Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([NH:17][NH2:18])=[N:11][CH:10]=1.[CH:19](O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]2[N:11]([CH:19]=[N:18][N:17]=2)[CH:10]=1
Reactant: N#Cc1cc(NN)ncc1-c1ccc(Cl)cc1Cl
Reactant: O=CO
Product: N#Cc1cc2nncn2cc1-c1ccc(Cl)cc1Cl
Yield: 86 %

Procedure:
A solution of the crude 5-(2,4-dichloro-phenyl)-2-hydrazino-isonicotinonitrile (520 mg) in formic acid (15 mL) was stirred and refluxed for 1 h. The reaction mixture was concentrated under vacuum, then the remaining residue was diluted in AcOEt (50 mL) and washed with a 2.0 M aqueous NaHCO3 solution (2×25 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM→DCM/MeOH 7:3) to yield the title compound (397 mg, 1.37 mmol, 86% over 2 steps). MS: 289 [M+1]+; HPLC: AtRet=1.79; TLC: RF 0.41 (DCM/MeOH 95:5).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:13][CH2:14][CH:15]=O)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:18][C:19]([S@@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:19]([S@@:22]([N:24]=[CH:15][CH2:14][CH2:13][C:2]([CH3:17])([CH3:1])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:23])([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(CCC=O)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(CCC=N[S@@](=O)C(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 22 h

Procedure:
To a mixture of benzyl 2,2-dimethyl-5-oxopentanoate (1.06 g, 4.54 mmol, Step C) and anhydrous CuSO4 (1.59 g, 9.98 mmol) in DCM (10 mL) was added (S)-2-methylpropane-2-sulfinamide (0.550 g, 4.54 mmol). This mixture was stirred for 22 hours, before being filtered through a pad of celite. Additional DCM was used to wash the celite. The combined organics were concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM—0.5:99.5 to 1.5:98.5, to give the title compound. MS: m/z=338 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C:16](=[O:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:19][Mg]Br>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[F:9][C:6]1[CH:5]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C:16]([OH:18])([CH3:19])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:3]=[C:2]([F:1])[C:7]=1[F:8]
Reactant: CC(=O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1

Procedure:
To a solution of 1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanone (529 mg) in tetrahydrofuran (25 mL) was, under a nitrogen atmosphere, dropwise added methylmagnesium bromide (0.97 M tetrahydrofuran solution, 4.63 mL) at 0° C. The resultant solution was stirred for 1 hour at the same temperature, and then diluted with aqueous ammonium chloride and ethyl acetate. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate), to thereby obtain the titled compound (330 mg). The physical properties of this crude product were as follows.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[NH:12][CH2:13][CH2:14][CH2:15][O:16][C:10]=2[CH:9]=1)([O-:7])=[O:6]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[N:12]([C:1](=[O:3])[CH3:2])[CH2:13][CH2:14][CH2:15][O:16][C:10]=2[CH:9]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCCN2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Acetyl chloride (0.080 mL, 1.1 mmol) was added to 3-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (203 mg, 1.04 mmol) and 4-Dimethylaminopyridine (13 mg, 0.10 mmol) in Pyridine (3.5 mL) and the reaction was stirred at room temperature overnight. The mixture was partitioned between 20 mL EtOAc and 20 mL satd. sodium bicarbonate, the org. was then washed with 1N HCl (20 mL) and brine (20 mL), dried and conc. in vacuo to give 1-(3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone as yellow solids (225 mg, 91%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1)[NH2:2].[C:16]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=O)[CH3:17]>>[O:15]=[C:12]1[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([NH:1][N:2]=[C:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH3:17])=[CH:8][CH:7]=2)=[N:14][NH:13]1
Reactant: NNc1ccc(C2=NNC(=O)CO2)cc1
Reactant: CC(=O)c1ccncc1
Product: CC(=NNc1ccc(C2=NNC(=O)CO2)cc1)c1ccncc1
Reaction time: 3 h

Procedure:
Analogously to Example 2 (a), from the so obtained amine there is prepared 2-(4-hydrazinophenyl)-4,5-dihydro-6H-1,3,4-oxadiazin-5-one and the suspension obtained after reduction thereof is mixed, without isolation of the hydrozine, with the 4-acetylpyridine. The reaction mixture is further stirred for 3 hours with suction and washed with water. There is thus obtained, as a crude product, 4-acetylpyridine-[4-(5-oxo-4,5-dihydro-6H-1,3,4-oxadiazin-2-yl)-phenylhydrazone]; m.p. 195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4Cl)cc3)c2cc1OC
Yield: 72.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (58 mg) was dissolved in toluene (5 ml) with heat, 2,4-dichlorophenyl isocyanate (93 mg) was added, and the admixture was refluxed with heat for 20 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 69 mg of the title compound (yield: 73%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[NH:8]2)=[CH:4][C:3]=1[F:14].[H-].[Na+].I[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:13])[C:7]([CH3:11])([CH3:12])[N:8]2[CH3:18])=[CH:4][C:3]=1[F:14]
Reactant: CC1(C)Nc2cc(Br)c(F)cc2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cc(Br)c(F)cc2C(=O)C1(C)C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To a stirred solution of 6-bromo-5-fluoro-2,2-dimethylindolin-3-one (D90) (240 mg, 0.930 mmol) in DMF (3 mL) at 0° C. was added sodium hydride (55.8 mg, 1.395 mmol). After stirring for 10 min, iodomethane (0.116 mL, 1.860 mmol) was added to the mixture and the mixture was stirred for 30 min at 0° C. The reaction was quenched with addition of saturated NH4Cl (1 mL) and the mixture was poured into water (60 mL). The mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give the title compound (247.7 mg). LCMS (A): m/z (M+H)+ 272/274, C11H11BrFNO requires 271/273 (acidic).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[C:26]([CH3:28])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[N:10]=[C:9]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[N:8]=2)=[C:4]([CH3:29])[CH:3]=1.C(O[CH:35](N(C)C)[N:36]([CH3:38])[CH3:37])(C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:27]=[C:26]([CH3:28])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11](/[CH:16]=[CH:35]/[N:36]([CH3:38])[CH3:37])[N:10]=[C:9]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[N:8]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(C)c1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a homogenous mixture of 4-(4-(4-bromo-2,6-dimethylphenoxy)-6-methyl-5-nitropyrimidin-2-ylamino)benzonitrile (22.71 g, 50 mmol) in DMF (300 ml) was added tert-butoxybis (dimethylamino) methane (12.39 ml, 60 mmol) over 15 minutes. The mixture was stirred at room temperature overnight. DMF was partially removed. The residue was washed with water and extracted with ethyl acetate (×3). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated to dryness yielding to the desired product as a yellow solid (23.41 g, 46.0 mmol, 92%) which was used in next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 2.14 (s, 6H), 2.98 (bs, 3H), 3.13 (bs, 3H), 5.54 (d, J=12.4 Hz, 1H), 7.03 (s, 1H), 7.27 (d, J=8.6, 2H), 7.28 (s, 2H), 7.40 (d, J=8.6, 2H), 8.03 (d, J=12.2 Hz, 1H).
Reaction SMILES: [Cl:1][CH:2]([C:8]([CH3:10])=O)[C:3](OCC)=[O:4].COC1C=CC([C:17]([NH2:19])=[NH:18])=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:8]([CH3:10])=[N:18][CH:17]=[N:19][C:3]=1[OH:4]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1ccc(C(=N)N)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ncnc(O)c1Cl
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Under N2, a solution of ethyl 2-chloroacetoacetate (1.8 ml, d=1.15, 0.013 mol) in CHCl3 (50 ml) was added dropwise to a solution 4-methoxybenzamidine (3.9 g, 0.026 mol) in CHCl3 (100 ml). After stirring overnight, the reaction mixture was filtered and the filtrate was washed with dilute NaOH solution. The aqueous layer was extracted with CH2Cl2 (3×) and the organic layer was dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 2% CH3OH-CHCl3 (v/v) to yield 0.7 g (22%) of product m.p. 250°-251° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[OH:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:30]([O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Cl)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:39][CH:40]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)cc1
Yield: 50.5 %

Procedure:
(2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic acid methyl ester (302 mg, 50%) was prepared from (2S)-3-Biphenyl-4-yl-2-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (400 mg, 0.92 mmol) and 4-benzyloxybenzyl chloride (256 mg, 0.39) as described in general procedure H and purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH2:11])=[C:4]([NH2:12])[CH:3]=1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C1COCC1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[NH:11][C:18](=[O:19])[NH:12][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1N
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]1
Yield: 83.5 %

Procedure:
A stirred solution of 4-chloro-5-nitro-1,2-phenylenediamine (2.0 g, 10.66 mmol) and CDI (2.59 g, 16 mmol) in anhydrous THF (50 mL) was heated to 85° C. for 4 h. The reaction was allowed to cool and the solvents were removed under reduced pressure. The resulting residue was washed with 2M aqueous hydrochloric acid and recrystallised from methanol to afford 5-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one as a brown solid (1.9 g, 84%), which was taken through to the next step with no further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39])[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([N+:38]([O-:40])=[O:39])=[C:29]([O:28][CH3:27])[CH:30]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
1.2 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.08 g of 3-methoxy-4-nitrobenzoic acid and 0.96 g of dicyclohexylcarbodiimide are dissolved in a mixture of 30 ml of methylene chloride and 8 ml of dimethylformamide under ice-cooling. A catalytic amount of 4-(dimethylamino)pyridine is added to the solution, and said mixture is stirred at room temperature overnight. After the reaction, the precipitates are removed by filtration. The filtrate is washed with an aqueous potassium carbonate solution and then with water, dried and evaporated to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:methanol=20:0.3). 1.2 g of (+)-cis-2-(4-methoxyphenyl)-3-(3-methoxy-4-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as an oil. Yield: 67.4%.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([Cl:20])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCn1cc(C#N)c2ccc(C(=O)O)cc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(C#N)c2ccc(C(=O)Cl)cc21
Temperature: 0 °C
Yield: 100.9 %

Procedure:
A suspension of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.42 g, 1.96 mmol) in CH2Cl2 (15 mL) is cooled to 0° C. The suspension is treated with DMF (2 drops) and then oxalyl chloride (0.34 mL, 3.92 mmol) is added via syringe during 2 minutes after which the ice bath is removed and the reaction mixture is allowed to warm to ambient temperature during 1.5 h during which time the reaction becomes a yellow solution. The solution is then concentrated in vacuo to afford 0.46 g (quantitative yield) of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[OH:11][C:12]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=O.[H-].[Na+].S(OC)(OC)(=O)=O>C1COCC1>[CH3:17][O:16][C:14]1[C:13]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:12]=2[O:11][C:2]=1[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COC(=O)c1cc(C)ccc1O
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: COc1c(-c2ccccc2C#N)oc2ccc(C)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
2-(Bromomethyl)benzonitrile (17.6 g) was added to a mixture of methyl 2-hydroxy-5-methylbenzoate (15 g) and sodium hydride (2.7 g, 80% dispersion in oil) in dry THF (150 ml) and the resulting mixture heated at reflux for 5 h. Further sodium hydride (2.7 g, 80% dispersion in oil) was added and heating continued overnight. The mixture was cooled (0° C.), sodium hydride (2.7 g, 80% dispersion in oil) and dimethyl sulphate (17 ml) were added, and the resulting solution stirred at room temperature for 4 h. Solvent was removed in vacuo, the residue taken up in dichloromethane (200 ml) and cone. ammonia solution (200 ml) added carefully. The organic solution was removed and the aqueous solution extracted with dichloromethane (2×200 ml). The combined, dried organic phases were evaporated in vacuo and the residue purified by chromatography, eluting with dichloromethane: hexane (1:1) to give the title compound as a white solid (17 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]#[N:21])[CH:14]=1.C[O-].[Na+]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[C:19]([C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[C:20]#[N:21])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: N#CCc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(=Cc1ccc2c(c1)OCCO2)c1cccnc1
Reaction time: 18 h
Yield: 88.3 %

Procedure:
To the solution of 2,3-dihydro-benzo[1,4]dioxin-6-carboxaldehyde (4.92 g; 0.03 mol) and 3-pyridylacetonitrile (3.54 g; 0.03 mol) in ethanol (100 mL) was added sodium methoxide (6.48 g, of 25% methanol solution, 0.03 mol). The mixture was allowed to stand at ambient temperature for 18 hours. The mixture was concentrated to half volume. The solid was collected by filtration and dried to give 7.0 g (88.4% yield) of the title compound as an off-white solid, m.p. 158°-159° C. Anal. Calcd. for C16H12N2O2 : C, 72.72; H, 4.58; N, 10.60. Found: C, 72.53; H, 4.48; N, 10.97. Mass spectrum (DEI; M+) m/z 264. 1 H-NMR (DMSO-d6 ; 400 MHz) δ 8.91 (d, 1H), 8.59 (d, 1H), 8.08 (d, 1H), 8.00 (s, 1H), 7.57 (d, 1H), 7.47-7.53 (m, 2H), 7.02 (d, 2H), and 4.31 ppm (m, 4H).
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OO.CN(C=[O:39])C>CO.C(O)(=O)C.[Pd]>[NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17]([CH3:18])=[O:39])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: CN(C)C=O
Agent: [Pd]
Agent: OO
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)CC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 5 h

Procedure:
In a mixed solvent comprising 10 ml of MeOH and 5 ml of acetic acid is dissolved 2.2 g of BOC-Tyr-(D)-Met-Gly-OH, followed by adding 0.6 ml of 30% aqueous hydrogen peroxide solution, and the mixture is stirred at roomtemperature for 5 hours. Following the addition of a small amount of palladium black, the mixture is stirred. The catalyst is filtered out, andthe solvent is distilled off, whereby the precipitated crystals are collected by filtration. Thus obtained is 2.1 g of the desired product, m.p. 185° C. (decomposed), Rf1 =0.20, [α]D21 +1.8° (c=0.5, DMF)
Reaction SMILES: [OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[H-].[Na+].CN(C)C=O.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([O:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: NC(=O)CC1CCC(O)c2sccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)CC1CCC(OCc2ccccc2)c2sccc21
Temperature: 25 °C

Procedure:
A sample (0.5 g) of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylacetamide is suspended in 20 ml of dry tetrahydrofuran under a nitrogen atmosphere and the mixture is cooled in an ice bath while 2.1 equivalents or 120 mg of 57% sodium hydride in an oil dispersion is added. The mixture is then stirred at room temperature for an hour and 5 ml of dry N,N-dimethylformamide is added to facilitate dissolution of the sodium hydride. After stirring for an hour, the mixture is cooled in an ice bath and 330 mg of benzyl chloride in 5 ml of dry tetrahydrofuran is added dropwise. The bath is removed and the mixture is stirred at room temperature for several hours. It is then warmed (below boiling point) for an overnight period. Water (25 ml) is carefully added to the reaction mixture and the solvents are stripped off on a rotary evaporator. The residue (yellowish semisolid) is dissolved in dichloromethane and water is added. The dichloromethane layer is collected and the aqueous portion is further extracted with dichloromethane. The combined dichloromethane solutions are washed with 2N hydrochloric acid, water, and dried (magnesium sulfate). The solution is then evaporated in vacuo and the residue is triturated with diethyl oxide. The title product is collected and washed with diethyl oxide to afford 320 mg, m.p. 139° C to 143° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH:25]([CH2:27][C:28]([OH:30])=[O:29])[CH2:24]1.CCN(C(C)C)C(C)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([N:23]3[CH2:26][CH:25]([CH2:27][C:28]([OH:30])=[O:29])[CH2:24]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CC1CNC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(CC(=O)O)C3)c2CC1
Temperature: 75 °C

Procedure:
2.5 g (7.75 mmol) 10-Chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester, 1.1 g (9.1 mmol) azetidin-3-yl-acetic acid and 3 mL (17.4 mmol) DIPEA were suspended in 18 mL ethanol. The reaction mixture was stirred at 75° C. over night. The solvent was evaporated and the residue was taken up in EtOAc and water and was acidified using a KHSO4 solution. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by prep. HPLC to yield the corresponding acid (72% of theory).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].[Cl-].[NH4+]>ClCCl>[C:1]([O:5]/[N:6]=[C:7]1\[CH:8]=[C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)[O:10][C:11]2[C:16]\1=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:13][CH:12]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(CCCCO)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)O/N=c1\cc(-c2cc3cccn3cn2)oc2ccc(CCCCOS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A ice-cooled solution of 6-(4-Hydroxy-butyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (115 mg, 0.28 mmol) (example 102B) in dichloromethane (5 ml) was treated with triethylamine (100 μl, 0.7 mmol) and dropwise with methanesulfonyl chloride (26 μl, 0.34 mmol). The mixture was stirred at room temperature for 3 hours and treated with a saturated solution of ammonium chloride, extracted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated to dryness. The crude mesylate was used for the next step without further purification.