Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1ccc(C(F)(F)F)cc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Bromo-4-(trifluoromethyl)benzyl alcohol (4.0 g, 15.88 mmol) and Dess-Martin periodinane (7.14 g, 16.67 mmol) were combined in CH2Cl2 and stirred for 1.5 hours at room temperature. Saturated aqueous Na2CO3 was added, and a white precipitate was formed. The mixture was diluted with CH2Cl2 and saturated aqueous Na2CO3 and stirred for 1 hour. 1N Aqueous NaOH was added, and the organic layer was separated and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[N:10]=[C:11]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]2[CH3:26])[C:12]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=2[N:14]=1)[NH2:5].[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>>[CH2:27]([NH:29][C:30]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:12]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=3[N:14]=2)=[C:2]([CH3:1])[CH:3]=1)=[O:31])[CH3:28]
Reactant: Cc1cc(N)ccc1-c1nc2c(c(N3CCOC[C@@H]3C)n1)CCN(C)C2
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)c(C)c1
Yield: 20 %

Procedure:
Method as example 85 using (S)-3-methyl-4-(7-methyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline and ethyl isocyanate as starting materials. The solvent was removed in vacuo and purified by prep HPLC (high pH) yielding the title compound (11.8 mg, 0.027 mmol, 20%).
Reaction SMILES: CN1C2C(=CC=CC=2)C=C1C(OC)=O.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25](=[O:30])[CH:26](SC)[OH:27]>>[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25]([CH:26]=[O:27])=[O:30]
Reactant: CSC(O)C(=O)c1cc2ccccc2n1C
Agent: COC(=O)c1cc2ccccc2n1C
Product: Cn1c(C(=O)C=O)cc2ccccc21

Procedure:
By the method of Preparations 4 to 6, methyl N-methylindole-2-carboxylate was converted, 2-(N-methyl-2-indolyl)-2-oxo-1-(methylthio)ethanol. The latter (31.21 g., 0.13 mol) was converted to present title product according to Preparation 7, except that the combined filtrate and CHCl3 washes was simply washed 1×120 ml. saturated NaHCO3 and 1×120 ml. H2O, dried and stripped to an oil which was chromatographed on silica gel with 4:1 CH2Cl2 :ethyl acetate as eluant to yield purified hydrate of title product as an oil. On distillation (bp 130°/0.65) title product was obtained as a solid, 10.5 g.; 1H-nmr 4.06 (s, 3H), 7.45 (m, 5H), 9.57 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
2-(tert-butoxycarbonylamino)-5-hydroxyindan (100 mg, 0.40 mmol) synthesized in Reference Production Example 1 was dissolved in dry methylene chloride (2 ml), to which pyridine (0.15 ml, 1.8 mmol) and benzoyl chloride (0.14 ml, 1.1 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, to which diethylether was added. The organic layer was washed with, in the order of, an aqueous solution of saturated potassium hydrogen sulfate, brine, an aqueous solution of saturated sodium hydrogen carbonate, and brine, and then was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 2-(tert-butoxycarbonylamino)-5-benzoyloxyindan (130 mg, 0.37 mmol) having the following physical properties:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH3:54][O:55][C:56]1[CH:63]=[CH:62][C:59]([NH:60][CH3:61])=[CH:58][CH:57]=1>CN(C=O)C.CCOC(C)=O>[Br:20][C:16]1[CH:15]=[C:14]([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:60]([C:59]2[CH:62]=[CH:63][C:56]([O:55][CH3:54])=[CH:57][CH:58]=2)[CH3:61])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)O
Reactant: CNc1ccc(OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(Br)c2)NC(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 86.5 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(3-bromophenyl)propanoic acid (660 mg, 1.92 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 803 mg, 2.1 mmol) and DIPEA (0.43 ml, 2.5 mmol) were dissolved in DMF (10 ml) and treated with 4-methoxy-N-methylaniline (316 g, 2.3 mmol). The mixture was stirred vigorously overnight. The mixture was diluted with EtOAc (100 ml) and washed with brine (2×50 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The oily crude product was introduced to a silica gel loading column and purified by column chromatography (15-38% EtOAc/hexanes) to provide the desired product (770 mg, 1.66 mmol), 86.5%. MS (m/z) 463 [M+H]+.
Reaction SMILES: C([N:8]([CH2:33][C@@H:34]([C:36]1[CH:47]=[CH:46][C:39]2[O:40]C(C)(C)[O:42][CH2:43][C:38]=2[CH:37]=1)[OH:35])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]#[C:19][C:20]1[CH:21]=[C:22]([N:26]2[C:30](=[O:31])[CH2:29][NH:28][C:27]2=[O:32])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1.Cl>C(O)(C)C.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[OH:35][C@H:34]([C:36]1[CH:47]=[CH:46][C:39]([OH:40])=[C:38]([CH2:43][OH:42])[CH:37]=1)[CH2:33][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([N:26]2[C:30](=[O:31])[CH2:29][NH:28][C:27]2=[O:32])[CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCC#Cc3cccc(N4C(=O)CNC4=O)c3)Cc3ccccc3)ccc2O1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C1CNC(=O)N1c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A solution of 3-(3-{4-[(6-{benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione (9.05 g) in a mixture of isopropanol-EtOAc (9:1, 200 ml) was hydrogenated over Pearlman's catalyst (1.8 g). After 2 days aqueous 2M HCl (10 ml) was added and the mixture was hydrogenated for a further 2 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on Biotage eluting with dichloromethane-isopropanol-880 ammonia (34:7:1) to give the title compound (2.8 g) LCMS RT=2.34 min ES+ve 514 (MH)+.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1([C@H:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][NH:25][CH2:24][CH2:23][NH:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:35]1[N:40]([CH3:41])[C:39](=[O:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[N:36]=1>O1CCCC1>[N:5]1([CH:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([C@@H:21]4[NH:22][CH2:23][CH2:24][N:25]([C:35]5[N:40]([CH3:41])[C:39](=[O:42])[CH:38]=[C:37]([C:43]6[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=6)[N:36]=5)[CH2:26]4)=[CH:19][CH:20]=3)[CH2:11]2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: c1cc(N2CC[C@H](N3CCCC3)C2)ccc1[C@H]1CNCCN1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCC(N5CCCC5)C4)cc3)C2)nc(-c2ccncc2)cc1=O
Reaction time: 24 h
Yield: 82.4 %

Procedure:
To a suspension of (S)-2-(4-((S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl) piperazine tetrahydrochloride (98 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.20 mL, 1.40 mmol) and 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (44 mg, 0.20 mmol) at room temperature. After stirring for 24 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and sodium bicarbonate aqueous solution, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated, and the resulting crystals were washed in a mixture of diisopropyl ether and ethanol to afford (S)-2-(3-(4-(3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)piperazin-1-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (80 mg, 82%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH:16]=1)=[O:14]>>[C:2]1([CH2:1][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[CH:16]=2)=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Reactant: Cl[Mg]Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)Cc2ccccc2)c2cccnc21
Yield: 92 %

Procedure:
This compound was prepared by the reaction of benzylmagnesium chloride (2.0 M solution in THF) with N-methoxy-N-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide as described in General Method 1. The desired compound was obtained in 92% yield as a light yellow viscous oil.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 104.4 %

Procedure:
Example 12bh, Step 1: A solution of (1R,2S,5S)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate (200 mg, 0.4 mmol, obtained from Example 12b, Step 6 above), in methanol was treated with 60 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 130 mg of (1R,2S,5S)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)-cyclohexanecarboxylate as a white solid. This was used without further purification. MS found: (M.+H)+=312.3.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[CH2:30][C:20]3([C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:29])[CH2:19][C:16]2=[N:17][CH:18]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:29]=[C:21]1[NH:22][C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]21[CH2:19][C:16]1=[N:17][CH:18]=[C:13]([NH:12][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:14]=[C:15]1[CH2:30]2
Reactant: O=C(O)CCc1ccccc1
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-phenylpropionic acid (35 mg, 0.23 mmol), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1

Procedure:
To a flask were added 3 g 2-phenylbenzimidazole, 2.8 g potassium carbonate, 40 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 3.6 g Benzyl chloride were added and the mixture was heated to 75 C for 8 hrs. The reaction was cooled to 50 C and quenched with 40 ml of water and cooled to 5 C. The product was filtered, washed with water. The product was recrystallized by dissolving in 57 ml acetonitrile at reflux and 39 ml water were added. After cooling to 5 C, the product was filtered, washed and dried giving 3.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:28][CH3:29])=[C:20]2[O:24][C:23]([CH:25]([CH3:27])[CH3:26])=[CH:22][C:21]=12)=[O:15].S(=O)(=O)(O)O>C(O)COCCO.[OH-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:28][CH3:29])=[C:20]2[O:24][C:23]([CH:25]([CH3:27])[CH3:26])=[CH:22][C:21]=12)=[O:15]
Reactant: COC(=O)c1cc(Cl)c(NC(=O)c2ccc(OC)c3oc(C(C)C)cc23)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(C(=O)Nc2c(Cl)cc(C(=O)O)cc2Cl)c2cc(C(C)C)oc12

Procedure:
3.7 g of N-(2,6-Dichloro-4-methoxycarbonylphenyl)-7-methoxy-2-(1-methylethyl)benzofuran-4-carboxamide are refluxed for 15 min. in 20 ml of diethylene glycol and 30 ml of water in which 0.41 g of caustic soda is dissolved. The solution is diluted with water and acidified to pH 2 using 2 N sulfuric acid. The product precipitates in this process. It is filtered off with suction on a suction filter, washed free of acid with water and dried in vacuo: m.p. 279° C.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[Cl:9][CH2:10][CH2:11][CH2:12][C:13](N(OC)C)=[O:14].[Cl-].[NH4+]>C1COCC1.CCOCC>[Cl:9][CH2:10][CH2:11][CH2:12][C:13](=[O:14])[CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: C=CCCBr
Reactant: CON(C)C(=O)CCCCl
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC(=O)CCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
In a flame-dried flask, under an argon atmosphere, magnesium (7.8 g, 0.33 mol) and a small crystal of iodine in just enough THF to cover the magnesium was heated to a gentle reflux until the color had disappeared. Approximately 10% of a solution of 4-bromo-1-buten (32.5 mL, 0.321 mol) in THF (100 mL) was added all at once and reflux was continued until a brown coloration appeared. The remainder of the solution was added dropwise with continued reflux. After the addition was complete heating was maintained for 10 min, at which point almost all of the Mg had dissolved. The Grignard reagent solution was added to a second cooled (ice-bath) solution of 4-chloro-N-methoxy-N-methylbutanamide (21.3 g, 0.128 mol) in THF (200 mL). The resulting mixture was stirred for at room temperature for 2 h, poured into a mixture of ether and saturated aqueous ammonium chloride. The layers were separated and the aqueous phase was extracted with ether. The combined extracts were dried over Mg2SO4, filtered and concentrated under reduced pressure to give crude 1-chlorooct-7-en-4-one (17 g, 85%) as yellow liquid. 1H NMR (CDCl3, 500 MHz) δ 5.93-5.69 (m, 1H), 5.11-4.92 (m, 2H), 3.58 (t, J=6.5 Hz, 2H), 2.65-2.50 (m, 4H), 2.41-2.26 (m, 2H), 2.11-1.98 (qw, J=6.5 Hz, 2H).
Reaction SMILES: [CH2:1]([C@:4]1([CH2:18][O:19][CH3:20])[CH2:8][N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1)[CH:2]=C.[O:21]=[O+][O-].[BH4-].[Na+].[Cl-].[NH4+]>CO.O.C(OCC)(=O)C.ClCCl>[OH:21][CH2:2][CH2:1][C@:4]1([CH2:18][O:19][CH3:20])[CH2:8][N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1
Reactant: C=CC[C@@]1(COC)CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC[C@]1(CCO)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of (4R)-4-allyl-4-methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (3.28 g, 12.0 mmol) in methanol (20 mL)-dichloromethane (20 mL) was bubbled with ozone gas at −70° C. and stirred at the same temperature for 30 minutes. Ozone bubbling was stopped when the reaction solution was turned dark blue, and then the reaction solution was bubbled with nitrogen gas until the solution turned colorless. Sodium borohydride (454 mg, 12.0 mmol) was added at the same temperature, and the mixture was heated to room temperature over two hours. After heating, sodium borohydride (227 mg, 6.0 mmol) was added and the mixture was stirred for 24 hours. Then, sodium borohydride (113 mg, 3.0 mmol) was further added and the mixture was stirred for 0.5 hour. A saturated ammonium chloride solution (10 mL) was added, and the mixture was stirred for 10 minutes. Then, the reaction solution was poured into a mixture of ethyl acetate (50 mL) and water (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), and then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→10:1) to give 2.85 g (86%) of the title compound as a colorless viscous oil.
Reaction SMILES: [NH2:1][C:2](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:3](=[N:6][O:7][CH:8]([CH3:10])[CH3:9])[C:4]#[N:5].OO.C(=O)([O-])[O-:19].[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[NH2:1][C:2](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:3](=[N:6][O:7][CH:8]([CH3:9])[CH3:10])[C:4]([NH2:5])=[O:19]
Reactant: CC(C)ON=C(N)C(C#N)=NOC(C)C
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: CO
Product: CC(C)ON=C(N)C(=NOC(C)C)C(N)=O
Reaction time: 4 h
Yield: 889.9 %

Procedure:
To a methanol solution (140 ml) of 29.0 g (137 mM) of 3-amino-2,3-bis(isopropoxyimino)propionitrile were added, at room temperature, 47 g (415 mM) of a 30% aqueous hydrogen peroxide solution, 1.5 g (15 mM) of sodium carbonate and 2.3 g (7.1 mM) of tetrabutylammonium bromide. Stirring was conducted at room temperature for 4 hours. Since the raw materials remained, further 24 g (212 mM) of a 30% aqueous hydrogen peroxide solution was added, followed by stirring at room temperature for 3 hours. Excessive hydrogen peroxide was treated with an aqueous sodium thiosulfate solution. The solvent was distilled off under reduced pressure. Water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered to remove inorganic matter. The solvent was distilled off under reduced pressure. The crystal obtained was washed with a 1:2 mixed solution of diisopropyl ether and n-hexane to obtain 29.0 g (yield: 92%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>CN(C)C=O>[F:19][C:17]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([CH2:10][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:18]=1
Reactant: N#Cc1ccc(F)cc1CBr
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1COCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
336 μl 2,2,2-Trifluoroethanol were dissolved in 10 ml dimethylformamide. 243 mg sodium hydride were added and the mixture stirred at room temperature for one hour. Then 1.0 g 2-Bromomethyl-4-fluoro-benzonitrile were added in one portion and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was poured on 50 ml water and extracted five times with portion of 25 ml ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=4:1 to obtain 750 mg 4-Fluoro-2-(2,2,2-trifluoro-ethoxymethyl)-benzonitrile.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-])=O)=[CH:9][CH:10]=2)[C:5]=1[OH:23])[CH:2]=[CH2:3].C(O)C.[H][H]>CC(C)=O.[Pd]>[CH2:1]([C:4]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]2[C:6](=[CH:7][C:8]([NH2:20])=[CH:9][CH:10]=2)[C:5]=1[OH:23])[CH2:2][CH3:3]
Reactant: C=CCc1c(-c2ccccc2)cc2ccc([N+](=O)[O-])cc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCc1c(-c2ccccc2)cc2ccc(N)cc2c1O

Procedure:
14 g of 2-Allyl-3-phenyl-7-nitro-1-naphthol prepared in step (4) were dissolved in 200 ml of acetone. 300 ml of ethanol and one pinchful of a 10% palladium on charcoal catalyst were added. The resulting mixture was hydrogenated at room pressure and temperature until the theoretical amount of hydrogen was absorbed. The catalyst was then removed by filtration and the residual solution was evaporated to dryness under reduced pressure. The resulting crystals were washed with petroleum ether, filtered off and dried under sulfuric vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[CH2:30]([NH2:33])[C:31]#[CH:32].ClCCl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14]([NH:33][CH2:30][C:31]#[CH:32])=[O:25])[CH2:7]1
Reactant: C#CCN
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 79.1 %

Procedure:
Example 57 was prepared in an analogous manner to Example 43 from Intermediate 13 (0.1 g) and propargylamine (0.014 g) using dichloromethane and triethylamine at a temperature of 22° C. to yield the title compound (0.064 g).