 g, 27.4 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated, and the crude product was crudely purified by silica gel column chromatography (20% AcOEt/hexane) to obtain 4-[(1,3-dioxoisoindolin-2-yl)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[NH2:10].[CH:12]1([S:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:21](Cl)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1>[CH:12]1([S:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:21]([NH:10][C:9]2[C:8]([Cl:11])=[CH:7][N:6]=[CH:5][C:4]=2[Cl:3])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1SC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1SC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil; 3.2 g; 80 mmol) in dry tetrahydrofuran (70 mL) under nitrogen at 4° C. is treated with 3,5-dichloro-4-aminopyridine (6.5 g) in dry tetrahydrofuran (80 mL) during 15 minutes and the solution is stirred at room temperature for 1 hour. After cooling to 5° C., it is treated with 3-cyclopentylthio-4-methoxybenzoyl chloride (that is prepared from 9.0 g of 3-cyclopentylthio-4-methoxybenzoic acid as described in Reference Example 47) in dry tetrahydrofuran (80 mL) during 45 minutes, and the temperature is allowed to rise to room temperature. The mixture is treated with a further quantity of tetrahydrofuran (200 mL) and then it is stirred for a further 6 hours. It is then treated with a saturated aqueous solution of ammonium chloride (300 mL), and concentrated in vacuo to low volume. The aqueous residue is extracted with ethyl acetate (2×200 mL). The combined extracts are washed with brine (2×200 mL), dried over magnesium sulfate, and concentrated. The resulting residue is subjected to flash chromatography on silica gel, using a mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) (1:1 v/v), to give 3-cyclopentylthio-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide (2.5 g), in the form of a colorless solid, m.p. 198° C. [Elemental analysis: C,54.5, H,4.6; N,6.95; S,8.2%; calculated: C,54.4; H,4.6; N,7.05; S,8.1%].
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([CH3:23])[C:21]4[CH:24]=[CH:25][C:26]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[CH:27][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([CH3:23])[C:21]4[CH:24]=[CH:25][C:26]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[CH:27][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C3(NC(=O)OC(C)(C)C)CC3)cc1)n2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C3(N)CC3)cc1)n2C

Procedure:
Prepared from 2-[4-(1-tert.butyloxycarbonylamino-cyclopropyl)-phenyl]-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole by treating with trifluoroacetic acid in methylene chloride at ambient temperature.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[F:47][CH2:48][C@@H:49]([NH2:51])[CH3:50]>ClCCl.O.C(N(CC)CC)C>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:51][C@@H:49]([CH3:50])[CH2:48][F:47])=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: C[C@H](N)CF
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CF)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (100 mg) and 1-hydroxybenzotriazole (61.5 mg) were dissolved in dichloromethane (4 mL). While this solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (119 mg) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, a mixture of (2S)-1-fluoro-2-propylamine hydrochloride (32.0 mg), triethylamine (56.0 μL) and dichloromethane (2 mL) was added and the resulting mixture was stirred at room temperature for further 8 hours. Following addition of water, the dichloromethane layer was collected. The dichloromethane layer washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-4-fluoro-1-[[N-(4-[N-[(2S)-1-fluoro-2-propyl]amino]carbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (34.0 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:25]=[CH:24][C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1>>[F:28][C:4]1[CH:3]=[C:2]([NH:1][C:43]([C:40]2[C:41](=[O:42])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=[CH:38][CH:39]=2)=[O:44])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20](=[O:21])[NH:22][CH3:23])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)cc1
Yield: 40 %

Procedure:
Prepared from 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide (Example 95, Step A) and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C) according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (3% MeOH in CH2Cl2) to afford 12.5 mg (40%) of the desired product. LRMS (APCI pos) m/e 610.2 (M+1). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.46 (d, 1H), 8.41 (d, 1H), 8.33 (d, 1H), 8.01 (dd, 1H), 7.94 (m, 2H), 7.87 (m, 3H), 7.65 (m, 2H), 7.47 (m, 1H), 7.37 (t, 1H), 7.28 (t, 2H), 6.63 (d, 1H), 2.98 (s, 3H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −112.8, −127.6.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].CI.[C:13](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:13])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1ccccc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.2 %

Procedure:
A mixture of 2-isopropylphenol (1) (12.0 g, 88.1 mmol), methyl iodide (25.0 g, 176.2 mmol), and potassium carbonate (24.3 g, 176.2 mmol) in 44 mL of DMF was stirred for 20 hours at room temperature. The reaction mixture was diluted with 300 mL of ether and washed with 250 mL of water and 5×100 mL of brine. The organic portion was dried (MgSO4), filtered, and evaporated to give an oil, which was purified by flash column chromatography (silica gel, 90:10 hexane/ethylacetate) to give 2-isopropylanisole (2) (12.5 g, 82.1 mmol, 93%); 1HNMR (CDCl3) δ 1.2 (d, 6H), 3.3 (heptet, 1H), 3.8 (s, 3H), 6.8 (d, 1H), 6.88 (t, 1H), 7.13 (d, 1H), 7.2 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:32]2[CH:31]=[C:30]([F:29])[CH:37]=[C:36]([F:38])[CH:35]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(F)cc(CCl)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3,5-difluorobenzyl chloride gave the title compound. ES-MS m/e (%): 525.4 (M+H+).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:39]I>ClCCl>[I:39][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: II
Reactant: CCCCCCCCCCCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCI
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of tridecanol (1.08 g, 5.31 mmol) in dichloromethane (20 mL), triphenyl phosphine (1.53 g, 5.84 mmol) and imidazole (0.39 g, 5.84 mmol) were added and cooled to 0° C. I2 (1.48 g, 5.84 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. After completion of starting materials, the reaction mixture was evaporated and diluted with hexane and passed through a Celite™ pad. The combined organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, eluent hexane) to furnish iodotridecane (1.43 g, 84%) as a low melting solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Product: O=C(Cc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2NC1=O

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3(R,S)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylacetyl chloride. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C: m.p. 238°-240° C.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][C@H:18]([CH2:23][O:24][CH3:25])[C:19]([F:22])([F:21])[F:20])[C:14]([N+:26]([O-])=O)=[C:13]([F:29])[CH:12]=2)[CH2:6][S@@:5](=[O:30])[CH2:4]1.[CH3:31][C:32]([CH3:42])([CH3:41])[CH2:33][N:34]1[CH:38]=[C:37]([CH:39]=O)[CH:36]=[N:35]1.Cl>CCOCC>[ClH:1].[ClH:1].[NH2:26][C:14]1[C:15]([O:17][C@H:18]([CH2:23][O:24][CH3:25])[C:19]([F:22])([F:21])[F:20])=[CH:16][C:11]([CH2:10][C@H:7]2[C@H:8]([OH:9])[C@@H:3]([NH:2][CH2:39][C:37]3[CH:36]=[N:35][N:34]([CH2:33][C:32]([CH3:42])([CH3:41])[CH3:31])[CH:38]=3)[CH2:4][S@:5](=[O:30])[CH2:6]2)=[CH:12][C:13]=1[F:29]
Reactant: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](N)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Reactant: CC(C)(C)Cn1cc(C=O)cn1
Agent: Cl
Solvent: CCOCC
Product: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NCc3cnn(CC(C)(C)C)c3)[C@H]2O)cc(F)c1N)C(F)(F)F

Procedure:
The title compound can be prepared in an analogous manner as described for example 41 steps c) and d) from (1R,3R,4S,5S)-3-amino-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol hydrochloride and 1-(2,2-dimethyl-propyl)-1H-pyrazole-4-carbaldehyde and subsequent transformation into the hydrochloride salt with 5N HCl in Et2O to afford the title compound as a beige foam: TLC (CH2Cl2-MeOH 9:1) Rf=0.35; HPLC RtG3=1.51 min; ESIMS [M+H]+=565; 1H NMR (400 MHz, DMSO-d6): δ 7.53 (s, 1H), 7.34 (s, 1H), 6.72 (s, 1H), 6.64 (d, 1H), 5.12-5.06 (m, 1H), 4.96 (d, 1H), 4.59 (s, 2H), 3.84 (s, 2H), 3.77-3.64 (m, 3H), 3.48 (d, 1H), 3.33 (s, 3H), 3.18-3.05 (m, 3H), 2.98 (dd, 1H), 2.71 (d, 1H), 2.46-2.26 (m, 5H), 0.88 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:11].O>C1COCC1>[CH2:1]([NH:8][C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)NCc1ccccc1
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
96.3 g (366 mmoles) of benzylisothiocyanate were dissolved in 100 ml of THF and treated with 44.2 ml (732 mmoles) of 32% ammonia solution. After 0.5 hour at 40-45° C., 300 ml of water were added and the THF removed in vacuo. The gummy suspension is treated with 200 ml of ether, the crystals collected and washed with water and ether. Suspension in 30 ml of methylenechloride and collection gave 65.77 g (64.2%) of benzyl-2-thiourea with mp 144-5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a suspension of 4-ethyl benzoic acid (4.53 g, 30.16 mmol) in concentrated sulfuric acid (24 mL) at 0° C. was added nitric acid (12 mL). The mixture was stirred for 1.5 h at 0° C. Poured into ice water, filtered and dried the solid to give 5.79 g of the title compound (98%). 1H NMR (400 MHz, DMSO-d6): δ 1.23 (3H, t, J=7.2 Hz), 2.88 (2H, q, J=7.2 Hz), 7.67 (1H, d, J=8.0 Hz), 8.15 (1H, dd, J=1.6, 8.0 Hz), 8.36 (1H, d, J=1.6 Hz).
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23]N)=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N(OCCC(C)C)=O.N[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].Cl>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NN
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a solution of Boc-Leu-DTrp-NHNH2 (39 mg) obtained in Example 1-(2) in DMF (0.5 ml ) was added 3.1 M HCl/14,-dioxane (81 μl) at -60° C. The temperature of the solution was raised to -20° C. and isoamyl nitrite (15 μl) was added. The reaction mixture was stirred at -20° C. to -15° C. for 1.5 h and cooled at -60° C. A solution of βAla-OEt.HCl (17 mg) in DMF (0.5 ml) and TEA (50 μl) were added. The reaction mixture was stirred at 5° C. overnight and concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol=30/1 for development to give the product (41 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][NH:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:3].[O:31]([C:38](Cl)=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COC1C=CC=CC=1C(Cl)=O>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][N:16]([CH:17]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:19]2[C:18]1=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:38](=[O:39])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: COc1ccccc1C(=O)Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=O)Oc1ccccc1)C1c2ccccc2-c2ccccc21

Procedure:
When in the procedure of Example 94 an appropriate amount of the product of Example 77 was substituted for the product of Example 4 and an appropriate amount of phenoxycarbonyl chloride was substituted for 2-methoxybenzoyl chloride and the general procedure of Example 94 was followed the title compound was obtained. Total yield, 0.94 g (82%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH3:2].[CH2:16]([O:18]CC)C.C([Li])CCC.CN(C=O)C>O>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:10][C:11]=1[CH:16]=[O:18])[CH3:2]
Reactant: CCOCC
Reactant: CCOCOc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOCOc1cc(C(F)(F)F)ccc1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4.0 g of 1-ethoxymethoxy-3-trifluoromethylbenzene and 160 ml of diethyl ether was added dropwise 16 ml of n-butyllithium (1.6 N, n-hexane solution) under a nitrogen atmosphere at −70° C. This mixture was stirred at room temperature for 3 hours. Subsequently, 5.5 ml of DMF was added to this mixture at −70° C., and the temperature was returned to room temperature. The reaction mixture was added to water. This mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.90 g of 2-ethoxymethoxy-4-(trifluoromethyl)benzaldehyde.