Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]#[C:13][C:14]2[O:18][C:17]([C:19]([NH:21][C@@H:22]([CH2:27][N+:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][C:24]([O-:26])=[O:25])=[O:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Pd]>[CH2:1]([C:7]1[S:11][C:10]([CH2:12][CH2:13][C:14]2[O:18][C:17]([C:19]([NH:21][C@@H:22]([CH2:27][N+:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][C:24]([O-:26])=[O:25])=[O:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C#Cc2ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)o2)s1
Agent: [Pd]
Product: CCCCCCc1ccc(CCc2ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)o2)s1
Yield: 72 %

Procedure:
According to the method described in example S64, (R)-3-(5-((5-hexylthiophen-2-yl)ethynyl)furan-2-carboxamido)-4-(trimethylammonio)butanoate was treated with 10% Pd/C under hydrogen and the product purified to give the title compound as a white powder (14.6 mg, 72%), 1H NMR (400 MHz, D2O) δ 6.85 (br, 1H), 6.32 (br, 1H), 6.21 (br, 1H), 5.65 (br, 1H), 3.64 (m, 1H), 3.41-3.38 (m, 2H), 3.01 (s, 9H), 2.72 (br, 2H), 2.61 (br, 2H), 2.38-2.23 (m, 4H); 1.34 (br, 2H), 1.07 (br, 6H), 0.68 (br, 3H); MS ESI [M+H]+, calcd for [C24H36N2O4S+H]+ 449.25; found m/z 449.3.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:17]=2[Cl:16])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1cccc(Cl)c1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 73 and 2,3-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH3:28])=[O:26]>C(OCC)C>[CH:9]1([N:8]([CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:25](=[O:26])[O:27][CH3:28])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COc1cccc(CCNC2CCCC2)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)N(CCc1cccc(OC)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of N-(3-methoxyphenethyl)cyclopentanamine (1.31 g, 6 mmol) in diethyl ether (50 mL) was added triethylamine (1.3 mL, 9 mmol) and methyl chloroformate (0.7 mL, 9 mmol) at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 30 min. Filtration and removal of solvent under reduced pressure followed by silica gel column chromatography using hexanes/ethyl acetate afforded methyl cyclopentyl(3-methoxyphenethyl)-carbamate as a pale yellow liquid (1.41 g, 84%). 1H NMR (400 MHz, CDCl3): δ 7.19 (t, 1H, J=7.6 Hz), 6.78-6.73 (overlapping doublets and singlet, 3H), 4.27-4.24 (m, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.28 (t, 2H, J=7.9 Hz), 2.80 (t, 2H, J=7.9 Hz), 1.68-1.67 (m, 2H), 1.53-1.50 (m, 6H). LC-MS (ESI) Calcd for C16H23NO3 [M+H]+: 278.17. Found: 278.00.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][N:11]=[C:10]([CH2:13][CH2:14][C:15](OC)=[O:16])[CH:9]=1.O>O1CCCC1>[CH3:7][C:8]1[O:12][N:11]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=1
Reactant: COC(=O)CCc1cc(C)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CCCO)no1
Yield: 81.4 %

Procedure:
To a suspension of 7.6 g of lithium aluminum hydride in 250 ml of tetrahydrofuran was added a solution of 64.9 g of methyl 5-methyl-3-isoxazolepropanoate in 100 ml of tetrahydrofuran. The reaction mixture was stirred at reflux for three hours, then cooled and 15.2 ml of water in 30 ml of tetrahydrofuran added. The mixture was filtered and the filtrate concentrated in vacuo. The residue was distilled to give 44.1 g of 5-methyl-3-(3-hydroxypropyl)isoxazole, b.p. 84°-85° C.(0.1 mm).
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+:8].[Na+].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].[OH-].[Na+].[Cl-]>O>[Cl:11][CH2:10][CH:12]([OH:14])[CH2:13][S:1]([O-:4])(=[O:3])=[O:2].[Na+:8]
Reactant: ClCC1CO1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])CC(O)CCl
Yield: 50 %

Procedure:
The title alkylating agent was made by reacting sodium metabisulfite (104.5 g) with epichlorohydrin (101.8 g) in water (481 g). To this solution of alkylating agent at 50°-60° C. was added the product from Part A (157 g). This mixture was stirred and heated to 85°-90° C. Reaction was continued with the pH maintained in the range 8 to 9 by the incremental addition of 50% aqueous NaOH. Reaction was continued until the pH had stabilized and the ratio of ionic chloride to total chloride exceeded 0.99. Vacuum was applied to remove water until sufficient water had been removed to give a 50% solids product which was a clear, yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccnc(Br)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Temperature: -76 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
In a round-bottomed flask, 2-bromo-4-tert-butylpyridine (149 mg, 0.70 mmol) was dissolved in THF (4 mL). The colorless solution was cooled to −76° C. and n-butyllithium (1.6M solution in hexanes, 0.57 mL, 0.91 mmol) was added dropwise. The brown solution was stirred at −76° C. for 30 min then tributylchlorostannane (0.23 mL, 0.85 mmol) was slowly added. The reaction mixture was stirred at −76° C. for 15 min and then warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with 50 mL EtOAc (2×). The combined organic layers were washed with 5 mL water and 5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 24 g SiO2 with EtOAc/Hexanes (gradient: 0-20% EtOAc). All fractions containing product were combined and concentrated to give 147 mg (30%, purity=60%) of 4-tert-butyl-2-(tributylstannyl)pyridine as a colorless oil.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:29][CH3:30])[CH:12]=3)[N:17]=[CH:16][N:15]=2)=[C:22]([F:28])[CH:23]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Yield: 71.9 %

Procedure:
A solution of 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (892 mg, 2 mmol) in TFA (10 ml) was heated at reflux for 50 minutes. The mixture was allowed to cool and then poured on to ice. The precipitate was collected by filtration, dissolved in methanol (10 ml) and basified to pH11 with aqueous ammonia. The mixture was concentrated by evaporation, the resulting solid product was collected by filtration, washed with water then ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (460 mg, 72%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH:7](O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CC(C)(N)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(N)COC(c1ccccc1)c1ccccc1
Yield: 69.3 %

Procedure:
A mixture of 2-amino-2-methylpropanol (89.1 g), benzhydrol (190 g) and para-toluenesulphonic acid monohydrate (200 g) in toluene (1200 ml) was heated under reflux in a Dean-Stark apparatus for four hours and evaporated. The residue was partitioned between ether and water and the organic layer was washed with water and extracted into 10% aqueous citric acid. The acidic extract was washed with ether, basified with solid sodium carbonate and extracted into ether. The organic extract was washed with water, dried over sodium sulphate and evaporated to give the title compound as a pale yellow oil (177 g, 69%) which was characterised by its 1H-n.m.r. spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Br[C:14]1[CH:19]=[N:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[CH3:21][O:20][C:17]1[N:18]=[CH:19][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=2)=[N:15][CH:16]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: COc1cnc(Br)cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(Oc2cc(C)c(C(C)=O)c(C)c2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 3.50 g, 21.3 mmol), 2-bromo-5-methoxypyrazine (6.04 g, 32.0 mmol), copper (271 mg, 4.26 mmol), and potassium carbonate (8.84 g, 64.0 mmol) in 35.5 mL of DMF was stirred at 100° C. overnight. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), concentrated under reduced pressure, and purified by column chromatography on silica gel (20% EtOAc in hexanes as eluant) to give 1-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (15-1, 2.90 g) as yellow oils: 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1 H), 7.87 (s, 1 H), 6.72 (s, 2 H), 3.96 (s, 3 H), 2.47 (s, 3 H), 2.24 (s, 6 H).
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][NH:9][CH2:8][C@H:7]2[OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:13]([CH3:17])([CH3:16])[C:14]#[CH:15].CCN(CC)CC>[Cu]I.C1COCC1>[CH3:16][C:13]([N:9]1[CH2:10][C@@H:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C@H:7]([OH:11])[CH2:8]1)([C:14]#[CH:15])[CH3:17]
Reactant: C#CC(C)(C)Cl
Reactant: O[C@@H]1CNC[C@H]1N1CCCC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CC(C)(C)N1C[C@@H](O)[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45 %

Procedure:
A mixture of (3R,4R)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol (Lexicon Pharma, 1.56 g, 10.0 mmol) and 3-chloro-3-methyl-1-butyne (GFS Chmeical, Inc., 1.36 g, 13.2 mmol), THF (15 mL) and Et3N (13.3 mmol) was treated with CuI (77 mg, 0.78 mmol). An exothermic reaction ensued with concomitant formation of a precipitate. After stirring at RT for 15 h, the mixture was concentrated in vacuo and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted twice with EtOAc and the combined EtOAc phases were dried (MgSO4) and concentrated to give a light brown solid (1.0 g, 45%). 1H NMR (CDCl3) δ 4.20 (br s, 1H), 3.13-3.04 (m, 1H), 2.95 (dd, 1H, J=10.1, 6.6 Hz), 2.77 (dd, 1H, J=10.1, 2.6 Hz), 2.64 (m, 3H), 2.61 (m, 2H), 2.55-2.46 (m, 1H), 2.26 (s, 1H), 1.85-1.74 (m, 4H), 1.38 (s, 3H), 1.36 (s, 3H); MS(ESI+): m/z 223.29 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[N:2]=1.Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Reactant: OCc1cccnn1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnn2)n1

Procedure:
Prepared by the method of Example 20 using pyridazine-3-methanol (0.1 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.15 g). Yield 0.038 g.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1.CC(O)=O>C(O)C.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=2[O:16][CH3:17])[NH2:13])=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(C)noc1C
Reaction time: 4 h

Procedure:
To a solution of 3,5-dimethyl-4-[2-(methoxy)-5-nitrophenyl]isoxazole (for a preparation see intermediate 3, 1.7 g, 6.85 mmol, 1 eq.) in ethanol (170 ml), was added Pd/C (10% on carbon, 85 mg) and the reaction was stirred under hydrogen for 4 h. AcOH (1.7 ml) was added and the reaction was hydrogenated for 20 h. After filtration, the solvent was evaporated in vacuo. The crude compound was dissolved into DCM and washed with saturated aqueous Sodium hydrogen carbonate, dried over Na2SO4, filtered and evaporated. The title compound was obtained as a red oil (1.38 g, 88%). GC/MS m/z: 218.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N+:23]([O-])=O)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2cccc3c(N4CCCC4)c(Br)cc(c23)C(=O)N1OCc1ccccc1
Yield: 90.1 %

Procedure:
To a solution of 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.25 g, 0.59 mmol, from Example S1-A) in DMF (5 mL) was added pyrrolidine (0.05 g, 0.70 mmol) and triethyl amine (0.18 g, 1.8 mmol). The reaction was reacted at 85° C. for 24 hours, cooled, and concentrated under vacuum. The residue was triturated with methanol to give 0.24 g of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C1COCC1>[CH2:19]([N:21]([CH2:22][CH3:23])[C:14](=[O:16])/[C:13](/[O:17][CH3:18])=[CH:12]/[CH:11]=[CH:10]/[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:20]
Reactant: CCNCC
Reactant: CO/C(=C\C=C\c1cc2ccccc2[nH]1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)/C(=C/C=C/c1cc2ccccc2[nH]1)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
To a solution of (2Z,4E)-5-(2-indolyl)-2-methoxy-2,4-pentadienoic acid (0.1 g, 0.41 mmol), diethylamine (0.042 ml, 0.41 mmol) and 1-hydroxybenzotriazole (55 mg, 0.41 nmol) in DMF/THF 1:1 (50 Ml), DCC (0.093 g, 0.45 mmol) was added at 0° C. The resulting solution was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane, washed successively with 10% HCl, saturated solution of NaHCO3 and water, dried and evaporated under vacuum. The crude material was purified by column chromatography (EtOAc/hexane 4:6) and triturated with isopropyl ether to yield 21 mg (17.2%) of the title compound as a light yellow solid, m.p.=141-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22]Br)([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22][N:9]1[CH2:8][CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)[CH2:10]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Clc1ccc(CC2CNC2)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCN1CC(Cc2ccc(Cl)cc2)C1

Procedure:
A solution of 3-(4-chloro-benzyl)-azetidine (1.0 g, 5.50 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester (1.31 g, 5.50 mmol) and diisopropylethylamine (1.91 ml, 11.0 mmol) in dry dimethylformamide (20 ml) is stirred at ambient temperature for 18 hours. The reaction mixture is partitioned between ethylacetate and water. The organic phase is washed with water and brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 5% methanol in dichloromethane as eluent to afford {3-[3-(4-Chloro-benzyl)-azetidin-1-yl]-propyl]-carbamic acid tert-butyl ester. [M+H] 339.15
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([NH:40][CH2:39][C:38]1[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=1[Cl:36])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1Cl
Temperature: 25 °C

Procedure:
To a solution of N-(t-butoxycarbonyl)tryptophan (21.28 g, 70 mmol) in 140 ml of acetone was added triethylamine (9.76 ml, 7.08 g, 70 mmol) in a portionwise manner. The resulting mixture was stirred for about thirty-five minutes at room temperature and then stirred at 45° C. for 30 minutes under nitrogen. To the resulting mixture ethyl chloroformate (7.35 ml, 8.36 g, 77 mmol) was added with continued cooling and the reaction mixture was stirred for about one hour. Next, 2-chlorobenzylamine (9.30 ml, 10.9 g, 77 mmol) was added and the reaction mixture was then stirred until a white precipitate formed. The ice bath was removed and additional acetone was added. The reaction mixture was then stirred overnight.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N:12]3[CH:18]4[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]4)[CH2:14][CH2:13]3)=[N:9][C:8]=2[CH:21]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N:12]3[CH:18]4[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[N:9][C:8]=2[CH:21]=1
Reactant: O=[N+]([O-])c1ccc2oc(N3CCN4CCC3CC4)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2oc(N3CCN4CCC3CC4)nc2c1
Yield: 80.9 %

Procedure:
10% Palladium on carbon (300 mg) was added to a solution of 4-(5-nitro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (288 mg, 1 mmol, prepared as in Example 21) in ethanol (5 mL) and subjected to hydrogen gas at 50 PSI at RT for a period of 16 h. The reation mixture was diluted with ethanol (20 mL) and filtered through a pad of celite. Concentration in vacuo gave 209 mg of the title compound as a brown oil: 1H NMR (CD3OD, 400 MHz) δ 7.06 (d, 1H, J=8.3 Hz), 6.75 (d, 1H, J=1.3 Hz), 6.50 (dd, 1H, J=8.3, 1.3 Hz), 4.56 (br s, 1H), 4.08 (br s, 2H), 3.62-3.47 (m, 6H), 2.34-2.31 (m, 2H), 2.20-2.16 (m, 2H); MS (Cl) m/z 259.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([F:18])[C:8]=2[Cl:19])[N:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].NC(N)=O>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[C:9]([F:18])[C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Agent: NC(N)=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
10 g (0.032 mol) of 5-amino-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-pyrazole are introduced in portions into a boiling solution of 2.3 ml (0.034 mol) of 67% strength nitric acid and 0.1 g of urea in 30 ml of water. The suspension is allowed to cool, and the precipitate is filtered off and dried in vacuo at room temperature. The dry precipitate is introduced into 40 ml of 98% strength sulphuric acid at -5° C., and the mixture is stirred for 12 hours at 0°-5° C. Thereafter, the reaction mixture is introduced into 350 ml of water, boiled up for a short time and allowed to cool to room temperature and the precipitate is filtered off. The precipitate is washed neutral with water and dried in vacuo at 40°-50° C. 7.0 g (61% of theory) of 5-amino-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-4-nitropyrazole of melting point 156° C. are obtained.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:11]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:13][CH:14]=[CH2:15])[CH:7]([CH2:8][CH2:9][CH:10]2[OH:22])[CH2:6]1)#[N:4].[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br.C1OCCOCCOCCOCCOCCOC1>C1COCC1>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH2:28][O:22][C@@H:10]2[CH2:9][CH2:8][C@@H:7]3[N:12]([CH2:13][CH:14]=[CH2:15])[C@@:11]2([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:5]([C:3]#[N:4])[CH2:6]3)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: C=CCN1C2CCC(O)C1(c1ccccc1)C(C#N)C2
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)[C@@H](C#N)C2
Reaction time: 20 h
Yield: 76.4 %

Procedure:
Sodium hydride (60% in oil, 28 mg, 0.7 mmol) was added to a stirred mixture of 1R*,2R*,5S*,7S*)-7-cyano-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octan-2-ol (Description 25; 50 mg, 0.18 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.6 ml, 3.27 mmol) and 18-crown-6 (38 mg, 0.14 mmol) in THF (4 ml) at room temperature. The reaction mixture was stirred for 20 hours, quenched with brine and extracted into dichloromethane. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (68 mg, 74%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 4-iodoaniline (208 g) (available from Aldrich) and diethyl (ethoxymethylene)malonate (210 ml) (available from Aldrich) was heated to ca. 60° C., whereupon the mixture set solid. Heating was continued to 100° C., and then the mixture was removed from heating and broken up. Heating was continued at 100° C. for 1 h, and the solid was collected, washed with cyclohexane (1 L) and ethanol (2×500 ml), and dried in vacuo at 40° C. overnight to give the title compound as a white solid (356 g).