Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](Cl)=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19]>C(Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([O:19][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: CN(C)CCO
Reactant: [N-]=[N+]=Nc1ccc(C=CC(=O)Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)CCOC(=O)C=Cc1ccc(N=[N+]=[N-])cc1

Procedure:
In carbon tetrachloride was dissolved 14 g (70 millimoles) of the p-azidocinnamic acid chloride obtained in Example 16, and 6 g (70 millimoles) of 2-dimethylaminoethanol was added dropwise to the resulting solution at 10° to 20° C., after which the resulting mixture was allowed to react for 1 hour. The deposited precipitate was collected by filtration, and 100 ml of water was added thereto.
Reaction SMILES: [C:1]1([C@H:7]([CH:10]([CH3:12])[CH3:11])[CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:14]([O:18][C:19]([NH:21][C@H:22]([CH:27]=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>O1CCCC1.BrCCBr.CCOCC>[OH:28][C@@H:27]([CH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:10]([CH3:12])[CH3:11])[C@@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)[C@H](CBr)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](c1ccccc1)C(C)C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
A solution of 40.9 g (0.18 mol) of (S)-(-)-2-phenyl-3-methylbromobutane in 110 ml of tetrahydrofuran and 0.5 ml of 1,2-dibromoethane was slowly added dropwise to a suspension of 6.6 g of magnesium in 25 ml of ether. The temperature rose to 50°. Thereafter, the reaction mixture was stirred at 50° for a further 2 hours and then cooled to -50°. Then, a solution of 13 g (0.06 mol) of N-t-butoxycarbonyl-L-leucinal in 40 ml of tetrahydrofuran was added slowly. After 16 hours at room temperature, the reaction mixture was treated with 200 ml of a 20% ammonium chloride solution. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue (24.3 g) was chromatographed on silica gel with a 4:1 mixture of hexane and ether, to obtain 9.3 g of t-butyl [(1S,2S,4S)-2-hydroxy-1-isobutyl-5 -methyl-4-phenylhexyl]carbamate which has a melting point of 95°-96° after crystallization from hexane.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[C:22](=[O:24])[CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>O1CCCC1.CCOCC.C(O)(C)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[CH2:1]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH:22]([OH:24])[CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCCc3ccccc3)c21
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)O
Product: OC1CCCc2nc3ccccc3c(NCCc3ccccc3)c21
Reaction time: 0.5 h
Yield: 32 %

Procedure:
In 75 ml of dry tetrahydrofuran was dissolved 2.45 g of 9-phenethylamino-3,4-dihydroacridin-1-(2H)-one. The solution was cooled in ice and 7.0 ml (1 eq) of 1.1M LiAlH4 in Et2O was added dropwise. After 0.5 hour the reaction was complete. It was neutralized with 0.5 ml saturated NH4Cl solution and the resulting inorganic salts were filtered off. The filtrate was evaporated to a solid and the meleate salt was formed by adding a solution of 1.1 eq maleic acid in isopropanol to a suspension of the product in isopropanol. A solution formed initially but the salt precipitated out over 0.5 hour at ambient temperatures. The salt was filtered off and recrystallized from 5:1 EtOAc/MeOH and dried at 80° C. in vacuo to yield 1.14 g (32%) of a solid, melting point 169° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:11]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.ClCC1N2C=C(C)C=CC2=NC=1C1C=CC(C)=CC=1.N1C=CN=C1[C:49]([O:51][CH2:52][CH3:53])=[O:50]>>[CH2:52]([O:51][C:49]([C:2]1[N:1]([CH2:6][C:7]2[N:11]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1)=[O:50])[CH3:53]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Product: CCOC(=O)c1nccn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and ethyl 1H-imidazole-2-carboxylate. m/e+ 375 for C22H23N4O2 [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 7.63 (m, 4H), 7.24 (m, 4H), 6.73 (d, J=0.9 Hz, 1H), 6.07 (s, 2H), 4.39 (m, 2H), 2.39 (s, 3H), 2.29 (s, 3H), 1.43 (m, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:23]
Reactant: COC(=O)Cc1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 65.7 %

Procedure:
A mixture of 33.5 g of methyl{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate and 19.6 g of N-bromosuccinimide in 400 ml of carbon tetrachloride is refluxed for 24 hours or until the reaction is complete. The mixture is cooled, filtered and the filtrate passed through a column of silica gel with carbon tetrachloride as eluent to give 27.2 g of product as an oil. Crystallization from petroleum ether gives white crystals, mp 49°-53° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][C:20]([N+:25]([O-:27])=[O:26])([CH2:23]O)[CH2:21][OH:22].Cl.CN(C)CCCN=C=NCC.N(C(C)C)(C(C)C)CC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:23][C:20]([CH2:21][OH:22])([N+:25]([O-:27])=[O:26])[CH2:19][OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=[N+]([O-])C(CO)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)OCC(CO)(CO)[N+](=O)[O-])ccc2c1
Yield: 36.9 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), 2-hydroxymethyl-2-nitro-1,3-propanediol (2.89 g, 19.1 mmol), N,N-dimethylaminopyridine (DMAP, 0.88 g, 7.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.86 g, 25.4 mmol) and NEt(i-Pr)2 (11 mL, 63.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between 3N HCl (100 mL) and CH2Cl2 (200 mL×2). The combined organic layer was back washed with water and brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (gradient from 1:2 to 1:1, Rf=0.1 in 1:2) to give the title compound as a white solid (2.48 g, 39% yield). Mp 124–126° C. 1H NMR (300 MHz, 10% CD3OD/CDCl3) δ 7.73–7.64 (m, 3H), 7.37–7.33 (m, 1H), 7.17–7.12 (m, 2H), 4.44 (d, J=2.6 Hz, 2H), 3.92 (s, 3H), 3.9–3.7 (m, 5H), 3.4 (br, 2H), 1.58 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, 10% CD3OD/CDCl3) δ 174.1, 157.4, 134.5, 133.5, 129.0, 128.6, 127.0, 125.7, 118.8, 105.4, 92.4, 61.2, 60.1, 55.0, 45.0, 17.7.
Reaction SMILES: N1C=CC(N)=N1.C(N=C=S)(=O)C1C=CC=CC=1.C([NH:26][C:27]([NH:29][C:30]1[CH:34]=[CH:33][NH:32][N:31]=1)=[S:28])(=O)C1C=CC=CC=1>CN(C=O)C>[NH:32]1[CH:33]=[CH:34][C:30]([NH:29][C:27]([NH2:26])=[S:28])=[N:31]1
Reactant: O=C(NC(=S)Nc1cc[nH]n1)c1ccccc1
Agent: Nc1cc[nH]n1
Agent: O=C(N=C=S)c1ccccc1
Solvent: CN(C)C=O
Product: NC(=S)Nc1cc[nH]n1
Temperature: 100 °C

Procedure:
1H-Pyrazol-3-ylamine (9.5 g, 114 mmol) is added to a stirred solution of benzoyl isothiocyanate (19.6 g, 120 mmol) in DMF (100 ml) at room temperature. The solution is heated at 100° C. for 30 minutes, allowed to cool and poured onto water (1000 ml). The yellow suspension of 1-benzoyl-3-(1H-pyrazol-3-yl)-thiourea is removed by filtration and washed with water. This material is dissolved in 2M aqueous sodium hydroxide (120 ml) and the solution is heated at reflux for 30 minutes. After cooling to room temperature the solution is brought to pH 4 by addition of 3M aqueous HCl and extracted with ethyl acetate. The organic extract is dried (MgSO4) and concentrated to afford the titled compound which is removed by filtration and recrystallised from dichloromethane.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>CN(C=O)C>[F:27][C:26]([F:28])([F:29])[O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol) in DMF (15 mL, 3 mL/mmol) was added sodium hydride (143 mg, 5.95 mmol). After being stirred for 0.5 h at 0° C. 1-(bromomethyl)-4-(trifluoromethoxy)benzene (1.9 g, 7.97 mmol) was added and the reaction was stirred for 24 h at RT. The reaction was quenched with water and extracted with EtOAc (2×20 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure and purified by silica gel column chromatography to give tert-butyl 4-(4-(trifluoromethoxy)benzyloxy)piperidine-1-carboxylate (1.8 g) which was taken to the next reaction without further purification. Observed mass (M+1): 376.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[CH:18]=[C:17]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][C:27]([C:28]5[CH:29]=[C:30]6[CH:36]=[CH:35][N:34](COCC[Si](C)(C)C)[C:31]6=[N:32][CH:33]=5)=[C:22]4[C:21]([CH:45]([CH3:47])[CH3:46])=[N:20]3)[CH:16]=[CH:15][C:11]=2[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[OH-].[Na+]>O.C1COCC1>[OH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]2[CH:18]=[C:17]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][C:27]([C:28]5[CH:29]=[C:30]6[CH:36]=[CH:35][NH:34][C:31]6=[N:32][CH:33]=5)=[C:22]4[C:21]([CH:45]([CH3:47])[CH3:46])=[N:20]3)[CH:16]=[CH:15][C:11]=2[C:12]([NH2:14])=[O:13])[CH2:7][CH2:8]1
Reactant: CC(C)c1nn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3cnc4c(ccn4COCC[Si](C)(C)C)c3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3cnc4[nH]ccc4c3)c12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Hydrochloric acid (a 6.0 M solution in water, 0.78 mL) was added to a solution of compound (13b) (0.100 g) in THF (0.78 mL), followed by stirring at 50° C. for 12 hr. The pH was adjusted to 10 with an aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. Chloroform and ether were added to the residue, and the precipitate was collected by filtration to obtain compound (13) (0.057 g, 71%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: NCc1ccccc1F
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccccc1CNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
To a magnetically stirred solution of 2,4-dichloro-5-fluoropyrimidine (0.105 g, 0.63 mmol) in anhydrous THF (5 mL) were added 2-fluorobenzylamine (0.085 g, 0.68 mmol) and triethylamine (0.127 g, 1.26 mmol), and the mixture was warmed to reflux and stirred for 5 h. The reaction mixture was cooled to room temperature and partitioned between CH2Cl2 (15 mL) and 1 N HCl (10 mL). The phases were separated and the aqueous phase was extracted with additional CH2Cl2 (15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to yield (2-chloro-5-fluoropyrimidin-4-yl)-(2-fluorobenzyl)amine (0.157 g, 97%) as a yellow solid: mp 117-118° C.; 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.45 (t, 1H), 7.35 (m, 1H), 7.15 (m, 2H), 5.60 (br s, 1H), 4.80 (d, 2H); ESIMS m/z 256 ([M+H]+). Alternatively, 2-chloro-5-fluoropyrimidin-4-yl)-(2-fluorobenzyl)amine was prepared using methods known in the literature, such as Boebel, T. et al. U.S. Patent Application Publication 2010/0022538.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si]([O:36][CH2:37][CH2:38][CH:39]([O:43][CH2:44][CH3:45])[CH2:40][CH:41]=[CH2:42])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C1COCC1>[CH2:44]([O:43][CH:39]([CH2:40][CH:41]=[CH2:42])[CH2:38][CH2:37][OH:36])[CH3:45]
Reactant: C=CCC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCC(CCO)OCC
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in THF, 13 mL) was added to a solution of tert-butyl-(3-ethoxy-5-hexenyloxy)diphenylsilane (4.1 g) in THF (40 mL) at room temperature, followed by stirring for one hour. The reaction solution was concentrated. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (1.1 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[F:9][C:10]1[C:11]([C:17]#[N:18])=[N:12][CH:13]=[C:14](F)[CH:15]=1.O>CN(C)P(=O)(N(C)C)N(C)C>[F:9][C:10]1[C:11]([C:17]#[N:18])=[N:12][CH:13]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:15]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1ncc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: N#Cc1ncc(OCC(F)(F)F)cc1F
Reaction time: 1 h
Yield: 50.6 %

Procedure:
60% sodium hydride (0.219 g, 5.71 mmol) was added to a solution of 2,2,2-trifluoroethanol (0.257 ml, 3.57 mmol) in N,N,N′,N′,N″,N″-hexamethylphosphoric triamide (6 ml) at 0 oC and stirred for 1 hour. Then 3,5-difluoropicolinonitrile (1.0 g, 7.1 mmol) in N,N,N′,N′,N″,N″-hexamethylphosphoric triamide (4 mL) was added to the reaction mixture and stirred at room temperature for 20 hours. Then 2,2,2-trifluoroethanol (0.257 ml, 3.57 mmol) and 60% sodium hydride (0.22 g, 5.7 mmol) were added to the reaction mixture and stirred at room temperature for 3 hours. After reaction, the mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (6:1-4:1) to give 398 mg (25% yield) of the title compound as a oily solution:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH2:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:23]1([C:28](N)=[NH:29])C=CC=N1.C(N(CC)C(C)C)C.O>CN(C=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH:21][C:28]([NH2:29])=[NH:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: N=C(N)n1cccn1
Agent: CCN(CC)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N=C(N)NCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 100 °C
Yield: 33.1 %

Procedure:
C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine (1.0 g, 3.5 mmol), 1H-pyrazol-1-carboxamidine hydrochloride (0.5 g, 3.5 mmol) and 1.2 mL of diethyl isopropylamine (7.0 mmol) were dissolved in 10 mL of DMF. The reaction mixture was heated to 100° C. for three hours and then cooled and diluted by addition of 75 mL of water. The aqueous mixture was extracted twice with 100 mL of EtOAc, and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure, and the resulting oil was purified by medium pressure chromatography (silica gel, MeOH/CHCl3/NH4OH 10:89:1) to yield 0.4 g (1.16 mmol, 33%) of N-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-guanidine, MS: 344 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].CCOCC>O1CCOCC1>[ClH:24].[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1OC1CCNCC1
Yield: 99 %

Procedure:
1H NMR (CDCl3): δ 7.8 (m, 1H), 7.6 (m, 1H), 7.0 (m, 2H), 4.7 (m, 1H), 3.6 (m, 4H), 1.9 (m, 4H), 1.5 (s, 9H). A solution of 4-(2-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.00465 mole) in dioxane.HCl (10 mL) was stirred at ambient temperature for 1 hour. Ether was then added the resulting precipitate was isolated by filtration and dried to afford 1 g (99%) of 4-(2-nitro-phenoxy)-piperidine hydrochloride. LCMS: 223.1 (M+1)+, 55%, 1H NMR (DMSO-d6): δ 9.0 (bs, 2H), 7.9 (m, 1H), 7.8 (m, 1H), 7.4 (m, 1H), 7.0 (m, 1H), 5.0 (m, 1H), 3.2 (m, 4H), 2.2 (m, 2H), 2.0 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.CCOCC.[Br:21]Br>C(Cl)Cl>[Br:21][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10]
Reactant: BrBr
Reactant: O=C(Cc1ccc(F)cc1)c1cccs1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1cccs1)C(Br)c1ccc(F)cc1
Yield: 101.9 %

Procedure:
To a solution of 94.1 g (0.43 mole) of 2-(4-fluorophenyl)-1-(2-thienyl)ethanone in 700 ml. of ether was added dropwise a solution of 65.0 g. (0.41 mole of bromine in 140 ml. of methylene chloride at room temperature with stirring. The solvent was removed under vacuum to give 125.0 g of 2-bromo-2-(4-fluorophenyl)-1-(2-thienyl)ethanone.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1.Cl>C1COCC1>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.9 %

Procedure:
Cinnamoyl chloride (89.2 g, 535 mmol) was dissolved in THF (170 mL) and added dropwise to a 0° C. solution of 2-fluoroaniline (54.1 g, 486 mmol) and pyridine (39.35 mL, 486.5 mmol) dissolved in THF (170 mL). The mixture was allowed to warm to ambient temperature after the addition and stirred for 15 hours. A solution of 2M HCl was added (1250 mL) and the mixture was stirred at ambient temperature for 8 hours, during which the initial oil solidified to a light pink solid. This material was collected by filtration, washed with several portions of water, and air-dried to provide the desired product (119.5 g).
Reaction SMILES: Cl[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH:7]=[O:8].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O-:18])=[O:17]>>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH:7]=[O:8])(=[O:18])=[O:17]
Reactant: O=S([O-])c1ccccn1
Reactant: O=Cc1ncsc1Cl
Agent: [Na+]
Product: O=Cc1ncsc1S(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared by the method of Preparation 5a using 5-chloro-thiazole-4-carbaldehyde and pyridine-2-sulfinic acid sodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][NH2:11].[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][NH:11][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([I:12])[CH:14]=1
Reactant: O=Cc1cccc(I)c1
Reactant: NCCc1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1cccc(Cl)c1CCNCc1cccc(I)c1
Reaction time: 1 h

Procedure:
2-(2,6-Dichlorophenyl)ethylamine (1.0 g) and 3-iodobenzaldehyde (1.2 g) were combined in dichloromethane (50 mL). After 1 hour, sodium triacetoxyborohydride (2.2 g) was added. After 3.5 hours, the reaction mixture was poured onto 1M aqueous sodium hydroxide (200 mL) and extracted twice with dichloromethane. The organics were combined, dried (sodium sulfate) and evaporated to give the subtitle product, as an oil (2.0 g).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH:11](NC(C)C)(C)C.[Li].C1CCCCC1.CI.[NH4+].[Cl-]>>[Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][C:6]=1[CH3:11]
Reactant: CC(C)NC(C)C
Reactant: Brc1csc2ccccc12
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CI
Product: Cc1sc2ccccc2c1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1.06 g of 3-Bromo-benzo[b]thiophene (5.0 mmol) is dissolved in 10 ml of dry tetrahedrofuran and cooled to −78° C. and 3.67 ml of lithium diisopropylamine 1.5M in cyclohexane (5.5 mmol) is added slowly and stirred at −78° C. for 15 min. 0.35 ml of Methyl iodide (5.6 mmol) is added and the reaction mixture is stirred at room temperature for 1 h, sat. NH4Cl is added, and the mixture is extracted with CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=10:1) to give the title compound. 835 mg (74%). 1H-NMR (CDCl3): 7.76 (t, 2H, J=7.7 Hz), 7.46 (t, 1H, J=7.7 Hz), 7.37 (t, 1H, J=7.7 Hz), 2.60 (s, 3H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[C:18]1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[Li+].C[Sn](C)(C)C>COCCOCCOC.C(Cl)(Cl)Cl.CO>[CH3:18][C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: C[Sn](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: COCCOCCOC
Solvent: ClC(Cl)Cl
Product: Cc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Temperature: 100 °C
Reaction time: 3 h
Yield: 166.3 %

Procedure:
A solution containing 5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (203 mg, 0.687 mmol), tris(dibenzylidineacetone)dipalladium (0) (33 mg, 0.036 mmol), tri(o-tolyl)phosphine (95 mg, 0.312 mmol), lithium chloride (241 mg, 5.69 mmol), and tetramethylstannane (1.0 ml, 1.3 g, 7.2 mmol) in 2-methoxyethyl ether (5 ml) was heated in a bath maintained at 100° C. After 3 h, a further portion of tetramethylstannane (1 ml, 1.3 g, 7.2 mmol) was added, and heating was continued overnight. The solution was filtered, and subjected to purification by HPLC using a gradient of 0-20% 1:1:2 7M methanolic ammonia:methanol:chloroform and chloroform to obtain the title compound (120 mg, 0.519 mmol, 76%) as a pale solid: electrospray MS (m/z, relative intensity) 231 ([MH]+, 100).