Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)(=[O:14])=[O:13]
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1

Procedure:
2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride (174a) (2.0 g, 7.5 mmol) is dissolved in dioxan (50 ml) with stirring. Sodium carbonate (7.5 ml, 2M solution, 2 eq.) is added followed by 1-methyl piperazine (0.75 g, 7.5 mmol). After 30 min the reaction mixture is poured onto water (250 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts are washed with water (2×100 ml) followed by brine (100 ml) and dried (MgSO4). After filtration the solvent is removed and the product is purified by chromatography on silica, eluting with ethyl acetate/hexane (1:2) to afford the titled compound.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:15]([O:17]C)=[O:16])[C:6]2[C:11]([C:12]=1[O:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:2].C1COCC1.[OH-].[Na+]>O>[CH3:2][O:1][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=[O:16])[C:6]2[C:11]([C:12]=1[O:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1cc(OC)c(OC)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)c2ccccc2c1OC
Yield: 92.3 %

Procedure:
A solution of methyl 3,4-dimethoxyl-1-naphthalenecarboxylate (2.93 g, 11.9 mmol), THF (145 mL), water (58 mL), and 1N NaOH (25 mL, 25.0 mmol) was stirred at room temperature overnight. The THF was removed in vacuo and the mixture acidified to pH 1 with 1N HCl. The resulting white precipitate was extracted with EtOAc (2×50 mL), dried (MgSO4) and filtered to give the product as a white solid (2.55 g, 92%). 1H NMR (DMSO) δ 13.19 (s, 1H), 8.89 (d, 1H), 8.13 (d, 1H), 8.08 (s, 1H), 7.54 (m, 2H), 3.97 (s, 3H), 3.98 (s, 3H); MS (APCI) m/z 231 (M−H+).
Reaction SMILES: Cl.[CH2:2]([N:8]1[CH2:13][CH2:12][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:25]([NH2:27])[CH3:26].Cl>>[CH2:25]([NH:27][C:14]([C:11]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:9][N:8]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]1)=[O:16])[CH3:26]
Reactant: CCCCCCN1CCC(C(=O)OCC)(c2ccccc2)CC1
Reactant: CCN
Agent: Cl
Product: CCCCCCN1CCC(C(=O)NCC)(c2ccccc2)CC1

Procedure:
This compound was prepared as above from ethyl 1-hexyl-4-phenyl-4-piperidinecarboxylate hydrochloride (3.54 g, 10 mmol) and ethylamine (2.25 g, 50 mmol). Reaction time 2 days. The crude product (1.0 g) was recrystallized from disopropyl ether, yielding 0.81 g with m.p. 92°-94° C. Hydrochloride m.p. 221°-223° C. (from 2% aqueous acetone).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21]C(=O)OCC4C=CC=CC=4)[C:16]3=[O:32])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H][H]>CCO.CCOC(C)=O.[Pd]>[NH2:21][C@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)[CH2:10][CH2:11]2)[C:16]1=[O:32]
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](NC(=O)OCc4ccccc4)C3=O)CC2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](N)C3=O)CC2)nc1
Yield: 115.3 %

Procedure:
(S)-benzyl 1′-(5-ethylpyrimidin-2-yl)-2-oxo-1,4′-bipiperidin-3-ylcarbamate (275 mg, 0.629 mmol) was dissolved in 1:1 EtOH/EtOAc and 10% Pd/C (50 mg) was added, and the reaction was stirred under a balloon pressure of hydrogen for 1.5 hours. The reaction was filtered through celite and concentrated to afford crude (S)-3-amino-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (220 mg, 0.725 mmol, 115% yield) as an oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1)([CH3:3])[CH3:2].[CH2:31]([NH2:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:31]([NH:33][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:30])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:14])[CH3:32]
Reactant: CC(C)n1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C(C)C

Procedure:
1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (50.0 mg) was prepared by following General Procedure F starting from 1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), ethylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (1H, m), 8.11 (1H, m), 7.92 (1H, m), 7.71-7.67 (2H, m), 7.36-7.35 (1H, m), 5.15-5.12 (1H, m), 3.32 (2H, m), 1.58-1.57 (6H, d), 1.16-1.13 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12].O>C(O)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cc([N+](=O)[O-])ccc1O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 2-isopropylphenol (4.1 ml) in acetic acid (30 ml) was added 69% nitric acid (4 ml) in an ice bath and the mixture was stirred at the same temperature for 30 minutes. After addition of iced water, the reaction mixture was extracted with t-butyl methyl ether. The extractant was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (2.66 g, yield 49%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1C=O.[CH3:11][S-:12].[Na+].[CH3:14]N(C)C=O>C(OC)(C)(C)C>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:14])[C:3]=1[CH:11]=[S:12]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CN(C)C=O
Reactant: C[S-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cccc(Cl)c1C=S
Temperature: -15 °C
Reaction time: 12 h

Procedure:
20.0 g (0.114 mol) of 2,6-dichlorobenzaldehyde were dissolved in 100 ml of dimethylformamide and, while stirring at -15° C. under nitrogen protective gas, 7.54 g (0.107 mol) of sodium methanethiolate were added. The mixture was stirred at -10 to -15° C. for 5 h and then at room temperature for 12 h. The mixture was taken up in methyl tert-butyl ether, washed with water, dried over sodium sulfate and concentrated under reduced pressure. Yield 19.6 g (92%) of solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]1([S:21]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]2=3)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cnc2c(c1)NCCO2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a solution of methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (278.9 mg, 1.436 mmol) in DCM (20 mL) was added benzenesulfonyl chloride (278 μL, 2.156 mmol), DIPEA (753 μL, 4.31 mmol) and DMAP (88 mg, 0.719 mmol). The reaction was stirred at room temperature for 16 hours. LCMS analysis indicated a predominance of product in the reaction mixture. The solvent was removed under reduced pressure and the resulting oil was purified by flash column chromatography using a gradient elution of hexanes with 25-70% EtOAc to provide methyl 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (280 mg, 0.837 mmol, 58.3% yield) as a yellow glass. LCMS (+ESI) m/z=334.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.NC(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][N+:3]=1[O-:14]
Reactant: NC(N)=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Temperature: 0 °C

Procedure:
2-Chloro-5-trifluoromethyl-pyridine (16, 10 mmol) was dissolved in CH2Cl2 (20 mL) and UHP (Urea-hydrogen peroxide addition compound, 21 mmol) was added. The mixture was cooled to 0° C., trifluoroacetic anhydride (20 mmol) was then slowly added to the reaction mixture. It was allowed to warm to room temperature and stirred until the reaction was completed judged by TLC. The reaction was quenched with aqueous Na2SO3, stirred for 4 h, washed with saturated aqueous NaHCO3, and dried over anhydrous MgSO4. Column chromatography afforded 1.8 g of compound 17 as oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[N:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[C:5]2=[N:6][C:7]([CH3:11])=[N:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Fc1ccccc1CBr
Reactant: Cc1ncc2c(I)n[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc2c(I)nn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
7.950 g (13.76 mmol) of 3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 4.930 g (15.13 mmol) of caesium carbonate were put in 20 ml DMF and 2.860 g (15.13 mmol) of 2-fluorobenzyl bromide dissolved in 5 ml DMF was added. The reaction mixture was stirred overnight at RT, diluted with 100 ml water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated in a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). 1.030 g of the target compound was obtained (20% of theor.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 38 g of p-hydroxyphenylacetic acid, 39.4 g of 4-nitrochlorobenzene and 69 g of anhydrous potassium carbonate in 275 ml of N,N-dimethylacetamide is heated to 155°-160° C over 2 hours, and maintained at that temperature, under Argon atmosphere for 4 hours with vigorous stirring. On cooling, an orange solid separated. A 1000 g solution of 5% NaHCO3 is added, resulting in a red brown solution. The solution is extracted with 4 × 100 ml of ether. The aqueous layer is acidified by the dropwise addition of 150 ml of concentrated HCl. A light yellow solid precipitates and is filtered and washed with 1500 ml of H2O to give the product, mp 132°-136° C. A sample is recrystallized from 19:1 methanol-water, to give the product, mp 135°-137° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][N:3]1[P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cu]I.C1COCC1>[C:13]1([CH2:4][CH:2]([NH:3][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOP(=O)(OCC)N1CC1C
Reactant: Cl[Mg]c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOP(=O)(NC(C)Cc1ccccc1)OCC
Temperature: 30 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
A 250 mL, jacketed, three necked flask equipped with an overhead stirrer, 50 mL pressure equalizing addition funnel and a temperature probe was charged with 2a (10 g, 51.7 mmol), THF (50 mL) and CuI (98 mg, 1.0 mol %) and the stirred mixture was heated to 30° C. The pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 32.36 mL) and the solution was added over 20 minutes while maintaining an internal temperature of 30-32° C. After the addition was complete, the reaction mixture was heated to 45-50° C. for an additional 30 minutes and then cooled to ambient temperature. The reaction was quenched by slow addition to a cooled mixture of saturated aqueous ammonium chloride solution and water (50/50 v/v, 100 mL) while maintaining an internal temperature below 20° C. The flask was rinsed with methyl t-butyl ether (100 mL) and the rinse was transferred to the quenched reaction mixture. The biphasic mixture was stirred for 5 minutes, allowed to separate for 20 minutes and then the aqueous phase was removed. The organic phase washed with saturated sodium chloride solution (50 mL) and the organic phase was dried over sodium sulfate. The solution (a 97:7 mixture of 6a: 8a by GC analysis) was filtered and concentrated under reduced pressure until the product began to crystallize. Heptane (40 mL) was added to the slurry and the mixture was heated until a solution was obtained. The stirred solution allowed to cool to room temperature and stirred for 18 hours. The solid was collected by filtration and dried under reduced pressure at 30° C. for 18 hours affording diethyl (1-phenylpropan-2-yl)phosphoramidate (6a) as a white crystalline solid (9.12 g, 65% yield; 99.72% GC purity with 0.04% 8a present). Mp 66-67° C. (lit1 57-58° C.). 1H NMR (300 MHz, CDCl3) δ 7.36-7.08 (m, 5H), 4.14-3.85 (m, 3H), 3.85-3.66 (m, 1H), 3.58-3.32 (m, 1H), 2.81-2.61 (m, 2H), 2.38 (t, J=9.8 Hz, 1H), 1.38-1.18 (m, 6H), 1.15 (d, J=6.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[I:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[I:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccccc1I
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccccc1I

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-iodoaniline to yield 2-[(2-iodophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(O)CO.CS(C)=O>[CH:13]12[O:18][CH:16]([CH2:15][CH2:14]1)[CH2:17][N:11]([C:4]1[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:3]=1)[CH2:12]2
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2sccc2n1
Solvent: CS(C)=O
Solvent: OCCO
Product: Oc1ccc(Nc2nc(N3CC4CCC(C3)O4)c3sccc3n2)cc1
Yield: 63.6 %

Procedure:
30 mg (0.11 mmol) of 2-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-thieno[3,2-d]pyrimidine was dissolved in 1 mL ethylene glycol. 0.5 mmol (54 mg) 4-aminophenol was added and the mixture was heated under microwave irradiation to 220 C (2×30 min). The mixture was diluted with 1 mL DMSO and purified by HPLC (TFA buffers) to give 25 mg (0.07 mmol, 66%) of the title compound.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl.Cl[CH2:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][NH+:9]=1.ClCCl.CO>C(O)C.C(=O)([O-])O.[Na+]>[CH3:15][O:14][C:13]1[C:8]([CH2:7][NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][C:12]=1[O:16][CH3:17]
Reactant: NC1CC1
Reactant: COc1cc[nH+]c(CCl)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: COc1ccnc(CNC2CC2)c1OC
Temperature: 58 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
1.05 ml (14.9 mmol) of cyclopropylamine was added to a solution of 695 mg (2.66 mmol) of 2-chloromethyl-3,4-dimethoxypyridinium hydrochloride in 4 ml ethanol and 4 ml of saturated aqueous sodium hydrogen carbonate. The reaction mixture was stirred for 1.5 hrs at 58° C. and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient dichloromethane/methanol) yielded 263 mg (42% yield) of N-[(3,4-dimethoxypyridin-2-yl)methyl]cyclopropylamine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CC1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[CH3:10].[C:11](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=1)=[O:9]
Reactant: Cc1cc(C(=O)O)sc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
5-Bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) was dissolved in dimethylformamide (50 ml), and potassium carbonate (4.0 g) and iodomethane (4.0 ml) were added. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (3.47 g). A mixture of 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (2.36 g), zinc powder (1.65 g), acetic acid (10 ml) and water (10 ml) was stirred under reflux for 3 hours. Zinc powder (1 g) and acetic acid (10 ml) were further added. The mixture was stirred under reflux for 1 day, cooled, poured into concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid methyl ester (1.42 g). 4-Methyl-2-thiophenecarboxylic acid methyl ester (1.42 g) was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (30 ml), and 1N aqueous sodium hydroxide (15 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid (1.16 g).
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH2+:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:22]=2[N:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:19]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]3[C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])=[N:23][C:22]=2[CH:24]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Reactant: Clc1ccc2oc(Cl)nc2c1
Agent: [Cl-]
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1c1nc2cc(Cl)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from (2S)-2-[(benzyloxy)carbonyl]piperidinium chloride [see EP 530167 A1 930303] and 2,5-dichloro-1,3-benzoxazole [see J.O.C. (1996), 61(10), 3289-3297]. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 95:5, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-(5-chloro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:17][NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([N:18]([CH3:17])[C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: CNC1CCCCC1
Product: CN(c1ncnc2[nH]c(-c3ccccc3)cc12)C1CCCCC1
Yield: 10.5 %

Procedure:
The product from Method D (50 mg/0.218 mmol) was reacted with 0.12 mL of N-methylcyclohexylamine (0.920 mmol) as described in Method A. The reaction mixture was concentrate in vacuo, methanol was added, and the resulting precipitate filtered to provide 7 mg (10%) of the title compound as a yellow solid 1H NMR (400 MHz, CDCl3)δ: 1.18-1.25 (m, 1H), 1.47-1.66 (m, 4H), 1.75-1.90 (m, 5H), 3.30 (s, 3H), 4.74 (br, 1H), 6.79 (s, 1H), 7.32-7.36 (m, 1H), 7.47-7.51 (m, 2H), 7.77 (d, 2H, J=7.9 Hz), 8.33 (s, 1H). LRMS: 307 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:15][CH:14]2[CH2:16][CH:6]([C:7](=[O:25])[C:8]3[C:9](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:33]([O-:36])(=[O:35])C.[K+].[CH:38]1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CS(C)=O>[CH3:38][O:36][C:33]([C:9]1[C:8]2[C:7](=[O:25])[CH:6]3[CH2:16][CH:14]([CH2:15][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:35]
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: C=CCN1CC2CC(C1)c1cccc(OS(=O)(=O)C(F)(F)F)c1C2=O
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CCN1CC2CC(C1)c1cccc(C(=O)OC)c1C2=O
Temperature: 70 °C
Yield: 569.5 %

Procedure:
Trifluoro-methanesulfonic acid 11-allyl-8-oxo-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-6-yl ester (600 mg, 1.60 mmol) was dissolved in methanol (4 mL) and DMSO (10 mL) under a N2 atmosphere and treated with triethylamine (356 g, 3.5 mmol), potassium acetate (16 mg, 0.16 mmol) and 1,3-bis(diphenylphosphine)propane (66 mg, 0.16 mmol). This mixture was stirred and degassed (3 vacuum/N2 purge cycles) and then treated with palladium acetate (36 mg, 0.16 mmol). The reaction vessel was flushed with carbon monoxide for 1 minute (bubbling through a needle) then placed under the balloon. After 10 min. the mixture was warmed to 70° C. for 2 h, cooled and poured into saturated aqueous NaCl solution (50 mL). The resulting mixture was extracted with EtOAc (4×25 mL) and the combined organic layer was washed with H2O (10 mL), saturated aqueous NaHCO3 solution (10 mL) and saturated aqueous NaCl solution (10 mL), dried over MgSO4, filtered, concentrated and purified by chromatography on silica gel eluting with 50% EtOAc/hexanes to provide an oil (260 mg, 57%). (TLC 50% EtOAc/hexanes Rf 0.30); 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=7.5 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 7.23 (dd, J=7.5, 1.3 Hz, 1H), 5.47 (m, 1H), 4.93 (m, 2H), 3.91 (s, 3H), 3.16 (dd, J=8.9, 1.6 Hz, 1H), 3.11 (d, J=1.9 Hz, 1H), 2.80 (m, 3H), 2.65 (d, J=1.7 Hz, 1H), 2.45 (dd, J=11.0, 2.5 Hz, 1H), 2.31 (m, 2H), 1.88 (ddd, J=12.8, 5.5, 2.7 Hz, 1H); GCMS m/z 285 (M)+; IR (cm−1) 2941, 2786, 1732, 1685, 1286, 1146, 1142.