Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58]O>>[ClH:1].[CH3:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1
Reactant: COCCOCCOCCOCCOCCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COCCOCCOCCOCCOCCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2,5,8,11,14-pentaoxahexadecan-16-ol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethyl ester, hydrochloride. MS (ES+) m/z calcd. for C42H52Cl2F2N3O9: [(M+H)+]851. found: 851.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[CH:10]([O:13][CH2:14]Cl)([CH3:12])[CH3:11]>>[CH:10]([O:13][CH2:14][O:2][C:1]1[CH:9]=[CH:8][CH:7]=[C:5]([O:6][CH2:14][O:13][CH:10]([CH3:12])[CH3:11])[C:3]=1[O:4][CH2:14][O:13][CH:10]([CH3:12])[CH3:11])([CH3:12])[CH3:11]
Reactant: CC(C)OCCl
Reactant: Oc1cccc(O)c1O
Product: CC(C)OCOc1cccc(OCOC(C)C)c1OCOC(C)C

Procedure:
Using pyrogallol in place of phloroglucinol used in Synthesis Example 13 and isopropoxymethylchloride obtained in Synthesis Example 2, the reaction and treatment were carried out in the same manner as described in Synthesis Example 13 to give the corresponding 1,2,3-tris(isopropoxymethoxy)benzene as a yellow oil.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[H-].[Na+].[OH:18][C:19]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20]1.Cl>O1CCCC1.O>[CH3:25][O:24][C:22]([C:19]1([O:18][C:2]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=2)[CH2:21][CH2:20]1)=[O:23]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C
Reactant: COC(=O)C1(O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(OC2(C(=O)OC)CC2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Methyl 4-fluoro-2-methyl-5-nitrobenzoate (43.0 g) was dissolved in tetrahydrofuran (300 ml), and thereto was added sodium hydride (55%, 9.60 g) at 0° C., and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of methyl 1-hydroxy-1-cyclopropanecarboxylate (22.0 g) in tetrahydrofuran (300 ml) at 0° C., and the mixture was further stirred at room temperature for 3 hours. The mixture was cooled to room temperature, and water (100 ml) was added to the reaction mixture. The mixture was neutralized by addition of 1N aqueous hydrochloric acid solution, and extracted twice with ethyl acetate (300 ml). The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resultant was purified by silica gel column (hexane/ethyl acetate=3:1) to give the title compound (58.0 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([NH2:8])=[NH:7].[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[F:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:7][C:6](=[NH:8])[C:5]2[CH:9]=[CH:10][C:11]([F:12])=[C:3]([Cl:2])[CH:4]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: N=C(N)c1ccc(F)c(Cl)c1
Agent: Cl
Product: N=C(NS(=O)(=O)c1ccc(F)c(Cl)c1)c1ccc(F)c(Cl)c1

Procedure:
A mixture of 3-chloro-4-fluorobenzamidine hydrochloride (0.025 g, 0.133 mmol) and 3-chloro-4-fluorophenyl sulfonylchloride (0.0304 g, 0.133 mmol); the title compound is prepared essentially as described in Example 115. ES Positive Ion MS [M+H]+ ions observed: m/z 365 (35Cl, 35Cl), m/z 367 (35Cl, 37Cl) and m/z 369 (37Cl, 37Cl).
Reaction SMILES: [N:1]1([C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2CC2C=CC=CC=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[N:1]1([C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C1CCCN1Cc1ccccc1)N1CCCC1
Agent: [Pd]
Solvent: CCO
Product: O=C(C1CCCN1)N1CCCC1
Yield: 92.1 %

Procedure:
In ethanol (300 ml) is suspended 5% palladium-carbon (3 g), and thereto is added 2-(1-pyrrolidinyl)carbonyl-1-benzylpyrrolidine (30 g), and the mixture is subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The mixture is filtered, and the filtrate is concentrated under reduced pressure to remove the solvent to give 2-(1-pyrrolidinyl)carbonylpyrrolidine (about 18 g) as an oily product.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14].[H-].[Na+]>CN(C=O)C>[I:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc2[nH]cnc2c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ncn2COCC[Si](C)(C)C)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 4-Iodo-5-methyl-1H-benzoimidazole (100 mg, 0.39 mmol, Example 287: step a) and SEMCl (71 mg 0.43 mmol) in 2 mL of DMF under Ar was added NaH (11 mg, 0.43 mmol). The mixture was stirred at RT for 4 h and purified directly by PTLC (25% EtOAc/hexane) to give 122 mg (81%) of product as a colorless oil: 1HMR (CDCl3; 400 MHz) δ 7.95 (s, 1H), 7.37 (d, 1H, J=8.4 Hz), 7.21 (d, 1H, J=8.4 Hz), 5.48 (s, 2H), 3.47 (t, 2H, J=8.3 Hz), 2.59 (s, 3H), 0.89 (t, 2H, J=8.3 Hz), −0.06 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C14H21IN2OSi, 389.1 (M+H), found 389.0.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([N:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[O:9][C:10]([F:11])([F:12])[F:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)Oc1cc(Br)ccc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
To a mixture of 4-bromo-2-(trifluoromethoxy)aniline (5 g, 19.53 mmol) and potassium carbonate (8.09 g, 58.89 mmol) in acetonitrile (200 mL) was added (bromomethyl)benzene (6.96 mL, 58.59 mmol) and the mixture was refluxed for 20 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 5/1 petroleum ether/ethyl acetate to give the title compound. MS: 436 (M+H+)
Reaction SMILES: Cl.[F:2][C:3]1([F:38])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])[C:14](=[O:37])[CH:13]=3)=[CH:11][C:5]=2[O:4]1>C(O)C.O>[F:38][C:3]1([F:2])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([NH:24][OH:25])=[O:23])[C:14](=[O:37])[CH:13]=3)=[CH:11][C:5]=2[O:4]1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc3c(c2)OC(F)(F)O3)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@@](CCn1cc(F)c(-c2ccc3c(c2)OC(F)(F)O3)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Aqueous HCl (1.42 mL, 1.42 mmol) was added to a solution of (2R)-4-[4-(2,2-Difluoro-1,3-benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (259 mg, 0.474 mmol) in ethanol (5 mL) and water (2 mL) and the reaction was stirred overnight at rt. The solid was collected via filtration, washed with water (5×3 mL) and dried under reduced pressure to afford the title compound (143 mg, 65.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.07-2.24 (m, 1H) 2.36-2.49 (m, 1H) 3.11 (s, 3H) 3.68-3.86 (m, 1H) 3.98-4.13 (m, 1H) 6.58 (d, J=7.61 Hz, 1H) 7.36-7.49 (m, 1H) 7.55 (d, J=8.39 Hz, 1H) 7.68 (s, 1H) 8.06 (d, J=6.63 Hz, 1H) 9.24 (br. s., 1H) 11.08 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][NH:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CNCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCNCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}glycinate (D86) (132 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (40 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated to about 5 mL and then HCl aquous solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL) and water (5 mL). The mixture was acidified with HCl (1 M) solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}glycine (E63) (80 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 3.11-3.38 (4H, m), 3.61 (2H, s), 4.88-4.94 (1H, m), 7.26 (1H, t), 7.38 (1H, d), 7.47 (1H, d), 7.86 (1H, d), 7.97 (1H, d), 8.21 (1H, dd), 8.38 (1H, d), 11.00 (1H, br s). MS (ES): C23H23ClN4O4 requires 454; found 455.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[BrH:30].[S:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:30].[CH3:29][C:2]1([CH3:1])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([O:19][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][N:34]3[CH2:33][CH2:32][S:31][CH2:36][CH2:35]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(C)C
Reactant: O=C(O)CCCN1CCSCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCSCC3)cc(C(C)C(C)CCCCC)cc1OC2(C)C

Procedure:
Equimolar amounts of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-thiomorpholinobutyric acid hydrobromide and dicyclohexylcarbodiimide are reacted to form the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:29]([C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:30]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)c1

Procedure:
Prepared analogously to Example 1 from 3-methoxybenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of 4-fluorophenylmagnesiumbromide (1.0 M in THF, 4.4 mL, 4.4 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1973 g, 1.08 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.3152 g, 88.9%). EI-MS m/z 330(M+H+) Rt (1.65 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:24]([CH3:27])([O-:26])=[O:25]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:27]/[N+:24]([O-:26])=[O:25])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
Commercially available 3-benzyloxy-4-methoxybenzaldehyde (30 g, 124 mmol) was dissolved in acetic acid (100 mL), then ammonium acetate (10.8 g, 140 mmol) and nitromethane (16.8 mL, 310 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2 hours and 20 minutes. The mixture was cooled to room temperature, then the precipitate was collected by filteration and washed with ethanol to obtain the title compound (28.5 g, 81%).
Reaction SMILES: [C:1]([C:3]1[CH2:4][O:5][CH2:6][CH:7]=1)#[N:2].C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:22]([N:29]([CH2:35]OC)[CH2:30][Si](C)(C)C)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([N:29]1[CH2:30][C:3]2([C:1]#[N:2])[CH:7]([CH2:6][O:5][CH2:4]2)[CH2:35]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#CC1=CCOC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#CC12COCC1CN(Cc1ccccc1)C2

Procedure:
A solution of 5.2 g (24.6 mmol, 46% strength) of 3-cyano-2,5-dihydrofuran in 50 ml of absolute methylene chloride is mixed with 0.3 g of triethylamine and 0.3 g of trifluoroacetic acid, the mixture is heated under reflux and then 7 g (29.5 mmol) of N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)-amine are added dropwise. Subsequently, the mixture is heated under reflux for 2 hours and the solution is washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulphate, concentrated and distilled. Yield: 4.5 g (80% of theory). Boiling point: 140°-145° C./0.03 mbar
Reaction SMILES: N1C(C)=CC=CC=1C.[C:9]([O:17][C@@H:18]([CH3:39])[C:19](=[O:38])[C@H:20]([CH3:37])[C@H:21]([OH:36])/[C:22](/[CH3:35])=[CH:23]/[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Si:40](OS(C(F)(F)F)(=O)=O)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].C(=O)([O-])O.[Na+]>ClCCl>[C:9]([O:17][C@@H:18]([CH3:39])[C:19](=[O:38])[C@H:20]([CH3:37])[C@H:21]([O:36][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])/[C:22](/[CH3:35])=[CH:23]/[CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(COC/C=C(\C)[C@@H](O)[C@@H](C)C(=O)[C@H](C)OC(=O)c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(COC/C=C(\C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)[C@H](C)OC(=O)c2ccccc2)cc1
Temperature: -78 °C
Yield: 100.4 %

Procedure:
2,6-Lutidine (38.2 ml, 328 mmol) was added to an anhydrous dichloromethane (1.00 l) solution of (1S,3R,4S,5E)-4-hydroxy-7-[(4-methoxybenzyl)oxy]-1,3,5-trimethyl-2-oxohept-5-en-1-yl benzoate (70.0 g, 164 mmol) at −78° C. under nitrogen atmosphere. Trifluoromethanesulfonic acid tert-butyldimethylsilyl ester (56.5 ml, 246 mmol) was added dropwise to the reaction solution over 10 minutes. After the reaction solution was stirred at −78° C. for one and a half hour, a saturated sodium hydrogen carbonate aqueous solution was added at −78° C. The reaction solution was warmed to room temperature, which was then extracted with dichloromethane. After the organic layer was washed with water and brine sequentially, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=8:1) to obtain the title compound (89.0 g) as a colorless oil.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[N+:12]([C:15]1[CH:24]=[CH:23][C:18](/[CH:19]=[CH:20]/[CH:21]=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].[N:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>ClCCl>[OH:26][N:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21](=[O:22])/[CH:20]=[CH:19]/[C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:24][CH:23]=1
Reactant: O=C/C=C/c1ccc([N+](=O)[O-])cc1
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(/C=C/c1ccc([N+](=O)[O-])cc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (7.5 mg, 0.05 mmol) was added under argon to a solution of (E)-4-nitrocinnamaldehyde (177 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (18.2 mg, 0.05 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH2:1]([N:6]([CH2:10][CH:11]=[CH2:12])C(=O)C)/[CH:2]=[CH:3]/[CH:4]=[CH2:5]>C1(C)C(C)=CC=CC=1>[CH:11]12[CH2:10][NH:6][CH2:1][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:12]2
Reactant: C=C/C=C/CN(CC=C)C(C)=O
Solvent: Cc1ccccc1C
Product: C1=CC2CNCC2CC1

Procedure:
Dissolve 33.1 g (0.2 mol) of N-[(E)-2,4-pentadienyl]-N-(2-propenyl)-acetamide (title compound of Example A.3.) in 200 ml of xylene, pass through a vigorous stream of nitrogen for 15 min, add 0.1 g of 4-hydroxyanisole, then reflux overnight. Concentrate and distil under a high vacuum.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][C:7]=1[C:19]([F:22])([F:21])[F:20])=[O:5])C.[OH-].[K+].O.Cl>C1COCC1.C(O)C>[C:15]([O:14][C:12]([NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:19]([F:21])([F:22])[F:20])[N:8]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)nc1C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(C(F)(F)F)c(C(=O)O)s1
Temperature: 60 °C
Yield: 98.5 %

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (6.67 g, 19.60 mmol) in THF (42 mL) and ethanol (63 mL) was added aqueous 6N potassium hydroxide (100 mL) cautiously at 25° C. and heated at 60° C. for 20 h. The reaction mixture was cooled to room temperature, added water (200 mL), cooled in an ice bath with stirring at 0° C., cautiously acidified to pH 1 with concentrated HCl and extracted with ethyl acetate (3×200 mL). The organic layers were combined, washed with brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 2-tert-Butoxycarbonylamino-4-trifluoromethyl-thiazole-5-carboxylic acid (6.03 g, 100%) as a pale yellow solid.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[O:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[O:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:13]([O:12][C@@H:10]([C@@H:6]1[C@@H:5]([C@H:22]2[C:21](=[O:20])[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=3)[O:24][CH2:23]2)[NH:8][C:7]1=[O:9])[CH3:11])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCO2
Reactant: CC(=O)O[C@H]1NC(=O)[C@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(=O)[C@H]([C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C)CO2

Procedure:
Starting from 960 mg (3.35 mmol) of (3S, 4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one and 1.03 g (5.0 mmol) of methyl 4-oxochroman-6-yl carboxylate, 370 mg (25%) of the less polar diastereomer were obtained after chromatography (eluent: toluene/ethyl acetate=10: 1, 1.11, then 2:1) as described under step 1 in Example 14. -1H-NMR (270 MHz, CDCl3): 6 m 0.08 and 0.10 (2×1s, 2×3H, SiCH3); 0.90 (s, 9H, SiC(CH3)3); 1.28 (d, 3H, CH--CH3); 2.85-2.98 (m, 2H, O--CH2 --CH and H-3); 3.72 (dd, 1H, H-4); 3.92 (s, 3H, CO2CH3); 4.18 (mc, 1H, CH--CH3); 4.32 and 4.65 (2×mc, 2×1H, O--CH2 --CH); 6.26 (bs, 1H, NH); 7.03 (d, 1H, aromatic H); 8.18 (dd, 1H, aromatic H) 8.59 (d, 1H, aromatic H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-n1cccc1
Agent: [Pd]
Product: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1-n1cccc1

Procedure:
The title compound was prepared from (5-methoxy-2-nitro-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example A4) (5.52 g, 16.6 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light pink solid (4.1 g).