Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:39])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.Cl.O1CCOCC1>CO>[NH2:31][CH2:30][CH2:29][C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:39])=[CH:6][CH:5]=3)[C:8]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)=[O:9])[CH2:16][CH2:17]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNC(=O)OC(C)(C)C)CCCCC3)CC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.9 %

Procedure:
To a solution of tert-butyl 2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethylcarbamate (synthesized in Example 17) (1.14 g) in methanol (4 mL) was added a 4N hydrochloric acid/dioxane solution (3 mL). The solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, chloroform-methanol (20:1)] to give the title compound (1.01 g).
Reaction SMILES: ClCC([O:5][C:6]1[C:19]([C:20]([O:22]CC)=O)=[C:18]2[C:9]([N:10]=[C:11]3[C:16](=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12]3)=[C:8]2[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=12)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>N1C=CC=CC=1>[OH:5][C:6]1[C:19]([C:20]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:22])=[C:18]2[C:9]([N:10]=[C:11]3[C:16](=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12]3)=[C:8]2[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=12
Reactant: CCOC(=O)c1c(OC(=O)CCl)c2ccccc2c2nc3ccccc3nc12
Reactant: C1COCCN1
Solvent: c1ccncc1
Product: O=C(c1c(O)c2ccccc2c2nc3ccccc3nc12)N1CCOCC1
Yield: 71.4 %

Procedure:
In 4 ml of pyridine were dissolved 200 mg of ethyl 5-chloroacetoxybenzo[a]phenazine-6-carboxylate and 220 mg of morpholine, and the solution was heated at 80°-100° C., for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure. Water was added, and the precipitated solid was collected to give 130 mg (71.1% yield) of 5-hydroxy-6-morpholinocarbonylbenzo[a]phenazine as red amorphous powder, m.p. 223°-225° C., Anal. Calcd. (%) for C21H17N2O3 : C, 70.18; H, 4.77; N, 11.69; Found: C, 69.94; H, 4.86; N, 11.86
Reaction SMILES: O(CC([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.C(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>C(OCC)(=O)C.CO.N1C=CC=CC=1>[C:43]1([CH3:53])[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=1.[NH2:11][CH:12]1[C:32](=[O:33])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12
Reactant: C=C1CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 937 mg. of p-methoxybenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate in 10 ml. of methylene chloride was added 0.18 ml. of dry pyridine and 460 mg. of phosphorus pentachloride. The mixture was stirred at room temperature for 2 hours and was then cooled to 5°C. To the cold mixture was added 50 ml. of cold methanol and the mixture was allowed to warm to room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The pH of the solution was adjusted to pH 7 and the ethyl acetate layer was separated, washed with water and dried. To the dried ethyl acetate layer was added one equivalent of p-toluene sulfonic acid. On cooling 600 mg. of p-methoxybenzyl 3-methylenecepham-4-carboxylate p-toluenesulfonate precipitated as a crystalline solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH:11]1[CH2:16][NH:15][C:14](=[O:17])[CH2:13][CH2:12]1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:9][CH2:10][CH:11]1[CH2:16][NH:15][C:14](=[O:17])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1CCC(CO)CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCC(=O)NC1
Temperature: 22 °C
Reaction time: 36 h
Yield: 50.2 %

Procedure:
To a solution of 5.8 g tert-butyl(dimethyl)silyl chloride and 5.0 g of 5-hydroxymethyl-2-piperidone in 150 ml of anhydrous DMF was added 5.3 g of imidazole. After stirring for 36 hours at 22° C., the mixture was evaporated under vacuum to remove most of the DMF. Following the addition of water, the residue was extracted with three portions of ethyl acetate. The combined organic extracts were washed with water, 0.5N HCl, water and brine, dried over magnesium sulfate and evaporated. The resulting oil was chromatographed over silica gel eluting with 5% methanol in chloroform to give 4.7 g of the title compound as an oil: MS m/z 244 (M+), 186 [M+ -58(t-butyl)]; 300-MHz 1H NMR (CDCl3) δ0.05 (s, 6H), 0.85 (s, 9H), 1.42-1.57 (m, 1H), 1.77-1.88 (m, 1H), 1.89-2.03 (m, 1H), 2.25-2.45 (m, 2H), 3.03 (t, J=9 Hz, 1H), 3.30-3.41 (m, 1H), 3.45-3.59 (m, 2H), 5.95 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21]C)=[CH:18][CH:19]=2)[CH2:14][C:13]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=1.[CH2:31]([SH:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[H-].[Na+]>CN(C)C=O>[CH2:31]([S:37][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[CH2:14][C:13]=1[C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: COc1ccc(C2=C(CCCCCCCCCCBr)c3ccc(OC)cc3C2)cc1
Reactant: CCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCSCCCCCCCCCCC1=C(c2ccc(O)cc2)Cc2cc(O)ccc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-(10-bromodecyl)-5-methoxy-2-p-methoxyphenylind-1-ene (0.24 g.) in dimethylformamide (1 ml.) was added to a stirred solution of hexanethiol (0.07 g.) and sodium hydride (0.029 g. of a 50% dispersion in mineral oil from which the oil had been washed with petroleum ether) in dimethylformamide which had been stirred at laboratory temperature under an atmosphere of argon for 15 minutes, and the mixture was heated at 60° C. for 2 hours, cooled and water (5 ml.) was added. The mixture was extracted 3 times with ethyl acetate (5 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 1:1 v/v mixture of toluene and petroleum ether (b.p. 60°-80° C.) as eluant. The methoxy groups were removed by treatment with boron tribromide in a similar manner to that described in Example 7, and the residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 1-(10-hexylthiodecyl)-2-p-hydroxyphenylind-1-en-5-ol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]2)=[C:6]([F:19])[CH:5]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35](O)=[O:36])[N:26]=1>>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:35](=[O:36])[CH2:34][N:27]3[C:28]4=[N:29][CH:30]=[CH:31][CH:32]=[C:33]4[C:25]([C:21]4[NH:20][CH:24]=[CH:23][N:22]=4)=[N:26]3)[C@@H:14]([CH3:18])[CH2:13]2)=[C:6]([F:19])[CH:5]=1
Reactant: COc1cc(N2CCN[C@@H](C)C2)c(F)cc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl

Procedure:
The title compound was prepared following protocol A. (S)-1-(4-Chloro-2-fluoro-5-methoxy-phenyl)-3-methylpiperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (2% to 3% MeOH in CH2Cl2) to provide 1-[(S)-4-(4-chloro-2-fluoro-5-methoxyphenyl)-2-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid (29 mg): 1H NMR (CDCl3, 400 MHz) δ □8.79 (dd, 1H), 8.55 (dd, 1H), 7.27-7.21 (m, 3H), 7.07 (d, 1H), 6.43 (br. d, 1H), 5.46-5.37 (m, 2H), 4.83 (br. s, 0.3H), 4.51-4.48 (m, 0.6H), 4.28-4.21 (m, 0.6H), 3.86 (s, 0.9H), 3.85 (s, 2.1H), 3.79 (br. s, 0.3H), 3.67 (br. s, 0.3H), 3.33-3.21 (m, 2.5H), 2.95-2.93 (m, 0.9H), 2.83-2.76 (m, 1.6H), 1.48-1.40 (m, 3H); LC/MS m/z (M+H)+ 484.4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:2][CH2:3][CH2:4][C:5]#[N:6])=[CH:9][CH:10]=1)#[N:16]
Reactant: N#CCCCBr
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCOc1ccc(CC#N)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 26.6 %

Procedure:
12.2 g (82.6 mmol) of 4-bromobutyronitrile, 10 g (95.1 mmol) of (4-hydroxyphenyl)acetonitrile and 31.1 g (225 mmol) of potassium carbonate are dissolved in 100 mL of DMF. The mixture is heated to 80° C. overnight. After 20 hours, the reaction mixture is partitioned between EtOAc and water. The organic phase is washed repeatedly with brine, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Purification by column chromatography on silica gel using ethylacetate:hexane 1:1 as eluent yields to 4.4 g of 4-[4-(cyanomethyl)phenoxy]butanenitrile as a thick yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].[I-].[K+].Cl[CH:27]([CH3:31])[C:28](=[O:30])[CH3:29]>CC#N>[CH3:1][C:2]1[N:10]([CH:27]([C:28](=[O:30])[CH3:29])[CH3:31])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(=O)C(C)Cl
Reactant: Cc1[nH]c2ncccc2c1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (5.0 g, 21.53 mmol) in CH3CN (50 mL) was added Cs2CO3 (21.0 g, 64.58 mmol), potassium iodide (3.57 g, 21.53 mmol). The mixture was stirred at 27° C. for 30 minutes. Then 3-chlorobutan-2-one (2.75 g, 25.83 mmol) was added and the mixture was stirred at 70° C. for 12 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column (Elute: Petroleum ether:Ethyl acetate=50:1) to give tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a yellow-green oil. (3.23 g, yield 50%) LCMS (M+H+) m/z: calcd 303.37. found 302.9. 1H NMR (400 MHz, CDCl3): ä 8.32-8.30 (m, 1H), 8.25-8.23 (m, 1H), 7.17-7.14 (m, 1H), 5.50-5.44 (m, 1H), 2.71 (s, 3H), 1.96 (s, 3H), 1.65-1.67 (d, 3H), 1.64 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([C@@:4]1([OH:29])[CH2:27][C@H:26]([OH:28])[C:7]2=[C:8]([OH:25])[C:9]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]=4[O:23]C)[C:13](=[O:14])[C:10]=3[C:11]([OH:12])=[C:6]2[CH2:5]1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1.C(O)(=O)C(O)=O>[CH3:1][C:2]([C@:4]1([OH:29])[CH2:5][C:6]2[C:7](=[C:8]([OH:25])[C:9]3[C:21](=[O:22])[C:20]4[C:19]([OH:23])=[CH:18][CH:17]=[CH:16][C:15]=4[C:13](=[O:14])[C:10]=3[C:11]=2[OH:12])[C@@H:26]([OH:28])[CH2:27]1)=[O:3]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](O)C1)C(=O)c1c(O)cccc1C3=O
Reaction time: 8 h

Procedure:
Natural daunomycinone (14.7 mg) was taken up in anhydrous benzene (100 ml). Sea sand (1 g) was added and the mixture was stirred until all the daunomycinone went into solution. The reaction was stirred under nitrogen and anhydrous aluminum chloride (0.22 g) was added. The reaction gradually turned purple; stirring was continued at room temperature overnight. The reaction was worked up by pouring in aqueous oxalic acid (25 ml., 25%) and the layers mixed thoroughly until the color was discharged. The aqueous phase was extracted once with chloroform (10 ml) and the chloroform added to the benzene. The combined organic phases were washed once with water, dried over anhydrous sodium sulfate and concentrated to give (+)-carminomycinone, Rf = 0.16 (on silica gel, 3% methanol in methylene chloride, v/v). The mass spectrum showed 384 (M+, 45%), 366 (7%), 348 (100%), 341 (3%), 333 (21%), 323 (67%), 305 (19%), 295 (39%, 277 (16%), 249 (8%). The NMR (CDCl3) taken using Fourier-transform spectroscopy gave δ 13.47, 12.96, 12.17 (s, 1H ea); 7.14-7.25 (m, 3H), 2.43 (s, 3H), 2.27 (m, 2H); the vv spectrum showed maxma at 527, 512, 492, 480 and 466 nm.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18]2)=[O:16])=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][CH:7]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18]2)=[O:16])=[CH:12][CH:13]=1)=[O:4]
Reactant: NC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)NC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
) A solution of chloroacetylchloride (0.0089 mol) in CH2Cl2 (20 ml, dried over MgSO4) was added to a cooled solution of (±)-N-[4-(aminophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.0081 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.0093 mol) in CH2Cl2 (100 ml). The reaction mixture was stirred for one hour at 0° C. Water was added. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue (crude oil) was purified by short column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated under reduced pressure. The residue was stirred in EtOAc. The precipitate was filtered off, washed with EtOAc, and dried, yielding 2.47 g (68%) of (±)-N-[4-[[(chloroacetyl)amino]phenylmethyl]phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide. (compound 127)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:21]=[N:22][CH:23]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][C:13]=1[F:20])=[O:4].[OH-].[Na+]>>[F:20][C:13]1[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[N:9]2[CH:21]=[N:22][CH:23]=[C:8]2[CH:7]=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(SC)cc1F
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(Nc2c(C(=O)O)ccc3cncn23)c(F)c1
Temperature: 65 °C
Yield: 76.3 %

Procedure:
To a solution of 5-(2-fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (150 mg, 0.45 mmol) in IMS (10 mL) was added sodium hydroxide (0.5 mL, 1M aqueous solution, 0.5 mmol), the reaction mixture heated at 65° C. for 1.5 hours. The reaction mixture was concentrated in vacuo then taken up in water (ca. 15 mL), the aqueous solution was washed with diethyl ether before the pH was adjusted to pH 3 using 1M HCl, resulting in precipitation of a brown solid. The precipitate was extracted using ethyl acetate, the organic phase was isolated and washed with water followed by brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound as a brown solid (109 mg, 76%). 1H NMR (CD3OD): 7.67 (1H, s), 7.44 (1H, d, J=9.53 Hz), 7.39 (1H, d, J=0.83 Hz), 7.24 (1H, dd, J=9.57, 0.80 Hz), 7.15 (1H, dd, J=11.47, 2.12 Hz), 7.02-7.01 (1H, m), 6.76 (1H, t, J=8.49 Hz), 2.49 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: C#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C#Cc1cccc(OCCOC)c1
Yield: 70.1 %

Procedure:
3-Hydroxyphenylacetylene (237 mg, 2 mmol) was heated with 2-bromoethylmethylether (0.23 mL, 2.4 mmol) and potassium carbonate (322 mg, 2.4 mmol) in acetone (5 mL) to 110° C. in a microwave oven (CEM Discover) for 45 minutes. Water (1 mL) was added to the mixture and the whole was extracted with dichloromethane (2×25 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a brown oil. The oil was purified by column chromatography (SiO2, dichloromethane) to afford 3-(2-methoxyethoxy)phenylacetylene as a colourless oil (247 mg, 70% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH:18]=1.Cl>[Pd].CO>[F:1][C:2]1[C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]1
Reactant: CCCN1CC=C(c2cccc(OC(F)(F)F)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCN1CCC(c2cccc(OC(F)(F)F)c2F)CC1
Yield: 40 %

Procedure:
A mixture of 4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1-propyl-1,2,3,6-tetrahydro-pyridine (0.55 g, 1.8 mmol), palladium on carbon (0.09 g), hydrochloric acid (0.5 ml, conc), in methanol (30 ml) was hydrogenated at 50 psi for 15 h under hydrogen. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 0.55 g of crude product. Purification by flash column chromatography (Isooctane/ethylacetate, 1:1) gave the title compound 0.22 g (40%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 221-222° C. MS m/z (relative intensity, 70 eV) 305 (M+, 3), 277 (14), 276 (bp), 233 (6) 193 (8).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: CC(=O)Cl
Agent: Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(NC(C)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate hydrobromide (80 g), pyridine (52.5 g) and dichloromethane (800 ml) was added acetyl chloride (27.3 g) dropwise at 0° C., and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with water (500 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with ethyl acetate to give ethyl 2-(acetylamino)-1,3-thiazole-4-carboxylate (60 g).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[NH:27][CH:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30].C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50]([O:30][C:29](=[O:31])[CH:28]([NH:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[O:18][CH3:17])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:49]2
Reactant: COc1ccc(OC)c(NC(C(=O)O)c2ccccc2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(OC)c(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
PS-DCC (715 mg, 0.951 mmol, loading: 1.33 mmol/g) is suspended in dry THF (10 mL). (2,5-Dimethoxy-phenylamino)-phenyl-acetic acid hydrochloride (I54) (154 mg, 0.48 mmol), HOBT (146 mg, 0.95 mmol) and (R)-quinuclidin-3-ol (181 mg, 1.43 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off and the filtrate is evaporated. The residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and evaporated to dryness. The crude compound is purified by flash chromatography (DCM/MeOH=95/5) to achieve the title compound as a colorless oil (108 mg, 57% yield, mixture of diastereoisomers).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12]2[C:13]3[CH2:21][NH:20][CH2:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH3:10])=[CH:5][CH:4]=1.[Br:24][C:25]1[CH:26]=[CH:27][C:28](F)=[C:29]([CH:32]=1)[C:30]#[N:31].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([N:20]2[CH2:19][CH2:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C@@H:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][CH:5]=4)[CH3:10])[C:13]=3[CH2:21]2)=[C:29]([CH:32]=1)[C:30]#[N:31]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C[C@@H](Nc1ncnc2c1CNCC2)c1ccc(C(F)(F)F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](Nc1ncnc2c1CN(c1ccc(Br)cc1C#N)CC2)c1ccc(C(F)(F)F)nc1
Yield: 54.5 %

Procedure:
A mixture of (R)—N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (300 mg, 0.93 mmol), 5-bromo-2-fluorobenzonitrile (560 mg, 2.8 mmol), N,N-diisopropylethylamine (480 μL, 2.8 mmol), and acetonitrile (4 mL) was subjected to microwave irradiation at 180° C. for 2 h. More 5-bromo-2-fluorobenzonitrile (500 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. Additional 5-bromo-2-fluorobenzonitrile (500 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for an additional 2 h. LC-MS indicated the amine was nearly completely consumed. After cooling the mixture was concentrated in vacuo, and the residue was purified by silica gel column (100% EtOAc) to yield a light yellow solid (255 mg, 54%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>ClCCl>[CH3:27][O:26][C:24]([NH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.0 equiv.) and triethylamine (3.0 equiv.) in dichloromethane (0.1 M) was added methyl chloroformate (1.1 equiv.). The resulting mixture was stirred at RT for 45 min. After concentration, the residue was partitioned between EtOAc and water. The organic phase was washed with water and then with brine. After drying over sodium sulfate the solution was concentrated in vaccuo to give crude (R)-tert-butyl 2-(((methoxycarbonyl)amino)methyl)morpholine-4-carboxylate which was used in the next step without further purification. LCMS (m/z) (M+H)=175.1 (-Boc), Rt=0.63 min.