Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:11](=[O:36])[CH2:12][N:13](C(OCC1C=CC=CC=1)=O)[C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>C(O)C.[C].[Pd].CO>[ClH:44].[C:1]([NH:9][CH:10]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:11](=[O:36])[CH2:12][NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)N1CCC[C@H]1C(=O)O)N(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: C[C@H](NCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
1-[N-[3-(Benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline, phneylmethyl ester (1.0 g.) is dissolved in absolute ethanol (30 ml.) and 1N hydrochloric acid (2.25 ml.). Palladium-carbon catalyst (10%, 200 mg.) is added and the solution is stirred under an atmosphere of hydrogen overnight. The catalyst is filtered off and the solution is evaporated. The crude product (700 mg.) is combined with 300 mg. of crude product from a previous small scale reaction and passed through a column of LH-20 (1 inch×15 inch) in methanol. The fractions containing the desired product are pooled, evaporated, dissolved in water and filtered. The clear aqueous solution is lyophilized to give 800 mg. of 1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline, monohydrochloride; [α]D25 =-59.6 (c=1.4, methanol); m.p. 98°-130° (dec.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:27][C:28]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:6][CH2:7]1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: Cc1ccccc1
Product: O=C(NC(=S)NC1CCN(Cc2ccc3ccccc3c2)CC1)c1ccccc1

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0042 m) and benzoylisothiocyanate (0.69 g, 0.0042 m) in toluene (120 cm3) was stirred at room temperature for 6 hours. The solvent was evaporated and the gum dissolved in isopropyl alcohol and acidified with ethanolic HCl. The solvent was evaporated and the residue dissolved in ethyl acetate. The title compound crystallised and was filtered and dried as the monohydrochloride quarterhydrate salt, m.p. 212°-214° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18](Cl)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([NH:8][S:18]([C:15]2[CH:14]=[CH:13][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:17][N:16]=2)(=[O:19])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)C)cn2)cc1

Procedure:
prepared by reaction of p-tolylamine with 5-isopropyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([C:31](O)=[O:32])[NH:29][CH:30]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([C:31]([NH:1][C:2]3[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8](=[O:9])[N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)=[C:4]([O:17][CH3:18])[CH:3]=3)=[O:32])[NH:29][CH:30]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: COc1cc(N)ccc1OCC(=O)N1CCCC1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCC(=O)N1CCCC1
Yield: 95 %

Procedure:
Acylation of 2-(4-amino-2-methoxyphenoxy)-1-(pyrrolidin-1-yl)ethanone with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid to generate the title compound was achieved following the procedure described in step C of Example 1 in 95% yield. MS (ESI) 401 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].CN(C=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:23]Cl>C(OCC)(=O)C>[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:23][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[C:2]([F:1])([F:10])[F:11]
Reactant: O=C(c1ccc[nH]1)C(F)(F)F
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cccc2C(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
2-(Trifluoroacetyl)-1H-pyrrole (0.97 g) was added to DMF solution (10 ml) of 60% sodium hydride (0.16 g) and the mixture was stirred at room temperature for 30 minutes. 3-Methyl-4-nitrobenzyl chloride (1.0 g) was added thereto and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-2-(trifluoroacetyl)-1H-pyrrole (1.53 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][N:13]2[N:12]=1)[CH2:9][CH3:10])(C)(C)C.[ClH:22].C(OCC)C>CO>[ClH:22].[NH2:7][CH:8]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][N:13]2[N:12]=1)[CH2:9][CH3:10]
Reactant: CCC(NC(=O)OC(C)(C)C)c1nn2cccc2c(=O)[nH]1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCC(N)c1nn2cccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of [1-(4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propyl]-carbamic acid tert-butyl ester (10 mg, 0.034 mmol) in absolute methanol (0.5 mL) was treated with 2 N HCl/diethyl ether (2 mL) and the mixture stirred at room temperature overnight. The resulting white suspension was concentrated under vacuum and the solid residue triturated with diethyl ether and dried under vacuum to give the title compound (6 mg, 77%) as white powder: 1H NMR (DMSO-d6) δ 1.08 (t, 3H, J=7.15 Hz), 2.02 (m, 1H), 2.11 (m, 1H), 4.20 (s, 1H), 6.60 (s, 1H), 7.03 (s, 1H), 7.54 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][CH2:3]1.[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([N:4]1[CH2:3][CH:2]([OH:1])[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5]1(=[O:12])=[O:11])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: O=S1(=O)NCC(O)c2ccsc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CC(O)c2ccsc2S1(=O)=O
Temperature: -10 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
The product from Step C of Example 2 (4.0 g, 19.5 mmol) was dissolved in anhydrous DMF (70 mL) cooled to -10° C. and sodium hydride (21.5 mmol) was added. After stirring for five minutes allyl bromide (2.53 mL, 29.25 mmol) was added and this mixture stirred for 2 h at 0° C. The reaction mixture was poured onto ice water (100 mL) and this solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporated to give a crude product which was purified by column chromatography (silica, methylene chloride:methanol, 20:1) to provide the desired product (4.2 g, 88%) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[OH-:20].[K+]>O1CCCC1>[Cl:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Reactant: [OH-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(Cl)nc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
A solution of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (336.5 mg, 1.06 mmol) in tetrahydrofuran (6 mL) was treated with a 2N aqueous potassium hydroxide solution (6 mL) and was warmed to 80° C., where it stirred overnight. At this time, the reaction was concentrated in vacuo and was then carefully brought to pH ˜7 with a 2N aqueous hydrochloric acid solution. The material was then diluted with water (25 mL) and extracted with a 10% methanol/methylene chloride solution (2×25 mL). The combined organics were dried over magnesium sulfate, filtered and rinsed with methylene chloride, and concentrated in vacuo onto Celite®. Flash chromatography (40 g silica gel column, 1-50% ethyl acetate/hexanes) afforded 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one as an off-white solid (53.7 mg, 16.9%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.08 (s, 9H) 0.82 (t, J=8.10 Hz, 2H) 3.50 (t, J=8.10 Hz, 2H) 5.42 (s, 2H) 6.53 (d, J=3.20 Hz, 1H) 7.26 (br. s., 1H) 12.98 (br. s., 1H). LC-MS calcd. for C12H19ClN3O2Si [(M+H)+] 300, obsd. 300.0.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7](Cl)=[CH:6][N:5]=1.[CH3:15][Zn]C.O>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:10][C:9]1[C:4]([CH:3]=[O:2])=[N:5][CH:6]=[C:7]([CH3:15])[N:8]=1
Reactant: COc1nc(Cl)cnc1C(OC)OC
Reactant: C[Zn]C
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C)cnc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
After dissolving 3.34 g of 5-chloro-3-methoxypyrazine-2-carboxaldehyde dimethylacetal in 50 ml of tetrahydrofuran, 400 mg of [1,3-bis(diphenylphosphino)propane]dichloronickel (II) was added, 9.17 ml of dimethyl zinc (2.0 M, toluene solution) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours and then at 50° C. for 1.5 hours. The reaction solution was cooled on ice, water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 16 ml of acetone, 4 ml of 5N hydrochloric acid was added and the mixture was allowed to stand at room temperature for 15 minutes. A sodium bicarbonate solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.43 g, 61% yield).
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)[CH2:8][CH3:9].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:5]([C:19]1([OH:22])[CH2:20][CH2:21][CH:16]([CH:13]2[CH2:12][CH2:11][CH:10]([CH2:7][CH2:8][CH3:9])[CH2:15][CH2:14]2)[CH2:17][CH2:18]1)#[CH:6]
Reactant: C#C[Si](C)(C)C
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC1(O)CCC(C2CCC(CCC)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
24.32 ml of (trimethylsilyl)acetylene are added dropwise at −30° C. to a solution of 30.0 g of 4′-propylbicyclohexyl-4-one and 3.41 g of tetrabutylammonium fluoride trihydrate in 300 ml of THF. The cooling bath is removed after 5 minutes, and the reaction mixture is stirred at RT for 2 hours. A suspension of 39.2 g of potassium fluoride in methanol is subsequently added, and the mixture is stirred at RT for 3 days. Conventional work-up gives 4-ethynyl-4′-propylbicyclohexyl-4-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]N(C=O)C>>[CH3:18][N:9]1[C:8](=[O:13])[C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:12][CH2:11][CH2:10]1
Reactant: CN(C)C=O
Reactant: O=C1NCCOc2cc([N+](=O)[O-])ccc21
Agent: [H-]
Agent: [Na+]
Product: CN1CCOc2cc([N+](=O)[O-])ccc2C1=O
Reaction time: 15 h
Yield: 77 %

Procedure:
A solution of 8-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.25 g, 0.0012 mol) in DMF (8 mL) at 5° C. under nitrogen, was treated with sodium hydride (0.058 g, 0.0015 mol). After stirring 15 hrs. at room temperature, the reaction was evaporated. The residue was treated with ethyl acetate and 1N HCl (pH 5), separated, washed, dried (MgSO4) to give 4-methyl-8-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.2 g, 77%) as a tan solid. MP: 130-2° C.; 1H-NMR (DMSO-d6) δ 7.90-8 (d, 1H), 7.88 (d, 1H), 7.80 (d, 1H), 4.46-8 (m, 2H), 3.56-9 (m, 2H), 3.11 (s, 3H); LC/MS (ESI+): 223 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)[N:15]=1
Reactant: NC(N)=S
Reactant: O=C1Cc2cc(C(=O)CBr)ccc2N1
Solvent: CCO
Product: Nc1nc(-c2ccc3c(c2)CC(=O)N3)cs1
Temperature: 25 °C

Procedure:
A solution of 5-(α-bromoacetyl)oxindole (5 g) and thiourea (1.67 g) in absolute EtOH (250 ml) is refluxed for 30 minutes. The reaction mixture is cooled to RT, filtered, and washed with absolute EtOH affording the desired product. The free base is converted to its methanesulfonate salt by the procedure previously described in Example 12, affording the desired product, M.P.=244°-246° C.
Reaction SMILES: N[C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[CH:3][C:4]#[N:5].Cl.C[OH:13]>>[O:13]=[C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH2:3][C:4]#[N:5]
Reactant: CO
Reactant: N#CC=C(N)c1ccsc1
Agent: Cl
Product: N#CCC(=O)c1ccsc1
Reaction time: 3 h

Procedure:
A 1.2 g. portion of β-amino-3-thiopheneacrylonitrile is added to 10 ml. of 1 N hydrochloric acid. A 40 ml. portion of methanol is added and the mixture is stirred for 3 hours. The mixture is evaporated in vacuo to a residue which is dissolved in 35 ml. of hot methanol and treated with charcoal. After cooling, petroleum ether is added, the mixture is filtered and the solid collected is discarded. The filtrate is allowed to evaporate and the residue is dissolved in 35 ml. of hot isopropanol and isoluble material filtered and discarded. The filtrate is cooled and the solid is collected giving the desired product as white plates, m.p. 87°-88° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([C:18]2[C:19]3[CH:20]=[N:21][N:22]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:23]=3[CH:24]=[CH:25][CH:26]=2)=[O:17])=[CH:10][N:9]=1)(C)(C)C.NCC1C=CC(NC(=O)OC(C)(C)C)=NC=1.Cl.O1CCOCC1>>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([CH2:14][NH:15][C:16]([C:18]2[C:19]3[CH:20]=[N:21][N:22]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:23]=3[CH:24]=[CH:25][CH:26]=2)=[O:17])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Agent: CC(C)(C)OC(=O)Nc1ccc(CN)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
[5-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (0.200 g, 0.433 mmol) synthesized as described in Example 4, via the acid chloride and tert-butyl [5-(aminomethyl)pyridine-2-yl]carbamate) was treated with a solution of 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 6 hours at room temperature. A solid was obtained by filtration, and partitioned between saturated aqueous NaHCO3 (10 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with ethyl acetate (1 mL), filtered and air dried to afford the title compound as a white crystalline solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:20]1[N:25]=[CH:24][C:23]2=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:22]2[N:21]=1)=O>>[CH3:36][O:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[N:22]2[C:23]([CH:24]=[N:25][C:20]([NH:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:11]=3)=[N:21]2)=[CH:26][CH:27]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(OCCN4CCOCC4)c3)nn12

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(2-Morpholin-4-yl-ethoxy)-phenylamine and 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine. 1H-NMR (DMSO) δ 9.9 (br s, 1H), 9.46 (s, 1H), 8.97 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.5 (t, 1H), 7.4 (brs, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.15 (m, 2H), 6.9 (s, 2H), 6.6 (d, J=7.8 Hz, 1H), 4.4-3.3 (m, 12H), 3.8 (s, 3H); LC/MS (ESI+): 446 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH3:34])[C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:28]3[C:27]([CH3:34])=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: Cc1cc(Cl)cnc1C(=O)O
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CCOC(N)=N2)c1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R1=Me) and 5-chloro-3-methyl-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=377.0 [M+H]+.
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[CH3:6][C:7]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]([OH:15])[CH3:14])[CH2:8]1.[CH3:17][C:18]1([O:21][CH2:20]1)[CH3:19]>C1(C)C=CC=CC=1.C1CCCCC1>[CH3:16][C:7]1([CH3:6])[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]([O:15][C:18]([CH3:19])([CH3:17])[CH2:20][OH:21])[CH3:14])[CH2:8]1
Reactant: CC1(C)CO1
Reactant: CC(O)C1CCCC(C)(C)C1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CC(OC(C)(C)CO)C1CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.6 %

Procedure:
At 0° C. under an atmosphere of nitrogen, 178 ml (321 mmol) of a 1.8 M solution of ethyl aluminium dichloride in toluene was slowly added to a stirred solution of 100 g (641 mmol) of 1-(3′,3′-dimethylcyclohexyl)ethanol and 55.4 g (769 mmol) of isobutylenoxide in 500 ml of cyclohexane. After complete addition, the cooling bath was removed, the reaction mixture was allowed to warm to room temperature, and stirring was continued at this temperature for 15 h. The reaction mixture was then poured into 1 L of brine, acidified with concentrated phosphoric acid, and thrice extracted with ether. The combined organic extracts were washed with brine and water, dried with sodium sulphate, and concentrated on a rotary evaporator. Distillation of the crude material (136 g) provided at 78-85° C./0.3 mbar 55.1 g (38%) of pure 2-[1′-(3″,3″-dimethylcyclohexyl)-ethoxy]-2-methylpropan-1-ol, while 60.4 g of starting material were recovered.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=1.[H][H]>[Pd].C(O)C>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:14]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=1
Reactant: CCOC(=O)C=Cc1c[nH]c2cnc(-n3cnnc3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1c[nH]c2cnc(-n3cnnc3)cc12
Yield: 80.1 %

Procedure:
Ethyl 3-(5-(1,2,4-triazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)prop-2-enoate (0.4 g, 1.4 mmol) was hydrogenated over palladium on carbon (10%, 0.25 g) in ethanol (50 mL) at 45 psi of hydrogen for 6 hours. The catalyst was removed by filtration and the solvent evaporated in vacuo to give the title compound (0.32 g, 80%) as a colourless solid. mp 215°-218° C. 1H NMR (360 MHz, CDCl3 : d4 -MeOH 9:1) δ 1.23 (3H, t, J=7.1Hz), 2.72 (2H, t, J=7.4Hz), 3.12 (2H, t, J=7.4Hz), 4.13 (2H, q, J=7.1Hz), 7.36 (1H, s), 7.61 (1H, s), 8.60 (1H, s) and 8.89 (2H, s).
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][Cl:19])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: c1ccc(OCC2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: ClCCCN1CCC(COc2ccccc2)CC1
Yield: 83.6 %

Procedure:
A mixture of 28.6 g (0.15 mole) of 4-phenoxymethyl-piperidine, 23.5 g (0.15 mole) of 1-bromo-3-chloropropane, 40.4 g (0.4 mole) of triethylamine and 150 ml of tetrahydrofuran is heated under reflux for 5 hours. After cooling, the reaction mixture is filtered, the filtrate is evaporated in a vacuum, the residue is extracted with diethyl ether and the extract is evaporated. There are obtained 33.6 g (84% of theory) of crude 3-(4-phenoxymethylpiperidino)-propyl chloride in the form of an oil which can be further used in this form. The pure compound is obtained by distillation and boils at 180°-183° C./0.4 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:19])[CH3:18])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)c(C)c1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A stirred solution of 4-bromo-3-methylaniline (3.0 g, 0.016 mole) and triethylamine (4.5 ml, 0.032 mole) in dichloromethane (30 ml) at 0° C. was treated with acetyl chloride (1.2 ml, 0.017 mole) and allowed to warm to room temperature over 1 h. The mixture was washed with water, then 5M HCl acid and dried (Na2SO4), then concentrated in vacuo to afford the title compound as a pale yellow solid (3.07 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][Br:31])=[CH:7][CH:6]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)NC(=O)Nc2ccc(N)cc2)cc1
Reactant: O=C(Cl)CCCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC(=O)Nc2ccc(NC(=O)CCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
The deprotected amine (368 mg, 0.70 mmol) was stirred in dry CH2Cl2 (10 mL) under N2 atmosphere and NEt3 (98 μL, 0.70 mmol) was added to give a clear brown solution. 5-Bromovaleryl chloride (140 μL, 1.05 mmol, 1.5. equiv.) was added followed by triethylamine (98 μL, 0.70 mmol). The reaction mixture was stirred at rt for 16 h then diluted with CH2Cl2 (1×20 mL) and washed with 1 M aqueous hydrochloric acid (1×20 mL), 1 M aqueous sodium hydroxide (1×20 mL) and saturated brine (1×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give a crude yellow chalky solid which was purified by column chromatography on silica (50% ethyl acetate/petroleum ether) to give 29 (153 mg, 48%) as a yellow solid.