Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]1[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]1[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC1CC(O)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)CC1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a stirred solution of tert-butyl-4-hydroxy-2-isobutylpiperidine-1-carboxylate (4.6 g, 0.018 mol) in DCM (50 mL) at 0° C., 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (9.1 g, 0.02146 mol) was added portionwise and the resulting solution was warmed to room temperature and stirred under N2 overnight. The reaction mixture was quenched with satd NaHCO3 solution (50 mL) and was filtered through a Celite® pad. The filtrate was extracted several times with DCM (50 mL), the combined organic phases were washed with water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated. The concentrated product was purified by column chromatography using 10% EtOAc in petroleum ether to yield the product with HPLC purity 90%. The impure product was further purified by preparative HPLC to yield 2-isobutyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester as a liquid (2.1 g, 46%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].[OH:33][CH2:34][C:35]([CH3:39])([CH2:37]O)[CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:36][C:35]1([CH3:39])[CH2:34][O:33][C:6]2([CH2:7][C:2]([CH3:1])([CH3:32])[P:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=3[CH:29]([CH3:31])[CH3:30])[C:4]([CH3:9])([CH3:10])[CH2:5]2)[O:8][CH2:37]1
Reactant: CC(C)(CO)CO
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC3(CC2(C)C)OCC(C)(C)CO3)c(C(C)C)c1
Temperature: 110 °C
Yield: 90.2 %

Procedure:
A flask was charged with 4.0 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (8.88 mmol, 1.0 equiv) 4.6 g of neopentyl glycol (44 mmol, 5 equiv) and 0.15 g of p-toluenesulfonic acid monohydrate (0.89 mmol, 0.1 equiv). The atmosphere was purged with argon and the flask was charged with 80 mL of argon-sparged toluene. The reaction flask was equipped with a Dean-Stark trap and warmed to an internal temperature of 110° C. for 2 h under argon atmosphere. The distilled toluene was collected in the Dean-Stark trap. The reaction mixture was cooled to room temperature under argon gas. The reaction was quenched with 1.7 mL of aqueous 10 wt % sodium carbonate solution and partitioned between 65 mL of heptane and 35 mL of water. The organic solution was washed three times with 20 mL portions of water and concentrated in vacuo with gentle heating. Anhydrous ethanol (78 g) was added to the crystalline residue and removed in vacuo with gentle heating. Anhydrous ethanol (24 mL) was added to the unpurified solids and the solids slurry was warmed to 80° C., held for an hour, and cooled to room temperature. The product was isolated by filtration, washed with ethanol and dried in vacuo at 50° C. to give 4.3 g of 3,3,8,8,10,10-hexamethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane (98 area % by HPLC, 88% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[CH:9].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:9][C:8]#[CH:7])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 79.7 %

Procedure:
Potassium carbonate (1.04 g, 7.5 mmol) and propargyl bromide (654 mg, 5.5 mmol) were added to a solution of tert-butyl-1-piperazinecarboxylate (931 mg, 5.0 mmol) in acetone (5 ml). The reaction mixture was heated at 60° C. for 1 hour, and then filtered to remove the inorganics. The solvent was removed under vacuum to give a crude product which was purified by column chromatography (10-30% ethyl acetate/hexane) yielding 4-propargylpiperazine-1-carboxylic acid tert-butyl ester (894 mg, 80%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:11]([CH2:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16][CH2:15]1)#[N:12].[OH-].[Na+]>C(OCC)C.O1CCCC1.O>[NH2:12][CH2:11][CH2:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16][CH2:15]1
Reactant: N#CCC1COc2ccccc2C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
First 4.44 g (33.3 mmol) of aluminium chloride in 150 ml of absolute diethyl ether are added dropwise while stirring at room temperature to a suspension of 7.59 g (200 mmol) of lithium aluminium hydride in 300 ml of absolute diethyl ether. Then 17.32 g (100 mmol) of 3-cyanomethylchroman, dissolved in 200 ml of tetrahydrofuran, are added dropwise within a period of 15 minutes. The reaction mixture is stirred for 16 hours at room temperature and then decomposed with 7.6 ml of water, 7.6 ml of sodium hydroxide solution (15% strength) and 22.8 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether and washed with water. The organic phase is then extracted by shaking with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 15.95 g (90%) of 3-(2-aminoethyl)chroman are obtained in the form of a colourless oil. The 3-(2-aminoethyl)chroman hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and has a melting point of 244°-245°.
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][NH:5][C:6](=O)[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[N:15]([CH2:19][C:20]#[C:21][CH3:22])[C:14]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]3)=[N:13][C:12]=2[N:11]([CH3:37])[C:9]1=[O:10]>C(O)(=O)C>[N:1]1[C:2]2[C:3](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:4][NH:5][C:6]=1[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[N:15]([CH2:19][C:20]#[C:21][CH3:22])[C:14]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]3)=[N:13][C:12]=2[N:11]([CH3:37])[C:9]1=[O:10]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)NCc1ccccc1N)c(=O)n2C
Solvent: CC(=O)O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC1=Nc3ccccc3CN1)c(=O)n2C
Reaction time: 2 h

Procedure:
A mixture of 280 mg of 1-[2-(2-amino-benzylamino)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine and 4 ml glacial acetic acid is heated to boiling for two hours. Then the reaction mixture is evaporated down and the flask residue is purified through a column of aluminium oxide (activity stage III) with methylene chloride/ethyl acetate/methanol (5:5:0 to 5:4:1) as eluant. In addition to the desired 1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine, deprotected 1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine is also obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17]CC)=O)[C:3]1=2.[NH2:20][CH2:21][CH:22]([OH:34])[CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][N:24]1[CH2:23][CH:22]([OH:34])[CH2:21][NH:20][C:15](=[O:17])[CH2:14][O:13][C:12]1[C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH2:6][O:5][C:4]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1cccc2c1N(C)C(=O)CO2
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: CN1C(=O)COc2cccc(OCC(=O)NCC(O)CN3CCc4ccccc4C3)c21
Yield: 27.9 %

Procedure:
A reaction vessel containing a mixture of ethyl 2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yloxy)acetate (43.0 mg, 0.162 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (33.0 mg, 0.163 mmol) and EtOH (0.5 mL) was placed in a microwave reactor and the mixture irradiated at external temperature of 120° C. for 1 h. The reaction mixture was purified in two steps by preparative TLC followed by preparative HPLC to render the title product (19.2 mg, 19% yield)
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>C(Cl)(Cl)Cl.[Ag]=O>[CH2:1]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=2)[CH2:16]1)[CH2:2][CH3:3]
Reactant: COc1ccc(C2CCCNC2)cc1OC
Reactant: CCCI
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: CCCN1CCCC(c2ccc(OC)c(OC)c2)C1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
2 g of silver oxide and then 2 ml of propyl iodide were added to a solution of 4 g of 3-(3',4'-dimethoxyphenyl)-piperidine in 20 ml of chloroform and the mixture was stirred for 8 hours at 20° C under an inert atmosphere. Another 1 g of silver oxide and 1 ml of propyl iodide were added and the mixture was stirred for 15 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 3.2 g of N-propyl-3-(3',4'-dimethoxyphenyl)-piperidine.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[F:21][C:22]1[CH:23]=[C:24]([C:28]2([NH2:35])[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:9]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:7]=1)[C:3]([NH:35][C:28]1([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]1)=[O:4]
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2cccc(F)c2)CCC(=O)CC1
Agent: Cl
Product: CC(C(=O)NC1(c2cccc(F)c2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 4) and 1-(3-fluorophenyl)-4-oxocyclohexylamine hydrochloride (Description 181) according to the method of Example 1. 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.73 (2H, s), 7.29–7.24 (1H, m), 7.06–7.03 (1H, m), 6.97–6.94 (2H, m), 5.78 (1H, s), 3.72 (1H, q, J 7.0 Hz), 2.81–2.75 (1H, m), 2.63–2.57 (1×, m), 2.44–2.24 (6H, m), and 1.53 (3H, d, J 7.0 Hz).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1>C(O)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.[Ru](I)I.[Ru](I)I>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C/C(=C\[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: I[Ru]I
Solvent: CCO
Solvent: Cc1ccc(C(C)C)cc1
Product: C[C@@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 60 °C
Reaction time: 120 h

Procedure:
To a suspension of (E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid [2(ii-a)] (10 g, 26.1 mmol) in degassed ethanol (90 ml) is added a solution of diiodo(p-cymene)ruthenium(II) dimer (0.156 g, 0.16 mmol) and (αS,αS)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (=Mandyphos SL-M004-2) (0.348 g, 0.33 mmol) in degassed ethanol (30 ml) portion wise over the entire reaction time of 5 days. The solution is degassed using vacuum and a pressure of 5.5 bar hydrogen is applied. The mixture is heated to 60° C. and stirred at this temperature for 5 days. The vessel is then purged with nitrogen. The solvent is removed in vacuo. The resulting solid is dissolved in isopropyl acetate (34 ml) and heated to reflux. An heptane fraction (68 ml) is added and the mixture is cooled to room temperature. The solid is collected by filtration and washed with an heptane-isopropyl acetate 2:1 mixture (20 ml). The solid is dried overnight at 50° C. under 1-50 mbar vacuum to afford the title compound [Ratio 2(i-a): 2(i-b) 6:94, as determined by HPLC analysis] as a grey solid. δH (500 MHz; DMSO) 1.06 (3H, d, J 7.0, 1-CH3), 1.32 (9H, s, (CH3)3), 1.42 (1H, m, 3-HA), 1.78 (1H, m, 3-HB), 2.39 (1H, m, 2-H), 2.73 (2H, d, J 7.0, 5-H), 3.73 (1H, m, 4-H), 6.75 (1H, d, J 9.5, NH), 7.29 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.35 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); δC (500 MHz, DMSO) 16.2 (1-CH3), 28.2 [(CH3)3], 35.7 (2-C), 37.9 (3-C), 40.7 (5-C), 49.2 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.7 (Ar—CH), 137.8 (Ar-ipso-C(Ph)), 138.4 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.3 (NCO), 177.6 (CO2H); m/z (+ESI) 406 ([MNa]+, 4%), 384 ([MH]+, 44), 328 (100), 284 (22); Found: [MH]+, 384.21696. C23H30NO4 requires MH 384.21693.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:18]1[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 19 %

Procedure:
Chloroacetyl chloride (6.63 ml) and triethylamine (13.4 ml) in DCM (20 ml) was added dropwise to 1-ethylpiperazine (10 g) in DCM (60 ml) under nitrogen. The mixture was stirred at room temperature for 17 hours then partitioned between DCM and H2O (100 ml). The aqueous layer was neutralised using 1M NaOH before extracting into DCM. Organic layer dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (silica, 0 to 5% MeOH in DCM) gave the title compound as a pale oil (3.23 g, 19%). δH (CDCl3) 4.08 (2H, s), 3.65 (2H, m), 3.55 (2H, m), 2.52-2.40 (6H, m), 1.10 (3H, t, J 7.2 Hz).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:1]([O:8][C@@H:9]([CH3:14])[CH2:10][C:11]([N:17]([O:18][CH3:19])[CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CC(=O)O)OCc1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C[C@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of the above (3S)-3-(benzyloxy)butanoic acid (225 g) in DMF (1.5 L), N,O-dimethylhydroxylamine hydrochloride (111 g, 1.1 mol) and triethylamine (0.32 mL, 2.3 mol) were added, and the mixture was stirred at room temperature for 40 minutes. Subsequently, 1-hydroxybenzotriazole (112 g, 0.83 mol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (160 g, 0.83 mol) were successively added, and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction mixture was poured to ice-water, and it was extracted with diethyl ether. After it was successively washed with 1N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure to give (3S)-3-(benzyloxy)-N-methoxy-N-methylbutanamide (196 g) as a mixture. The present compound was used for the subsequent reaction without further purification.
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[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH: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[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)COC)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH2:14](O)CCCCCCCCCCC>[Ni]>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:14])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccnc2)cc1
Reactant: CCCCCCCCCCCCO
Agent: [Ni]
Solvent: O
Product: Cc1ccc(-c2ccccc2)cn1
Temperature: 25 °C

Procedure:
A suspension of 100 g of wet Raney Nickel in 1.5 L of dodecanol in a three-neck round bottom flask equipped with a Dean Stark apparatus was heated until the temperature reached 130° C., then 3-phenylpyridine (Aldrich) was added and the reaction was heated at 190°-200° C., for 6 hours. During the reaction, water was constantly eliminated. When the reaction was over, half of the dodecanol was removed by distillation. After cooling the reaction mixture to r.t., 200 mL of H2O and 400 mL of hexane were added, the mixture was shaken and the hexane layer decanted. This process was repeated several times. The combined hexane fractions were washed with 10N HCl until the disappearance of 5-phenyl-2-picoline from the organic phase. The combined aqueous layers were filtered, washed with hexane, basified with 10N NaOH, and extracted with CH2Cl2. The organic layer was washed with NH4OAc (25%), dried over MgSO4 and evaporated to dryness. The crude residue was then distilled under vacuum (100° C. at 0.1 mm of Hg) to afford the pure title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[O:45][CH3:46]>CO>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]3=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]3[N:22]=2)=[CH:4][C:5]([C:18]#[N:19])=[CH:6][C:7]=1[N:8]1[CH2:17][CH2:16][C@@H:15]2[C@H:10]([O:11][CH2:12][CH2:13][N:14]2[C:44]([O:45][CH3:46])=[O:47])[CH2:9]1
Reactant: COC(=O)Cl
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NCCO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OCCN4C(=O)OC)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 371)(10 mg, 0.021 mmol, was taken up in MeOH (1 mL) and DIPEA 20 μL was added. The reaction was stirred at 5° C. (ice bath) and methyl carbonochloridate (1.617 μl, 0.021 mmol) was added; the reaction stirred at 25° C. 1 hr. The solvents removed and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 40-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-(4aR,8aR)-methyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (7.8 mg).
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:14][C:15](=[S:17])[NH2:16])[CH2:13][CH2:12][CH2:11]1)C1C=CC=CC=1.Br[CH2:19][C:20](=O)[CH2:21]C(F)(F)F>>[CH3:21][C:20]1[N:16]=[C:15]([CH2:14][C:10]2([CH2:9][OH:8])[CH2:11][CH2:12][CH2:13]2)[S:17][CH:19]=1
Reactant: NC(=S)CC1(COCc2ccccc2)CCC1
Reactant: O=C(CBr)CC(F)(F)F
Product: Cc1csc(CC2(CO)CCC2)n1

Procedure:
The title compound was prepared using the same experimental procedure as in examples 18f and 18g from 2-{1-[(benzyloxy)methyl]cyclobutyl}ethanethioamide and 1-bromo-4,4,4-trifluoro-2-butanone. 1H NMR (300 MHz, CDCl3) δ 7.25 (s, 1H), 3.35 (s, 2H), 2.82 (br s, 2H), 2.02-1.91 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[CH3:37][Zn]C>>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[S:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:9]2[N:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:37])[N:7]=2)[C:19]=1[F:36])(=[O:27])=[O:26]
Reactant: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Product: Cc1nccc(-c2sc(C(C)(C)CO)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (200 mg, 0.360 mmol) and dimethylzinc (0.360 mL, 0.721 mmol) at 80° C. for 3 hours, the title compound was obtained as a solid (8 mg, 4% yield). MS (ESI): 534.9 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:21]([F:22])([F:23])[F:24])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(4-fluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.102) (0.40 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white foam (0.37 g), which was subsequently deprotected.