Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.CN([CH:23]=[O:24])C>C1COCC1.C(OCC)(=O)C.O.C(O)(=O)C>[Br:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:23]=[O:24])[N:14]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
To a stirred solution of 2.5 M n-butyllithium in hexane (8.6 mL, 21.5 mmol) under N2, cooled to −78° C., was added dropwise a solution of 2,6-dibromopyridine (5.10 g, 21.5 mmol) in dry THF (30 mL) at such a rate that the internal temperature was below −70° C. After complete addition, the reaction mixture was stirred at −78° C. for 15 min, and then treated with anhydrous DMF (2.6 mL, 33.3 mmol). After 15 min, the reaction mixture was treated successively with acetic acid (1.36 mL) and water (21.5 mL) and then warmed to RT. The reaction mixture was poured into ethyl acetate (75 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (25 mL). The combined organic phases were washed with brine (35 mL), dried (MgSO4), filtered and concentrated to afford 3.33 g (18.0 mmol, 84%) of the desired product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (25 g, 0.1 mol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol, 1.25 equiv), EDC.HCl (26.3 g, 0.14 mol, 1.25 equiv), and diisopropylethylamine (48 mL, 0.28 mol, 2.5 equiv) were dissolved in CH2Cl2 (400 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc, washed with 5% aq HCl (2×150 mL), satd aq NaHCO3 (150 mL), and brine (100 mL) and dried over Na2SO4. Concentration afforded (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (24.42 g, 82%) as a clear oil. LC-MS (3 min) tR=1.41 min, m/z 295 (M+Na). 1H NMR (CDCl3) δ 4.19-4.00 (m, 2H), 3.77 (m, 3H), 3.12 (s, 3H), 2.79 (m, 2H), 2.64 (m, 1H), 1.89 (m, 1H), 1.71-1.52 (m, 2H), 1.51-1.33 (m, 10H). Chiral HPLC indicated 100% purity. The crude product was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCCBr)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 2,3-dichloroanisole (89 g., 0.50 mole) and 6-bromohexanoyl chloride (120 g., 0.59 mole) is methylene chloride (500 ml.) is cooled to 5° C. and treated with aluminum chloride (74 g., 0.56 mole) in portions during a one-half hour period. The reaction mixture is kept at 25° C. for 18 hours, then poured into ice water (1 liter) containing hydrochloric acid (100 ml.). The organic phase is separated, washed with water, 2% sodium hydroxide, and dilute hydrochloric acid. The methylene chloride is evaporated at reduced pressure, the residual oil dissolved in ether, dried over magnesium sulfate, evaporated to 200 ml. and treated with hexane (600 ml.) affording 2,3-dichloro-4-(6-bromohexanoyl)-anisole which melts at 52°-53° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)(=O)C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[NH2:24].[OH-].[Na+].Cl>C(O)(C)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CC(=O)OCCCCCn1ccc2ncnc(Cl)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: OCCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of 5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl acetate (200 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (265 mg) in isopropyl alcohol (3.5 mL) was stirred at 80° C. for 14 hrs. 1N Aqueous sodium hydroxide solution (2.1 mL) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=1:19) to give a colorless solid. Recrystallization from ethyl acetate-hexane gave the title compound (275 mg) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:28])[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[C:15]([C:17]1[N:21]=[CH:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1)=[O:16].[CH3:29][NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[N+:40]([O-:42])=[O:41])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:8][C:9]1([CH3:28])[CH2:14][N:13]([C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:39]([N+:40]([O-:42])=[O:41])=[C:31]([NH:30][CH3:29])[CH:32]=2)[CH2:12][CH2:11][N:10]1[C:15]([C:17]1[N:21]=[CH:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1)=[O:16]
Reactant: CNc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(C(=O)N2CCN(C(=O)c3ncn(-c4ccccc4)n3)C(C)(C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 399 mg (1.00 mmol) (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]triazol-3-yl)-methanone trifluoroacetate, 196 mg (1.00 mmol) 3-methylamino-4-nitro-benzoic acid, 353 mg (1.10 mmol) TBTU and 600 μL (3.50 mmol) DIPEA in 1.00 mL DMF was stirred at RT for 1 h. The reaction mixture was poured into ice water. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[NH:21][C:22]([C:24]2[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:23])=[CH:6][CH:5]=1.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CCN(CC)CC>C1COCC1>[Cl:33][C:31]1[C:30]([Cl:34])=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([C:22]([NH:21][C:12]2[CH:13]=[C:14]([C:17]([F:19])([F:20])[F:18])[CH:15]=[CH:16][C:11]=2[NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:41]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:42])=[CH:9][CH:8]=2)=[O:23])[CH:32]=1
Reactant: NCc1ccc(Nc2ccc(C(F)(F)F)cc2NC(=O)c2cc(Cl)c(Cl)cc2C(=O)O)cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1Nc1ccc(CNC(=O)N2CCOCC2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Into a vial are placed 2-({[2-{[4-(aminomethyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid hydrochloride (100 mg, 0.187 mmol), 4-morpholine-carbonylchloride (28 mg, 0.187 mmol), Et3N (0.08 mL, 0.573 mmol), and THF (10 mL). The mixture is heated with efficient stirring at 40° C. for 4 h. The solution is concentrated and purified by preparative thin layer chromatography. The yield is 31 mg of 4,5-dichloro-2-({[2-[(4{[(morpholin-4-ylcarbonyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)phenyl]amino}carbonyl)benzoic acid, 27%. 1H NMR (400 MHz, DMSO-d6): □ 13.88 (s, 1 H), 10.14 (s, 1 H), 8.09 (s, 2 H), 7.77 (s, 1 H), 7.70 (s, 1 H), 7.44-7.42 (m, 1 H), 7.26-7.23 (m, 3 H), 7.14-7.09 (m, 3 H), 4.22-4.21 (m, 2 H), 3.56-3.54 (m, 4 H), 3.30-3.28 (m, 4 H) 7.44-7.42 (m, 1 H), 7.26-7.23 (m, 3 H), 7.14-7.09 (m, 3 H), 4.22-4.21 (m, 2 H), 3.56-3.54 (m, 4 H), 3.30-3.28 (m, 4 H). HRMS for C27H23Cl2F3N4O5 m/z 611.1071 M+.
Reaction SMILES: [K].[CH:2]([O:5][C:6]1[N:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[N:7]=1)([CH3:4])[CH3:3].[CH3:17][O:18][CH:19]=[C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Br)[C:21]([O:23][CH3:24])=[O:22].C(OCC)(=O)C>CCCCCCCC>[CH3:17][O:18][CH:19]=[C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][O:12][C:10]1[CH:9]=[C:8]([C:13]([F:15])([F:16])[F:14])[N:7]=[C:6]([O:5][CH:2]([CH3:4])[CH3:3])[N:11]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: [K]
Solvent: CCCCCCCC
Solvent: CCOC(C)=O
Product: COC=C(C(=O)OC)c1ccccc1COc1cc(C(F)(F)F)nc(OC(C)C)n1
Temperature: 25 °C

Procedure:
3.04 g of potassium salt of 2-isopropoxy-6-trifluoromethyl-4-hydroxypyrimidine and 3.65 g of methyl 3-methoxy-2-(2-bromomethylphenyl)acrylate were suspended in 50 ml of octane. The resulting suspension was reacted at reflux of octane for 5 hours and cooled down to room temperature. 30 ml of ethyl acetate was added and insoluble matter was filtrated. The precipitate separated by filtration was washed with 20 ml of etyl acetate. A mixed solution of the obtained filtrate and washing was analyzed with high-performance liquid chromatography. The yield of the target compound was 13.3% and 75.0% for a byproduct of methyl 3-methoxy-2-[2-(2-isopropoxy-6-trifluoromethylpyrimidin-4-on-3 -ylmethyl)phenyl]acrylate.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH:9](=O)[CH2:10][CH3:11].[BH4-].[Na+]>CO>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:9][CH2:10][CH3:11]
Reactant: CCC=O
Reactant: CN(C)CCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNCCCCN(C)C
Reaction time: 0.33 h

Procedure:
A solution of N1,N1-dimethylbutane-1,4-diamine (0.64 g, 5.5 mmol) and propionaldehyde (0.38 mL, 5.2 mmol) in 20 mL methanol was stirred at rt overnight. Sodium borohydride (0.31 g, 8.3 mmol) was added and the reaction mixture was stirred for 20 min. The reaction was quenched with 1N NaOH, extracted with ether and washed with brine. Drying, solvent evaporation and flash chromatography (0-12% [10% NH4OH/MeOH]/CH2Cl2) gave N1,N1-dimethyl-N4-propylbutane-1,4-diamine. 1H NMR (CDCl3) δ 2.61 (t, J=6.7 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.21 (s, 6H), 1.49 (m, 6H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:7][C:6](=[O:8])[CH:5]([CH:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10](O)=[O:11])[O:4]1.[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:7][C:6](=[O:8])[CH:5]([CH:9]([C:10]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:34])=[O:11])[CH2:13][CH2:14][CH2:15][CH3:16])[O:4]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CCCCC(C(=O)O)C1OC(OC)(c2ccccc2)OC1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C1OC(OC)(c2ccccc2)OC1=O
Reaction time: 8 h
Yield: 50 %

Procedure:
To 2-(2-methoxy-2-phenyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid I-1 (10 mmol; prepared as described in Method I, above) in DMF (50 mL) was added proline O-t-butyl ester (10 mmol), DIEA (25 mmol) and PyBOP (10 mmol) and the solution stirred for 8 h. The reaction was diluted with ethyl acetate and washed with water, sodium bicarbonate, brine, and then dried (Na2SO4). The filtrate was concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford 1-(2-methoxy-2-phenyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)pentane 1-2 (5 mmol, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH3:11])[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.ClC1C=CC(C(O)=O)=CC=1OC.Cl.Cl.Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[S:37][C:38]([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([CH2:48][NH2:49])[CH2:44][CH2:43]2)=[CH:39][N:40]=1>>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH3:11])[N:5]=[C:4]([C:12]([NH:49][CH2:48][CH:45]2[CH2:46][CH2:47][N:42]([CH2:41][C:38]3[S:37][C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)=[N:40][CH:39]=3)[CH2:43][CH2:44]2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1Cl
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: COc1cc(C(=O)O)ccc1Cl
Agent: Cl
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)cc(N)c1Cl

Procedure:
According to the same procedure described in Example 16 and starting with 4-amino-5-chloro-6-ethoxypicolinic acid (prepared according to the reported preparation in J. Med. Chem. 2006, 49, 4455) instead of 4-chloro-3-methoxybenzoic acid and the compound prepared in Example 214 instead of the compound prepared in Example 9, the title compound having the following physical data was obtained. 1H NMR (DMSO-d6): δ 8.61 (d, J=4.7 Hz, 1H), 8.33 (t, J=6.4 Hz, 1H), 8.09 (d, J=7.9 Hz, 1H), 7.94 (td, J=1.7, 7.7 Hz, 2H), 7.78 (s, 1H), 7.47 (ddd, J=1.1, 4.8, 7.5 Hz, 1H), 7.09 (s, 1H), 6.50 (s, 1H), 4.45 (q, J=7.0 Hz, 2H), 3.73 (s, 2H), 3.16 (t, J=6.5 Hz, 2H), 2.85-2.88 (m, 2H), 1.97 (t, J=10.7 Hz, 2H), 1.60-1.63 (m, 2H), 1.50-1.55 (m, 1H), 1.31 (t, J=7.0 Hz, 3H), 1.15-1.24 (m, 2H);
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl>C1COCC1.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1]
Reactant: CN(C)CCCCCCO
Reactant: COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCCCCN(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
6-Dimethylamino-1-hexanol (8.80 g, 60.6 mmol) was dissolved in 2/1 mixture of THF/DMF (150 mL) and the solution was cooled in an ice/water bath. Sodium hydride (3.25 g, 80.8 mmol, 60% in oil ) was added. After 40 min., 2-methoxybenzyl chloride (6.28 g, 40.4 mmol) was added and the solution was allowed to warm to room temperature over 1 h. After 3 h, the reaction was quenched by the addition of 1M NaHSO4. Tetrahydrofuran was removed in vacuo, and the solution was washed with EtOAc. The aqueous phase was basified with 3M NaOH and extracted with ether. The combined ether phases were dried over K2CO3, filtered, and the product was crystallized by the addition of 4M HCl/dioxane to give O-(2-methoxybenzyl)-6-dimethylaminohexanol (10.4 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+:35].CO>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([O-:30])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[Li+:35]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)[O-])cc1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
2-[2-[4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid (0.20 g) was added to a mixture of lithium hydroxide monohydrate (19 mg), methanol (5 mL) and tetrahydrofuran (5 mL) at room temperature, and the mixture was stirred for 30 min. The reaction mixture was concentrated, and the residue was crystallized from methanol and diethyl ether to give crystals (0.18 g, yield 90%) of lithium 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetate. Recrystallization from methanol-diethyl ether gave colorless prism crystals. melting point: 207-209° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH2:32][C:33]([C:36]([O:38]CC)=[O:37])([CH3:35])[CH3:34])=[C:26]2[S:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH2:32][C:33]([C:36]([OH:38])=[O:37])([CH3:34])[CH3:35])=[C:26]2[S:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C)(C)Cc1[nH]c2ccc(OC(Cc3ccc(Cl)cc3)[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2c1SC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(Cc1ccc(Cl)cc1)Oc1ccc2[nH]c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c2c1

Procedure:
The ester from Step 4 (0.16 g, 0.26 mmol) was dissolved in MeOH (1 mL), THF (1 mL), and water (1 mL). Lithium hydroxide (0.6 g, 1.43 mmol) was added, and the reaction was heated for 12 hours until no starting material was seen by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid, and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (0 to 40% EtOAc in hexanes) to give the desired product (C-5; X=Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1cccc(Cl)c1
Yield: 93 %

Procedure:
A mixture of 3-[5-(3-chlorophenyl)-4-isoxazolyl]propionic acid (3.10 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3-chlorophenyl)-4-isoxazolyl]propionate (3.06 g, yield 93%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl3) δ: 2.59–2.71 (2H, m), 2.93–3.05 (2H, m), 3.69 (3H, s), 7.36–7.50 (2H, m), 7.54–7.65 (1H, m), 7.69–7.73 (1H, m), 8.23 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4][N:3]=1.O.[NH2:16][NH2:17].C(N(CC)CC)C.C1COCC1>O>[CH2:8]([C:7]1[C:2]([NH:16][NH2:17])=[N:3][CH:4]=[N:5][C:6]=1[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)[CH3:9]
Reactant: NN
Reactant: CCc1c(Cl)ncnc1-c1ccco1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1c(NN)ncnc1-c1ccco1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A mixture of 4-chloro-5-ethyl-6-(furan-2-yl)-pyrimidine (3.0 g), hydrazine monohydrate (3.0 g), triethylamine (3.0 g), and THF (20 ml) was stirred under reflux for 2 hours. To the mixture, hydrazine monohydrate (1 g) was added, and stirred under reflux for 3 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, water was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 2.85 g of [5-ethyl-6-(furan-2-yl)-pyrimidin-4-yl]-hydrazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([CH:13]=O)[N:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:25][NH:26][CH3:27].COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.ClCCCl>[CH3:25][N:26]([CH3:27])[CH2:13][C:11]1[N:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:7]2=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[CH:12]=1
Reactant: O=Cc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: COC(OC)OC
Solvent: ClCCCl
Product: CN(C)Cc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
A round-bottom flask was charged with 5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.30 g, 0.91 mmol), dimethylamine hydrochloride salt (0.10 g, 1.27 mmol), trimethoxymethane (0.99 mL, 9.1 mmol), sodium triacetoxyborohydride (0.25 g, 1.18 mmol), sodium acetate (0.10 g, 1.27 mmol) and 1,2-dichloroethane (9.0 mL). The mixture was stirred at room temperature for 24 hours, after which saturated aqueous sodium bicarbonate was added, then dichloromethane. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography to afford N,N-dimethyl-1-(5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanamine (0.16 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].C(N(CC)CC)C.[Cl:21][CH2:22][CH2:23][C:24](Cl)=[O:25].Cl>C(Cl)Cl>[Cl:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12])=[O:25]
Reactant: O=C(Cl)CCCl
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Reaction time: 2 h
Yield: 78.9 %

Procedure:
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (250 mg, 1.28 mmol) and triethylamine (0.18 mL, 1.28 mmol) were stirred in DCM (5 mL). 3-chloropropionylchloride (162 mg, 1.28 mmol) was added dropwise under a nitrogen atmosphere. Stirring was continued for 2 h. 2 M HCl (20 mL) was added and the reaction mixture extracted into DCM (3×50 mL). The combined DCM layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to give the desired product as a yellow solid (290 mg, 1.01 mmol, 79%).