Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]I)C.C(OC(=O)CCCCCCI)C.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35].C(Cl)(=O)C1C=CC=CC=1.[NH2:46][OH:47].Cl>C(N(CC)CC)C>[OH:47][NH:46][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:34]([C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1)=[O:35]
Reactant: CCOC(=O)CCCCCI
Reactant: NO
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: CCOC(=O)CCCCCCI
Agent: Cl
Solvent: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCCCCC(=O)c1ccc2ccccc2c1)NO
Yield: 55 %

Procedure:
Following the procedure described in Example 18, step 1, 2, 3, but substituting respectively ethyl-6-iodohexanoate for ethyl-7-iodoheptanoate and 2-naphthoyl chloride for benzoyl chloride, and then the resulting carboxylic acid was substituted for 37 in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 111 in 55% yield. 1H NMR (300 MHz, 20% CD3OD in CDCl3): δ 8.47 (s, 1H), 8.05-7.50 (m, 6H), 3.12 (br t, 2H), 2.15 (br t, 2H), 1.82-1.60 (m, 4H), 1.46 (m, 2H). 13C NMR (75 MHz, 20% CD30D in CDCl3): δ 23.59, 25.02, 28.36, 32.33, 38.06, 123.40, 126.56, 127.46, 128.21, 128.29, 129.29, 129.60, 132.25, 133.78, 135.37, 171.04, 201.04.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:19]([CH2:18][CH2:17][O:16][CH3:15])[CH3:20])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CNCCOC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCN(C)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
Amine preparation: A mixture of 1-BOC-3-piperidone (0.50 g), N-(2-methoxyethyl)methylamine (0.29 g), sodium triacetoxyborohydride (0.74 g) and acetic acid (0.14 mL) in 1,2-dichloroethane (30 mL) was stirred at room temperature for 6 h. The reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-[(2-methoxy-ethyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.556 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.[Li]CCCC.Cl>O.C1(C)C=CC=CC=1.C1COCC1>[CH:9]1([O:8][C:5]2[N:6]=[CH:7][C:2]([B:14]([OH:19])[OH:15])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(OC2CCCC2)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: OB(O)c1ccc(OC2CCCC2)nc1
Temperature: -70 °C
Reaction time: 0.67 h
Yield: 46.4 %

Procedure:
To a mixture of 5-bromo-2-cyclopentoxypyridine (2.5 g, 10.3 mmol, see step (b) above), B(O-iPr)3 (2.33 g, 13.4 mmol), THF (4.1 mL) and toluene (16.5 mL) was portion-wise-added BuLi (2.5 M in hexane; 4.96 ml, 13.4 mmol) at −70° C. over 1 h. The reaction mixture was stirred over a further 40 min at −70° C. and then allowed to warm to −20° C. The acidity of the reaction mixture was adjusted to about pH 1 by addition of HCl (2 M aq. solution). The reaction was diluted with water (50 mL) and extracted with Et2O (2×50 mL). The pH of the water phase was then adjusted to about pH 7 by the addition of NaOH (5 M aq. solution). Brine was added and the product was extracted with EtOAc (4×50 mL). Removal of the solvent afforded the sub-title compound (0.99 g, 46%).
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[N:21]=[C:20]([CH2:22][S:23][CH2:24][CH2:25][NH2:26])[CH:19]=[CH:18][CH:17]=1)[CH3:14].[CH3:27][NH2:28]>>[CH3:14][N:13]([CH2:15][C:16]1[N:21]=[C:20]([CH2:22][S:23][CH2:24][CH2:25][NH:26][C:3]2[C:7]([NH:28][CH3:27])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:12]
Reactant: CN(C)Cc1cccc(CSCCN)n1
Reactant: CN
Reactant: COC1=NS(=O)(=O)N=C1OC
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1cccc(CN(C)C)n1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is successively treated with an equimolar amount of 2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine [prepared in Example 136, Step C] and excess methylamine, the title compound is thereby produced.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=O>[Pd].C(O)(=O)C.C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[CH2:10][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(C(=O)c2ccncc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cccc(Cc2ccncc2)c1
Yield: 98.8 %

Procedure:
Ammonium formate (25 g) was added. to a mixture of 4-(3-methoxybenzoyl)-pyridine (27 g, 127 mmole) and 10% palladium on charcoal (7 g) in acetic acid (250 ml). The mixture was heated at reflux for 0.5 hr. The mixture was cooled and diluted with an equal volume of methylene chloride. The catalyst was removed and the solution concentrated in vacuo. The residue was dissolved in water and basified with sodium hydroxide. The mixture was extracted with ether. The extracts were dried and concentrated in vacuo to give the crude 4-(3-methoxybenzyl)pyridine (25 g, 98.8%) which was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[N+:10]([O-])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C-:18]#[N:19].[Na+]>P([O-])(O)(O)=O.[K+].CO.O.C(Cl)Cl>[C:11]1([N:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[C:18]#[N:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [C-]#N
Reactant: [O-][N+](=Cc1cccc(Cl)c1Cl)c1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: N#CC(=Nc1ccccc1)c1cccc(Cl)c1Cl
Temperature: 0 °C

Procedure:
635 mMol of N-(2,3-dichlorophenylmethylene)anilin-N-oxide (IX) are dissolved in a 5.61 mixture (1:1) of an aqueous 0.5 molar solution of potassium dihydrogenphosphate and methanol adjusted to pH5. To this are added 65 g (1.3 Mol) of sodium cyanide in 200 ml water at approximately 50° C. During the reaction the pH balance is held constant between 8.0 and 8.5. After the reaction is complete (DC control), the reaction mixture is neutralized and cooled to 0° C. The separated yellow-brown crystals are then dissolved in methylene dichloride. The organic phase is washed in water, dried and evaporated under vacuum. The residue is recrystallized from a small amount of methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:27][CH2:26][CH2:25][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl

Procedure:
To a solution of tert-butyl 2-(N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)ethylcarbamate (0.022 g, 0.36 mmol)/in DCM (0.400 mL, 4.93 mmol) was added a solution of 95% TFA/5% water. The reaction was monitored by LC/MS for desired product. Reaction mix concentrated in vacuo, taken into EA and washed with H20, dried (Na2SO4), concentrated and crude purified by preparative RP-HLPC to give 131 (yield=98% of theoretical). MS: (ESI+) 400.1
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:18][C:17]([C:28]#[N:29])=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43]([N:51]=C=O)[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1>C(Cl)Cl>[F:39][C:40]([F:54])([F:55])[C:41]1[CH:42]=[C:43]([NH:51][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:19]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)=[N:18][C:17]([C:28]#[N:29])=[C:16]([C:30]#[N:31])[N:15]=3)[CH2:12][CH2:13]2)=[O:5])[CH:44]=[C:45]([C:47]([F:48])([F:50])[F:49])[CH:46]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C#N)c(C#N)nc2OCc2ccncc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(OCc2ccncc2)c(N2CCN(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)nc1C#N
Reaction time: 2 h

Procedure:
A mixture of 5′,6′-Dicyano-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (100 mg) and 30% TFA in DCM (11 ml) was stirred for 2 hours. The mixture was concentrated in vacuo to dryness. To the residue was added DCM (5 ml), TEA (0.31 mmol, 51 ul), and 3,5-bis(trifluoromethyl)phenyl isocyanate (0.15 mmol, 26 ul). The resulting mixture was stirred at room temperature for 3 hours. After concentrated in vacuo, the crude product was purified by column on silica using 70% EtOAc/Hexanes to give the product N-[3,5-bis(trifluoromethyl)phenyl]-4-{5,6-dicyano-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide. 1H NMR (CD3OD) 8.594 (s, 2H), 8.073 (s, 2H), 7.555-7.534 (m, 3H), 5.584 (s, 2H), 4.043-4.029 (m, 4H), 3.739-3.713 (m, 4H) ppm.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[S:10]1[CH:14]=[C:13]([C@@H:15]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]([O:18][C@@H:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:12]2[CH:34]=[CH:35][CH:36]=[CH:37][C:11]1=2.C(OCC)C>CCOC(C)=O>[Cl-:1].[S:10]1[CH:14]=[C:13]([C@@H:15]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]([O:18][C@@H:19]2[CH:24]3[CH2:25][CH2:26][N+:21]([CH2:2][C:3](=[O:4])[C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:12]2[CH:34]=[CH:35][CH:36]=[CH:37][C:11]1=2
Reactant: O=C(CCl)c1cccs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1csc2ccccc12
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1csc3ccccc13)C2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
2-Chloro-1-(thiophen-2-yl)ethanone (32.7 mg, 0.20 mmol) was added to a solution of (R)—((R)-quinuclidin-3-yl) 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (diastereomer 1 of C19) (80 mg, 0.20 mmol) in EtOAc (3 ml). The reaction was stirred at r.t. overnight. Diethylether (10 ml) was added, and the precipitate was collected and dried under vacuum to obtain (R)-3-((R)-2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (101 mg, 90% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].CN(C)C=O.[CH3:18][O:19][CH2:20]Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:18][O:19][CH3:20])[CH:5]=[O:6]
Reactant: COCCl
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
3 g of 3,4-dihydroxybenzaldehyde and 0.87 g of 60% oily sodium hydride were suspended in 13 ml of tetrahydrofuran, and a dimethylformamide solution (10 ml) of 3.3 ml of methoxymethyl chloride was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was distributed between ethyl acetate and water, the organic layer was worked up in a customary manner, and then purified by silica gel column chromatography [Wakogel C-200, 150 g; eluting solvent: hexane/ethyl acetate=4/1] to give 1.78 g (yield 45%) of 3-hydroxy-4-methoxymethyloxybenzaldehyde.
Reaction SMILES: CC([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])C.[C:31]1([CH2:37][CH2:38][CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[H-].[Na+].C[O:44][C:45](C)([CH3:47])[CH3:46]>CN(C)C=O>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]1[C:8]([CH2:28][O:29][CH3:30])=[C:7]([C:5]([OH:4])=[O:6])[N:27]=[CH:26][C:10]=1[N:11]2[CH2:39][CH2:38][CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:46][CH:45]([O:44][CH:38]([CH3:37])[CH3:39])[CH3:47]
Reactant: COC(C)(C)C
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Product: COCc1c(C(=O)O)ncc2c1c1c(OCc3ccccc3)cccc1n2CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester (1 mmol) is dissolved in 20 ml of dimethylformamide, mixed with 597 mg of 3-phenylpropyl bromide and 40 mg of sodium hydride (60% suspension in oil), and it is stirred for one hour at room temperature. 300 ml of methyl-tert-butyl ether is added to the reaction mixture, and the organic phase is washed with 20% citric acid and saturated sodium chloride solution. The organic phase is dried on sodium sulfate and evaporated to dryness in a vacuum. The crude product that is obtained is purified on a silica gel column with ethyl acetate-hexane, and 338 mg of 5-benzyloxy-4-methoxymethyl-9-(3-phenylpropyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ether is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:16](=[O:17])[N:15]=[C:14]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:7]([OH:12])[C@@H:6]3[O:13]2)[CH:3]=1.[CH3:18][SH:19].CN(C)C(N(C)C)=N>CN(C)C=O>[CH3:18][S:19][C@@H:6]1[C@H:7]([OH:12])[C@@H:8]([CH2:10][OH:11])[O:9][C@H:5]1[N:4]1[CH:3]=[C:2]([CH3:1])[C:16](=[O:17])[NH:15][C:14]1=[O:13]
Reactant: Cc1cn2c(nc1=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Reactant: CS
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: CS[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reaction time: 12 h
Yield: 74.1 %

Procedure:
2.2′-Anhydro-5-methyluridine (17.02 g, 70.6 mmol), methanethiol (16.3 g, 339 mmol), 1,1,3,3-tetramethylguanidine (40.6 g, 353 mmol), and dimethylformamide (150 ml) were heated together at 60° C. After 12 hr, the products were cooled and concentrated under reduced pressure. The residual oil was purified by short silica gel (300 g) column chromatography. Concentration of appropriate fractions, which were eluted with CH2Cl2-MeOH (93:7, v/v), furnished the title compound as a white foam (15.08 g, 74.1%). Crystallization from EtOH-CH2Cl2 furnished white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cccc(Cl)c1
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromo-3′-chloroacetophenone (M. Kihara, M. Kashimoto, and Y. Kobayashi, Tetrahedron, 1992, 48, 67-78.).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].[N+:7]([O-:10])([OH:9])=[O:8].CC(OC(C)=O)=O>CCOC(C)=O.CCCCCC>[N+:7]([O-:10])([O-:9])=[O:8].[CH2:1]([NH2+:3][CH2:4][CH2:5][O:6][N+:7]([O-:9])=[O:8])[CH3:2]
Reactant: CCNCCO
Reactant: O=[N+]([O-])O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC[NH2+]CCO[N+](=O)[O-]
Product: O=[N+]([O-])[O-]
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
Ethyl(2-(hydroxy)ethyl)amine (5 g, 56 mmol) in EtOAc (60 mL) was added drop-wise to a mixture of fuming HNO3 (17.7 g, 11.8 mL, 280 mmol) and Ac2O (45.8 g, 42.3 mL, 448 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 30 minutes and diluted with EtOAc and hexane. The oil layer was separated and dried in high vacuo to give the title compound (8.4 g, 76% yield) as a pale green oil. 1H NMR (300 MHz, d6-DMSO) δ 8.60–8.95 (bs, 2H), 4.84 (m, 2H), 3.37–3.49 (m, 2H), 3.02–3.16 (m, 2H), 1.24 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ 69.1, 43.6, 42.6, 11.0. Mass spectrum (API-TIS) m/z 135 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([F:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a solution of 0.5 g (2.30 mmol) of N-Boc-3-fluoro-4-piperidinone 2 (J. Med. Chem. 1999, 42, 2087-2104) in 10 mL of dry THF was added dropwise 2.8 mL (2.76 mmol) of a 1M solution of Li-selectride in THF under N2-atmosphere at 0° C. The solution was stirred at 0° C. for 4 h, then 10 mL of NaOH 2M was added at 0° C. and the mixture was stirred overnight at rt. The reaction mixture was extracted with Et2O, dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was subjected to flash silicagel chromatography (hex/EtOAc/Et3N 1:1:0.1) to yield 0.27 g (56%) of pure cis-1-Boc-3-fluoro-4-hydroxypiperidine 3 as a colorless oil which solidified upon standing at −20° C. (freezer). Mp 48° C. 1H NMR (300 MHz, CDCl3): δ 1.46 (9H, s, 3×CH3), 1.67-1.91 (2H, m, CH2), 2.40-2.65 (1H, m, OH), 2.92-3.35 (2H, m, CH2CHaHbN and CHaHbCHF), 3.55-3.94 (3H, m, CH2CHaHbN and CHOH and CHaHbCHF), 4.52 (1H, dm, J=48.4 Hz, CHF). 19F NMR (282 MHz, CDCl3): δ −201.9 and −203.1 (1F, 2×m). 13C NMR (75 MHz, CDCl3): δ 28.4 (3×), 29.2, 40.4, 44.8, 68.0 (d, J=17.3 Hz), 80.2, 88.6 (d, J=177.7 Hz), 155.1. IR (KBr): ν 3413, 1674, 1429, 1167 cm−1. GC-MS (EI): m/z (%): 219 (M+, 4), 164 (46), 146 (50), 57 (C4H9+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11].[CH:12]([N:15]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][NH2:18])([CH3:14])[CH3:13]>C(O)C>[CH:12]([N:15]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][NH:18][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11])([CH3:14])[CH3:13]
Reactant: CC(C)N(CCN)C(C)C
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Solvent: CCO
Product: CC(C)N(CCNc1cc([N+](=O)[O-])cc[n+]1[O-])C(C)C

Procedure:
A mixture of 2-chloro-4-nitropyridine-N-oxide (20.9 g., 0.12 mole) and 2-diisopropylaminoethylamine (34.8 g., 0.24 mole) dissolved in absolute ethanol (200 ml) is refluxed for 31/2 hours. The solvent is evaporated and the residue is extracted with hot cyclohexane several times to give upon cooling orange crystalline product (20.9 g.), m.p. 94°-97° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.Cl[C:21]([O:23][CH2:24][CH2:25]Cl)=[O:22]>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1Br
Reactant: O=C(Cl)OCCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCOC2=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
To a stirred solution of 4-Bromo-3-methoxy-aniline (10.0 g) in acetonitrile (176 mL) was added Hünig Base (25 mL) and 2-chloroethyl chloroformate (10.6 g). The mixture was stirred at room temperature for 0.5 h. The solvent was removed in vacuum. The residue was dissolved in tetrahydrofurane (250 mL), and potassium tert-butoxide (16.2 g) was added. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuum. The residue was dissolved in ethyl acetate and the mixture was washed with water and with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave a compound that was crystallized from ethanol. Yield: 7.7 g of the title compound. The mother liquor was concentrated in vacuum and aminophase-silica-gel chromatography gave a solid that was recrystallized from ethanol to give further 2.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([O:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39])[CH3:34]>>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:29][C:30]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=1[O:35][CH2:33][CH3:34])=[O:31]
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)NCC2
Reactant: CCOc1ccccc1CN
Reactant: O=C(Br)CBr
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1OC

Procedure:
prepared by reaction of 1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:25]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]=2[O:32][CH3:33])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](F)=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C(C2C(=O)CCCC=2O)NC(NC2C=C(C(F)(F)[F:54])C=C(F)C=2)=O)=CC=1)#N>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:25]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]=2[O:32][CH3:33])[NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:17]=[C:18]([F:54])[CH:19]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC1=C(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1
Reactant: N#Cc1ccc(C(NC(=O)Nc2cc(F)cc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Product: COC1=C(C(NC(=O)Nc2cc(F)cc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-methoxy-6-oxocyclohex-1-enyl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea (intermediate 46), using 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)urea (intermediate 45, 378 mg, 0.85 mmol) as starting material. Yield: 367 mg; ESI mass spectrum [M+H]+=462; Retention time HPLC: 1.11 min (Z018_S04).