Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH:22]=[C:23]([OH:25])[CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([F:26])=[C:9]([CH3:27])[C:8]=1[F:28])#[N:2].[C:32](=O)([O-])[O-].[Cs+].[Cs+].IC>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH:22]=[C:23]([O:25][CH3:32])[CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([F:26])=[C:9]([CH3:27])[C:8]=1[F:28])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(O)cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1cc(OC)cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reaction time: 15 h

Procedure:
To acetonitrile (5 mL) was added 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoic acid, ethyl ester (0.20 g, 0.47 mmol), cesium carbonate (0.31 g, 0.94 mmol), and iodomethane (0.13 g, 0.94 mmol). After stirring for 15 hours the mixture was partitioned with ethyl acetate and water. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methyl-pyridin-2-yl)oxy]-5-methoxybenzoic acid, ethyl ester; NMR (CDCl3) 7.3 (m, 6), 6.8 (s, 1), 4.4 (q, 2), 3.8 (s, 3), 2.4 (s, 3), 1.4 (t, 3) ppm.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[NH:15]1[C:12]2[CH:13]=[CH:14][C:9]([C:1]3[CH:6]=[CH:5][C:4]4[NH:7][C:22]([C:21]5[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=5)=[N:8][C:3]=4[CH:2]=3)=[CH:10][C:11]=2[N:16]=[C:22]1[C:21]1[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Reactant: O=Cc1ccc(O)cc1
Product: Oc1ccc(-c2nc3cc(-c4ccc5[nH]c(-c6ccc(O)cc6)nc5c4)ccc3[nH]2)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 6 %

Procedure:
A mixture of biphenyl-3,3′,4,4′-tetraamine (214 mg, 2.00 mmol), 4-hydroxybenzaldehyde (489 mg, 4.00 mmol) and Na2S2O5 (380 mg, 2.00 mmol) in IMS-H2O (3:1, 20 mL) was heated under microwave irradiation for 160° C. for 10 min, then 180° C. for 10 min. The mixture was filtered and washed with IMS. H2O was added to the filtrate, and the resulting white precipitate was filtered, and washed with water and Et2O. Column chromatography of the crude solid (EtOAc to 95:5 EtOAc-MeOH) afforded the product as a yellow solid (50 mg, 6%).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15](=[O:31])[NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:46][C@H:47]1[CH2:53][CH2:52][S:51][C@H:50]2[CH2:54][CH2:55][CH2:56][C@@H:57]([C:58]3[O:59][CH:60]=[N:61][N:62]=3)[N:49]2[C:48]1=[O:63]>>[O:59]1[CH:60]=[N:61][N:62]=[C:58]1[C@H:57]1[N:49]2[C@@H:50]([S:51][CH2:52][CH2:53][C@H:47]([NH:46][C:9](=[O:10])[C@@H:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][CH2:13][C@H:14]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:15]([NH:16][C@H:17]3[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]3=[O:30])=[O:31])[C:48]2=[O:63])[CH2:54][CH2:55][CH2:56]1
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Reactant: N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCCCN(c2ccccc2)C1=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O)Cc1ccccc1

Procedure:
(2R,5R)—N1-((4S,7S,10aS)-7-(1,3,4-Oxadiazol-2-yl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-2,5-dibenzyl-N6-((S)-2-oxo-1-phenylazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 24 (10 mg, 0.020 mmol) and Intermediate 35 (7.1 mg, 0.023 mmol) to give a white solid (3.5 mg, 24% yield). Anal. Calcd. for C43H50N6O5S m/z 762.7. found: 763.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (1H, s), 7.40-7.32 (2H, m), 7.31-7.07 (13H, m), 7.02-6.90 (2H, m), 5.91 (1H, d, J=4.9 Hz), 5.27 (1H, t, J=4.4 Hz), 5.05-4.97 (1H, m), 4.78 (1H, dd, J=9.3, 6.6 Hz), 3.93 (1H, dd, J=15.1, 11.3 Hz), 3.59 (1H, dd, J=14.8, 4.9 Hz), 3.18-3.07 (1H, m), 2.90-2.68 (6H, m), 2.55 (1H, ddd, J=14.3, 5.5, 2.7 Hz), 2.46-2.33 (2H, m), 2.14-1.80 (8H, m), 1.77-1.65 (4H, m), 1.64-1.25 (4H, m).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.ClC1C=CC(C(N2C3C(=CC(OC)=CC=3)C(CC(O)=O)=C2C)=[O:24])=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:10]1([NH:9][C:8](=[O:24])[NH:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DCC (1.0 g, 4.84 mmol) was added to a stirred solution of the product of Example 13d (0.9 g, 4.40 mmol), 2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}acetic acid (1.57 g, 4.40 mmol), and DMAP (0.05 g) in CH2Cl2 (30 mL) at room temperature. The resulting suspension was stirred for 1 hour at room temperature. The precipitate was removed by filtration and washed with CH2Cl2 (25 mL). The filtrate was concentrated to give a green oil which was chromatographed on silica gel eluting with 5:95 MeOH:CH2Cl2 to afford a green solid (contaminated with dicyclohexyl urea). The solid was triturated with hexane (50 mL) and filtered. The filtrate was concentrated to give the title compound (1.85 g, 77%) as a viscous green oil. 1H NMR (300 MHz, CDCl3) δ 7.47-7.65 (mult, 4H), 6.84-6.91 (mult, 2H), 6.65 (dd, J=2.5 and 9.0 Hz, 1H), 4.29 (t, J=6.7 Hz, 2H), 3.81 (s, 3H), 3.61 (s, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 2.10-2.70 (mult, 10H); 13C NMR (75 MHz, CDCl3) δ 170.5, 168.2, 156.1, 139.2, 135.9, 133.9, 131.1, 130.7, 130.6, 129.1, 114.9, 112.2, 111.6, 101.3, 61.3, 57.5, 55.7, 51.4 (2C), 46.1, 36.6, 30.3, 13.3; mass spectrum (API-TIS) m/z 544 (M+H).
Reaction SMILES: C(OC(=O)C)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:19]1[CH2:23][CH2:22][O:21][CH2:20]1.C([N:27](C(=O)C)[C:28]1[NH:29][C:30](=[O:37])[C:31]2[NH:32][CH:33]=[N:34][C:35]=2[N:36]=1)(=O)C>C1(C)C=CC=CC=1>[OH:19][CH2:23][CH2:22][O:21][CH2:20][N:34]1[CH:33]=[N:32][C:31]2[C:30](=[O:37])[NH:29][C:28]([NH2:27])=[N:36][C:35]1=2
Reactant: C1COCO1
Reactant: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To a mixture of acetic anhydride (1.2 ml) and p-toluenesulfonic acid (0.09 g) was added with stirring dioxolane (1.02 g) --caution, exothermic. The solution was allowed to cool for several minutes. Diacetylguanine (1.45 g) and dry toluene (9 ml) were added and the reaction mixture was stirred at reflux for 18 hr. and then allowed to cool to room temperature. The toluene was decanted off and the residue triturated several times with benzene. Methanol (10 ml) was added to the residue and evaporated under reduced pressure. To the residue was added 40% aqueous methylamine (10 ml) and the mixture heated on a steam bath for 20 min. The water and methylamine were removed under reduced pressure, ethanol (10 ml) was added and evaporated. The residue was thoroughly extracted with boiling methanol (700 ml total) and the combined extracts evaporated. The resulting solid was triturated with cold ethanol and then recrystallized from methanol to give 9-(2-hydroxyethoxymethyl)guanine (0.3 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([Br:12])=[CH:8][C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1sccc1C#N
Solvent: CN(C)C=O
Product: CC(=O)Nc1sc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Acetylamino-3-cyanothiophene (13.5 g) was dissolved in dimethylformamide (110 ml) and cooled in an ice/water bath. N-Bromosuccinimide (15.9 g) was added portion wise over 20 minutes and then the mixture warmed to room temperature and stirred for 3 h. The mixture was concentrated to approximately half the volume and water added to precipitate the product. This was filtered off and dried at 60° C. under vacuum (18.8 g).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][CH:7]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:9]=2[O:8]1>>[Cl:1][S:2]([C:13]1[CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:9]2[O:8][CH:7]([CH3:6])[CH2:11][C:10]=2[CH:12]=1)(=[O:5])=[O:3]
Reactant: CC1Cc2cccc(C(=O)O)c2O1
Reactant: O=S(=O)(O)Cl
Product: CC1Cc2cc(S(=O)(=O)Cl)cc(C(=O)O)c2O1
Temperature: 0 °C

Procedure:
630 g of chlorosulphonic acid were introduced into a 1-liter round-bottomed flask. The contents were cooled to 0° C. and 160 g of finely ground 2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were then added in portions, maintaining the temperature between 0° and 5° C. by cooling in an ice bath.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5](=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].[S:14](=O)(=[O:17])([OH:16])[OH:15]>>[S:14]([C:11]1[CH:12]=[C:6]([CH:5]=[O:13])[C:7]([OH:8])=[CH:9][CH:10]=1)([OH:17])(=[O:16])=[O:15]
Reactant: O=Cc1ccccc1O
Reactant: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: O=Cc1cc(S(=O)(=O)O)ccc1O

Procedure:
The 3-(thiazolidin-2'-yl)-4-hydroxy-phenyl sulfonic acid hydrochloride used as the starting material for reaction with the thionyl chloride is prepared without isolating intermediates by reacting the salicylaldehyde with fuming sulfuric acid (25-45% SO3) to give 5-sulfosalicylaldehyde. Usually, the fuming sulfuric acid is employed in a quantity sufficient to provide a slight excess of SO3 over equimolar amounts of the starting aldehyde. The reaction is exothermic, usually reaching a temperature of 70° to 75° C. and may be cooled to lower temperatures of 40° to 50° C., if desired.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:23][NH:24][C:9]=2[CH3:21])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(Br)cc1
Solvent: O
Product: Cc1[nH]nc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(Br)cc1

Procedure:
This compounds was synthesised in the same manner as described above. 3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-2-methyl-chromen-4-one (0.5 g, 1.4 mmol), Hydrazine hydrate (5 ml). 4-[4-(4-Bromo-phenyl)-5-methyl-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol precipitated out as a pale orange solid (0.08 g, 63.7%); Rf 0.48 cf SM 0.8 [ethyl acetate/petroleum ether 40–60° C. (80/20)].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11][CH:12](Br)[CH3:13]>>[Br:11][CH2:12][CH2:13][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(Br)Br
Product: CC(=O)c1ccc(OCCBr)cc1

Procedure:
This compound was synthesized from 4′-hydroxyacetophenone and dibromoethane according to general method 4 described earlier.
Reaction SMILES: [C:1]([C:6]1[CH:14]=[CH:13][C:12]2[N:11]3[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:10]3=[CH:9][C:8]=2[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:22]([O:21][C:19]([N:17]1[CH2:16][CH2:15][N:11]2[C:12]3[CH:13]=[CH:14][C:6]([C:1](=[N:31][CH2:30][C:29]4[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:28]=4[O:27][CH3:26])[CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=3[CH:9]=[C:10]2[CH2:18]1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: CCCC(=O)c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 8-butyryl-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.0 g, 2.9 mmol) in CH2Cl2 (20 mL), cooled to 0° C., was added 2,4-dimethoxybenzyl amine (0.5 mL, 3.2 mmol) and Et3N (1.2 mL, 9 mmol). To this mixture was added a solution of TiCl4 (1.8 mL, 1M, 1.8 mmol) in CH2Cl2 dropwise via an addition funnel. Upon completion of addition, the reaction was stirred at room temperature for 6 h before it was quenched with a saturated solution of NaHCO3. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, filtered, and concentrated to give a crude product that was used immediately without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.C(#N)C.[BH4-].[Na+].O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a suitable reaction flask was charged (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (103.06 mmoles, 35.00 g) and acetonitrile (6.68 moles, 350.00 mL, 274.15 g) to afford a clear solution. The solution was cooled to 0 degrees Celsius and sodium borohydride (128.82 mmoles, 4.87 g) was added portionwise. The reaction was stirred for approximately 30 minutes at 0 degrees Celsius, and then at room temperature until completion (as determined by HPLC analysis). To the reaction mixture was then added water (40 mL), followed by brine (50 mL). The layers were shaken together, allowed to settle and then were separated. The organic phase was concentrated to an oil. Methyl tert-butyl ether (200 mL) was added followed by a slow addition of 1N hydrochloric acid. Vigorous gas evolution was observed. The layers were shaken together, allowed to settle and then were separated. The organic phase was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to afford the crude product as a pale yellow solid (35.38 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:14]CC2C=CC(OC)=C(OC)C=2)[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH2:14])[C:10]([F:11])([F:12])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CNC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(c1ccc(Cl)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a solution of 146 (4.11 g, 10.43 mmol) in DCM (50 mL) was added TFA (2.410 ml, 31.28 mmol) and reaction was stirred for 18 hr at RT. The reaction mixture was concentrated and dissolved in DCM. A solution of HCl (20 mL, 2M Et2O) was added and the solvent was decanted from the solids. The solids were dissolved in 15% MeOH/DCM and saturated NaHCO3 was added. The organic layer was separated and concentrated. The residue was triturated with EtOAc and allowed to stand. The resulting solids were filtered to afford 1.904 g (74.8%) of 1-(3,4-dichlorophenyl)-2,2,2-trifluoroethanamine (148).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24]Br)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(CCCCBr)c1ccccc1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 92 from 6-hydroxy-carbostyril and 4-phenylsulfinyl-butyl bromide.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4](Cl)=[C:3]([C:8]#[N:9])[CH:2]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>C(O)(C)C>[CH2:10]([NH:14][C:4]1[C:3]([C:8]#[N:9])=[CH:2][CH:1]=[CH:6][N:5]=1)[CH2:11][CH2:12][CH3:13]
Reactant: N#Cc1cccnc1Cl
Reactant: CCCCN
Solvent: CC(C)O
Product: CCCCNc1ncccc1C#N

Procedure:
2-Chloronicotinitrile (1.30 g, 9.60 mmol) was refluxed with 3 mL of n-butylamine and 10 mL of isopropyl alcohol overnight. The solvents were removed in vacuo and the residue obtained chromatographed on silica gel eluting with 2:1 hexane/ethyl acetate to give 1.6 g of the title compound.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:7]([CH2:15][O:16]C)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=1[CH3:12].O>C(Cl)Cl>[Cl:5][C:6]1[C:7]([CH2:15][OH:16])=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=1[CH3:12]
Reactant: COCc1nc(SC)nc(C)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CSc1nc(C)c(Cl)c(CO)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1M BBr3 in CH2Cl2 (9.5 ml, 9.5 mmol) was added to a solution of the title compound from Step C (0.52 g, 2.78 mmol) in CH2Cl2 (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. Water (1 mL) was added. The mixture was extracted with CH2Cl2 (3×10 mL), and dried over Na2SO4. The solvent was removed. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexane (3/7) to give the title compound as a colorless gum. 1H NMR (CDCl3, 500 MHz) δ 4.76 (d, J=4.5 Hz, 1H), 3.88 (m, 1H), 2.61 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(NCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.0 g (134.4 mmol) of tert-butyl 1-[3-(benzylamino)-4-chlorobenzyl]cyclopropanecarboxylate were dissolved in 1.5 liters of ethyl acetate, and 1.43 g (1.34 mmol) of palladium (10% on carbon) were added. The reaction mixture was stirred at RT under a hydrogen atmosphere at standard pressure overnight. The reaction mixture was then filtered off with suction through kieselguhr, and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 10:1). The resulting product was stirred in a methanol/water mixture (70:30) and the solid was isolated. 24.3 g (64.1% of theory) of the target compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=3[CH:12]=2)=[CH:6][C:7]=1[Cl:8].[CH2:23](OC(OCC)OCC)C>C(O)=O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[CH:23]=[N:22][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CSc1nc2ccc(CNc3cc(Cl)c(Br)cc3N)cc2o1
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of 4-bromo-5-chloro-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (622 mg, 2.40 mmol), triethoxymethane (5 mL) and HCOOH (0.08 mL) was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1:1 petroleum ether/ethyl acetate to give 6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole as a light brown solid (607 mg, 84.5%). 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.34 (d, J=6.6 Hz, 1H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:5][C:6](=[O:58])[C@H:7]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:46][CH:45]=1)[NH:8][C:9](=[O:42])[C@H:10]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([O:17]C(C)(C)C)=O.FC(F)(F)C(O)=O.[CH:71]1(C(O)=O)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:5][C:6](=[O:58])[C@H:7]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:46][CH:45]=1)[NH:8][C:9](=[O:42])[C@H:10]([CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1)=[O:17]
Reactant: O=C(O)C1CCCCC1
Reactant: COC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C1CCCCC1

Procedure:
Nα-t-Butoxycarbonyl-L-tryptophyl-O-benzyl-L-seryl-O-benzyl-L-tyrosyl-D-leucine methyl ester (Example 17), 1 g., 1.16 mmol, is reacted according to the appropriate part of Example 1 with 20 ml. of trifluoroacetic acid, neutralized with triethylamine and coupled with 150 mg., 1.17 mmol, of cyclohexane carboxylic acid using 180 mg., 1.17 mmol, of 1-hydroxybenzotriazole and 240 mg., 1.17 mmol, of dicyclohexylcarbodiimide. The solution is evaporated and the residue triturated with ether. The product is precipitated from isopropanol on cooling as a cream solid; 1 g.; m.p. 158°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](O)=[O:24])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1>C1COCC1>[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:21])([CH3:22])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:6]([Cl:26])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:24])=[CH:57][CH:56]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Cl)cc3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 9.8 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.080 g, 0.203 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.128 g, 0.400 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and 4-chloro aniline (0.052 g, 0.400 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.07 (s, 2H), 7.14 (s, 1H), 7.40 (d, J=9.0 Hz, 2H), 7.72 (d, J=12.3 Hz, 2H), 8.45 (s, 2H), 9.72 (s, 1H), 11.00 (s, 1H), 11.45 (s, 1H); MS [M−H]−: 500.25.