Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:49]=[CH:48][CH:47]=[CH:46][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[C:20]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]4[CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]4)=[CH:31][CH:30]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:37]1[CH2:38][CH:35]([C:32]2[CH:33]=[CH:34][C:29]([NH:28][C:20]3[N:19]=[C:18]([CH2:17][CH2:16][C:15]4[CH:46]=[CH:47][CH:48]=[CH:49][C:14]=4[C:11]4([C:8]([NH2:9])=[O:10])[CH2:12][CH2:13]4)[C:23]([C:24]([F:26])([F:25])[F:27])=[CH:22][N:21]=3)=[CH:30][CH:31]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CNC4)cc3)ncc2C(F)(F)F)CC1
Yield: 89.6 %

Procedure:
A solution of TFA (0.916 mL, 12.0 mmol) and tert-butyl 3-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A9) (174 mg, 0.299 mmol) in DCM (10 mL) was stirred for 16 hours at room temperature under nitrogen. The volatiles were removed in vacuo and the residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 5 column volumes of 5% v/v aqueous ammonia in MeOH to elute the amine product. The ammoniacal filtrate was evaporated under reduced pressure and dried under high vacuum to give the title compound 4 as a yellow solid (129 mg, 90%); 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 8.68 (s, 1H), 7.77-7.67 (m, 2H), 7.38-7.26 (m, 5H), 7.26-7.18 (m, 1H), 6.99 (s, 1H), 6.00 (s, 2H), 3.86 (s, 3H), 3.71 (s, 2H), 3.22-3.13 (m, 2H), 3.13-3.05 (m, 2H), 1.44 (s, 2H), 0.96 (s, 2H). LCMS-A: rt 4.591 min; m/z 482 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]#[N:13])[C:9]([OH:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH:25][NH2:26])=O)=[CH:18][CH:17]=1.O1CCOCC1>C(O)(=O)C>[Br:1][C:2]1[N:11]=[C:10]([C:12]2[NH:13][C:23]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)=[N:25][N:26]=2)[C:9]([OH:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NNC(=O)Cc1ccc(F)cc1
Reactant: N#Cc1nc(Br)c2cccnc2c1O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(Br)c2cccnc12
Temperature: 200 °C
Yield: 21.2 %

Procedure:
A suspension of 5-bromo-8-hydroxy-1,6-naphthyridine-7-carbonitrile (0.25 g, 9.99 mmol), 2-(4-fluorophenyl)acetic hydrazide (0.34 g, 2 mmol), 1,4-dioxane (2 mL) and acetic acid was heated at 200° C. for 10 minutes in a microwave chamber. The mixture was allowed to cool to room temperature, the precipitate was filtered and washed with dichloromethane. The filtrate was concentrated in vacuo, 1 N sodium hydroxide and ethyl acetate were added and the aqueous layer was washed with ethyl acetate. The aqueous layer was then acidified to pH 5 and the solids formed were collected. This material was azeotroped with methanol to provide 5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol (0.17 g, 42%) as a yellow solid. 1H NMR (CDCl3/CD3OD): δ 9.07 (dd, J=4.0, 1.2 Hz, 1 H), 8.50 (dd, J=8.4, 1.2 Hz, 1 H), 7.65 (dd, J=8.4, 4.0 Hz, 1 H), 7.26 (m, 2 H), 6.95 (m, 2 H), 4.11 (s, 2 H); MS m/z 400 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(N(CC)CC)C>[C:14]([O:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:16])[CH3:15]
Reactant: CCCCCC1C(=O)C=CC1(C)O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCC1C(=O)C=CC1(C)OC(C)=O

Procedure:
Into the same flask as used in Example 1, dl-3-hydroxy-2-n-pentyl-3-methyl-4-cyclopentenone (18.2 g), triethylamine (0.1 g) and acetic anhydride (36 g) were charged, and the resultant mixture was stirred at 60°-80° C. for 3 hours. After completion of the reaction, the reaction mixture was subjected to the same work-up as in Example 11, followed by purification to give 21.9 g of dl-3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone. Yield, 98%. B.P., 100°-110° C./0.1-0.3 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([NH:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: NC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)NC2CCCCC2)C1
Temperature: 80 °C
Yield: 2 %

Procedure:
A solution of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (500 mg, 1.63 mmol) in oxalyl chloride (2.0 g, 16.33 mmol) was stirred at 25° C. for 3 h. After completion of the reaction (monitored by LCMS), cyclohexyl amine (1.0 ml, excess) was added to it and the reaction mixture heated at 80° C. for 3 h. The reaction mixture was concentrated and basified with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was concentrated to dryness and the resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to obtain 10 mg (yield: 2.0%) of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-N-cyclohexylacetamide as TFA salt. 1H NMR (DMSO) 10.0 (bs, 1H), 8.30 (d, 1H), 7.60 (s, 1H), 7.5 (d, 1H), 7.21 (d, 1H), 4.80 (m, 2H), 4.6 (m, 1H), 4.30 (m, 1H), 3.80 (m, 1H), 3.41 (m, 2H), 3.10 (bs, 2H), 3.0 (s, 3H), 1.80-1.20 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=O)[O:19]C3C=CC([N+]([O-])=O)=CC=3)[C:12]([C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)=[CH:11][S:10]2)=[CH:4][CH:3]=1.[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][NH2:46].[OH-].[Na+]>ClCCl>[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][NH:46][C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:13]1[C:12]([C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[CH:11][S:10][C:9]1=[N:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:19]
Reactant: O=C(NCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)CCNC(=O)NCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Reaction time: 1 h
Yield: 85.3 %

Procedure:
The compound (108 mg) obtained in Example 348 was dissolved in dichloromethane (3 ml), and thereto was added N,N-dimethylethylenediamine (33 mg) at room temperature under nitrogen atmosphere, and the mixture was stirred for one hour. To the reaction mixture was added 1% aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (84 mg) as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[N:17]=[C:16]([C:18](=O)[CH3:19])[CH:15]=[CH:14][CH:13]=1)[CH3:11].[CH2:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:18]([C:16]1[N:17]=[C:12]([C:10](=[N:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH3:11])[CH:13]=[CH:14][CH:15]=1)[CH3:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1
Solvent: Cc1ccccc1
Product: CCCCc1ccccc1N=C(C)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
1-{6-[1-(2,6-Dimethyl-phenylimino)-ethyl]-pyridin-2-yl}ethanone 1 (2.3 g, 0.0088 mol), 1.68 g (0.0244 mol) of 2-n-Butyl-phenylamine 12, 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under the flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 5 ml of ethanol. The yield of (1-{6-[1-(2-n-butyl-phenylimino)-ethyl]-pyridin-2-yl}-ethylidene)-(2,6-dimethyl-phenyl)-amine 11 was 2.60 g (76%) as a yellow solid. 13C NMR (500 MHz, CD2Cl2, TMS (selected signals)): δ 166.8 (C═N), 166.1 (C═N).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[N+:14]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2[C:20]([O:22][C:23](=O)[C:18]=12)=[O:21])([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2[C:18]=1[C:23](=[O:22])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:20]2=[O:21])([O-:16])=[O:15]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.27 g, 28%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 3-nitrophthalic anhydride (0.57 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [NH2:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>CCO>[CH2:15]([O:14][C:10](=[O:13])[CH2:11][CH2:12][NH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:16]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CC(C)N
Solvent: CCO
Product: CCOC(=O)CCNC(C)CC(=O)OCC

Procedure:
A solution of ethyl 3-aminobutanoate (4.2 g) and of ethyl 2-propenoate (3.83 mL) in EtOH (20 mL) was stirred at room temperature for 8 h. The solvent was evaporated under reduced pressure and the residue purified by chromatography on NH column eluting with a gradient from 100% cyclohexane to 90% ethyl acetate/cyclohexane. The title compound was isolated as a colourless oil, 3.9 g (MS (m/z): 232 [MH]+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][OH:14])[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:4]1)[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>>[CH2:1]([C:3]1([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:4]1)[CH3:2]
Reactant: CCC1(CO)CCC2(CCOCC2)O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCC1(COCc2ccccc2)CCC2(CCOCC2)O1
Yield: 24.8 %

Procedure:
Following procedures similar to those of Embodiments XVII-XIX, 2.50 g of 2-ethyl-1,8-dioxaspiro[4.5]decane-2-methanol was treated with 2.35 g of benzyl bromide in the presence of sodium hydride to yield 0.90 g of the desired product as a clear liquid, b.p. 130° C. (0.15 mm).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:10][C@H:9]([OH:11])[C@H:8]([OH:12])[CH2:7]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:12][C@H:8]1[C@@H:9]([O:11][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][O:6][CH2:7]1)(=[O:4])=[O:3]
Reactant: O[C@@H]1COC[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1COC[C@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methanesulfonyl chloride (1.642 mL, 21.13 mmol) in DCM (5 mL) was added to a solution of (3R,4S)-tetrahydrofuran-3,4-diol (0.787 mL, 9.61 mmol) and Et3N (4.05 mL, 28.8 mmol) in DCM (10 mL) at 0° C. After stirring at 0° C. for 1 h, the mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO3, dried, and concentrated in vacuo to give the title compound as a yellowish white solid (2.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 3.09-3.20 (m, 6H), 3.90-4.07 (m, 2H), 4.10-4.22 (m, 2H), 5.19 (ddd, J=5.31, 3.54, 1.77 Hz, 2H).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].C(N(CC)CC)C.[CH2:14]([S:21][CH2:22][CH2:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:1][CH:2]([CH3:6])[C:3]([O:24][CH2:23][CH2:22][S:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: CC(Br)C(=O)Br
Reactant: OCCSCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)OCCSCc1ccccc1

Procedure:
A solution of 21.6 g of 2-bromopropionyl bromide in 30 ml of toluene was added dropwise to a solution of 10.1 g of triethylamine and 16.8 g of 2-benzylthioethanol in 150 ml of toluene at room temperature whilst stirring. After the addition was completed, the reaction mixture was stirred for a further 2 hours at room temperature. The mixture was then washed successively with 1% strength by weight aqueous solution of sodium hydroxide and water. After drying the organic phase over anhydrous sodium sulphate, the toluene was distilled off under reduced pressure, and the end product of 2-benzylthioethyl 2-bromopropionate was obtained in a yield of 28.8 g as a colorless product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccccn1
Product: O=C(C=Cc1ccccn1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (100 mg, 0.316 mmol) and 2-pyridine carboxaldehyde (30 ul, 0.316 mmol) similar to Example 15 and isolated as a yellow solid (13 mg, 10%) 1H NMR (CDCl3): 8.68-8.65 (m, 1H), 7.79 (d, J=15.6 Hz, 1H), 7.72 (dd, J=1.7, 7.7 Hz, 1H), 7.64 (d, J=15.6 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.31-7.28 (m, 1H), 7.25 (s, 1H), 7.12 (dd, J=3.2, 8.9 Hz, 1H), 6.96 (d, J=9.3 Hz, 1H), 4.44-4.33 (m, 4H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:8]=[CH:9][N:10]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:11]=1[CH2:12][CH2:13][CH3:14]>ClCCl>[Cl:3][CH2:6][C:7]1[N:8]=[CH:9][N:10]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCc1c(CO)ncn1S(=O)(=O)N(C)C
Solvent: ClCCl
Product: CCCc1c(CCl)ncn1S(=O)(=O)N(C)C

Procedure:
A solution of thionyl chloride (0.12 ml) in dry dichloromethane (1.2 ml) was added dropwise to a cold (0°) stirred solution of 4-(hydroxymethyl)-N,N-dimethyl-5-propyl-1H-imidazole-1-sulphonamide (340 mg) in dry dichloromethane (7.5 ml) under nitrogen. After 1.5 h the solution was washed with 8% sodium bicarbonate solution (2×15 ml) and the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic extracts were washed with water (15 ml), dried and evaporated to give the title compound (180 ml) as an oil, t.l.c. (ethyl acetate) Rf 0.68.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCc3ccc([N+](=O)[O-])cc3CC2)cc1
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCN2CCc3ccc(N)cc3CC2)cc1

Procedure:
7-Nitro-3-(2-[4-nitrophenoxy]ethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine (0.42 g) was stirred at room temperature under a hydrogen atmosphere [344.7 kPa (50 p.s.i.)] in ethyl acetate containing 5% Pd/C for 4 hours. The catalyst was then removed by filtration and the filtration evaporated in vacuo to give the title compound as an oil, which was used directly without further purification, yield 0.3 g.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:38]([O:42][C:43]([NH:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH:48]([C:52]([OH:54])=O)[CH2:47]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>ClCCl.C(OCC)(=O)C>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:52]([CH:48]1[CH2:49][CH2:50][CH2:51][CH:46]([NH:45][C:43]([O:42][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:44])[CH2:47]1)=[O:54])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A solution of dibenzylamine (0.448 g, 2.27 mmol) in dichloromethane (3 ml), 1-hydroxybenztriazole (0.337 g, 2.49 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.477 g, 2.49 mmol) were added to a solution of 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (0.502 g, 2.06 mmol) in dichloromethane (7 ml) and stirred overnight. The resulting solution was diluted with ethyl acetate and washed with a 5%-aqueous potassium hydrogensulfate solution (twice), a saturated aqueous sodium hydrogencarbonate solution (twice) and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel chromatography (eluent: chloroform/ethyl acetate=20/1) to obtain tert-butyl 3-[(dibenzylamino)carbonyl]cyclohexanecarbamate (0.796 g, 91%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:28](=[O:43])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][N:39]=[N:38]2)[CH:32]=1)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([N:37]5[CH:41]=[N:40][N:39]=[N:38]5)[CH:32]=4)[CH2:29][C:28](=[O:43])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cnnn3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) and 3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (Example H15) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige powder (5.5 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].C([Mg]Br)C.[CH3:14][C:15]1([CH3:37])[O:20][C:19](=[O:21])[C:18](=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[CH:25][CH:24]=2)[C:17](=[O:36])[O:16]1>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][CH:22]([CH:18]1[C:17](=[O:36])[O:16][C:15]([CH3:14])([CH3:37])[O:20][C:19]1=[O:21])[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:27][CH:28]=1)[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: CC1(C)OC(=O)C(=Cc2ccc(OC3CCCCO3)cc2)C(=O)O1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOC(C#CC(c1ccc(OC2CCCCO2)cc1)C1C(=O)OC(C)(C)OC1=O)OCC
Reaction time: 0.75 h

Procedure:
Propiolaldehyde diethyl acetal (5 g, 39 mmol) in anhydrous THF (65 mL) was cooled to −5° C. and treated with ethylmagnesium bromide (39 mmol in 14 mL of anhydrous THF) dropwise over 10 min. After 45 min., the solution of Grignard reagent was added to compound 52.1 in anhydrous THF (50 mL). After stirring 1 h, the reaction was quenched with saturated NH4Cl(aq) (20 mL) and diluted with hexanes (100 mL). After mixing vigorously, the layers were separated and the organic layer discarded. The aqueous layer was acidified and extracted twice with diethyl ether. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used immediately without further purification. MS ESI (pos.) m/e: 478.3 (M+NH4)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].IC.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][C@:10]1([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:14]([CH3:33])[C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a solution of tert-butyl (3S)-3-{[tert-butyl (dimethyl) silyloxy]methyl}-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (8.65 g, 19.9 mmol) and iodomethane (1.37 mL, 21.9 mmol) in tetrahydrofuran (173 mL), lithium bistrimethylsilyl amide (21.9 mL, 21.9 mmol, 1M solution in tetrahydrofuran) was added in an ice bath, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, saturated aqueous solution of ammonium chloride (300 mL) was added, and the mixture was extracted with ethyl acetate (300 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 7:1→1:1) to obtain 3.72 g (42%) of the title compound (single component) as a colorless oily substance.