Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].B(F)(F)F.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].Cl[CH2:20][CH:21]([NH+:41]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=1)[CH3:42])[CH2:22][CH2:23][CH2:24][C:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1)([C:29]#[N:30])[CH:26]([CH3:28])[CH3:27]>C(Cl)Cl.[N+](C)([O-])=O>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([C:25]([CH:26]([CH3:27])[CH3:28])([C:29]#[N:30])[CH2:24][CH2:23][CH2:22][CH:21]2[CH2:20][C:49]3[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=3)[CH2:43][N:41]2[CH3:42])[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: COc1ccc(C[NH+](C)C(CCl)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1OC
Agent: FB(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC

Procedure:
The ammonium compound of formula 29 is then cyclized to form a compound of formula 1 (step 7). This reaction is performed using 1-1.5 moles of a Lewis acid, such as AlCl3, FeCl3, BF3, and the like, in a suitable aprotic solvent, preferably a halogenated hydrocarbon solvent, nitromethane, or nitrobenzene, particularly CH2Cl2, at a temperature of about -10° to about 80° C., for a period of about 10 minutes to about five hours, preferably about two hours. For example, N-[1-chloro-6-(3,4-dimethoxyphenyl)-6-cyano-6-(prop-2-yl)hex-2-yl]-N-(3,4-dimethoxybenzyl)-N-methylammonium chloride (29) is suspended in CH2Cl2 at 0° C. and stirred with 1.5 moles of AlCl3 for 2 hours to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[C:11]=1[I:12].[Cl:13]C1N=C2C=C(Cl)C(Cl)=CN2C=1.C1C(=O)N(I)C(=O)C1>>[I:12][C:11]1[N:5]2[CH:6]=[C:7]([Cl:10])[C:8]([Cl:13])=[CH:9][C:4]2=[N:3][C:2]=1[Cl:1]
Reactant: Clc1cn2cc(Cl)c(Cl)cc2n1
Reactant: Clc1ccc2nc(Cl)c(I)n2c1
Agent: O=C1CCC(=O)N1I
Product: Clc1cc2nc(Cl)c(I)n2cc1Cl
Yield: 82 %

Procedure:
Following the preparation of compound 19, compound 16 (1.7 g, 7.7 mmol) was treated with NIS to give 2.2 g (82%) of compound 25 as a white crystalline solid.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[N+:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[C:19]([CH:5]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[CH3:2])[CH:18]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: Cc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: Cc1ccccc1C(c1cc(Cl)c2ccccc2c1O)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(2-methyl-benzylidene)-piperidinium chloride and 4-chloro-1-naphthol.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]1([CH3:16])[CH3:15].[H-].[Na+].[CH3:19]I.[NH4+].[Cl-]>CN(C=O)C.O>[CH3:19][O:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C(C)(C)C1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)CC1(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (6.43 g, 28.0 mmol) in DMF (100 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 2.24 g, 56.1 mmol), and the reaction mixture was stirred at room temperature for 15 min. Then, MeI (3.16 mL, 50.5 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was then cooled to 0° C. and sat. aq. NH4Cl was added slowly and stirred for 5 min. The solution was warmed to room temperature and diluted with water (250 mL) and extracted with Et2O (3×200 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (5-30% EtOAc/heptane) to provide (S)-tert-butyl 4-methoxy-3,3-dimethylpiperidine-1-carboxylate. 1H NMR (400 MHz, CDCl3) δ ppm 3.75 (br. s., 1 H), 3.41 (d, J=13.1 Hz, 1 H), 3.35 (s, 3 H), 3.09 (ddd, J=13.3, 9.3, 3.7 Hz, 1 H), 2.86 (dd, J=8.5, 3.7 Hz, 1 H), 2.80 (d, J=13.1 Hz, 1 H), 1.74-1.85 (m, 1 H), 1.48-1.59 (m, 1 H), 1.46 (s, 9 H), 0.94 (s, 3 H), 0.88 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][CH:7]=1.[ClH:18].Cl.[CH2:20]1[NH:25][CH2:24][CH2:23][N:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C@H:21]12>>[ClH:1].[ClH:18].[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:25]3[CH2:24][CH2:23][N:22]4[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:21]4[CH2:20]3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: C1CCN2CCNC[C@H]2C1
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1OC
Agent: Cl
Product: COc1ccc(-c2ccc(N3CCN4CCCC[C@@H]4C3)nn2)cc1OC

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(3,4-dimethoxy-phenyl)-pyridazine and (R)-octahydro-pyrido[1,2-a]-pyrazine, dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCc1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2ccc(F)c(Cl)c2)=N1

Procedure:
Similar procedure as described in example 15a was used, starting with 3-chloro-4-fluoro-benzylamine, rhodanine, mercuric chloride and DIEA to give 2-(3-chloro-4-fluoro-benzylamino)-thiazol-4-one. LC-MS m/e 259 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[Cl:13][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]([OH:24])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:13][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]([O:24][C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=2[CH3:12])=[CH:16][CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: Oc1ccc(Cl)c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Temperature: 140 °C
Yield: 55.2 %

Procedure:
To a solution of 35.62 g (0.19 mole) of 4-chloro-3,5-dimethyl-1-nitrobenzene and 38.54 g (0.21 mole) of 4-chloro-5,6,7,8-tetrahydro-1-naphthol in 300 mL of dry DMF under an atmosphere of nitrogen and at room temperature was added 29.16 g (0.21 mole) of anhydrous potassium carbonate. The resulting reaction mixture was heated to 140° C. (internal). The reaction mixture was then heated between 140° and 150° C. for 40 hrs. The reaction mixture was then cooled to room temperature. The DMF was removed on a rotary evaporator in vacuo. The remaining dark brown semi-solid was dissolved in 500 mL of hot toluene and filtered. The collected solids were thoroughly washed with hot toluene. The toluene washings were combined with the toluene filtrate and the solvents removed to afford 34.8 g of dark brown solid. Recrystallization from hot hexane containing a little ethylene acetate along with the use of decolorizing carbon afforded 22.04 g of pale yellow solid; m.p. 176° -179° C. NMR (CDCl3): δ1.7-2.0 (m, 4H), 2.20 (S, 6H), 2.7-3.0 (m, 4H), 5.95 (d, J=9 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 8.02 (S, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=3)[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=2)[CH:6]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:32]4[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example 35) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.065 g, 28%). MS (ISP) 469.2 [(M+H)+]; mp 309° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([Li])CCC.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH:25]=O.O>CCCCCC>[F:21][C:22]1[CH:23]=[C:24](/[CH:25]=[C:6](\[CH3:7])/[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)/C(C)=C/c1cc(F)cc(F)c1

Procedure:
5 a) 1 eq. of triethyl 2-phosphonopropionate was deprotonated at 0° C. with 1 eq. of n-butyllithium in hexane and then treated at RT with 1 eq. of 3,5-difluorobenzaldehyde. After the aldehyde had completely reacted, the mixture was worked up with water and extracted three times by shaking with toluene. After the combined organic phases had been dried over magnesium sulfate, the solvent was removed under vacuum and the residual crude product was separated by chromatography on silica gel using EE/HEP mixtures as the eluent. Ethyl E-3-(3,5-difluorophenyl)-2-methylacrylate was isolated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH2:13][CH2:14][Cl:15])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:16]O>O=S(Cl)Cl>[CH3:16][O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH2:14][Cl:15]
Reactant: O=C(O)C(CCCCl)c1ccc(Br)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(CCCCl)c1ccc(Br)cc1
Yield: 90 %

Procedure:
To a solution of 2-(4-Bromo-phenyl)-5-chloropentanoic acid (3 g, 10.38 mmol) in MeOH (60 mL), SOCl2 (2 mL) was added at 0 degrees Celsius, then the mixture refluxed for 5 h. After cooling, the solution was evaporated to dryness under reduced pressure, then EtOAc was added and the mixture was washed with aq. NaHCO3, the organic layer was dried with MgSO4, and evaporated to give the compound as an oil (2.85 g, 90%). MS: calc'd 304 (MH+), exp 304 (MH+).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:24])[C@@H:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[CH3:16])C1C=CC=CC=1.OO.[Li+].[OH-].[O-:29]S([O-])=O.[Na+].[Na+]>C1COCC1>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([C@@H:15]([CH3:16])[C:14]([OH:24])=[O:29])=[CH:22][CH:21]=1
Reactant: O=S([O-])[O-]
Reactant: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Br)cc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 76B (209 mg, 0.54 mmol) in THF (5 mL) at 0° C., was added H2O2 (0.33 mL, 50%, 5.4 mmol) dropwise, followed by aq. LiOH (1.1 mL, 1.0 M, 1.1 mmol). The solution was stirred at rt for 2 h. Aq. Na2SO3 (1M, 20 mL) was added and stirred rt for 30 min. The aqueous phase was extracted with CH2Cl2 (2×10 mL), acidified to pH=2 with 1N HCl, and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4) and concentrated to give 76C (110 mg, 90%). MS (ESI) m/z 229.0 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][NH2:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:17]>CCOC(C)=O>[ClH:17].[ClH:17].[NH2:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][NH2:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](ON)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NO[C@H]1CC[C@@H](N)CC1

Procedure:
cis-4-(tert-Butoxycarbonyl)aminocyclohexyloxyamine (0.80 g) was dissolved in a 5M HCl solution in EtOAc (20 mL). After 1 h the solvent was removed under reduced pressure to give the title compound III-c (0.64 g, 99%) as a white solid. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 11.03 (3H, bb), 8.08 (3H, bb), 4.26 (1H, m), 3.02 (1H, m), 1.50-2.10 (8H, m).
Reaction SMILES: [CH3:1][CH:2]([CH3:40])[CH:3]([N:9]1[CH2:12][CH:11]([CH2:13][C:14]2[N:15]([CH3:39])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18]([N:29]2[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[C:30]2[CH3:38])[N:17]=3)[CH2:10]1)[C:4]([O:6]CC)=[O:5].C(O)C.[OH-].[Li+].Cl>O>[CH3:1][CH:2]([CH3:40])[CH:3]([N:9]1[CH2:10][CH:11]([CH2:13][C:14]2[N:15]([CH3:39])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18]([N:29]2[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[C:30]2[CH3:38])[N:17]=3)[CH2:12]1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C(C)C)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C(=O)O)C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-methyl-2-(3-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)azetidin-1-yl)butanoate (0.180 g, 0.329 mmol) in ethanol (1.0 mL, 17 mmol) was added 1.0 M of lithium hydroxide in water (2.0 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1M HCl and concentrated. The residue was re-dissolved in MeOH and loaded onto a SCX-2 column. The column was first washed with MeOH. The product was then eluted with 2M NH3 in MeOH and concentrated. LCMS m/z: 519.3 (MH+)
Reaction SMILES: COC1C=CC(C([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]3[CH:28]=[C:27]([C:29]4[C:34]([Cl:35])=[CH:33][N:32]=[C:31]([NH:36][CH2:37][CH2:38][CH2:39][N:40]5[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)[N:30]=4)[S:26][C:25]=3[CH:47]=2)=[O:20])C2C=CC(OC)=CC=2)=CC=1>Cl.Cl.Cl.ClC1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCCN2CCN(C)CC2)=NC=1>[ClH:35].[ClH:35].[ClH:35].[Cl:35][C:34]1[C:29]([C:27]2[S:26][C:25]3[CH:47]=[C:21]([C:19]([NH2:18])=[O:20])[CH:22]=[CH:23][C:24]=3[CH:28]=2)=[N:30][C:31]([NH:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]2)=[N:32][CH:33]=1
Reactant: COc1ccc(C(NC(=O)c2ccc3cc(-c4nc(NCCCN5CCN(C)CC5)ncc4Cl)sc3c2)c2ccc(OC)cc2)cc1
Agent: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(C(N)=O)cc4s3)n2)CC1

Procedure:
Using the method of Preparation C in 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide tri-hydrochloride, the title compound is synthesized from 2-{5-chloro-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-6-carboxylic acid [bis-(4-methoxyphenyl)-methyl]-amide and isolated as a yellow solid. ES+(m/z) 445 (35Cl) and 447 (37Cl) [M+H].
Reaction SMILES: C([N:11]([C:28]1[CH:29]=[C:30]([C:33](Cl)=[O:34])[S:31][CH:32]=1)[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][CH3:27])(OCC1C=CC=CC=1)=O.[CH2:36]([N:38](CC)[CH2:39][CH3:40])[CH3:37].N1CCCC1>CCOCC>[CH2:12]([NH:11][C:28]1[CH:29]=[C:30]([C:33]([N:38]2[CH2:39][CH2:40][CH2:37][CH2:36]2)=[O:34])[S:31][CH:32]=1)[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][CH3:27]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1csc(C(=O)Cl)c1
Reactant: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCNC1
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)N2CCCC2)c1

Procedure:
A warm solution of 1.0 g. of 4-[N-(carbobenzyloxy)-N-hexadecylamino]-2-thiophenecarbonyl chloride and 1.3 g. of triethylamine in 100 ml. of ether is added to 1.2 g. of pyrrolidine. A precipitate forms; the mixture is stirred under reflux for 1 hour, filtered, and extracted with hot ether. The extract is evaporated and a solution of the resulting residue in 100 ml. of tetrahydrofuran is shaken under 50 psi of hydrogen in the presence of 0.6 g. of 10% palladium on carbon. The mixture is filtered and the filtrate evaporated. The residue is crystallized from acetic acid to yield the product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:24]=[CH:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C=CCS(C)(=O)=O)c3)cnc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(CCCS(C)(=O)=O)c3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
5% Pd on carbon (150 mg, 0.07 mmol) is added to a solution of 6-[5-(-3-methanesulfonyl-propenyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (340 mg, 0.79 mmol) in MeOH (30 mL). The mixture is stirred at room temperature under H2 atmosphere of 40 PSI for 16 hrs. After filtration, the filtrate is concentrated to give 240 mg of 6-[5-(3-methanesulfonyl-propyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester. This is then used to prepare 6-[5-(3-methanesulfonyl-propyl)-pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29]
Reactant: [H][H]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccn1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccn1
Yield: 42.7 %

Procedure:
Methyl cis(±)-4-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)pyridine-2-carboxylate obtained in Example (160b) (74.8 mg) was dissolved in ethanol (10 mL). A 10% palladium-carbon catalyst (100 mg) was added, and the mixture was stirred in a hydrogen atmosphere overnight. The reaction solution was filtered through celite and then concentrated under reduced pressure, to obtain 21.2 mg of the title compound as a colorless oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[O:9][CH2:10][O:11][C:3]=12.[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][O:28][C:29]2[CH:38]=[C:37]3[C:32]([C:33](Cl)=[N:34][CH:35]=[N:36]3)=[CH:31][C:30]=2[O:40][CH3:41])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][O:28][C:29]2[CH:38]=[C:37]3[C:32]([C:33]([NH:1][C:2]4[C:7]([Cl:8])=[CH:6][N:5]=[C:4]5[O:9][CH2:10][O:11][C:3]=45)=[N:34][CH:35]=[N:36]3)=[CH:31][C:30]=2[O:40][CH3:41])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Nc1c(Cl)cnc2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Using a similar procedure to that described in Example 1, a solution of 4-amino-5-chloro-2,3-methylenedioxypyridine (0.193 g) in DMF (2 ml) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.048 g) in DMF (2 ml) and the mixture was stirred at ambient temperature for 15 minutes. A solution of 7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-6-methoxyquinazoline [International Patent Application WO 02/16352 (Note [24] within Example 2 thereof; 0.38 g] in DMF (4 ml) was added and the resultant mixture was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 49:1 mixture of methylene chloride and methanol. There was thus obtained the title compound as a solid (0.24 g); NMR Spectrum: DMSOd6) 1.29 (m, 2H), 1.45 (s, 9H), 1.8 (m, 2H), 2.04 (m, 1H), 2.83 (m, 2H), 4.0 (m, 7H), 8.12 (br s, 2H), 7.17 (br s, 1H), 7.72 (m, 2H), 8.37 (br s, 1H), 9.37 (br s, 1H); Mass Spectrum: M+H+ 544 and 546.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:29]1C(OC)=C(C(CS(C2CCCCC2)(=O)=O)=CC=1)C(OC)=O>>[CH:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:22][CH3:29])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)C2CCCCC2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)C2CCCCC2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(cyclohexanesulphonylmethyl)-2-methoxybenzoate (Intermediate 157).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH2:27][OH:28])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH:27]=[O:28])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CO)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(C=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.7 %

Procedure:
To a solution of [4-(5-methyl-3-phenyl-isoxazol-4-yl)-1-(4-nitro-phenyl)-1H-imidazol-2-yl]-methanol (50 mg, 0.13 mmol) in DCM (3 mL) was added manganese(IV) oxide (46 mg, 0.5 mmol) and the resulting mixture stirred at room temperature for 5 h. The mixture was then filtered over dicalite and washed with DCM. Then another aliquot of manganese(IV) oxide (46 mg, 0.5 mmol) was added and the mixture stirred overnight and then another aliquot of manganese(IV) oxide (120 mg, 1.3 mmol) was added and the mixture stirred for 5 h. The mixture was then filtered over dicalite and washed with DCM and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (16.4 mg, 33%) which was obtained as a yellow gum. MS: m/e=375.3 [M+H]+.