Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>O1CCOCC1.O>[N:30]([CH2:12][CH2:13][CH:14]1[CH2:16][CH:15]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=NCCC1CC1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from step 1 of this example (309 mg, 0.709 mmol) was in 5.67 mL dioxane. NaN3 (106 mg, 1.63 mmol) was added, followed by addition of 1.418 mL water. Reaction mixture was stirred at 100° C. for 2.5 hours before cooled back to room temperature. The reaction mixture was diluted with water and aqueous phase was further extracted with ethyl acetate for 3 times. The combined organic layers were washed with water and brine, then dried over Na2SO4 and concentrated. The residue was purified by column chromatography using gradient elution (0 to 30% ethyl acetate in hexane) to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1=[CH:3][CH2:4][C:5]([CH3:15])([CH3:14])[CH:6]=[CH:7][CH2:8][C:9]([CH3:13])=[CH:10][CH2:11][CH2:12]1.C[C@H]1[C@@]23CCC(=C)[C@@H]2[C@H]3[C@H](C(C)C)CC1.CC1[C@@H]2C[C@H](C(C)=C)CC[C@@]2(C)CCC=1.CC1C2CC(CCC2(C)CCC=1)=C(C)C.CC1CCC2[C@H]([C@H](C(C)C)CCC=2C)C=1.C[C@@H]1C2CC[C@H](C)C=2C[C@H](C(C)=C)CC1>>[CH3:13][C:9]1=[CH:10][CH2:11][CH2:12][C:2]([CH3:1])=[CH:3][CH:4]=[C:6]([CH:5]([CH3:14])[CH3:15])[CH2:7][CH2:8]1
Reactant: CC1=CCCC(C)=CCC(C)(C)C=CC1
Agent: C/C1=C\C=C(\C(C)C)CC/C(C)=C/CC1
Agent: C/C1=C\CC/C(C)=C/CC(C)(C)/C=C/C1
Agent: C=C(C)[C@@H]1CC[C@@]2(C)CCC=C(C)[C@@H]2C1
Product: CC1=CC=C(C(C)C)CCC(C)=CCC1

Procedure:
The sources of authentic terpene standards were as follows: α-longipinene, cyclosativene, sativene and α-ylangene were from Abies balsamea oleoresin; δ-selinene was from Abies alba oleoresin, α-, β-, and γ-himachalene, α-and δ-amorphene, α-muurolene, guaia-6,9-diene, α-cadinene, δ-selinene, germacrene A, β-ylangene, β-longipinene, E-α-and β-bisabolene were (lifts from Larry Cool (University of California, Berkeley); germacrene B, and black pepper oleoresin containing α-cubebene and α-copaene, were gifts from Robert Adams (Baylor University); γ-humulene was from allspice seeds and as a gift from Ron Binder (USDA, Albany, Calif.); sibirene and longicyclene were from Pinus sibirica oleoresin; longifolene was purchased from Sigma Chemical Co.; E-α-larnesene was from parsley leaf oil; germacrene D was from the essential oil of caraway and Nepeta mussini; β-caryophyllene was a gift from Rudolf Hopp (Haarmann and Reimer GmbH); γ-bisabolene was isolated from carrot roots; α-humulene was purchased from Fluka Chemical Co.; β-cubebene was from the essential oil of Valencia orange peels; α-selinene and seli-3,7 (11)-diene were from celery seed, δ-cadinene was a gift from Margaret Essenberg (Oklahoma State University); α-guaiene was from patchouli essential oil; germacrene C was isolated from tomato leaf oil; bicyclogermacrene was from the essential oil of marjoram; and β-gurjunene was from ginger root. All other biochemicals and reagents were purchased from Sigma Chemical Co. or Aldrich Chemical Co., unless otherwise noted.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20])[CH2:15][CH2:14][CH2:13][CH:12]1[C:23](O)=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH:12]([C:23](=[O:24])[NH:36][CH2:35][CH2:34][CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CC1CCCC(C(=O)O)N1C(=O)OCc1ccccc1)OC
Reactant: NCCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COC(CC1CCCC(C(=O)NCCCCc2ccccc2)N1C(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
6-(2,2-Dimethoxy-ethyl)-piperidine-1,2-dicarboxylic acid 1-benzyl ester (Compound 238, 1 g, 2.85 mmol) and 4-phenylbutyl amine (0.51 g, 3.42 mmol) were dissolved in CH2Cl2 (60 mL). HOBt (0.462 g, 3.42 mmol) was added followed by EDC.HCl (0.655 g, 3.42 mmol). The reaction was stirred at room temperature for 12 hours. Saturated NaHCO3 (25 mL) was added and the reaction was extracted with CHCl3 (2×50 mL). The combined organic layers were dried over Na2SO4, and then concentrated. Flash chromatographic purification of the residue (1:1 EtOAc/hexanes) gave Compound 242 (1.294 g, 94%). Rf=0.62 (1:1 EtOAC/hexanes).
Reaction SMILES: C[Si]1(C)O[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=2[O:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=3[OH:3])=[CH:31][CH:32]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Reactant: Cc1ccc2c(c1)O[Si](C)(C)OC2=O
Product: COc1ccc(CCc2ccc(NC(=O)c3ccc(C)cc3O)cc2)cc1OC
Yield: 48.5 %

Procedure:
The preparation is as described for Example 45 using 2,2,7trimethyl-4H-1,3,2-benzodioxasilin-4-one (2.0 g, 10 mmol) and 4[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (2.5 g, 10 mmol). Recrystallization from methanol/DMF gives the pure product (1.9 g) mp 162°-164° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH:9]=[O:10])[CH3:2].O1C[CH2:33][CH2:32][CH2:31]1>>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH:9]([OH:10])[CH:32]([CH3:33])[CH3:31])[CH3:2]
Reactant: CCCc1nc(CC)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C1CCOC1
Product: CCCc1nc(CC)c(C(O)C(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A mixture of 4′-[(4-ethyl-5-formyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.6 g) and tetrahydrofuran (10 mL) was cooled to −78° C., isopropyl Grignard reagent tetrahydrofuran solution (1.0 M, 1.9 mL) was added dropwise, and the mixture was stirred for 1 hr. Then, the mixture was gradually warmed to room temperature, and the mixture was stirred for 12 hr. The solvent was evaporated from the reaction mixture under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.38 g, 57%).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([Si:8]([CH3:24])([CH3:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)([CH3:7])([CH3:6])[CH3:5]>N1C=CC=CC=1>[C:4]([Si:8]([CH3:24])([CH3:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:2][OH:3])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 80.2 %

Procedure:
Hydroxylamine hydrochloride (6.55 g, 94.3 mmol) was added to a pyridine (30 mL) solution of 1-(4-((tert.-butyldimethylsilyloxy)methyl)phenyl)-2,2,2-trifluoroethanone (10 g, 31.4 mmol). The solution was stirred a reflux (4 h). The pyridine was evaporated and 150 mL of an aqueous solution of citric acid (10%) and CH2Cl2 (100 mL) were added to the residue and the organic layer was extracted. The aqueous layer was washed 2 times with CH2Cl2 (2×100 mL). Finally, the organic layers were combined and concentrated in vacuum. The residue was purified by silica gel flash chromatography (MPLC) to obtain 8.4 g of a white solid. Rf=0.31 (1/9 EtOAc/hexanes); mp 63-65° C.; 1H NMR (CDCl3): δ 0.12 (s, (CH3)2Si), 0.96 (s, CH3)3C), 4.73 (s, CH2), 7.44 (d, J=8.2 Hz, C6H4), 7.50 (d, J=8.2 Hz, C6H4), 8.61 (s, OH); 13C NMR (CDCl3): δ −5.3 (CH3Si), 18.4 (C(CH3)3), 25.9 (C(CH3)3), 64.4 (CH2O), 120.6 (q, J=273.2 Hz, CF3), 124.4 (C6H2), 125.9 (C6H2), 128.6 (C6H2), 144.2, (C6H2), 147.9 (q, J=32.1 Hz, CN).
Reaction SMILES: [CH3:1][S:2]([C:4]1[C:5](=[O:29])[C:6](=[CH:20]/[CH:21]=[CH:22]\[CH:23]([OH:28])[CH2:24][CH2:25][CH2:26][OH:27])[C:7](=[CH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)=[O:3].ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([C:4]1[C:5](=[O:29])[C:6](=[CH:20]/[CH:21]=[CH:22]\[CH:23]([OH:28])[CH2:24][CH2:25][CH2:26][OH:27])[C:7](=[CH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=1)(=[O:38])=[O:3]
Reactant: CS(=O)C1=CC(=CCCCOc2ccccc2)C(=C/C=C\C(O)CCCO)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)C1=CC(=CCCCOc2ccccc2)C(=C/C=C\C(O)CCCO)C1=O
Reaction time: 4 h
Yield: 57.8 %

Procedure:
To a solution of 6.5 mg of 2-methylsulfinyl-5-[(Z)-4,7-dihydroxy-2-heptenylidene]-4-(4-phenoxybutylidene)-2-cyclopentenone obtained in Example 573 or Example 574 dissolved in 1.5 ml of dichloromethane was added 3 mg of 3-chloroperbenzoic acid, and the mixture was stirred for 4 hours. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated, followed by silica gel chromatography to give 3.9 mg (yield 60%) of 2-methylsulfonyl-5-[(Z)-4,7-dihydroxy-2-heptenylidene]-4-(4-phenoxybutylidene)-2-cyclopentenone.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[CH2:9][N:8]([C:10](=[O:29])[C@H:11]([NH:21]C(=O)OC(C)(C)C)[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:7]2)[CH2:3][CH2:2]1.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:21][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10]([N:8]1[CH2:7][C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:9]1)=[O:29]
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CC(OCC3CC3)(c3ccccc3C)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@@H](N)C(=O)N2CC(OCC3CC3)(c3ccccc3C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
1.7 g (3.5 mmol) of tert-butyl [(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate are placed in 45 ml of a 3M solution of hydrogen chloride in ethyl acetate and are stirred at room temperature for 3 hours. After evaporation under a stream of nitrogen, the crude product is taken up in a mixture of heptane and ethyl acetate, and then concentrated under vacuum. 1.6 g (100%) of (R)-2-amino-1-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one hydrochloride are obtained in the form of a beige-coloured solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])=[O:4].O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=CC(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=CC=1>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@H](Oc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O

Procedure:
The sugar standards, (1 mg each) rhamnose, fructose, galactose, glucose and the internal standard Phenyl-β-D-Glucoside (E. Merck, Darmstadt) and the sugars (1 mg each) obtained from the hydrolysis of crude and pure anthocyanins (1-3) were reacted separately with 30 mg/ml Hydroxylamine HCl in dry pyridine (2 ml). The resulting oximes were then reacted with 1.0 ml hexamethyldisilazane (HMDS) and 0.1 ml trifluoroacetic acid (TFA) to yield their silyl derivatives. The samples were then analyzed by GC using an autosampler. Sugars from anthocyanins 1, 2 and 3 were identified by comparing with the retention times of sugar standards. The retention times were 6.97, 9.83, 10.58, 10.90, 19.82 minutes, respectively, for rhamnose, fructose, galactose, glucose and Phenyl-β-D-Glucoside. The GC analysis of sugars yielded from the hydrolysis of anthocyanins showed that anthocyanin 1 contained a 2:1 ratio of glucose and rhamnose. Anthocyanin 2 showed a 1:1 ratio of glucose and rhamnose and anthocyanin 3 had only glucose. Similarly, the GC analysis of sugars from the crude anthocyanin powder indicated that it contained only rhamnose and glucose at a ratio of 2:4, respectively.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](Cl)=[C:5]2[S:4][CH:3]=1.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>C1(OC)C=CC=CC=1>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[C:5]2[S:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(C)csc2c1Cl
Reactant: Cc1ccccc1N
Solvent: COc1ccccc1
Product: CCOC(=O)c1cnc2c(C)csc2c1Nc1ccccc1C

Procedure:
Ethyl 3-methyl-7-chlorothieno[3,2-b]pyridine-6-carboxylate (3.0 g, 0.0117 mol) and o-toluidine (2.51 g, 0.0234 mol) in anisole (30 ml) were heated under reflux for three hours. The solvent was evaporated under reduced pressure, taken up in chloroform and washed in turn with 2NHCl, H2O, aqNa2CO3, H2O and brine, dried and evaporated to give an oil. This oil was purified by flash chromatography (silica, 40-60 mesh) using dichloromethane as eluant to give a buff coloured solid. This was crystallised from methanol to give the title compound, 2.3 g, m.p. 132°-134°.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.N(OCCCCC)=O>O1CCOCC1>[S:3]1[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=[CH:2]1
Reactant: COC(=O)c1cnc(N)s1
Agent: CCCCCON=O
Solvent: C1COCCO1
Product: COC(=O)c1cncs1
Yield: 44.7 %

Procedure:
Methyl 2-aminothiazole-5-carboxylate (79 g, 0.5 mol) was added over a period of 2 hours to a boiling solution of amyl nitrite (117.0 g, 1.0 mol) in dioxan (1 liter). After refluxing for a further half hour, the solvent was removed under reduced pressure and the residue was steam distilled to give a yellow oil which, on trituration with petroleum ether, gave the desired product as a white solid (32.0 g), m.pt. 68° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH:18]([N:21]([CH:36]([CH3:38])[CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:20])[CH3:19]>C(O)C.N1CCCCC1>[CH:36]([N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:37])[CH3:38]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.4 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellow solid (40 mg, 28%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:42][CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:42][CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: O=C(O)C1CCCNC1
Agent: OC1CCNC1
Product: O=C(O)C1CCCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with nipecotic acid. A yellow solid 128 was obtained (0.034 g, 66%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][C:7]1[CH:30]=[CH:29][C:10]2[CH2:11][C:12]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:17][CH:16]=3)([CH3:14])[O:13][C:9]=2[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:5]1([CH2:4][O:6][C:7]2[CH:30]=[CH:29][C:10]3[CH2:11][C:12]([C:15]4[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:17][CH:16]=4)([CH3:14])[O:13][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@@H](C)COc1ccc(C2(C)Cc3ccc(O)cc3O2)nc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1ccc(C2(C)Cc3ccc(OCC4CC4)cc3O2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
A mixture of (bromomethyl)cyclopropane (177 mg), diastereomer of N-[(1S)-2-{[6-(6-hydroxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)pyridin-3-yl]oxy}-1-methylethyl]acetamide (150 mg) and potassium carbonate (72.7 mg) in DMF (3 mL) was stirred at 80° C. for 3 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (150 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[N:9]=[C:8]([S:15][CH2:16][CH3:17])[N:7]=1)(=O)C.[OH-].[Na+]>C(O)C.C(OCC)C>[CH2:16]([S:15][C:8]1[N:7]=[C:6]([CH2:5][OH:4])[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[N:9]=1)[CH3:17]
Reactant: CCSc1cc(COC(C)=O)nc(SCC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCSc1cc(CO)nc(SCC)n1

Procedure:
A solution of 1.6 g (0.0059 mol) of 4-acetoxymethyl-2,6-diethylthio-pyrimidine in 3 ml of ethanol is treated at 0° C. with a solution of 0.86 g (0.0065 mol) of sodium hydroxide in 2.5 ml of ethanol. After 5 minutes the mixture is diluted with 150 ml of diethyl ether and washed neutral with water. The organic phase is dried over anhydrous magnesium sulphate and evaporated. In this manner there is obtained as the residue 2,6-diethylthio-4-hydroxymethyl-pyrimidine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: Brc1ncccn1
Reactant: OCc1ccc(B(O)O)cc1
Product: OCc1ccc(-c2ncccn2)cc1
Yield: 100.6 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 13 except for using 4-hydroxymethylphenylboronic acid (144 mg, 0.948 mmol), and using 2-bromopyrimidine (101 mg, 0.635 mmol) in place of 4-bromopyridazine to afford the title compound (119 mg) substantially quantitatively as a slightly yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1([NH:17][C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])[CH3:4].[CH3:30]I>C1COCC1>[CH2:3]([O:5][C:6]([C:8]1([N:17]([CH3:30])[C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(N(C)C(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of NaH (sodium hydride, 60% dispersion, 124 mg, 3.08 mmol) in anhydrous THF (20 mL) is added dropwise the solution of 2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (37) (280 mg, 0.77 mmol) in THF (5 mL) at 0° C. After stirring for 20 min, methyl iodide (377 μL, 6.05 mmol) is added dropwise and the resulting suspension is warmed up to RT and continued stirring overnight. After being quenched by saturated ammonium chloride aqueous solution (5 mL), the reaction mixture is diluted in EtOAc (50 mL). The organic layer is separated, washed with water (1×5 mL) and brine (2×5 mL), dried over anhydrous Na2SO4 and concentrated in in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 0%-30% EtOAc in heptane) to give a pure product (120) as a colorless semisolid (250 mg, 86%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: COc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 61 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-methoxybenzenesulfonyl chloride under the conditions used in example 2 giving 61% of the title compound.
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6](N)=[N:7][CH:8]=1.BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:1][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([CH3:2])=[CH:8][N:7]=1
Reactant: Br
Reactant: Cc1cnc(N)c([N+](=O)[O-])c1
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc(Br)c([N+](=O)[O-])c1

Procedure:
To concentrated HBr (48%, 28.6 mL) was added 5-methyl-3-nitro-pyridin-2-ylamine (5 g, 32.6 mmol) in portions at 0° C. temperature with stirring. The mixture was stirred until the internal temperature reached to −10° C., then bromine was added drop wise. A solution of NaNO2 (7.6 g, 110.84 mmol) in water (11 mL) was added slowly to maintain the reaction mixture temperature below 0° C. The dark mixture (gas evolution was observed) was stirred for 1 h at 0° C. then was carefully treated (slow addition) with a solution of NaOH (12 g, 300 mmol) in water (17 mL) while maintaining the internal temperature below 20° C. The mixture was stirred for an additional 1 h, then was filtered, dried under vacuum for 6 h and purified by recrystallization using 95% EtOH to get pure 2-bromo-5-methyl-3-nitro-pyridine (1.96 g) as yellow solid in 28% first crop yield. ESMS m/z (relative intensity): 217 (M+H)+ (100).