Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[NH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][NH:25][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1
Reactant: NCCO
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Product: Cc1ccc(-c2cc(CNCCO)c(=O)n(CC(C)C)n2)cc1

Procedure:
Following the procedure of Example 9(4), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and 2-aminoethanol were reacted to yield the title compound as a slightly yellow oil (yield: 80.3%). 1H NMR(400 MHz, CDCl3)δ: 0.98(6H, d, J=6.8 Hz), 2.20–2.38(3H, m), 2.39(3H, s), 2.84(2H, t, J=5.1 Hz), 3.72(2H, t, J=5.1 Hz), 3.82(2H, d, J=1.2 Hz), 4.07(2H, d, J=7.3 Hz), 7.26(2H, d, J=8.1 Hz), 7.68(1H, s), 7.70(2H, d, J=8.1 Hz). IR(Neat) cm−1: 3429, 1652, 1601, 1519. Mass m/z: 315(M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:19])[CH2:11][NH:12][C@@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](ON1C(=O)CCC1=O)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>ClCCl>[CH2:23]([O:22][C:20]([N:12]([CH2:11][CH:10]([CH3:19])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@H](C)NCC(C)CNC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: COC(=O)[C@@H](C)N(CC(C)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of methyl N-{3-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-D-alaninate (2.5 g, −8.9 mmol) in dichloromethane (50 mL) was added Cbz-OSu (2.25 g, 9.0 mmol). The resulting mixture was stirred at room temperature for 3 days. The solvent was removed on a rotavap, and the crude product was purified by flash chromatography on a Biotage® system (silica, 25-80% ethyl acetate in hexanes) to yield methyl N-[(benzyloxy)carbonyl]-N-{3-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-D-alaninate as colorless viscous oil. MS (M+1−Boc): 309.4
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CCCCCCC>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][NH:10][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCl
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CNCc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(3-(Trifluoromethyl)phenyl)methanamine (25 g, 143 mmol), (chloromethyl)trimethylsilane (19.92 mL, 143 mmol), and triethylamine (23.87 mL, 171 mmol) were combined neat. The resultant reaction mixture was refluxed overnight. The reaction was cooled to room temperature, and heptane (150 mL) was added. The HCl salts were removed by filtration, washing with heptane. The solvent was removed under reduced pressure, and the product was isolated by vacuum distillation (bp 70-90° C./3.2 torr) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.59 (s, 1H), 7.53-7.38 (m, 3H), 3.86 (s, 2H), 2.04 (s, 2H), 1.34 (s, 1H), 0.06 (s, 9H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)Cl>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: BrBr
Solvent: ClCCl
Product: Oc1ccc(Br)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
3-Phenoxyphenol (700 mg, 3.8 mmol) was stirred at 0° C. in DCM (7 mL) and bromine (0.154 mL, 3.0 mmol) was added dropwise. The reaction was stirred at ambient temperature for 10 min and then the solvents removed in vacuo to afford a crude oil which was purified by preparative HPLC to afford, in order of elution, 4-bromo-3-phenoxyphenol (126 mg, 0.5 mmol, 16%) M.S. (ESI) (m/z): 263,265 [M−H]−; and 4,6-dibromo-3-phenoxyphenol (201 mg, 0.6 mmol, 39%) M.S. (ESI) (m/z): 341, 343, 345 [M−H]−
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)#[N:13].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>>[C:12]([C:14]1([C:2]2[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)#[N:13]
Reactant: COCOc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: COCOc1cccnc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
2-Chloro-3-methoxymethoxy-pyridine (Tetrahedron 58 (2002), 309-314) (2 g, 11.5 mmol) and tert-butyl 4-cyanopiperidine-1-carboxylate (1.6 g, 7.7 mmol) were reacted in the presence of potassium hexamethyldisilazide (9.2 mmol) using the method in example 8-1 to afford the desired product: tert-Butyl 4-cyano-4-[3-(methoxymethoxy)pyridin-2-yl]piperidine-1-carboxylate: 1H NMR δ (ppm) (CDCl3): 8.21 (1H, d, J=4.6 Hz), 7.53 (1H, d, J=8.3 Hz), 7.27-7.23 (1H, m), 5.31 (2H, s), 4.20 (2H, br s), 3.55 (3H, s), 3.28 (2H, br s), 2.35 (2H, s), 2.10 (2H, br s), 1.47 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[O:16]([NH2:18])[CH3:17].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH3:17][O:16][NH:18][C:12]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]1)=[O:14]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CONC(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 35.8 %

Procedure:
1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (2.00 g, 9.94 mmol), methoxylamine hydrochloride (1.09 g, 13.02 mmol), EDC.HCl (2.50 g, 13.02 mmol), HOBT (1.99 g, 13.02 mmol) and N-methylmorpholine (2.61 g, 25.8 mmol) were dissolved in anhydrous DMF (20.0 mL) and the resulting reaction mixture was stirred at RT for 5 days. The reaction mixture was evaporated to dryness and the residue was taken up in DCM and washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column eluting with 70% EtOAc/hexanes to afford the title compound (0.82 g, 36%): 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.23 (s, 1H), 3.53 (s, 3H), 1.38 (s, 9H), 1.20 (q, J=4.3 Hz, 2H), 0.85 (q, J=4.3 Hz, 2H). This material is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:16][CH3:17])[CH:10]([CH3:15])[CH2:11][N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](=[CH:16]\[CH3:17])/[C@H:10]([CH3:15])[CH2:11][N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC(c1cccc(OC)c1)C(C)CN(C)C
Agent: Cl
Product: C/C=C(\c1cccc(OC)c1)[C@H](C)CN(C)C

Procedure:
The yield of [3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine; hydrochloride (3) was >96% with a ratio of the enantiomer (−)-(2R,3R) to the diastereoisomer (−)-(2R,3S) of 76:24. The (−)-(2R,3R) enantiomer is preferably used as an active ingredient in medicaments.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:30]4[N:26]([C:23]5[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:34])[F:35])=[CH:25][CH:24]=5)[N:27]=[CH:28][CH:29]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(C(F)(F)F)cc1
Product: Fc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(C(F)(F)F)cc4)cc32)cc1

Procedure:
The title compound, yellow solid (45 mg, 31%), MS (ISP) m/z=423.5 [(M+H)+], mp 167° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (100 mg, 344 μmol) and 1-(4-trifluoromethyl-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate C) (96.7 mg, 378 μmol).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C1C=CC=CC=1>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]2[CH:5]=[CH:6][C:1]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:2][CH:3]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCCNc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Yield: 63.1 %

Procedure:
Analogously to Example 47b), 10.0 g of ethyl 4-(biphenyl-4-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine in 70 ml of benzene are reacted with 6.2 g of p-chlorobenzoyl chloride to obtain 9.4 g (62.9% of theory) of ethyl 4-[p-chloro-N-(biphenyl-4-yl)benzamido]butyrate as a viscous non-distillable oil. Saponification of this ester, analogously to Example 47c), yields 7.0 g (79.7% of theory) of 4-[p-chloro-N-(biphenyl-4-yl)-benzamido]butyric acid, MP 192° to 194°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:22](=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[CH3:27][O:26][C:24](=[O:25])[CH2:23][C:22]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:28]
Reactant: COC(=O)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(tert-Butoxycarbonyl)piperazine (2.50 g; 13.4 mmol) and triethylamine (1.77 g; 2.43 mmol) are dissolved in methylene chloride (40 mL). The solution is cooled in an ice-bath and a solution of methyl 3-chloro-3-oxopropionate (2.02 g; 14.8 mmol) in 10 mL methylene chloride is added dropwise over a 10-minute period. The ice-bath is removed and the reaction mixture is stirred for 1 hour at room temperature. The reaction mixture is then poured onto ice-cold 0.1N HCl (100 mL) and extracted with methylene chloride (200 mL). The organic extract is washed with saturated sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (60%→80% ethyl acetate in hexanes) to afford the desired product as a white solid. ESMS: MH+ 287.2
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:19][N:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22][CH2:21]1
Reactant: CN1CCCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)N3CCCN(C)CC3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 1-methyl-[1,4]diazepane by the method described in Example 41. Yellow colored solid (49 mg, 37%). 1H NMR (CDCl3) 1.97-2.05 (m, 2 H), 2.36 (d, J=1.4, 3 H), 2.40 (s, 3 H), 2.62 (br s, 2 H), 2.74 (br s, 2 H), 3.80 (br s, 2 H), 7.37 (br s, 1 H), 7.45 (d, J=3.8, 1 H). 19F NMR −63.1. LC/MS 4.43 min, [M+1]+ 374.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(Br)cc4)cc3c2C1
Yield: 19 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 14.7 mg (0.051 mMol) 4-bromobenzoyl chloride, 3.6 mg (20%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[CH3:10]I>O1CCCC1>[CH3:10][C:4]1([C:7]([OH:9])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C(O)C1CCOCC1
Reactant: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
nButyllithium (21.1 ml, 33.8 mmol, 1.6 M in hexanes) was added dropwise over 10 minutes to a stirred solution of duisopropylamine (4.7 ml, 33.8 mmol) in anhydrous tetrahydrofuran (40 ml) under an atmosphere of nitrogen at <10° C. Upon addition, tetrahydropyran-4-carboxylic acid (J. Am. Chem. Soc., 1993, 115, 8407) was added in anhydrous tetrahydrofuran (20 ml) under nitrogen at <5° C. The mixture was stirred at room temperature for one hour after which methyl iodide (2.4 ml, 38.4 mmol) was added dropwise at <5° C. The resultant solution was stirred at <5° C. for 30 minutes, allowed to warm to room temperature and stirred for a further 3.5 days. The solvent was removed by evaporation and the residue dissolved in dichloromethane (100 ml) and 2N hydrochloric acid (100 ml) added. The aqueous layer was extracted with dichloromethane (3×100 ml) and the combined organic layers were washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered and evaporated to yield the title product (1.4 g) which was used in the next step without purification. Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 1.00 (3H, s), 1.47-1.58 (2H, m), 2.06-2.11 (2H, m), 3.49-3.60 (2H, m), 3.78-3.86 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38]Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N>[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: Cc1cccnc1CNCCCCNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Yield: 76 %

Procedure:
Using General Procedure A: A solution of {4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.605 g, 2.06 mmol), 1-(tert-butoxycarbonyl)-2-(chloromethyl)-benzimidazole (0.804 g, 3.01 mmol), KI (72 mg, 0.43 mmol) and DIPEA (0.70 mL, 4.02 mmol) in CH3CN (10 mL) was heated at 80° C. for 6 hours. Purification of the crude material by column chromatography on silica gel (15:1 CH2Cl2-MeOH) followed by column chromatography on silica gel (NH4OH saturated Et2O) provided 0.82 g (76%) of 2-{[(4-tert-Butoxycarbonylamino-butyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a white foam.
Reaction SMILES: [OH:1][C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16]C(=O)OCC3C=CC=CC=3)[CH2:11][CH2:10]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>[Pd].CO>[NH2:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:2]2([OH:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH2:10][CH2:11]1
Reactant: O=C(NCC1CCN(CC2(O)CCOCC2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCC1CCN(CC2(O)CCOCC2)CC1
Reaction time: 20 h
Yield: 94 %

Procedure:
A mixture of benzyl ({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)carbamate as prepared in 1(1) (5.60 g, 15.5 mmol) and palladium on activated carbon (10 wt. %, 1.20 g) in methanol (250 mL) was hydrogenated at room temperature for 20 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 3.30 g (94%) of the title compound as slightly yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[OH:23])[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8])[CH:18]=[O:19]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cc1Br
Temperature: 90 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (4.62 g), 3-bromo-4-hydroxybenzaldehyde (4.28 g), potassium carbonate (2.94 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 4 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzaldehyde as pale-brown crystals (5.20 g, yield 67%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-147° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:31][CH:30]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(OC(F)(F)F)cc1

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)lactate (4.50 g), which is the product of Reference example 1(b), 4-trifluoromethoxyphenol (2.33 ml), triphenylphosphine (4.71 g) and solution of diethylazodicarboxylate in toluene (40%, 8.15 ml) and the reaction mixture was treated to afford the desired compound (4.19 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH:12]C(=O)COC>Cl.CCO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH2:12]
Reactant: COCC(=O)N[C@@H]1CCOc2c(F)cccc21
Agent: Cl
Solvent: CCO
Product: N[C@@H]1CCOc2c(F)cccc21
Yield: 88.1 %

Procedure:
A mixture of 8-fluorochroman-4-amine (3.40 g), methyl 2-methoxyacetate (2.44 g) and Novozyme 435 (Aldrich, 0.68 g) in anhydrous tert-butyl methyl ether (75 mL) was heated at reflux under argon for two hours (at which time the ratio of acylated to unacylated product was 1:1 by HPLC). The solid that formed upon cooling was collected via filtration and dissolved in EtOAc. The mixture was filtered to remove the biocatalyst and washed once with 0.5M HCl to remove any lingering (S)-amine. The solvent was evaporated and the product was recrystallized from tert-butyl methyl ether to yield (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g). The reaction solvent and recrystallization mother liquor was washed three times with 0.5 M HCl and concentrated to yield additional (R)-N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.83 g). The combined acidic aqueous layers were made basic by NaOH and extracted with methylene chloride to yield (S)-8-fluorochroman-4-amine (5a) (1.6 g). A solution of (R)-N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g) in 8M HCl in EtOH (50 mL) was heated at reflux for four hours. The solvents were removed from the cooled reaction mixture, the resulting solid was taken up in 50 mL of 0.5M NaOH, salted out with NaCl(s), and extracted four times with methylene chloride to yield (R)-8-fluorochroman-4-amine (0.48 g (87%)) (5b). The % ee was checked via chiral HPLC: Chiralcel OD-H (0.46×25 cm analytical column, Daicel Chemical Industries) method: isocratic 5% (0.05% TFA/EtOH) 95% (0.05% TFA/Hex), Rt=7.2 min (S)-enantiomer, Rt=9.2 min (R)-enantiomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:51][CH2:52][C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:49][CH:50]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: NCc1cccnc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCc4cccnc4)cc3F)cn2)cc1
Yield: 167.8 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 3-(aminomethyl)pyridine (24.0 μl, 0.237 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-N-pyridin-3-ylmethyl-benzamide as a yellow solid (152 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-305) as a yellow powder (47.9 mg, 77%).