Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:2].[CH3:20][C:21]1([CH3:32])[O:26][C:25](=[O:27])[C:24](=[CH:28]OC)[C:23](=[O:31])[O:22]1>C(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:28]=[C:24]2[C:23](=[O:31])[O:22][C:21]([CH3:20])([CH3:32])[O:26][C:25]2=[O:27])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:2]
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: N#Cc1ccc(N)cc1OCCCN1CCOCC1
Solvent: CCO
Product: CC1(C)OC(=O)C(=CNc2ccc(C#N)c(OCCCN3CCOCC3)c2)C(=O)O1
Yield: 74.2 %

Procedure:
4-Cyano-3-(3-morpholinopropoxy)aniline (2.5 g, 9.6 mmol) and 2,2-dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (2.4 g, 13 mmol), (Montatsh. Chem. 1967, 98, 564), in ethanol (40 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the solid was collected by filtration to give 5-((4-cyano-3-(3-morpholinopropoxy)anilino)methylene)-2,2-dimethyl-1,3-dioxane-4.6-dione (2.96 g, 74%).
Reaction SMILES: C(OC(=O)C[C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(C)(C)C.Cl>CCOC(C)=O>[C:17]([CH2:8][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[C:17]([OH:19])=[O:18])([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)O)Cc2ccccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CC1c2ccccc2CC1C(=O)O
Reaction time: 1 h

Procedure:
A solution of 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylic acid from Step B (1.50 g, 5.43 mmol) in EtOAc (100 mL) was saturated with HCl (g) and aged at ambient temperature for 1 h, then concentrated to dryness in vacuo to give the title compound. MS: 7 m/z=284 (M+Na+CH3CN).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:31]#N)[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.CC(C[AlH]CC(C)C)C.Cl.C([O-])(O)=[O:44].[Na+]>C1(C)C=CC=CC=1>[CH3:6][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3([CH:31]=[O:44])[CH2:29][CH2:30]3)=[CH:26][CH:27]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(C3(C#N)CC3)cc2)cc1
Reactant: O=C([O-])O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@@H]1COc1ccc(Oc2ccc(C3(C=O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a 25 mL vial which contained a solution of (R)-2-{4-[4-(1-Cyano-cyclopropyl)-phenoxy]-phenoxymethyl}-pyrrolidine-1-carboxylic acid tert-butyl ester 3 (110 mg, 0.25 mmol) in anhydrous toluene (2 mL) were added DIBAL (0.5 mL 1M in hexane)) at −78° C. under the atmosphere of argon. The reaction mixture was allowed to warm to rt and stir at rt for 0.5 h. After cooled to ° C., 0.5 mL HCl was added to the mixture, the mixture was stirred for 10 min and then was neutralized with the addition of sat. NaHCO3 solution. This mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried over anhydrous Na2SO4. The solvent was removed under vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product, (50 mg, 65%); LCMS; 95%, APCI+ Calcd: 351.5, found m/z: 353.1 (M+1); 1HNMR (400 MHz, CDCl3); δ 1.36-1.39 (m, 2H), 1.54-1.56 (m, 2H), 1.70-2.10 (m, 4H), 2.26-2.33 (m, 1H), 2.48 (s, 3H), 2.60-2.70 (m, 1H), 3.09-3.13 (m, 1H), 3.85-3.99 (m, 2H), 6.88-6.93 (m, 4H), 6.95-6.99 (m, 2H), 7.20-7.30 (m, 2H) 9.22 (s, 1H),
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>O1CCCC1.[Pd]>[NH2:16][C:15]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1NCCCO
Temperature: 25 °C
Reaction time: 23 h
Yield: 78.3 %

Procedure:
To a solution of methyl 2-[(3-hydroxypropyl)amino]-3-nitrobenzoate (86.6 g, 0.341 mol) in tetrahydrofuran (1000 mL) was added 10% palladium on carbon (50% wet; 8.70 g), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 23 hr. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (59.8 g, 0.267 mol, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH:32]2[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C.C(OCC)(=O)C>[CH:32]1([S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH:17]([O:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH2:33][CH2:34]1
Reactant: Oc1ccc(F)cc1F
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 12 h

Procedure:
To a solution of 2,4-difluorophenol in acetonitrile, was added potassium carbonate followed by bromo-(4-cyclopropanesulfonyl-phenyl)-acetic acid ethyl ester (obtained in step I) and stirred for 10-14 hours. After completion, the reaction mixture was filtered; the filtrate was concentrated to obtain a residue which was dissolved in ethyl acetate; this solution was washed with water followed by brine solution, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to provide a crude product which was purified by column chromatography to provide the compound A1-II.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S-:11].[K+].[CH:13](OC)=O>>[CH3:13][S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: COC=O
Reactant: [S-]c1ccc2ccccc2c1
Agent: [K+]
Product: CSc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A mixture of 30 g of potassium naphthalene-2-thiolate and 120 g of methyl formate was introduced into a 0.3 liter stirred autoclave at room temperature and heated at 150° C. for 15 hours, during which the pressure (partial pressure of CO+partial pressure of the reaction mixture) reached 210 bar. The mixture was worked up by a procedure similar to that described in Example 1 to give 23.5 g (89% of theory) of naphth-2-yl methyl thioether. ##STR3##
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)=[N:8]2.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)=[N:8]3)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a cooled (ice bath) and stirred solution of (5-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (100 mg, 0.345 mmol) and triethyl amine (38 mg, 0.38 mmol) in tetrahydrofuran (THF) (2 ml) was added 4-fluorobenzoyl chloride (60 mg, 0.38 mmol) and the mixture was allowed to stir at room temperature for 16 h. Evaporation and purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as white solid (90 mg, 63%). M.p. 145° C.; MS: m/e=412.3 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH:10]=[CH2:11])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>Cl>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH:10]=[CH2:11])=[CH:6][CH:5]=1
Reactant: C=CCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCOc1ccc(N)cc1
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
To 3-[(4-nitro)phenoxy]-1-propene prepared by the process of Example 1, Step 1, (12.65 g, 70.67 mmol) in concentrated HCl (85 mL) at 0° C. was slowly added stannous chloride (48 g, 212 mmol). After stirring for 20 minutes at 55° C., the mixture was cooled to 0° C. and carefully basified with 50% NaOH. The cloudy mixture was extracted with ether. The organic phase was decolorized (charcoal), dried (MgSO4), and concentrated to afford product (8.50 g, 81%) as a yellow oil which was used directly in the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:13])=[C:5]([C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])[CH:6]=[O:7].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(#N)C>[CH3:12][C:8]1[C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:10]([CH3:11])[C:3]([CH3:2])=[C:4]([CH3:13])[C:5]=1[CH:6]=[O:7]
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CCl)c(C)c1C=O
Solvent: CC#N
Product: Cc1c(C)c(C=O)c(C)c(N2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.98 g of 3-chloromethyl-2,4,6-trimethylbenzaldehyde in 20 ml of acetonitrile was treated with 0.87 ml of morpholine. The mixture was stirred at room temperature for 4 hours and thereafter filtered. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed twice with water, dried over anhydrous magnesium sulphate and evaporated to dryness. Distillation of the residue yielded 1.05 g of 2,4,6-trimethyl-3-morpholin-4-yl-methylbenzaldenhyde, b.p. 150° C./0.3 Torr.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@@H:10]12
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O[C@@H]1C[C@H]2CNCCN2C1

Procedure:
A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 19D, 1 g, 4.30 mmol) and ethanol (10 mL) was added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. The title compound was prepared according to the procedure described in Example 17E substituting (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol for (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.58 (m, 2H), 1.97 (m, 2H), 2.10-2.35 (m, 3H), 2.90 (m, 1H), 3.20 (m, 1H), 3.62 (m, 1H), 3.77 (m, 1H), 4.14 (m, 1H), 4.80 (m, 1H), 7.92 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.OC[CH2:15][N:16]1[C:20](=O)C2=CC=CC=C2[C:17]1=O>CN(C)C=O>[CH3:15][N:16]([CH3:20])[CH:17]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: COc1ccc(CC(C)=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=CN(C)C)C(C)=O)cc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(4-methoxy-phenyl)-propan-2-one (1, 8.37 g, 51.0 mmol) in N,N-dimethylformamide (200 mL) was added dimethoxymethyl-dimethyl-amine (2, 27 mL, 203 mmol). The reaction mixture was then stirred for 18 h at 85° C., allowed to cool to ambient temperature and excess solvent and reagents were removed under reduced pressure to give crude 4-dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one (3) as yellow oil which was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[OH:7])=[CH2:5].[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([O:7][C:16](=[O:18])[CH3:17])[C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[CH2:5]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C(=O)OC)C(O)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C(=O)OC)C(OC(C)=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a solution of 2-[(6-chloro-pyridin-3-yl)-hydroxymethyl]acrylic acid methyl ester (4.788 mmol, 1 eq) in dichloromethane (10 ml), molecular sievies 4 Å and 4-DMAP (1.915 mmol, 0.4 eq) were added. Reaction mixture was cooled to 0° C. and acetic anhydride (7.182 mmol, 1.5 eq) was added. Mixture allowed to reach room temperature and stirred for 2 hours. The reaction mixture was poured in 50 ml NaHCO3 (sat.) and extraction with DCM (3×100 ml) followed. Organic layers were combined and evaporated to give crude product which was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of EtOAc in Cyclohexan: 10-45% in 15 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-(acetoxy-(6-chloro-pyridin-3-yl)-methyl]-acrylic acid methyl ester (2.099 mmol, yield=44%, purity=100%). [M+H]+=270.19 1H NMR (300 MHz, CDCl3) δ/ppm 2.10 (s, 3H), 3.69 (s, 3H), 5.97 (d, J=0.9 Hz, 1H), 6.44 (s, 1H), 6.62 (s, 1H), 7.19-7.33 (m, 1H), 7.58-7.70 (m, 1H), 8.35-8.44 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[S:15]1[CH:19]=[C:18](B(O)O)[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2>>[S:15]1[CH:19]=[C:18]([C:9]2[N:8]=[C:7]3[C:3]([N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])=[C:2]([Cl:1])[N:10]=2)[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Product: CC(C)n1cnc2c(Cl)nc(-c3csc4ccccc34)nc21

Procedure:
Following the procedure of Example 15d, 6-chloro-2-iodo-9-isopropyl-9H-purine (3.31 g, 0.0103 mol) was reacted with benzo[b]thiophen-3-ylboronic acid. The crude product was purified by silica gel chromatography (20 to 50% ethyl acetate in hexane) to afford the title compound as a solid. MS m/z 329.0 (M+1). 1H NMR (400 MHz, DMSO-d6): δ=9.15 (d, 1H), 8.85 (s, 2H), 8.17 (d, 1H), 7.62 (t, 1H), 7.53 (t, 1H), 5.06 (m, 1H), 1.71 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19](O)=[O:20])=[C:8]2[CH3:22])=[CH:4][CH:3]=1.C([N:27](CC)CC)C.C(OC(Cl)=O)C(C)C>C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([NH2:27])=[O:20])=[C:8]2[CH3:22])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a solution of 1-(4-bromobenzyl)-5-methoxy-2-methylindole-3-acetic acid (8.5 g, 21.9 mmol) in 85 mL of THF at -10° C. was added triethylamine (3.8 mL, 27.4 mmol) and isobutylchloroformate (3.4 mL, 26.3 mmol). The reaction mixture was stirred for 15 min. then ammonia gas was bubbled through the solution for 5 min. A white precipitate formed whiCh was collected by vacuum filtration. The solid was washed with H2O then THF to give 6.8 g (80%) of the desired amide.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1)([CH3:7])[CH3:6])C.[BH4-].[Na+]>C(O)C>[N:8]1([C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1
Reactant: CCOC(=O)C(C)(C)n1cnc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CO)n1cnc2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2-Imidazo[4,5-b]pyridin-1-yl-2-methyl-propionic acid ethyl ester (1 eq) in ethanol was added sodium borohydride (4 eq) at room temperature. The reaction mixture was left stirring at room temperature overnight and then quenched by addition of H2O. Once the reaction solvent was removed in vacuo, the residue was dissolved in dichloromethane, washed with NaCl(sat), dried over sodium sulfate, filtered and concentrated to give compound 2-Imidazo[4,5-b]pyridin-1-yl-2-methyl-propan-1-ol (92%) MH+(192).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH2:14]([N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23](B(O)O)[CH:24]=2)[C:19]1=[O:30])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:7]=3)[CH:24]=2)[C:19]1=[O:30])[CH2:15][CH2:16][CH3:17]
Reactant: Brc1cncc(-c2ccccc2)c1
Reactant: CCCCN1Cc2cc(B(O)O)ccc2C1=O
Product: CCCCN1Cc2cc(-c3cncc(-c4ccccc4)c3)ccc2C1=O
Yield: 14 %

Procedure:
As described for Example 23 starting from 3-bromo-5-phenylpyridine (50 mg, 0.214 mmol, commercially available) and 2-butyl-1-oxoisoindolin-5-ylboronic acid (49.8 mg, 0.214 mmol, s. above). Yield 14% (10 mg).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][N:12]2[CH2:14][C@@H:15]([OH:18])[CH2:16][CH2:17][C@@H:11]2[CH2:10][N:9]1[C:19]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH2:1]([C@@H:8]1[CH2:13][N:12]2[CH2:14][C@@H:15]([O:18][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:16][CH2:17][C@@H:11]2[CH2:10][N:9]1[C:19](=[O:20])[C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](O)CN2C[C@H]1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CC[C@@H]2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccccc3)CN2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (3R,7S,9aR)-(3-benzyl-7-hydroxy-octahydropyrido[1,2-a]pyrazin-2-yl)-(3,5-bis(trifluoromethyl)phenyl)-methanone (3.3 g, prepared analogous to example 3 steps 1–8) in dichloromethane (100 mL) was added diisopropylethylamine (2.4 mL) and methanesulfonyl chloride (0.8 mL), at 5° C. The resulting mixture was stirred at room temperature for 15 min. and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 95:5) to afford methanesulfonic acid (3R,7S,9aR)-3-benzyl-2-(3,5-bis(trifluoromethyl)benzoyl)-octahydropyrido[1,2-a]pyrazin-7-yl ester (3.8 g). Rf 0.67 (CH2Cl2/MeOH 95:5) (intermediate 18).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH2:7][CH:8]([OH:19])[CH2:9][NH:10][C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([O-:3])=[O:2].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[OH:19][CH:8]([CH2:7][O:6][C:5]1[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:9][N:10]([C@@H:11]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@@H](NCC(O)COc1ccccc1[N+](=O)[O-])c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(CC(O)COc1ccccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
The product from Example 1B (31.3 g, 100 mmol) in THF (300 mL) and 10% Na2CO3 (250 mL) at 0° C. was treated dropwise with benzyl chloroformate (18.0 g, 105 mmol), stirred vigorously for 30 minutes, and extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO4), and concentrated to provide the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Clc1ccc(C2=CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.5 g), triethylamine (4.2 cc) and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (5.7 g) in toluene (80 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (50 cc), 2-{3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-l-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.9 g) is obtained, m.p. 111° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10])[CH3:2].[S:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[CH:23]1.[BH4-].[Na+].C(Cl)Cl.CO>CO>[CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[CH:28]=2)[CH:16]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10])[CH3:2]
Reactant: CCN(C/C=C/C#CC(C)(C)OC)Cc1cccc(N)c1
Reactant: O=Cc1cccc(-c2ccsc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1cccc(NCc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
65 mg of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-aminobenzylamine and 43 mg of 3-(3thienyl)benzaldehyde were dissolved in 2 ml of methanol, and the solution was stirred overnight at room temperature. With stirring under ice cooling, 12.9 mg of sodium borohydride was added, and stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and water. The organic layer was separated, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated. The residue was purified by silica gel column chromatography Wakogel C-200, 5 g; eluting solvent: methylene chloride/ methanol=60/1] to give 87 mg (yield 84%) of the captioned compound as a pale yellow oil.
Reaction SMILES: COC1C=C(C[C:21]([OH:23])=[O:22])C=CC=1NC(NC1C=CC=CC=1C)=O.[CH:24]1[CH:25]=[CH:26][C:27]2N(O)N=N[C:28]=2[CH:29]=1.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:21]([OH:23])(=[O:22])[C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:29]=1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: On1nnc2ccccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of ethyl 4-(2-allylaminoethoxy)-3-methoxy benzoate (578 mg, 2.1 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylaceticacid (650 mg, 2.1 mmol), HOBt (420 mg, 3.11 mmol), and DMAP (catalytic amount) in DMF (4 mL) was added EDC (596 mg, 3.11 mmol) at room temp. The resulting mixture was stirred for a further 18 hr at room temp. The mixture was poured into 1N HCl and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was chromatographed on silica-gel with CHCl3:EtOAc (95:5 to 1:1, v/v) as eluent to give 1 g (84%) 3-methoxy-4-[[2-3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]allylamino]ethoxy]benzoic acid as a pale-yellow gum. 1H-NMR (CDCl3, 400 MHz) δ1.39 (t, 3H, J=7.3 Hz), 2.29 (s, 3H), 3.58 and 3.63 (s, total 3H), 3.70-3.77 (m, 2H), 3.83 and 3.87 (s, 3H), 4.054.13 (m, 2H), 4.25 (m, 1H), 4.36 (q, 1H, J=7.0 Hz), 5.04-5.22 (m, 2H), 5.73 (m, 1H), 6.32 and 6.47 (s, 1H), 6.69-6.85 (m, 2H, 7.12 (m, 2H), 7.23 (m, 2H), 7.50-7.65 (m, 2H), 8.05 (d, 1H, J=7.8 Hz); MS (FAB) m/z 576(M+H)30.