Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:21][N:22]([CH3:31])[C:23]1[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][N:24]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl>[CH3:21][N:22]([CH3:31])[C:23]1[N:28]=[CH:27][C:26]([CH2:29][N:18]2[CH2:19][CH2:20][CH:15]([C:10]3[N:9]=[C:8]([N:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)[N:13]=[C:12]([OH:14])[CH:11]=3)[CH2:16][CH2:17]2)=[CH:25][N:24]=1
Reactant: CN(C)c1ncc(C=O)cn1
Reactant: Oc1cc(C2CCNCC2)nc(N2CCOCC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)c1ncc(CN2CCC(c3cc(O)nc(N4CCOCC4)n3)CC2)cn1
Reaction time: 72 h
Yield: 58.6 %

Procedure:
2-Morpholin-4-yl-6-piperidin-4-yl-pyrimidin-4-ol, hydrochloride salt (0.16 g, 0.47 mmol), 2-dimethylamino-pyrimidine-5-carboxaldehyde (86 mg, 0.57 mmol), and one drop of acetic acid were mixed in dry dichloromethane (10 mL) for 3 hours at room temperature. Sodium cyanoborohydride (88 mg, 1.42 mmol) was added and the mixture stirred for 3 days. The mixture was poured into saturated sodium bicarbonate solution and extracted with dichloromethane (3×50 mL). The material was purified on silica gel, eluting with 10% methanol in dichloromethane to provide 6-[1-(2-Dimethylaminopyrimidin-5-ylmethyl)-piperidin-4-yl]-2-morpholin-4-yl-pyrimidin-4-ol (Compound IIa, 0.11 g, 69% yield) as a white solid. CHN Analysis: Calculated for C20H29N7O2: 60.13 C, 7.32 H, 24.54 N; found 57.31 C, 7.11 H, 23.68 H. Bestfit is C20H29N7O2+1H2O; 57.54 C, 7.48 H, 23.48 N. 1H NMR (300 MHz, CDCl3/CD3OD/TMS): δ=8.26 (s, 2H), 5.65 (s, 1H), 3.85-3.60 (m, 8H), 3.42 (m, 2H), 3.19 (s, 6H), 3.15-2.85 (m, 3H), 2.40-2.00 (m, 2H), 2.18-1.60 (m, 4H). 13C NMR (75 MHz, CDCl3/CD3OD/TMS): δ=173.66, 161.63, 158.91, 153.90, 116.63, 98.76, 66.56, 57.62, 53.12, 44.94, 43.65, 37.48, 30.26.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Cl:31])=[CH:26][N:25]=1>>[CH:1]1([NH:7][C:26]2[C:27]([Cl:31])=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC1CCCCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Cl)c(NC2CCCCC2)n1
Temperature: 100 °C
Yield: 87.3 %

Procedure:
Into a round bottom flask was added cyclohexanamine (1.0 mL, 8.7 mmol) and 1,4-dioxane (30 mL, 380 mmol). N,N-Diisopropylethylamine (1.83 mL, 10.5 mmol) was added followed by 2,4,5-trichloro-pyrimidine (1.20 mL, 10.5 mmol) and the mixture was heated at 100° C. overnight and then concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and washed with water (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-20% EtOAc/hex as the eluting solvent to obtain cyclohexyl-(2,5-dichloro-pyrimidin-4-yl)-amine as a white solid (1.87 g, 87%). m.p.=93-94° C.; LCMS (m/e) 246 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 5.45-5.30 (m, 1H), 4.13-4.00 (m, 1H), 2.10-1.99 (m, 2H), 1.85-1.74 (m, 2H), 1.74-1.63 (m, 1H), 1.55-1.39 (m, 2H), 1.36-1.18 (m, 3H).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]2[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:38]([C:40]([NH2:42])=O)[S:39][C:31]1=2.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]2[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:38]([C:40](=[S:10])[NH2:42])[S:39][C:31]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC(=S)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Yield: 38.8 %

Procedure:
To a mixture of Lawesson's reagent (26.3 mg, 0.065 mmol) and the compound of Example 127 (50 mg, 0.13 mmol) was added toluene (10 mL) and the reaction heated at 110° for 1 h. A further portion of Lawesson's reagent (52.6 mg, 0.13 mmol) was added and reaction heated for 6.5 h. The reaction was diluted with DCM, washed with water, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 5–10% EtOAc in DCM) to give the title compound as a yellow solid (10 mg, 20%). δH (MeOH-d4) 7.67 (1H, m), 7.58–7.46 (7H, m), 7.40 (3H, m), 6.48 (1H, d, J 9.6 Hz). LCMS (ES+) RT 3.41 minutes, 397 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][OH:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1>>[O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][O:23][CH2:31][C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Reactant: ClCc1ccncc1
Agent: Cl
Product: c1ccc(Oc2nc3ccccc3c3c2ncn3CCOCc2ccncc2)cc1
Yield: 21 %

Procedure:
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (1.1 g, 3.61 mmol) was reacted with 4-picolyl chloride hydrogen chloride (0.649 g, 3.96 mmol) and the product purified to provide ˜0.3 g of 4-phenoxy-1-[2-(pyridin-4-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]1([NH2:36])[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[NH:36][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Nc1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Temperature: 95 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
A mixture of 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (1.21 g, 2.96 mmol), benzene-1,2-diamine (520 mg, 4.8 mmol), palladium acetate (66 mg, 0.29 mmol), bist(tri-t-butylphosphine)palladium (150 mg, 0.29 mmol) and sodium tert-butoxide (620 mg, 6.4 mmol) in toluene (30 mL) was stirred at 95° C. for 18 hours. The reaction mixture was then filtered through paper and then concentrated. The crude product was then purified by flash chromatography using a Biotage KP—NH column (0-10% gradient MeOH in DCM) to give 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (1.2 g, 84%). LCMS: M+H+=481.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[CH2:24])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[CH:2]1>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([CH3:24])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[CH:2]1
Reactant: C=C(COc1ccccc1-c1c[nH]cn1)c1coc2ccccc12
Agent: [Pd]
Solvent: CO
Product: CC(COc1ccccc1-c1c[nH]cn1)c1coc2ccccc12
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 4-(2-((2-(benzofuran-3-yl)allyl)oxy)phenyl)-1H-imidazole (0.126 mmol) in MeOH (3 mL) at room temperature was added 10% Pd/C (0.019 mmol) and the mixture was flushed with hydrogen gas after evacuating under vacuum. After stirring overnight the solution was filtered through a celite bed and the solvent was evaporated under reduced pressure to afford the crude product. Chromatographic purification afforded the final product. Yield 75%. 1H NMR: 1.55 (d, 3H, J=5.22 Hz), 3.60 (m, 1H), 4.36 (m, 2H), 7.01 (t, 2H J=5.97 Hz), 7.19-7.36 (m, 5H), 7.38 (s, 1H), 7.53 (d, 1H, J=6.09 Hz), 7.58 (s, 1H), 7.64 (d, 1H, J=5.76 Hz), 7.75 (d, 1H, J=5.01 Hz)
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[N:28]=[C:29]([CH3:35])[S:30][C:31]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[N:28]=[C:29]([CH3:35])[S:30][C:31]=2[C:32]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:33])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(-c2cccc(F)c2)c(C(=O)O)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc(-c2cccc(F)c2)c(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic Acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 4-(3-Fluoro-phenyl)-2-methyl-thiazole-5-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=1.[O:16]1[CH:18]2[CH2:19][C:20]3[C:25]([CH:17]12)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(CC)CC)C.[Cl-].[NH4+]>CO.O>[OH:16][C@@H:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:17]1[O:1][C:2]1[C:3]2[N:4]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=1
Reactant: COCc1cc(O)c2nc(C)c(C)n2c1
Reactant: c1ccc2c(c1)CC1OC21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: COCc1cc(O[C@@H]2c3ccccc3C[C@H]2O)c2nc(C)c(C)n2c1
Temperature: 50 °C
Yield: 42.2 %

Procedure:
To a suspension of 1.0 g (4.9 mmol) 8-hydroxy-6-methoxymethyl-2,3-dimethyl-imidazo[1,2-a]pyridine and 1.3 g (9.7 mmol) 1,2-epoxyindane in 12 ml methanol and 3 ml water are added 1.4 ml triethylamine and the mixture is heated to 50° C. for 24 h. After cooling down, the reaction mixture is poured into 100 ml saturated aqueous ammonium chloride and extracted with dichloromethane. The organic phase is dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (20:1) yields 0.7 g (45%) of the title compound as a colourless solid (m.p. 142-143° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:7])=[O:6].C1(C)C=CC=CC=1.C(Cl)(=O)[C:22](Cl)=[O:23].Cl>O>[CH3:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([N:7]=[C:22]=[O:23])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(OC)c1C(N)=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(OC)c1C(=O)N=C=O
Temperature: 60 °C

Procedure:
A 167 g. portion of 2,6-dimethoxybenzamide was slurried in 2 l. of toluene under a nitrogen atmosphere. To this solution was added 145 g. of oxalyl chloride over a one hour period. The solution was heated to 60° C. and maintained at this temperature overnight. HCl was allowed to escape while attempting to prevent water from condensing and going into the reaction mixture. Nitrogen was bubbled subsurface through a gas inlet tube while heating the reaction mixture at reflux (about 110° C.) for 11/2 hours. As stirring continued, the mixture was allowed to come to about 30° C. The solution was filtered through infusorial earth while maintaining a nitrogen atmosphere and the solvent was removed in vacuo. Yield 185 g. (97%). The oil was then stored under nitrogen.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3]1[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:3]1[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1cccnc1-c1ccc(N)cc1
Product: CN(CCOc1ccc(C=O)cc1)c1cccnc1-c1ccc(N)cc1
Yield: 58.2 %

Procedure:
The title compound (3.19 g) was prepared by the same procedure as the preparation 3 except for using 2-[N-methyl-N-(2-(4-anilinyl)pyridinyl)amino]ethanol (3.84 g) and 4-fluorobenzaldehyde (3.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.C(=O)([O-])O.[Na+]>C(O)C.[Fe]>[NH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C#N
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: COc1cc(N)ccc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
2-Methoxy-4-nitrobenzonitrile (5.0 g) and iron powder (7.84 g) were suspended in ethanol (150 mL), and concentrated hydrochloric acid (35 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hr, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained solid was washed with hexane to give the title compound as a red-brown solid (yield: 3.05 g, 73%).
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(CO)C=2)C1)(OC(C)(C)C)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:37][CH:38]([F:48])[O:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42]Br>>[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[O:39][CH:38]([F:37])[F:48])[C:31]1=[O:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)Oc1ccccc1CBr
Reactant: O=C1COCCN1Cc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Product: O=C1C(Cc2ccccc2OC(F)F)OCCN1Cc1ccccc1

Procedure:
N-Benzyl-2-(2-difluoromethoxy-benzyl)-morpholin-3-one was prepared as described for example 70, intermediate (b), but using 4-benzylmorpholine-3-one and 2-difluoromethoxybenzyl bromide and was isolated as a pale yellow oil.
Reaction SMILES: N[C:2]1[C:3]([CH3:12])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.N(OCCC(C)C)=O.[I-:21]>C(Cl)(Cl)Cl>[I:21][C:2]1[C:3]([CH3:12])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1
Reactant: Cc1nc(C(F)(F)F)ccc1N
Reactant: [I-]
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(C(F)(F)F)ccc1I
Temperature: 80 °C

Procedure:
A mixture of 3-amino-2-methyl-6-(trifluoromethyl)pyridine (500 mg, 2.84 mmol), isoamyl nitrite 760 μL, 5.68 mmol) and iodide. (793 mg, 3.12 mmol) in dry CHCl3 (10 mL) was stirred at room temperature for 0.5 h. The mixture was heated at 80° C. under N2 for 4 h. The reaction mixture was quenched with saturated Na2S2O3 then partitioned between CH2Cl2 and water. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, 1% EtOAc in hexanes) to afford 3-iodo-2-methyl-6-(trifluoromethyl)pyridine. LCMS calc.=288.0; found=288.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J=8.0 Hz, 1H); 7.22 (d, J=8.1 Hz, 1H); 2.83 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH:5]([N:32]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:46])[CH:5]([NH2:32])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12

Procedure:
The above prepared 2-(benzhydrylidene-amino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid ethyl ester was dissolved in 20 ml of THF and treated at 0° with 5 ml of 2N HCl. The cleavage of the protecting group was monitored by TLC. After 5 h the reaction mixture was poured onto crushed ice/NaHCO3 and extracted twice with AcOEt, washed with water, dried over sodium sulfate, and the solvents were removed i.V. Flash chromatography (SiO2, AcOEt) produced 0.505 g of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH2:2][CH2:3][CH3:4].[NH2:14][CH:15]1[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1.N[C@H]1C2CCN(CC2)C1>>[N:17]12[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18]1)[C@H:15]([NH:14][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:16]2
Reactant: CCCCc1ccccc1C(=O)O
Reactant: NC1CN2CCC1CC2
Agent: N[C@@H]1CN2CCC1CC2
Product: CCCCc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2

Procedure:
Proceeding as in Example 1, Method A, but replacing 2,3-dimethyl benzoic acid with 2-butylbenzoic acid and (RS)-3-amino-1-azabicyclo[2.2.2]octane with (S)-3-amino-1-azabicyclo[2.2.2]octane gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-butylbenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)[O:8][C:4]=2[CH:3]=1.Cl.C(OC(N1CC[C@@H](CN)C1)=O)(C)(C)C.ClC1OC2C([F:43])=CC=CC=2N=1>O1CCOCC1>[ClH:1].[F:43][C:3]1[C:4]2[O:8][C:7]([NH:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)=[N:6][C:5]=2[CH:16]=[CH:17][CH:2]=1
Reactant: Fc1cccc2nc(Cl)oc12
Reactant: Clc1ccc2nc(NCC3CCNC3)oc2c1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cccc2nc(NC[C@@H]3CCNC3)oc12

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride (example 1, step 2) the title compound was prepared from (S)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-chloro-7-fluoro-benzooxazole (Bioorganic & Medicinal Chemistry Letters 2007, 17, 4689) and subsequent cleavage of the tert-butyloxy carbonyl-protecting group through treatment with HCl in dioxane. MS (m/e): 236.1 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].I[CH:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:28]([N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:3]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]1=[O:1])([CH3:30])[CH3:29]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (125 mg, 0.352 mmol) in dry DMF (3 mL) under nitrogen was added 2-iodopropane (90 mg, 0.529 mmol) and powdered cesium carbonate (172 mg, 0.529 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate three times. The residue from the organic extract was purified by flash chromatography on silica gel eluting with 5:1 (v/v) hexane:ethyl acetate to afford the title compound (82 mg, 58%) as a white solid. TLC Rf=0.35 (5:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.28 (d, 6H, J=7.0 Hz), 1.37 (s, 9H), 4.81 (m, 2H), 4.99 (m, 1H), 5.58 (d, 1H, J=7.0 Hz), 7.19-7.48 (m, 9H). MS APCI, m/z=397 (M+1). LC/MS: 2.75 min.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH3:22][O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH3:22][O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[N:32]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:25]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL). (1R,2S)-2-(4-Fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester (0.79 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.07 mL, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 2 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, (1R,2S)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid methyl ester (0.3 mmol), as a yellow oil. LC-MS (ESI) calcd for C25H29FN4O7S2 580.15, found 581.3 [M+H+].
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:45])[CH2:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:18])=[O:11])[CH2:3]1.[CH2:46]=O>>[CH3:46][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:45])[CH2:25][C:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:18])=[O:11])[CH2:3]1
Reactant: C=O
Reactant: O=C(NCC1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: CN1CCCC(CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 7 of Example 1 using (2R)-N-(3-piperidylmethyl)-1-{(2S)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide monohydrochloride and 37% aqueous formaldehyde solution. The compound was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)C)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:1][NH:8][CH2:10][CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cccc(OCC(Cc2ccccc2)CN(C)Cc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CNCC(COc1cccc(OC)c1)Cc1ccccc1

Procedure:
A solution of N-benzyl-N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine (7.0 g) in ethanol (100 ml) is hydrogenated at room temperature and atmospheric pressure until uptake ceases, using 10% palladium on charcoal (2.0 g) as catalyst. The catalyst is filtered off (Hi-flo) and the solvent removed under reduced pressure to give N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine as an oil, which is converted with oxalic acid in ether to N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine oxalate, m.p. 127°-129°.