Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15](O)=[O:16])[C:8]2=[O:21])=[CH:4][CH:3]=1.C([N:27](C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15]([NH2:27])=[O:16])[C:8]2=[O:21])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 40.1 %

Procedure:
A solution of 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid (0.35 g, 1.11 mmol), diisopropylethylamine (0.58 g, 4.44 mmol), 1-hydroxybenzotriazole monohydrate (0.30 g, 2.22 mmol) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.71 g, 2.22 mmol) and ammonium chloride (0.36 g, 6.66 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 23 hours and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution (15 mL) and water (30 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide as a colorless solid (0.14 g, 40%): mp 206-208° C.; 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 8.34 (d, 4.8 Hz, 1H), 8.13 (s, 1H), 7.62 (s, 1H), 7.33-7.13 (m, 5H), 4.38 (s, 2H), 3.92 (t, J=7.8 Hz, 2H), 3.34 (t, J=8.1 Hz, 2H); MS (ES+) m/z 314.9 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[Br:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Br.CCOCC>CN(C)C=O.CCOCC.O>[BrH:19].[C:22]1([CH2:21][CH2:20][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[N:11]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: BrCCc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCC(c2nn(CCc3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a stirred mixture of 0.86 g of sodium hydride (50% oil dispersion) in 50 ml of dimethylformamide was added, dropwise, 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 15 ml of hot dimethylformamide. The reaction mixture was stirred at ambient temperature for 1 hr and then a solution of 3.33 g of (2-bromoethyl)benzene in 10 ml of dimethylformamide was added dropwise. The reaction mixture was stirred for 21/2 days at ambient temperature, cooled to 0° , and water was added dropwise. The mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was dissolved in ether and a saturated hydrogen bromide/ether solution was added dropwise. The resultant solid was recrystallized two times from ethanol to yield 2.0 g (36%) of product, mp 163°-164° C.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][C@H:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Reactant: CCCOC1CCNCC1
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)CSc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 48.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.433 g, 1.25 mmol) and 4-propoxypiperidine (79KS66) (0.225 g, 1.55 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 60° C. for 4 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:20) to give the title compound (108LM49-46) (0.220 g, 49%). 1H NMR (CDCl3) δ 7.37 (d, J=8.1 Hz, 1H), 7.25-7.20 (m, 2H), 7.05-6.97 (m, 1H), 4.18-4.00 (m, 2H), 3.42-3.35 (m, 4H), 3.30-3.20 (m, 1H), 2.80-2.70 (m, 1H), 2.65-2.55 (m, 1H), 2.20-2.05 (m, 3H), 2.00-1.82 (m, 4H), 1.62-1.50 (m, 4H), 0.92 (t, J=7.4, CH3), 0.82 (d, J=6.8 Hz, CH3), 13C NMR (CDCl3) δ 166.1, 139.2, 128.8, 127.1, 124.9, 123.5, 118.8, 75.5, 69.8, 63.3, 52.7, 51.9, 47.6, 32.1, 32.0, 29.6, 23.5, 16.6, 10.9; HPLC-MS (ammonium acetate) [M+H]+=363.3.
Reaction SMILES: [Li+].[BH4-].C[Si](Cl)(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:16]1[C:21](O)=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[OH:20][C@H:17]1[CH2:18][CH2:19][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[C@@H:16]1[CH2:21][OH:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a 0° C. suspension of LiBH4 (2.0 equiv) in THF (0.5 M) was slowly added TMSCl (4.0 equiv) by syringe. After stirring at room temperature for 30 minutes, (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (1.0 equiv) was then added, and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by the careful addition of sat'd. aq. NaHCO3, and the mixture was diluted with EtOAc, and the organice layer was washed twice with sat'd. aq. NaHCO3, once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The title compound was isolated in 55% yield and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].S(Cl)(Cl)=O.[CH3:21]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:21])=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: COc1cc(CC(=O)O)ccc1C(F)(F)F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(C(F)(F)F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-methoxy-4-(trifluoromethyl)phenyl)acetic acid (17.0 g, 72.6 mmol) in MeOH (200 mL), thionyl chloride (10 mL, 141 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 h and concentrated under vacuum to afford the title compound (18.8 g). 1H NMR (DMSO-d6): δ 7.49 (s, 1H), 7.40 (d, 1H), 6.96 (d, 1H), 3.87 (s, 3H), 3.68 (s, 3H), 3.64-3.58 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC([O-])(C)C.[K+].C(O)(=O)C.C(=O)CC.C[N:25]1C(=O)[CH2:28][CH2:27][CH2:26]1>CCCCCCC.O>[CH:26](=[N:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:27][CH3:28]
Reactant: CN1CCCC1=O
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCC=O
Solvent: O
Solvent: CC(=O)O
Product: CCC=Nn1ccc2ccccc21
Temperature: 15 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Prepare a solution of 6.4 kg (54.6 mol) indole in 25 kg NMP. Add to this solution the HOSA and the KOtBu solutions as prepared above over a period of 180 min simultaneously and proportionally over mass flow meters and maintain the reaction mixture at 15° C. After the addition is completed, add to the resulting dark brown suspension 4.3 L (239 mol) water, 9.7 kg (161.5 mol) acetic acid (100%) and 5.3 kg (91.3 mol) propionaldehyde. Stir the mixture at 20° C. for ˜1 h, until completion of the reaction. The reaction mixture is then worked-up by adding 180 L water and 21 kg n-heptane. Unwanted salts precipitate from the reaction mixture. The resulting suspension is filtered and the phases are separated. The water phase is again extracted 4-times with 21 kg n-heptane. The combined organic phases are washed two times with 45 L water. The resulting brown heptane-solution is evaporated to a 15–25% solution. This results in 6.3–7.0 kg N-(propylidene)-1H-indol-1-amine (yield 67–74%, corrected for 19.7–24.1% assay) as a brown liquid.
Reaction SMILES: C1(SC2CCNCC=2)C=CC=CC=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.[H-].[Al+3].[H-].[H-].[ClH:32]>>[ClH:32].[F:14][C:15]1[CH:16]=[CH:17][C:18]([S:21][C:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(Sc2ccncc2)cc1
Agent: C1=C(Sc2ccccc2)CCNC1
Agent: Cl
Agent: [Al+3]
Product: Fc1ccc(SC2=CCNCC2)cc1
Yield: 83.1 %

Procedure:
According to the procedure for synthesis of 4-(phenylthio)-1,2,3,6-tetrahydropyridine, 58.5 g of 4-[(4-fluorophenyl)thio]pyridine is reduced with aluminum hydride. The crude oil is treated with ethereal hydrogen chloride to give 58.2 g (83.1%) of white powder, m.p. 136°-142° C. Recrystallization from acetonitrile gives white crystals, m.p. 158°-159° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1cccnc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=Cc2cccnc2)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (33 g, 200 mmol), pyridine-3-carbaldehyde (24.0 g, 220 mmol) and p-toluenesulfonic acid (760 mg, 4 mmol) in toluene (600 mL) was heated to reflux for 12 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(pyridin-3-ylmethylene)-amino]-benzoic acid ethyl ester (51 g, quant.) as a light yellow solid: LC/MS m/e calcd for C15H14N2O2 (M+H)+: 255.29, observed: 255.4.
Reaction SMILES: [CH2:1]([C@@H:4]([N:14]=[C:15]=[O:16])[C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)[CH:2]=[CH2:3].[OH-].[NH4+:18]>C1COCC1>[CH2:1]([C@@H:4]([NH:14][C:15]([NH2:18])=[O:16])[C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)[CH:2]=[CH2:3]
Reactant: [NH4+]
Reactant: C=CC[C@@H](N=C=O)c1ccc2c(c1)OCO2
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@@H](NC(N)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of (R)-α-allyl-(3,4-methylenedioxy)benzyl isocyanate (6) (400 mg, 1.84 mmol) in THF (10 mL) was added 7.4 M ammonium hydroxide (0.75 mL, 5.5 mmol). The reaction was stirred at room temperature for 1 hour and was then evaporated to dryness in vacuo. The residue was flash chromatographed using 60%-100% ethyl acetate/hexanes to obtain 400 mg (93%) of the title compound as a white solid. NMR (CDCl3): δ 2.46 (t, J=7 Hz, 2 H), 3.8-4.8 (v b s, 2 H), 4.59 (v br q, J=7 Hz, 1 H), 5.0-5.2 (m, 3 H), 5.6-5.8 (m, 1 H), 5.95 (s, 2 H), 6.76 (s, 2 H), 6.79 (s, 1 H).
Reaction SMILES: [OH-].[Na+].[C:3](=O)=O.[CH2:6]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15]([OH:17])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9].S(Cl)(Cl)=O>CO>[CH2:6]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15]([O:17][CH3:3])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OCCC(C)C)cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
In a three-neck reaction flask with a reflux condensor attached to 2 gas wash bottles, the second one filled with NaOH(aq) for absorption of developing CO2 and SO2, 3.7 g (14.6 mmol) 3-iso-pentyloxy-5-nitrobenzoic acid (10) were dissolved in methanol and cooled to 0° C., then 1.6 mL (21.9 mmol) thionyl chloride were added dropwise under stirring. The mixture was refluxed for 4 h, then stirred overnight at r.t.. It was concentrated, then repeatedly taken up in methanol and concentrated again, and put under vacuum. Finally, 2.97 g (76%) of a red-brown liquid, which was found to be sufficiently pure by NMR, were obtained. 1H NMR (CDCl3) δ 8.44 (dd, J1=1.4 Hz, J2=2.2 Hz, 1H), 7.88 (t, J1=2.2 Hz, J2=2.2 Hz, 1H), 7.87 (dd, J1=1.4 Hz, J2=2.2 Hz, 1H), 4.41 (t, J=6.8 Hz, 2H, PhOCH2CH2CH(CH3)2), 3.94 (s, 3H, OCH3), 1.88-1.65 (m, 3H), 0.99 (d, J=6.6 Hz, 6H, CH(CH3)2).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.NC(N)=[S:16].N.Cl>C(O)C>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][SH:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCCCCc1ccccc1
Reactant: NC(N)=S
Agent: Cl
Agent: N
Solvent: CCO
Product: SCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
15.0 g (62.2 mmol) 1-bromo-6-phenyl-hexane (described in the unexamined laid-open patent application of the int. Appl. PCT/EP95/04413) dissolved in 40 ml ethanol was added under a nitrogen atmosphere to a solution of 7.10 g (93.3 mmol) thiourea in 30 ml ethanol. After boiling for 7 hours at reflux temperature, it was allowed to cool to room temperature, admixed with 33 ml concentrated ammonia and heated for 4 h to reflux. Subsequently it was acidified to pH 1 with 15 ml concentrated HCl. It was extracted three times with 200 ml ether each time, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent was removed in a vacuum. The residue was taken up in dichloromethane, the solid was suction filled, rewashed with dichloromethane and the filtrate was evaporated in a vaccum. 9.80 g (82%) 13 as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:18]=2[F:26])=[CH:4][C:3]=1[N:27]1[C:35](=[O:36])[NH:34][C:33]2[C:28]1=[N:29][C:30]([CH:39]([OH:41])[CH3:40])=[N:31][C:32]=2[O:37][CH3:38].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:39]([C:30]1[N:29]=[C:28]2[C:33]([NH:34][C:35](=[O:36])[N:27]2[C:3]2[CH:4]=[C:5]([O:15][CH2:16][C:17]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:18]=3[F:26])[C:6]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:2]=2[Cl:1])=[C:32]([O:37][CH3:38])[N:31]=1)(=[O:41])[CH3:40]
Reactant: CCOC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C(C)O)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C(C)=O)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of 9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxy-benzyloxy)phenyl]-2-(1-hydroxyethyl)-6-methoxy-7,9-dihydro-8H-purin-8-one (0.17 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.37 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/6) to give the title compound (0.1 g)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:4]([CH3:28])[CH2:3]1.ClC(O[C:33]1C=CC=C[CH:34]=1)=O.[OH-].[Na+].C(C1C=C(OC)C=C(C(C)(C)C)C=1C1C=C(N(C2C=CC=CC=2)C2CCN(C)CC2C)C=CC=1C([O-])=O)(C)(C)C.C(Br)C=C.C([O-])([O-])=O.[K+].[K+]>ClCCCl.C(O)C.C(N(CC)CC)C.C(O)C.C(O)(C)C.O.CO>[CH2:1]([N:2]1[CH2:7][CH2:6][CH:5]([N:8]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:4]([CH3:28])[CH2:3]1)[CH:33]=[CH2:34]
Reactant: CCN(CC)C(=O)c1ccc(N(c2ccccc2)C2CCN(C)CC2C)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: COc1cc(C(C)(C)C)c(-c2cc(N(c3ccccc3)C3CCN(C)CC3C)ccc2C(=O)[O-])c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: C=CCBr
Solvent: CO
Product: C=CCN1CCC(N(c2ccccc2)c2ccc(C(=O)N(CC)CC)cc2)C(C)C1
Yield: 21.6 %

Procedure:
(±)-4-[N-{(3RS,4SR)-N,3-Dimethyl-4-piperidinyl}phenylamino]-N,N-diethylbenzamide (7a) (4.1 g, 10.82 mmol) was treated with phenyl chloroformate (1.25 mL, 11.13 mmol) in 1,2-dichloroethane (35 mL) at room temperature for 24 h. The reaction was quenched with water and NaOH 30% then extracted with CHCl3. After drying over Na2SO4 and evaporation of the solvents under reduced pressure, the crude product was chromatographed on silica gel to give a mixture of starting material and product which was then treated with methanol (100 mL), water (60 mL), isopropanol (50 mL), and NaOH 50% (30 mL) at reflux for 5 h. The alcohols were evaporated under reduced pressure, and the aqueous layer was extracted with CHCl3/THF (3:1). After drying with Na2SO4, the solvents were evaporated under reduced pressure. Chromatography on silica gel using hexanes/ethyl acetate/ethanol/triethylamine (50:50:3:3) afforded starting material (6a), (548 mg, 13%), as a yellow oil followed by the N-demethylated material (924 mg, 30%) as a yellow oil using ethanol/triethylamine (80:20) as eluent. The latter material was dissolved in ethanol (40 mL) and treated with allyl bromide (220 μL, 2.54 mmol) and K2CO3 (1.0 g, 7.24 mmol) at room temperature for 24 h. After evaporation of the ethanol under reduced pressure, the residue was chromatographed on silica gel using hexanes/ethyl acetate/ethanol/triethylamine (50:50:3:3) to give 3a (950 mg, 93%) as a yellow oil. This was converted to the hydrochloride as previously described: 1H NMR (δ4-MeOH) 1.18 (m, 6H), 1.23 (d, 3H, J=7.4 Hz), 1.54 (d, 1H, J=13.0 Hz), 1.81 (ddd, 1H, J=13.0 Hz, 13.0 Hz,. 11.0 Hz), 2.91 (m, 1H), 3.09 (dd, 1H, J=13.0 Hz, 13.0 Hz), 3.44 (m, 7H), 3.75 (d, 1H, 7.4 Hz), 4.38 (d, 1H, J=13.5 Hz), 5.59 (d, 1H, J=9.9 Hz), 5.60 (d, 1H, J=17.0 Hz), 6.00 (ddd, 1H, J=17.0 Hz, 17.0 Hz, 7.4 Hz), 6.79 (d, 2H, J=8.5 Hz), 7.14 (d, 2H J=8.0 Hz), 7.23 (d, 2H, J=8.5 Hz), 7.28 (dd, 1H, J=8.0 Hz, 8.0 Hz), 7.40 (dd, 2H, J=8.0 Hz, 8.0 Hz). 13C NMR (d4-MeOH) 11.3, 13.2 (broad), 24.5, 29.3, 45.0 (broad), 52.4, 55.2, 56.7, 59.6, 118.3, 125.9, 126.4, 126.6, 127.7, 129.7, 145.0, 149.8, 172.7. Anal. (C26H36ClN3O.0.25H2O): C, H, N.
Reaction SMILES: C(O[C:9](=O)[NH:10][CH:11]([C:23](=[O:25])[NH2:24])[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13])C1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=1C=O>C(OCC)(=O)C.C(O)(=O)C.C(O)C.CN(C=O)C.CC(O)=O>[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=1[CH2:9][NH:10][CH:11]([C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13])[C:23]([NH2:24])=[O:25]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: NC(=O)C(NC(=O)OCc1ccccc1)C(=O)c1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CNC(C(N)=O)C(=O)c2c[nH]c3ccccc23)c(OC)c1
Yield: 85.1 %

Procedure:
A solution of 2.0 g (5.69 mmol) of [1-carbamoyl-2-(3-indolyl)-2-oxoethyl]-carbamic acid benzyl ester in 160 ml ethyl acetate:acetic acid:ethanol (1:2:1) was hydrogenolyzed at atmospheric pressure over 0.45 g of 10% Pd(C) for 3 h. The mixture was filtered and concentrated. 2.41 g (11.4 mmol) of NaBH(OAc)4 was added in portions to a solution of the residue and 0.95 g (5.69 mmol) of 2,4-dimethoxybenzaldehyde in 30 ml of DMF:HOAc (1:1). After 18 h at room temperature the reaction mixture was concentrated and purified by chromatography on SiO2 (PhMe—CH2Cl2—MeOH—NEt3, 30:60:20:2). The solid product was washed with ether to give the title compound (1.78 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18]>C(O)C>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CCO
Product: CCOC(=O)CCN1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture of tert-butyl(piperidin-4-ylmethyl)carbamate (3.0 g, 14 mmol) and ethyl acrylate (1.7 g, 17 mmol) in ethanol (30 mL) was refluxed for 1 h. After cooled to room temperature, the solution was concentrated to give clear colorless oil. The residue was chromatographed on a silica gel column eluting with CH2Cl2/methanol (14:1) to give 4.0 g (91%) of the title compound as clear colorless oil.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[N:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:21][CH:22]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(C)(C)OC(=O)N(c1ccncc1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1ccc(N(C(=O)OC(C)(C)C)c2ccncc2)cc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 55 mg) was added under argon to a stirred solution of the product from step iii) above (300 mg)in dry DMF (5 ml). After five minutes, ethyl 6-bromohexanoate (0.20 ml) was added and the mixture stirred for 16 hours. The DMF was evaporated in vacuo and the residue partitioned between dichloromethane and water. The aqueous phase was extracted with further dichloromethane. The combined organic extracts were washed with water then dried, and evaporated. The residue was purified by chromatography on alumina, eluting with dichloromethane and the 1% v/v methanol/dichloromethane. Evaporation of the appropriate fractions gave ethyl 6-[4-[N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino]phenoxy]hexanoate, 260 mg, as a yellow gum: NMR (CDCl3) δ8.40(2H,dd), 7.16(2H,dd), 7.07(2H,m), 6.90(2H,m), 4.13(2H,q), 3.98(2H,t), 2.34(2H,t), 1.78(4H,m), 1.57(2H,m), 1.44(9H,s), 1.26(3H;t); m/e 429 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 4-trifluoromethyl-phenyl boronic acid to give the title compound as off-white solid. MS: 461.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[NH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Br)ccnc1Br
Reactant: NCCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1c(NCCCc2ccccc2)ccnc1Br
Yield: 65.4 %

Procedure:
Prepared according to the methods above using 2,4-dibromonicotinonitrile (100 mg, 0.382 mmol), 3-aminopropylbenzene (0.058 mL, 0.401 mmol) and Hunig's Base (0.080 mL, 0.458 mmol) in DMF (1.5 mL) to give the desired product as a white solid (79 mg). LC/MS (316/318, [M−H]−/[M+H]+); 1H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (dd, J=6.0, 0.5 Hz, 1H), 7.37-7.30 (m, 2H), 7.28-7.15 (m, 3H), 6.42 (d, J=6.0 Hz, 1H), 5.26 (br. s., 1H), 3.28 (td, J=7.0, 5.8 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.03 (quin, J=7.3 Hz, 2H).