Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19])=[N:13][CH:14]=1)C1C=CC=CC=1.[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19])=[N:13][CH:14]=1
Reactant: CN(CCO)Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN(CCO)Cc1ccc(N)cn1
Temperature: 0 °C
Yield: 50.2 %

Procedure:
A stirred solution of 40 (400 mg, 1.1 mmol) in conc. sulfuric acid (1.3 mL) was heated at 50° C. for 3 h. The reaction mixture was cooled to 0° C., basified with 2N NaOH solution (15 mL) to pH ˜9 and extracted with 10% MeOH/CHCl3 (2×100 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and evaporated to obtain the desired amine (100 mg, 50%) as a brown liquid. Rf: 0.4 (10% MeOH/CHCl3, alumina plate); (m/z): 182 [MH]+; 1H NMR (400 MHz, DMSO-d6) δ 7.82 (1H, d, J=2.4 Hz), 7.05 (1H, d, J=8.4 Hz), 6.87 (1H, dd, J=2.8, 8.0 Hz), 5.15 (2H, s), 4.38 (1H, br s), 3.47-3.43 (4H, m), 2.42 (2H, t, J=6.4 Hz), 2.15 (3H, S).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:9]1\[C:8](=[O:13])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10]\1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1c1ccccc1
Product: CN(C)/C=C1/CCCC(c2ccccc2)C1=O
Yield: 101.2 %

Procedure:
A mixture of 2-phenylcyclohexanone (871 mg, 5.0 mmol) and of tert.-butoxy-bis(dimethylamino)methane (90%, 1.5 mL, 7 mmol) was stirred at 110° C. for 75 min. The reaction was evaporated to dryness under reduced pressure to give the crude title compound (1.16 g, 100%) as a red oil which was used directly in the next step without further purification. MS ISP (m/e): 230.2 (100) [(M+H)+].
Reaction SMILES: CC1C=CC(C2C=NN(C)C=2)=C(C=1)C(OC)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=1.Br[C:35]1[C:36]([C:42]#[N:43])=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:35]2[C:36]([C:42]#[N:43])=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[CH:23][CH:24]=1
Reactant: CC1(C)OB(c2ccc(F)cc2)OC1(C)C
Reactant: Cc1ccc(Br)c(C#N)n1
Agent: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Product: Cc1ccc(-c2ccc(F)cc2)c(C#N)n1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 3-bromo-6-methylpicolinonitrile. ESI-MS (m/z): 213 [M+1]+.
Reaction SMILES: [C:1]([N:8]([CH3:16])[C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN(C(C)C)C(C)C.C(OCC)C>[CH3:21][O:20][N:19]([CH3:18])[C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:16]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 75.3 %

Procedure:
To a cold (0° C.) solution of N-Boc-N-methylvaline (11) (5.0 g, 21.6 mmol), N,O-dimethylhydroxylamine hydrochloride (2.8 g, 28 mmol), and PyBOP® (11.2 g, 22 mmol) in CH2Cl2 (22 mL) was added DIEA (8.4 mL, 75 mmol). After 1 min., the reaction mixture was warmed to room temperature and stirring was continued for 1 h. If the pH value of the mixture was less than 7, the mixture could be treated with a few drops DIEA to allow the reaction to go to completion. The mixture was poured into 200 mL of diethyl ether and the resultant mixture was washed successively with 3 N hydrochloric acid (3×30 mL), saturated aqueous sodium hydrogen carbonate solution (3×30 mL), and saturated aqueous sodium chloride (3×30 mL). The organic layer was dried with magnesium sulfate and the solvent was evaporated, followed by chromatography of the crude product (silica gel, 1:3 diethyl ether-pet. ether), afforded 12 (4.46 g, 75% yield) as a colourless oil. 1H-NMR (200 MHz, CDCl3): 0.84 (d, J=6.6 Hz, 4H, (CH3)2), 0.85 (d, J=6.6 Hz, 2H, (CH3)2), 1.41 (s, 6H, Boc-(CH3)3), 1.44 (s, 3H, Boc-(CH3)3), 2.15-2.30 (m, 1H, CH), 2.75 (s, 1H, NCH3), 2.78 (s, 2H, NCH3), 3.10 (bs, 3H, NCH3), 3.64 (s, 1H, OCH3), 3.68 (s, 2H, OCH3), 4.66 (d, J=10 Hz, 0.4H, CH), 4.95 (d, J=10 Hz, 0.6H, CH); Exact mass calc'd for C13H27N2O4 (M+H)+: 275.19708. Found (DCI): 275.19710. Optical rotation obtained was [α]25 +128.3 (c 2.9, CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:28][CH:29]([CH3:31])[CH3:30])=[C:13]([C:15]2[NH:27][C:18]3=[N:19][C:20]([C:23](OC)=[O:24])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:28][CH:29]([CH3:31])[CH3:30])=[C:13]([C:15]2[NH:27][C:18]3=[N:19][C:20]([CH2:23][OH:24])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3cc(OCc4ccccc4)ccc3OC(C)C)[nH]c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CO)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a mixture of methyl 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine-5-carboxylate (0.45 g) in tetrahydrofuran (10 ml) was added lithium aluminum hydride (82 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (0.26 g, yield 61%) as colorless crystals. melting point 167-168° C. purity 99%. M+H: 390. 1H NMR (CDCl3) δ: 1.52 (6H, d, J=6.0 Hz), 4.74-4.82 (1H, m), 5.16 (2H, s), 7.00-7.50 (8H, m), 8.06 (1H, d, J=8.1 Hz), 8.19 (1H, d, J=3.0 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[C:4]([OH:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[C:4]([O:6][CH3:12])=[O:5]
Reactant: C=CCC(CO)(CO)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCC(CO)(CO)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A mixture of crude 2,2-bis(hydroxymethyl)pent-4-enoic acid (1 eq., 8.72 g), K2CO3 (3 eq., 22.9 g) and acetone (109 ml) was stirred at room temperature for 30 min. MeI (6 eq., 46.4 g) was added at 0° C. The mixture was stirred at room temperature for 2 days and concentrated. Water and EtOAc were added. The aqueous layer was extracted with 3×EtOAc. The organic layers were dried over MgSO4. Silica gel chromatography using 4-40% ACN (containing 5% MeOH)-DCM yields the title compound as colorless oil (2.2 g, 23% for two steps).
Reaction SMILES: [Na].[Cl-].C(C1C=CC(C[P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=CC=1)(C)C.[PH5].CC(=CCCC(CC=[O:43])C)C>C(O)C>[C:24]1([P:11](=[O:43])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)=CCCC(C)CC=O
Reactant: CC(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na]
Agent: [PH5]
Solvent: CCO
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of sodium (21 g, 0.9 at) in 1500 ml of absolute ethanol was added 388 g of p-isopropylbenzyltriphenylphosphonium chloride. The resulting phosphorane solution was cooled to 15°-20° C. (The light orange color fades when the temperature is lowered-) Freshly vacuum distilled citronellal (150 g, 1 mol.) was added dropwise while keeping the reaction mixture at reflux for 4 hours. The cooled reaction mixture was filtered to remove sodium chloride, most of the alcohol was distilled off in vacuo and 500 ml of hexane was added. The triphenylphosphineoxide was allowed to crystallize and filtered off. The solvents were removed from the mother liquors under vacuum and another 500 ml of hexane added. Cooling afforded another crop of triphenylphosphineoxide. The hexane was again evaporated and the residue distilled yielding, after a small forerun of isopulegol (a contaminant of citronellal), 200 g (82%) of the desired product. bp. 150°-145° C/0.1 mm. Ratio of E to Z is app. 40:60. nD25 =1.5172.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].CS(O[CH2:24][CH:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:26])(=O)=O.[H-].[Na+]>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:26][CH:25]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:24])=[CH:16][CH:17]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2ccc(O)cc2)nc1
Reactant: CC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(COc1ccc(Oc2ccc(OC(C)C)cn2)cc1)NC(=O)OC(C)(C)C

Procedure:
4-(5-Isopropoxypyridin-2-yloxy)phenol (592 mg, 2.41 mmol) and 2-tert-butoxycarbonylaminopropyl methanesulfonate (734 mg, 2.89 mmol) were reacted with sodium hydride in DMF in analogy to example 2c. Yield: 414 mg (43%), M+H+: 403.19.
Reaction SMILES: [C:1]([O:5][C:6](=[O:59])[NH:7][CH:8]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=1[Cl:58])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:29][CH2:30][CH2:31][NH:32][C:33]([NH:42]C(OC(C)(C)C)=O)=[N:34]C(OC(C)(C)C)=O)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:59])[NH:7][CH:8]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=1[Cl:58])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:29][CH2:30][CH2:31][NH:32][C:33]([NH2:42])=[NH:34])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N=C(NCCCC1CN(CCc2ccc3ccccc3c2)CCN1C(=O)C(Cc1ccc(Cl)cc1Cl)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1Cl)C(=O)N1CCN(CCc2ccc3ccccc3c2)CC1CCCNC(=N)N
Yield: 30.5 %

Procedure:
Alternatively, 20 mg (0.033 mmol) of the crude product H was reacted with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (10 mg, 1.1 eq) and silver nitrate (6 mg, 1.1 eq) and NMM (2.2 eq) in 5 mL of acetonitrile at room temperature for 24 hrs, followed by evaporation to remove the solvent and column chromatography purification to afford 4.5 mg of the product [2-[2-[3-(N′, N″-Di-tert-butoxycarbonyl-guanidino)-propyl]-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(2,4-dichloro-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (J). Product J (4.5 mg) was treated with 33% TFA in DCM at room temperature for 2 hours and the reaction mixture was concentrated and purified with HPLC to give 1.05 mg {1-(2,4-Dichloro-benzyl)-2-[2-(3-guanidino-propyl)-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (K).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]Br)=[CH:15][CH:14]=1>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CCBr)cc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: O
Product: CCOC(=O)N1CCN(CCc2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of 80 g 1-(ethoxycarbonyl)piperazine and 41 g of 2-(4-fluorophenyl)ethyl bromide is kept at room temperature overnight and then heated to 100° C. for 1 hour. After cooling, it is diluted with 50 ml water and extracted with benzene. The extract is washed with water and then shaken with 5% hydrochloric acid. The separated solid hydrochloride is filtered off, washed with a small quantity of water, decomposed by treatment with aqueous ammonia and the base isolated again by extraction with benzene. Processing of the extract affords 51 g (91%) of the crude 1-(ethoxycarbonyl)-4-(2-[4-fluorophenyl]ethyl)piperazine, b.p. 198° C./3 Torr.
Reaction SMILES: C(Cl)(=O)OCC.[C:7]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13])([OH:9])=O.C(N(CC)CC)C.Cl.[Cl:26][CH2:27][CH2:28][NH2:29]>C(Cl)(Cl)Cl>[OH:9][CH:7]1[C:10]2[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:13])[N:29]1[CH2:28][CH2:27][Cl:26]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: NCCCl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(O)N1CCCl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 32.7 %

Procedure:
9.7 ml (0.101 mole) of ethyl chlorocarbonate were dropwise added to a solution of 15.2 g (0.101 mole) of 2-carboxybenzaldehyde in 500 ml of chloroform and 14.1 ml (0.101 mole) of triethylamine, cooled to 0° C. After 45 minutes, a solution of 11.7 g (0.101 mole) of 2-chloroethylamine hydrochloride in 200 ml of chloroform and 14.1 ml (0.101 mole) of triethylamine was dropwise added thereto. The obtained solution was kept at 0°-5° C. for 5 hours. After warming to room temperature, the mixture was washed with water, 5% sodium bicarbonate, again with water and finally dried over sodium sulfate. 19 g of a crude product were obtained, which was purified on silica gel column eluting with methylene chloride-acetone 10/1 (v/v). 7 g of the title product were obtained; mp=133°-134° C. (methylene chloride).
Reaction SMILES: C(NCC)C.CC(O)(C)C.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[O:14].[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1)([O-:24])=[O:23].S(=O)(=O)(O)O>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][CH2:32][C:31]([C:28]2[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=2)=[O:33])=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCNCC
Product: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Added benzene (108 mL) to anhydrous zinc(II) chloride (19.62 g, 144 mmol), followed by the addition of diethylamine (11.16 mL, 108 mmol) and 2-methylpropan-2-ol (10.32 mL, 108 mmol) and stirred at room temperature for 2 h. Added 2-bromo-1-(4-bromophenyl)ethanone (20 g, 72.0 mmol) and 1-(4-nitrophenyl)ethanone (17.83 g, 108 mmol) together and stirred mixture for 18 h. Added 5% aq. sulfuric acid (50 mL) and stirred vigorously, then the product was collected by filtration, rinsed with benzene, water, methanol, dichloromethane and dried under vacuum to provide the product (15.0 g, 58% yield, colorless powder).
Reaction SMILES: [CH3:1]CCCCC.C[Si](C=[N+]=[N-])(C)C.[N+:14]([C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])([O-:16])=[O:15]>CC(C)=O>[N+:14]([C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([O:21][CH3:1])=[O:20])([O-:16])=[O:15]
Reactant: CCCCCC
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
2M hexane solution (4.5 mL) of trimethylsilyldiazomethane was added to the mixture of 2-Nitro-3-methylbenzoic acid (1.6 g) and acetone (15 mL) and stirred for 3 hours. After removing the solvent, the residue was diluted with ethyl acetate and washed with 1M sodium hydrate aqueous solution, water and saturated aqueous solution of sodium chloride respectively. Then the obtained substance was concentrated and dried to obtain methyl 2-nitro-3-methylbenzoate.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O1CCCC1.[CH3:37][S-:38].[Na+].C(OCC)(=O)C>CCCCCC.C(Cl)(Cl)Cl>[CH2:1]([O:19][CH2:20][CH:21]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22][S:38][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C[S-]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CBr)OCc1ccccc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCOCC(CSC)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 90 %

Procedure:
Racemic 1-O-octadecyl-2-O-benzyl-3-bromo-1,2-propanediol, 1.99 g (4.0 mmoles), was dissolved into 100 ml of dry tetrahydrofuran in a 250 ml round bottom flask equipped with a magnetic stir bar. To this solution was added 2.8 g (40.0 mmoles) of sodium thiomethoxide powder and the reaction mixture stirred for 4.5 hours at room temperature. The reaction was monitored by TLC (silica gel, 5% ethyl acetate in hexane; Rf=0.51). The mixture was filtered and the filtrate was washed with 50 ml tetrahydrofuran. The combined filtrates were concentrated under vacuum using a rotary evaporator to afford a yellow residue. This residue was dissolved into 50 ml chloroform and the organic solution washed twice with 30 ml of a concentrated solution of sodium bicarbonate. The organic phase was then dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator under vacuum to afford the crude product as a pale yellow oily residue. This crude product was purified by chromatography on silica gel 60 (E. Merck, Germany) using a step gradient of 0 to 10% ethyl acetate in hexane. The fractions collected were screened by TLC. Those fractions containing pure product (silica gel, 5% ethyl acetate in hexane, Rf=0.51) were pooled and concentrated to afford 1-O-octadecyl-2-O-benzyl-3-methylthio-1,2-propanediol in 90% yield.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:32]C(=O)OCC1C=CC=CC=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:14]=2)=[CH:9][CH:8]=1)=[O:5].C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[NH2:32][C@H:3]([CH2:2][OH:1])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[CH:22][CH:21]=3)[N:14]=2)=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(N[C@H](CO)C(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N[C@H](CO)C(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 60 °C
Yield: 68 %

Procedure:
To a stirred solution of (R)-benzyl 3-hydroxy-1-(4-(2-(4-morpholinophenylamino)-pyrimidin-4-yl)phenylamino)-1-oxopropan-2-ylcarbamate from the step above in MeOH (10 mL) was added Pd(OH)2 (134 mg) and ammonium formate (369 mg, 5.85). The mixture was heated at 60° C. for 2 hours, cooled down to room temperature, and filtered on Celite by eluting with MeOH. The filtrate was concentrated in vacuo and the residue was purified by preparatory HPLC (TFA). The TFA salt was removed by using basic resin to afford (R)-2-amino-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)propanamide 365 (346 mg, 68%). 1H-NMR (400 MHz, DMSO-d6): 9.39 (s, 1H), 8.44 (d, 1H), 8.13 (d, 2H), 7.83 (d, 2H), 7.67 (d, 2H), 7.29 (d, 1H), 6.94 pm (d, 2H), 4.94 (m, 1H), 3.75 (m, 4H), 3.60 (m, 2H), 3.46 (m, 1H), 3.05 (m, 4H); MS (EI) m/z for C23H26N6O3: 435.4 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:6]2[CH2:5][CH:4]([CH3:8])[N:3]([C:9]3[S:10][C:11]4[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:2]([CH3:1])[CH2:7]2)[CH:27]=1
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: CC1CNCC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CN2CC(C)N(c3nc4ccc(C(F)(F)F)cc4s3)C(C)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
A mixture of 2-(2,6-dimethyl piperazine-1-yl)-6-trifluoromethyl benzothiazole (163 mg), (3-bromomethylphenyl)acetic acid methyl ester (126 mg), potassium carbonate (75 mg) and dimethylformamide (4 mL) was stirred at room temperature for 18 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (171 mg). Yield: 65%.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH:11]([CH2:12][CH3:13])[CH2:10][C:9](=O)[C@@H:8]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6])([CH3:3])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH4-].[Na+]>CO.O.[OH-].[Na+].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:8]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCC1CC(=O)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Reactant: NCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC[C@@H]1C[C@H](NCc2ccccc2)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
To a solution of a diastereomeric mixture of (2S)-2-benzyl-5-ethyl-3-oxo-pyrrolidine-1-carboxylic acid isopropyl ester (0.29 mmol; 84 mg) and benzylamine (0.58 mmol; 62.1 mg) in MeOH (1.5 mL) is added titanium(IV) isopropoxide (0.58 mmol; 165 mg) at room temperature under nitrogen. After stirring for 5 hours, NaBH4 (0.58 mmol; 22 mg) is added to the mixture at 0° C. The mixture is stirred for 2 hours at room temperature and then diluted with water and aqueous 0.1 M NaOH solution. The solution is filtered and concentrated under reduced pressure. To the residue is added water and dichloromethane. The product is extracted twice with dichloromethane. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexane/EtOAc) to give (2S,3S,5R)-2-benzyl-3-benzylamino-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (61 mg, 55%); ESI-MS m/z: 381 [M++1], Retention time 1.77 min (condition A).