Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:12][C:11]=2[CH3:27])[CH:7]=[CH:8][CH:9]=1)=[O:3].[SiH](CC)(CC)CC.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)=[C:11]([CH3:27])[CH:12]=1
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)ccc1-c1cccc(C(N)=O)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCCN)ccc1-c1cccc(C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl (2-{[3′-(aminocarbonyl)-2-methyl-4-biphenylyl]oxy}ethyl)carbamate (0.090 g; 0.24 mmol; I-VII-2) and Et3SiH (0.1 mL; 0.6 mmol) in CH2Cl2 (5 mL) at room temperature was added TFA (1 mL) in one portion. The mixture was aged 2 h and concentrated in vacuo, affording the title compound as a pale yellow gum which was used without further purification. LC/MS (method A) 1.18 min, m/z 271 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl>[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[O:22])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(aminomethyl)-Boc-piperidine (0.313 g, 1.458 mmol), 4-aminobenzoic acid (0.200 g, 1.458 mmol) and N-methyl morpholine (0.242 mL, 2.187 mmol) in dichloromethane (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.422 g, 2.187 mmol) and the reaction mixture stirred at room temperature overnight. The reaction was then washed with water and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 0-100% EtOAc in hexane gradient to afford tert-butyl 4-((4-aminobenzamido)methyl)piperidine-1-carboxylate. LCMS (3) Rt: 1.91 min; m/z (ES+) 334.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:11]=[CH:12][C:13]2[CH:20]=[CH:19][C:16]([CH3:17])=[CH:15][CH:14]=2)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: Cc1ccc(C=O)cc1
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CCO
Product: Cc1ccc(C=Nc2cc(F)ccc2C(=O)O)cc1

Procedure:
4-Fluoroanthranilic acid (1.0 g) and 4-methylbenzaldehyde (0.77 g) were added to ethanol (100 ml). The mixture was heated under reflux for 6 hours, cooled and evaporated under reduced pressure. The residue was recrystallised from toluene to give 4-fluoro-N-(4-methylbenzylidene)-anthranilic acid, mp 144°-5°. (Compound 13).
Reaction SMILES: [Br:1][C:2]1[CH2:6][C:5]([CH2:9]I)([CH2:7]I)[CH2:4][C:3]=1[Br:11].C([BH3-])#N.[Na+]>CN(C)P(N(C)C)(N(C)C)=O.O>[Br:1][C:2]1[CH2:6][C:5]([CH3:9])([CH3:7])[CH2:4][C:3]=1[Br:11]
Reactant: BrC1=C(Br)CC(CI)(CI)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CC(Br)=C(Br)C1
Yield: 70.1 %

Procedure:
Under nitrogen, a stirred solution of 3.7 g (7.3 mmol) of 1,2-dibromo-4,4-di(iodomethyl)cyclopentene (Step 7) and 1.3 g (20.6 mmol) of sodium cyanoborohydride in 15 mL of hexamethylphosphoramide (HMPA) was heated to 100° C. in an oil bath overnight. The reaction was cooled, diluted with 50 mL of water, and extracted 5 times with ethyl acetate/hexane (1:5). The combined extracts were washed 3 times with water, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) with hexane gave 1.3 g (70%) of 1,2-dibromo-4,4-dimethylcyclopentene (16 in Synthetic Scheme V) as a colorless oil: NMR (CDCl3) δ1.16 (s, 6H), 2.44 (s, 4H); MS (EI) m/e (rel intensity) 256 (24), 254 (63), 252 (44), 175 (26), 173 (29), 94 (100).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:12][C:10](=O)[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.IC.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:10][NH:9][C:7](=[O:8])[C:5]1[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=1)[OH:12]
Reactant: O=c1[nH]c(=O)c2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1O
Temperature: 80 °C
Yield: 77.4 %

Procedure:
Carsalam (30.00 g, 0.1840 mol), iodomethane (10.23 ml, 0.1643 mol), sodium carbonate (19.51 g, 0.1840 mol) and dimethylformamide (150 ml) were placed in a 500 ml round bottom flask. The reaction mixture was heated overnight at 80° C. After cooling to room temperature, the reaction mixture was filtered and a white solid collected. This was washed with water and the remaining solid placed into a 250 ml round bottom flask. Water was added to the filtrate from the initial filtration and more, white solid precipitated. This material was combined with the solid already in the 250 ml flask and 2N aqueous sodium hydroxide (150 ml) was added. The mixture was heated for one hour before heating was discontinued and the reaction mixture was allowed to cool overnight. Overnight, a white solid precipitated and was isolated by filtration and allowed to dry in vacuo. 21.52 g of N-methylsalicylamide was isolated.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([OH:18])[CH2:14][CH2:15][CH2:16]O>C([O-])(=O)C.[Li+]>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:16][CH2:15][CH2:14][CH2:13][OH:18])=[O:11])=[CH:3][CH:4]=1
Reactant: OCCCCO
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Li+]
Product: O=C(OCCCCO)c1ccc(C(=O)OCCCCO)cc1

Procedure:
An autoclave equipped with a stirrer and distillation outlet was charged with 166 g (1.00 mole) of terephthalic acid, 180 g (2.00 moles) of 1,4-butanediol, and a small amount of lithium acetate as a catalyst. After the autoclave was provided with nitrogen at 3 kg/cm2, the mixture was reacted at 260° C. for 3 hours to obtain BHBT.
Reaction SMILES: [NH2:1][CH:2]([CH:10]([CH3:12])[CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[C:17]([F:23])[CH:16]=1)#[N:14].C([O-])(O)=O.[Na+].O>CN(C=O)C>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][CH:2]([CH:10]([CH3:12])[CH3:11])[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])=[C:17]([F:23])[CH:16]=1)#[N:14]
Reactant: CC(C)C(N)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 2-amino-3-methylbutanoate (8.5 g, 0.05 mol) in dry DMF (50 mL) under nitrogen, was added 4-cyano-2-fluoro-benzyl bromide (FluoroChem Ltd, 9.4 g, 0.044 mol) and NaHCO3 (10.2 g, 0.12 mol). The resulting mixture was stirred at RT for 16 h. Water (70 mL) was added and the desired product was extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×100 mL) and the solvent was dried over Na2SO4 and concentrated under vacuum. The resulted residue was purified by column chromatography using petroleum ether/ethyl acetate as eluent, affording of the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (d, J=10.2 Hz, 1H), 7.67 (t, J=1.5 Hz, 1H), 3.85-3.79 (m, 2H), 2.72 (m, 1H), 2.49 (m, 1H), 1.81 (m, 1H), 1.37 (s, 9H), 0.86 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C[O-].[Na+].Br[C@H:11]([CH2:15][CH3:16])[C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1.CO>[CH3:16][CH2:15][C@H:11]([N:1]1[C:2](=[O:6])[CH2:3][CH2:4][CH2:5]1)[C:12]([NH2:14])=[O:13]
Reactant: O=C1CCCN1
Reactant: CC[C@@H](Br)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of pyrrolidine-2-one (85 mg, 1 mmol) in 6 ml of toluene is added sodium methoxide (0. 19 ml of a 30% solution in MeOH, 1 mmol, 1 equiv.). The mixture is heated to 40° C. and concentrated to dryness under reduced pressure. The solid residue is taken up in 3 ml of tetrahydrofuran, cooled to 0° C. and (R)-2-bromobutyramide (IId) (optical purity >98%) (166 mg, 1 mmol, 1 equiv.) is added. The mixture is stirred for 1 h at 0° C. and further 16 h at room temperature. The mixture is then concentrated to dryness under reduce pressure.
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14](F)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][O:1][C:9]2=3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CNCc2ccoc21
Product: Clc1ccc(OC2CNCc3ccoc32)cc1Cl

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[OH:23][C:7]1[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])=[N:11][CH:10]=[C:9]2[N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[CH:14][C:8]=12
Reactant: CCOC(=O)c1ncc2c(ccn2CCc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(ccn2CCc2ccccc2)c1O

Procedure:
Prepared in analogy to that of Example 1(e) from 4-hydroxy-1-phenethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 340 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]([O:21]CC)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]([OH:21])=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of ethyl 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (E3, 247 mg) in ethanol (3 mL) and tetrahydrofuran (1.5 mL), 2.0 mol/L aqueous sodium hydroxide (0.78 mL) was added at room temperature, and the mixture was stirred at 50° C. for 1 hour. To the reaction mixture, 2.0 mol/L aqueous sodium hydroxide (0.39 mL) was added at 50° C., and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled to room temperature, and then 1.0 mol/L aqueous hydrochloric acid was added to the reaction mixture until the mixture became acidic. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (E22, 130 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10](=[O:32])[CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:29][CH2:30][CH3:31])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:5]([O:9][C:10](=[O:32])[CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]([C:1](=[O:3])[CH3:2])[CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:29][CH2:30][CH3:31])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(C)=O)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (25 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C25H31N3O3+H: 422, observed: 422.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:11][C:12]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14](F)[CH:13]=1.[CH2:27]([OH:29])[CH3:28].ClCCl>C1COCC1>[NH2:11][C:12]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([O:29][CH2:27][CH3:28])[CH:13]=1
Reactant: CCO
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC
Temperature: 60 °C
Reaction time: 16 h

Procedure:
KHMDS (1.92 g, 9.64 mmol) was added to a mixture of ethyl 4-amino-2-fluoro-5-nitro-benzoate (2.00 g, 8.77 mmol) and ethanol (0.56 mL, 9.64 mmol) in 70 mL THF at 0° C. The mixture was stirred at 60° C. for 16 h. Then KHMDS (1.92 g, 9.64 mmol) and ethanol (1.2 mL, 20.7 mmol) were added at ambient temperature and the mixture was stirred at 60° C. for 2 h. 100 mL dichloromethane were added and the mixture extracted with sat. NH4Cl (aq). The organic layer was evaporated, the residue mixed with ethyl acetate, washed with sat. NaCl (aq), dried over Na2SO4, filtered and evaporated. The residue was purified twice by chromatography (silica gel; eluens: petrol ether/ethyl acetate=1:1 and 2:1).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH2:23])=[CH:9][CH:8]=1>C(O)(=O)C>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH:23][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])=[CH:9][CH:8]=1
Reactant: ClCC1CO1
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2c(NCC(O)CCl)ccc(NCC(O)CCl)c21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Epichlorohydrin (84.5 mL, 1.08 mol) was added to a solution of 1,4 - diaminoanthraquinone (Aldrich Chemical Company, Milwaukee, Wis.) (10 g, 42 mmol) in glacial acetic acid (200 mL) at room temperature. The solution was stirred for 30 minutes at 90° C. and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH2Cl2 :MeOH/25:1) and recrystallized from CH2Cl2 -Ether-Hexanes to give a pure blue solid of the title compound (12.46 g, 70%), mp 167°-169° C.: 1H NMR (CDCl3) δ 3.21 (broad, 2H, OH), 3.5-3.6 (m, 6H, CHCH2), 3.75 (d, J=3Hz, 4H, CH2), 4.19 (broad, 2H, NH), 7.03 (d, J=3.2 Hz, 2H, ArH (2, 3)), 7.69 (m, 2H, ArH (6, 7)), 8.27 (m, 2H, ArH (5, 8)). Anal. Calcd for C20H20O4N2Cl2 ×0.25 H2O: C, 56.15; H, 4.83; N, 6.55. Found: C, 56.18; H, 4.76; N, 6.29.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccn1
Yield: 42.7 %

Procedure:
Methyl cis(±)-4-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)pyridine-2-carboxylate obtained in Example (160b) (74.8 mg) was dissolved in ethanol (10 mL). A 10% palladium-carbon catalyst (100 mg) was added, and the mixture was stirred in a hydrogen atmosphere overnight. The reaction solution was filtered through celite and then concentrated under reduced pressure, to obtain 21.2 mg of the title compound as a colorless oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH3:28])[OH:19])#[N:8].[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[S:39](Cl)(=[O:41])=[O:40].CO>CN(C)C=O>[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:39]([C:32]1[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=1[O:30][CH3:29])(=[O:41])=[O:40])[C:13](=[O:18])[C:12]2([OH:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH3:28])#[N:8]
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
1.7 g (15 mmol) of potassium tert-butanolate were added in portions to 4 g (13.6 mmol) of the intermediate 1b in 40 ml of anhydrous dimethylformamide at 0° C., and the mixture was stirred for about 90 minutes. Then 3.4 g (14.3 mmol) of 2,4-dimethoxybenzenesulfonyl chloride were rapidly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2 h. This solution was then poured into an ice-water/K2CO3 solution, resulting in a precipitate which was isolated. The resulting residue was treated with a little methanol, filtered off with suction and dried, resulting in 3.3 g of the product.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH2:6])=[C:4]([CH2:11][CH3:12])[CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH:6][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cc(Br)cc(CC)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(Br)cc(CC)c1NC(=O)c1ccccc1
Yield: 95.8 %

Procedure:
A solution of 4-bromo-2,6-diethylaniline (5.48 g, 24 mmol) in dichloromethane was added and stirred under nitrogen. Pyridine (5.7 g, 72.1 mmol) was added followed by benzoyl chloride (4.39 g, 31.2 mmol). The reaction was stirred for 1 h. The reaction was diluted with dichloromethane, washed with 10% sodium hydroxide solution, 1N HCl, and dried over magnesium sulfate, filtered, and evaporated. The residue was pre-absorbed onto Celite and purified by column chromatography. The column was eluted with 40 to 100% dichloromethane/hexanes. 7.64 g (96% yield) of product was obtained after purification.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.P(C#N)(OCC)(OCC)=O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C1COCCN1
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Agent: CCOP(=O)(C#N)OCC
Product: O=C(c1cc2c(O)cccc2s1)N1CCOCC1
Yield: 105.9 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 16 using 4-(methoxymethyloxy)-benzo(b)thiophene-2-carboxylic acid (3.5 g), morpholine (1.0 g) and diethyl cyanophosphate (3.1 g), 4-(4-hydroxybenzo(b)-thiophene-2-carbonyl)morpholine (3.2 g) was obtained as a brown oil. By the reactions in the same manner as in Starting Material Synthesis Example 1 using the brown oil (2.0 g) and (S)-glycidyl nosylate (2.1 g), the title compound (2.0 g) was obtained as brown crystals.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:19])[N:23]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1ccccn1
Temperature: 25 °C

Procedure:
A solution of (S)-1-(1-methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (50 mg, 0.198 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (50.4 mg, 0.297 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.104 mL, 0.594 mmol) in acetonitrile (6 mL), was heated in a microwave reactor at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated, re-dissolved in DMF, and purified by preparative HPLC (basic mode) using a 20-30% CH3CN gradient in H2O. The desired fractions were combined and solvent was removed in vacuo. The residue was purified again by preparative HPLC (basic mode) using a 25-35% CH3CN gradient in H2O. The pure fractions were combined and the solvent was removed in vacuo to give the title compound as a colorless film (24 mg, 31%). 1H NMR (500 MHz, CD3OD) δ ppm 1.59 (d, J=7.32 Hz, 3 H), 4.04 (br s, 3 H), 5.84 (q, J=7.32 Hz, 1 H), 6.88 (d, J=3.42 Hz, 1 H), 7.62-7.68 (m, 1 H), 7.90 (d, J=7.81 Hz, 1 H), 8.08 (d, J=2.93 Hz, 1 H), 8.16 (td, J=7.81, 1.95 Hz, 1H), 8.66 (s, 1H), 8.83 (d, J=4.88 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C20H19N9, 386. found 386.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15]OC(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([Cl:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OCl
Reactant: Oc1ccc(Cc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Cc2ccccc2)cc1Cl
Yield: 94.3 %

Procedure:
18.4 g of 4-benzylphenol was dissolved in 100 ml of carbon tetrachloride and thereto was added dropwise 10.85 g of t-butyl hypochlorite at -5°-0° C. with stirring. After stirring for 3 hours at room temperature, the reaction mixture was washed with a saturated aqueous sodium hydrogen-carbonate solution and then with water, then dried over anhydrous magnesium sulfate and thereafter, concentrated under reduced pressure. The resulting oily residue was chromatographed on a silica gel column (eluting solvent hexane : acetone=3 : 1 (v/v)) to obtain 20.6 g of 4-benzyl-2-chlorophenol.
Reaction SMILES: [H-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[O:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:10][CH2:9]1>O1CCCC1>[N+:3]([CH2:6][C:8]1([OH:7])[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:12][CH2:13]1)([O-:5])=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C[N+](=O)[O-])CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a stirred suspension of sodium hydride (0.72 g, 17.0 mmol) in dry tetrahydrofuran (40 ml) was added nitromethane (12.4 mmol) at 0° C. temperature. It was further stirred for 30 minutes and then (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (7.2 mmol) was added. The reaction mixture was stirred at 65° C. for 24 hours. The reaction mixture was poured on to crushed ice. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The removal of solvent afforded a crude compound, which was purified by column chromatography over silica gel to afford title compound in 17% yield. M.P. 186-187° C. and MS (M+1)=384 (MH+, 100%) M.F.=C18H23FN4O6.