Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]([O:24][CH3:6])=[N:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: C[O+](C)C
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
77.5 mg trimethyloxonium tetrafluoroborate was added to 100 mg 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 2 mL dichlormethane at 0-5° C. The reaction mixture was stirred over night at RT. The reaction was washed with saturated sodium hydrogencarbonate solution and water and evaporated to yield 100 mg of the desired product. Rt: 0.79 min (method B), (M+H)+: 229
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>ClCCl>[CH2:22]([O:21][C:19](=[O:20])[NH:7][C:4]1[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 68.8 %

Procedure:
1,4-Phenylenediamine (10 g, 0.093 mol) was stirred rapidly in dichloromethane (800 mL) with diisopropylethylamine (16 mL, 0.093 mol) and the solution cooled to 0° C. A solution of benzyl chloroformate (13 mL, 0.093 mol) in dichloromethane (100 mL) was added very slowly via a dropping funnel. The reaction was left to warm to room temperature over 16 h and concentrated in vacuo. The remaining residue was purified by column chromatography on silica eluting with ethyl acetate/petroleum ether (using a gradient from 25% to 80%) to give 1 as a cream solid (15.5 g, 69.6%). 1H NMR (CDCl3, 400 MHz) δ 3.56 (s(br), 2H, NH2), 5.18 (s, 2H, CH2), 6.45 (s(br), 1H, NH), 6.64 (d, 2H, J=8.8 Hz, ArH), 7.15 (d, 2H, J=6.9 Hz, ArH), 7.36 (m, 5H, ArH).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH2:18][OH:19])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[Cl:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[O:29])[CH2:27]Br)[N:25]=1>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:17][CH2:18][O:19][C:26]([OH:29])([C:24]3[N:25]=[C:21]([Cl:20])[S:22][CH:23]=3)[CH2:27]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: O=C(CBr)c1csc(Cl)n1
Product: COC(=O)COc1ccc(CC(C)N2CCOC(O)(c3csc(Cl)n3)C2)cc1

Procedure:
from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-ethanamine and 2-chloro-4-bromoacetyl-thiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[CH2:19][N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:20]([CH2:19][C:18]3[CH:26]=[CH:27][CH:28]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:21]2)=[CH:3][CH:4]=1
Reactant: COc1cccc(CN2CCC(=O)C2)c1
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(Cl)cc3)C2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To 1-bromo-4-chlorobenzene (424 mg, 2.21 mmol) in tetrahydrofuran (10 mL), at −78° C., was added n-butyllithium (1.0 mL of a 2.5 M solution in hexanes, 2.4 mmol) dropwise. After 0.5 h, a solution of the ketone (500 mg, 2.43 mmol) from Step B above in tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 0.5 h and then warmed to 0° C. After 1.5 h, the reaction mixture was quenched with saturated ammonium chloride (5 mL) and warmed to ambient temperature. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated ammonium chloride (20 mL), water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (5% ethyl acetate/methylene chloride to 80% ethyl acetate/methylene chloride) gave 3-(4-chlorophenyl)-1-(3-methoxybenzyl)pyrrolidin-3-ol (250 mg, 35%) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 7.50-7.42 (m, 2H), 7.34-7.29 (m, 2H), 7.27-7.22 (m, 1H), 6.96-6.91 (m, 2H), 6.83-6.80 (m, 1H), 3.82 (s, 3H), 3.57 (br s, 2H), 2.89-2.75 (m, 2H), 2.51-2.41 (m, 2H), 2.21-2.08 (m, 2H), 1.73-1.69 (m, 2H), 1.57 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]([O:24][CH3:25])[C:13](=[O:23])[CH:14]=[C:15]2[C:19](=[O:20])OC(C)(C)[O:16]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:26]=O.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]([O:24][CH3:25])[C:13]([C:14]2[CH2:26][N:28]([CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:19](=[O:20])[C:15]=2[OH:16])=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON(CCCc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NCCN1CCOCC1
Reactant: C=O
Solvent: CO
Product: CON(CCCc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 42 %

Procedure:
Reaction of N-[3-(3,4-dichlorophenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide (0.378 g, 0.97 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.196 g (42% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 1.98 (2H, m, CH2), 2.49 (4H, broad, 2×NCH2), 2.58 (2H, t, J=6.2 Hz, CH2), 2.63 (2H, t, J=7.5 Hz, CH2), 3.63 (2H, t, J=6.2 Hz, NCH2), 3.68 (4H, broad, 2×OCH2), 3.71 (3H, s, OCH3), 3.74 (2H, t, J=7.0 Hz, NCH2), 4.23 (2H, s, NCH2), 7.02 (1H, dd, J=2.0 Hz and J=8.2 Hz, aromatic), 7.28 (1H, d, J=2.0 Hz, aromatic), 7.34 (1H, d, J=8.2 Hz, aromatic). HRMS (FAB+) calculated for C21H28Cl2N3O5: [M+H]+: 472.140602. found: 472.138651.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[C:5]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:19])[CH:10]=1)(=[O:7])[CH3:6]>O>[C:5]([NH:8][C:9]1[C:18]([N+:1]([O-:4])=[O:2])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:19])[CH:10]=1)(=[O:7])[CH3:6].[C:5]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:19])[C:10]=1[N+:1]([O-:3])=[O:2])(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(NC(C)=O)cc1Cl
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1Cl
Product: COC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1Cl
Yield: 22 %

Procedure:
Fuming nitric acid (26 ml) was cooled to −35° C. and stirred. Methyl 4-acetamido-2-chlorobenzoate (6.5 g) was added at from −35° C. to −25° C., and the mixture was stirred for 3 hr. The reaction mixture was ice-cooled and H2O (260 ml) was poured therein, which was followed by stirring. The resulting crystals were collected by filtration, washed with water and dried with air. This was applied to flash silica gel column chromatography (silica gel 100 g) to give methyl 4-acetamido-2-chloro-5-nitrobenzoate as thin yellow crystals (5.32 g) and methyl 4-acetamido-2-chloro-3-nitrobenzoate as a yellow solid (ca. 1.7 g, 22% yield).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CC[N:25](C(C)C)[CH:26]([CH3:28])[CH3:27].CC(N)C>CS(C)=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(C)N
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)C)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol) in DMSO (10 mL) was added DIEA (489 mg, 3.79 mmol) and propan-2-amine (149.4 mg, 2.53 mmol) under nitrogen atmosphere. After stirring overnight at 70° C., the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3×80 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue. Purification via silica gel column chromatography (2% ethyl acetate in petroleum ether) afforded methyl 2-(4-fluorophenyl)-3-(isopropylamino)quinoxaline-6-carboxylate as a light yellow solid (100 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][C:12](SC)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH:20]([OH:36])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:24]=1.C(OCC)C>C(Cl)(Cl)Cl>[OH:36][CH:20]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:24]=1)[CH2:19][NH:18][C:12]1[NH:11][C:10](=[O:17])[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:14][N:13]=1
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Reactant: NCC(O)COc1cccc(CN2CCCCC2)c1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cc2cnc(NCC(O)COc3cccc(CN4CCCCC4)c3)[nH]c2=O)cn1
Reaction time: 2.5 h
Yield: 38.9 %

Procedure:
A mixture of 5-(6-methyl-3-pyridinylmethyl)-2-methylthio-4(3H)-pyrimidinone (1.24 g) and 1-amino-3-[3-[1-piperidinylmethyl]phenoxy]-2-propanol (Compound A) (1.32 g) was heated at 120° for 1.5 h and then at 130°-140° for 2.5 h. The resulting brown glass was dissolved in chloroform (25 ml) and added to stirred dry diethyl ether (250 ml) to precipitate a white solid (1.5 g). This solid was recrystallised from ethyl acetate to give the title compound (0.9 g) as a white solid, m.p. 115°-117°.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH2:9]([C:11]1[C:33]([F:34])=[CH:32][C:14]([O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:21])=[CH:18][C:17]=2[F:31])=[C:13]([OH:35])[CH:12]=1)[CH3:10].[C:36](OCC)(=O)C>CO.O.O>[CH2:9]([C:11]1[C:33]([F:34])=[CH:32][C:14]([O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:36][N:3]4[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)[C:24](=[O:28])[CH2:23]3)=[O:21])=[CH:18][C:17]=2[F:31])=[C:13]([OH:35])[CH:12]=1)[CH3:10]
Reactant: CCc1cc(O)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Reactant: CCOC(C)=O
Reactant: C1COCCN1
Agent: C=O
Solvent: CO
Solvent: O
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CCN(CN4CCOCC4)C(=O)C3)cc2F)cc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Formaldehyde (37% in water, 30 μL, 0.32 mmol) and morpholine (28 μL, 0.32 mmol) were successively added to a solution of 4-[4-(4-ethyl-5-fluoro-2-hydroxyphenoxy)-3-fluorobenzoyl]-piperazin-2-one (which may be prepared in accordance with the experimental described in Example 7, step 1; 100 mg, 0.26 mmol) in a mixture of methanol/H2O (0.8 mL/0.8 mL). The mixture was stirred at 40° C. for 2 hours prior to the addition of more formaldehyde (37% in water, 30 μL, 0.4 mmol) and more morpholine (32 μL, 0.4 mmol). The reaction mixture was then stirred at 40° C. for two days. The reaction mixture was diluted by addition of ethyl acetate (20 mL) and water (20 mL). After separation, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (98:2 to 96:4) as eluent. The title product was obtained as a white solid (55 mg, 44%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([O:15][C@@H:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33]>CCOC(C)=O>[Br-:30].[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([O:15][C@@H:16]1[CH:21]2[CH2:20][CH2:19][N+:18]([CH2:31][C:32](=[O:33])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([CH2:23][CH2:22]2)[CH2:17]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OCc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1)OCc1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.9 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(benzyloxycarbonylamino)-2-phenylacetate (C29) (100 mg, 0.25 mmol) in EtOAc (5 ml), was added 2-bromo-1-phenylethanone (55.5 mg, 0.28 mmol), and the reaction was stirred at RT for 15 hours. The solvent was evaporated, and the resulting crude was purified by silica gel flash chromatography (DCM/MeOH=93/7) to obtain (3R)-3-(2-(benzyloxycarbonylamino)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (127.5 mg; 85% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: ClCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 3-chlorobenzyl chloride (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 307 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH3:23].N1C=CC=CC=1>ClCCl>[NH3:1].[CH2:14]([N:11]1[CH2:12][CH2:13][C:8]([CH3:20])([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:24]([CH2:21][CH2:22][CH3:23])(=[O:26])=[O:25])[CH:3]=2)[CH2:9][CH2:10]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN1CCC(C)(c2cccc(N)c2)CC1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CCC(C)(c2cccc(NS(=O)(=O)CCC)c2)CC1
Product: N
Temperature: 25 °C
Reaction time: 20 h
Yield: 161.7 %

Procedure:
To 4-(3-aminophenyl)-N-hexyl-4-methylpiperidine (Preparation 56, 72.0 mg, 0.26 mmol) in dichloromethane (1 ml) was added n-propanesulfonyl chloride (75 mg, 0.53 mmol) in dichloromethane (1 ml) and pyridine (42 mg, 0.53 mmol) in dichloromethane (1 ml) at room temperature. The solution was stirred at room temperature for 20 h, then it was concentrated in vacuo to give the crude product. This was purified by silica column chromatography eluting with ethyl acetate:0.880 ammonia (100:1) to give the title compound as a colourless oil (80 mg, 80%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].NC[C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([OH:38])=[O:37].O.[CH3:44][N:45]1C(=O)CCC1>>[C:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([NH:45][CH2:44][C:41]1[CH:42]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:39][CH:40]=1)=[O:31])=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: NCc1ccccc1C(=O)O
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hexadecanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (370 mg, 0.842 mmol) was dissolved in NMP (8 mL), 4 aminomethyl benzoic acid (127.2 mg, 0.842 mmol) was added, the mixture was stirred at room temperature overnight, followed by heating at for 2 hours at 50 degrees celcius. After cooling to room temperature the mixture was poured into water. Product isolated by filtration dried and used for the next step without any further purification.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][C:3]1([CH3:31])[CH3:30].[H-].[Na+].Br[CH2:35][CH2:36][CH2:37][CH2:38]Br>O1CCCC1>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([O:1][CH2:35][CH2:36][CH2:37][CH2:38][O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][C:3]2([CH3:30])[CH3:31])[C:3]([CH3:30])([CH3:31])[CH2:4]1)(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OCCCCON2C(C)(C)CC(OC(=O)CCCCCCCCCCCCCCCCC)CC2(C)C)C(C)(C)C1

Procedure:
The title compound is prepared by reaction of a tetrahydrofuran solution of 1-hydroxy-4-octadecanoyloxy-2,2,6,6-tetramethylpiperidine with sodium hydride followed by reaction with 0.5 molar equivalent of 1,4-dibromobutane.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][C:2]1=[CH:6][CH:7]=[CH:8]N.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH3:12][CH:11]1[CH2:7][CH:6]=[CH:2][CH2:3][CH2:4][CH:5]=[CH:8][CH2:7][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:13]=[CH:10]1
Reactant: C=CCN
Reactant: NC=CC=C1CC=CO1
Product: CC1C=NC(c2ccco2)CC=CCCC=CC1

Procedure:
The procedure described in Example (1a) is repeated, except that 273 g (2.02 mols) of N-2-furylidenepropenylamine [prepared by reaction of 2-furylaldehyde with allylamine and subsequent isomerisation in the presence of potassium tert.-butylate; boiling point 60°-62° C./67 Pa; nD20 =1.6004] are used. Distillation yields 210 g (0.865 mol) of 3-methyl-12-(2-furyl)-1-aza-1,5,9-cyclododecatriene; boiling point 106°-108° C./4 Pa; nD20 =1.5260.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CCN(C(C)C)C(C)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCCC1>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[NH:14][C:25](=[O:27])[O:1][N:2]=2)=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(N)=NO)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(=O)[nH]2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)—N′-hydroxy-4-methyl-3-nitrobenzimidamide (27) (30 g, 153.71 mmol, 1.00 equiv) and DIEA (39.7 g, 307.18 mmol, 2.00 equiv) in tetrahydrofuran (300 mL) was added dropwise to a solution of triphosgene (18.2 g) in tetrahydrofuran (50 mL). The reaction was stirred for 1 hour at room temperature then heated to reflux for an additional hour. The resulting solution was poured into 500 mL of water and extracted with 3×300 mL of ethyl acetate. The combined organic layers were washed with brine (3×200 mL), dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by flash chromatography (DCM/MeOH=20:1) to afford of 3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5(4H)-one as a pale yellow solid (106). MS m/z 222.1 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH:23]=2)[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][C:9]1([CH3:34])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH:23]=2)[CH2:10]1
Reactant: CS(N)(=O)=O
Reactant: Cn1nnnc1-c1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnnc1-c1cccc(C2CC(C)(C)c3cc(C(=O)NS(C)(=O)=O)ccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (655.5 mg, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A44. A solution of 4,4-dimethyl-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (254.1 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B44. Solution B44 was added to Solution A44 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{4,4-dimethyl-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (97.8 mg, 30%) as a white solid: MS (ESI) M+1=441.1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)OCC[O:3]1.CN(C)CCN(C)C.C([Li])CCC.[C:25](=[O:27])=[O:26]>O1CCCC1>[C:2]([C:7]1[S:8][C:9]([C:25]([OH:27])=[O:26])=[CH:10][CH:11]=1)(=[O:3])[CH3:1]
Reactant: O=C=O
Reactant: CC1(c2cccs2)OCCO1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)O)s1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-Methyl-2-(2-thienyl)-1,3-dioxolan (6.6 g) (synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) was dissolved in tetrahydrofuran (200 ml), and N,N,N', N'-tetramethylethylenediamine (5.87 ml) was added. The mixture was cooled to -78° C., and n-butyllithium (1.6M in hexane, 25 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours, and warmed slowly to room temperature for a period of 2 hours with introducing carbon dioxide gas. The reaction mixture was concentrated under reduced pressure, and 2N hydrochloric acid (200 ml) was added. The mixture was stirred for 3 hours, and precipitated crystals were collected by filtration, washed with water and dried to give 5-acetyl-2-thiophenecarboxylic acid (3.87 g) as crystals.