Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH:25](=[O:29])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:25]([OH:29])[CH2:26][CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CCCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere and at −78° C., n-butyl lithium (a 1.60M hexane solution, 0.688 ml, 1.10 mmol) was added to a tetrahydrofuran (5 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00 mmol) obtained in Example 5. The mixture was stirred at −78° C. for 1 hour. After addition of butanal (0.108 ml, 1.20 mmol), the mixture was stirred at −78° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane) as a low-polarity isomer to yield by a colorless solid. The solid thus obtained was washed with hexane, whereby the title compound (30.5 mg, 8%) was obtained as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[C:7]([C:12]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[CH:18]1([C:21]([NH2:23])=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[OH:17][C:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][N:11]=[C:2]([NH:23][C:21]([CH:18]4[CH2:20][CH2:19]4)=[O:22])[CH:3]=3)[N:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC(=O)C1CC1
Reactant: OC1(c2ccc3cc(Cl)ncc3n2)CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ccc(C3(O)CCCC3)nc2cn1)C1CC1
Temperature: 90 °C
Yield: 45.3 %

Procedure:
A mixture of 1-(6-chloro-1,7-naphthyridin-2-yl)cyclopentanol (65 mg, 0.26 mmol), cyclopropanecarboxamide (67 mg, 0.8 mmol), Chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-1-pr-1,1′-biphenyl)][2-(2-aminoethyl )Ph]Pd(II) (31 mg, 0.04 mmol), (dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl (21 mg, 0.04 mmol), and cesium carbonate (170 mg, 0.52 mmol) in 1,4-dioxane (1.5 mL) was heated at 90° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (35 mg, 45%). 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.12 (s, 1H), 8.47 (s, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 5.32 (s, 1H), 2.29-2.17 (m, 2H), 2.11-2.03 (m, 1H), 1.95-1.75 (m, 6H), 0.91-0.78 (m, 4H). LCMS (Method E): RT=3.811 min, M+H+=298.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27])([O-:22])=[O:21].[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[OH:27][CH:26]([C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:13][CH3:14])[CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: -78 °C
Yield: 49.5 %

Procedure:
N,N-Diethyl-4-iodobenzamide (5.0 g, 16 mmol) was dissolved in THF (150 mL) and cooled to −78° C. under nitrogen atmosphere. n-BuLi (15 mL, 1.07 M solution in hexane, 16 mmol) was added dropwise during 10 min at −65 to −78° C. The solution was then canulated into 3-nitrobenzaldehyde (2.4 g, 16 mmol) in toluene/THF (approx. 1:1, 100 mL) at −78° C. NH4Cl (aq.) was added after 30 min. After concentration in vacuo, extraction with EtOAc/water, drying (MgSO4) and evaporation of the organic phase, the residue was purified by chromatography on silica (0-75% EtOAc/heptane) to give INTERMEDIATE 2 (2.6 g, 50%). 1H NMR (CDCl3) δ 1.0-1.3 (m, 6H), 3.2, 3.5 (2m, 4H), 5.90 (s, 1H), 7.30-7.40 (m, 4H), 7.50 (m, 1H), 7.70 (d, J=8 Hz, 1H), 8.12 (m, 1H), 8.28 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:23][CH2:24][CH2:25][CH3:26])=[C:4]([F:27])[CH:3]=1.[CH2:28](Br)[C:29]#[CH:30].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:30][C:29]#[CH:28])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])[N:11]=[C:10]2[O:23][CH2:24][CH2:25][CH3:26])=[C:4]([F:27])[CH:3]=1
Reactant: C#CCBr
Reactant: CCCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OCCC)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-pentafluoroethyl-2-(n-propoxy)-6(1H)-pyrimidinone and propargyl bromide with sodium carbonate in acetone there is obtained 1-[4-chloro-2-fluoro-5-(2-propynyloxy)-phenyl]-4-pentafluoroethyl-2-(n-propoxy)-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.34 ppm (d,1H), 6.98 ppm (d,1H), 6.65 ppm (s,1H), 4.76 ppm (m,2H), 4.36 ppm (m,2H), 2.56 ppm (t,1H), 1.67 ppm (m,2H), 0.85 ppm (t,3H);
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:28]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3)nc21
Reactant: C1CNCCNC1
Product: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)N4CCCNCC4)cc3)nc21
Yield: 37 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 181 was used in place of the compound obtained in Example 48, and homopiperazine was used in place of N-methylpiperazine. In this manner, 64 mg (37%) of the captioned compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](O)=[N:8][C:7]([CH3:12])=[N:6][C:5]=2[C:4]([CH3:13])=[N:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>P(Cl)(Cl)(Cl)=O>[Cl:15][C:9]1[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:13])[C:5]=2[N:6]=[C:7]([CH3:12])[N:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nc(O)c2c(n1)c(C)nn2C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c2c(n1)c(C)nn2C
Yield: 89.7 %

Procedure:
A mixture of 30.5 g (0.17 mol) of 1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol and 37 g (0.18 mol) of phosphorus pentachloride in 350 ml of phosphorus oxychloride is stirred under reflux for seven hours and the resulting solution is evaporated in vacuo. The solid residue is redissolved in 300 ml of methylenedichloride and stirred with 200 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer is dried over MgSO4 and evaporated in vacuo to give 30 g (98%) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine, mp 91°-93° C. from ethyl acetate-pet ether.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[I:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:30]=1)[C:20](=[O:29])[C:21]([C:24](OCC)=[O:25])=[CH:22][N:23]=2.Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:24]([C:21]2[C:20](=[O:29])[N:19]3[CH:30]=[C:15]([I:14])[CH:16]=[CH:17][C:18]3=[N:23][CH:22]=2)=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2ccc(I)cn2c1=O
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cn2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To a solution of 4-chlorobenzylamine (0.071 mL) in toluene (1.5 mL) at 0° C. is added trimethylaluminum (2M solution in toluene, 0.29 mL). After stirring the solution at 0° C. for 5 min, ethyl 7-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (Preparation 2, 200 mg) is added. The solution is stirred at 0° C. for an additional 10 min, then allowed to stir at room temperature overnight. The reaction mixture is poured into 3 N HCl (7.5 mL) and water, then extracted with CH2Cl2 (3×). The combined organic layers are dried (Na2SO4), filtered, and concentrated to afford a solid. The impurities are removed by dissolving the crude product in CH2Cl2 and filtering the insoluble solid. The filtrated is concentrated to afford 148 mg (58%) of title compound as a yellow solid. Physical characteristics: m.p. 191-194° C.; 1H NMR (300 MHz, DMSO-d6) δ9.36, 9.27, 9.03, 8.38, 7.68, 7.40, 4.57; IR (drift) 3319, 1683, 1637, 1612, 1560, 1541, 1507, 1478, 1347, 1339, 1295, 837, 792, 641, 625 cm−1; MS (ESI+) m/z 440 (M+H)+; Anal. found: C, 43.58; H, 2.48; N, 9.38.
Reaction SMILES: [OH:1]O.[CH2:3]([S:6][C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)[CH:4]=[CH2:5]>C(O)(=O)C>[CH2:3]([S:6]([C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:1])[CH:4]=[CH2:5]
Reactant: C=CCSc1ncc(Cl)cn1
Reactant: OO
Solvent: CC(=O)O
Product: C=CCS(=O)c1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
30% Hydrogen peroxide (50 mmol) was added to a solution of 2-allylthio-5-chloropyrimidine (10 mmol) in acetic acid (15 ml) and the mixture stirred at room temperature for 24 h. The resultant solution was concentrated at reduced pressure to a small volume, water (20 ml) added and the mixture extracted with chloroform, the chloroform solution washed with potassium carbonate solution, the dried (MgSO4) solution evaporated and the residue crystallized from chloroform: pet. ether; yield 78%, m.p. 82° C. 1H NMR (CDCl3): δ3.7-4.0 (CH2, 5.0-6.2 (3H, CH2 =CH), 8.86 (H-4, H-6).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)Sc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Sc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
6-Amino-9-benzyl-2-(isopropylthio)purine (60 mg, 0.20 mmol) and bromine (0.4 ml) were dissolved in 85 ml of methylene chloride and the solution was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (20 mg, yield 26%).
Reaction SMILES: C([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH:24]=[CH:23]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[C@@H:25]1([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:26][C@H:22]([CH2:21][OH:20])[CH:23]=[CH:24]1
Reactant: O=c1ccn([C@H]2C=C[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5'O-trityl-2',3'-dideoxy-2',3'-didehydrouridine (0.5 gm., 1.1 mM) was dissolved in a chloroform (10 mL) and methanol (2 mL) mixture containing 2% p-toluenesulphonic acid. The reaction mixture was stirred at room temperature for 0.75 hr., and then neutralized with 2N NaOH (0.5 mL). The solvent was removed in vacuo and the residue chromatographed on silica using chloroform/acetone (2:1) as eluent. The desired product was isolated as a white crystalline solid with the same physical and spectroscopic characteristics as d4U produced by an alternative method.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.Cl[CH2:15][CH2:16][CH2:17][C:18]#[N:19]>C(Cl)(Cl)Cl>[N:1]1([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CCCCCl
Reactant: C1COCCN1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N#CCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
196.9 ml morpholine, 500 ml toluol and 100 ml chloroform were stirred in a round-bottomed flask under N2 atmosphere and at 80° C. After one hour 100 g 4-chlorobutyronitrile was added dropwise within one hour. The reaction was stirred one day at 80° C. and another day at room temperature. The mixture was fritted and the residue was washed two times with ether. The filtrate was concentrated and finally distilleed under vacuum. The product fractions were collected at 95-100° C. and 1.2-0.89 Torr. The purity of the colourless oil was judged by gas chromatography and 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:13]=[C:12]([C:24]([O:26]C)=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH:13]=[C:12]([C:24]([OH:26])=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(=O)O)c3[nH]c4cc(OC)ccc4c3n2)cc1
Yield: 9.9 %

Procedure:
Methyl 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole -4-carboxylate (150 mg, 0 4 mmol) was dissolved in a mixture of tetrahydrofuran (6 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (1.0 N, 1.8 mL, 1.8 mmol) was added. After 1 hr the organic solvents were removed on the rotary evaporator and the pH of the aqueous solution was adjusted to about 3 with 6 N aqueous HCl. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum in the presence of KOH to leave 7-methoxy-2-(4-methoxyphenyl)-5H -pyrido[3,2-b]indole-4-carboxylic acid (138 mg, 67% yield) as an orange solid. MS (ESI) m/z 349.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.47 (1H, s), 8.18 (1H, d, J=8.55 Hz), 8.16 (1H, s), 8.13 (2H, d, J=8.55 Hz), 7.29 (1H, d, J=1.83 Hz), 7.10 (2H, d, J=8.85 Hz), 6.94 (1H, dd, J=8.55, 1.83 Hz), 3.89 (3H, s), 3.85 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:20])[C:11]1[CH:19]=[CH:18][C:17]2[O:16][CH2:15][O:14][C:13]=2[CH:12]=1>>[Cl:1][C:2]1[C:3]([O:9][C:10](=[O:20])[C:11]2[CH:19]=[CH:18][C:17]3[O:16][CH2:15][O:14][C:13]=3[CH:12]=2)=[CH:4][C:5]([O:8][C:10](=[O:20])[C:11]2[CH:19]=[CH:18][C:17]3[O:16][CH2:15][O:14][C:13]=3[CH:12]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: O=c1cc(O)c(Cl)c[nH]1
Product: O=C(Oc1cc(OC(=O)c2ccc3c(c2)OCO3)c(Cl)cn1)c1ccc2c(c1)OCO2
Yield: 4 %

Procedure:
The general procedure of Example 45 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone and 3.80 g of piperonyloyl chloride, thereby producing 180 mg of the title compound in a yield of 3%.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][CH:16]=[CH:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][CH:16]=[CH:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: COC(=O)C(N)CC=CCOC(C)=O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)C(CC=CCOC(C)=O)N=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-6-acetyloxy-4-hexenoate, prepared as described by D. Ferroud, J. P. Genet, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-6-acetyloxy-4-hexenoate.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>C1COCC1>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1cnc2sccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cccnc2s1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 6.5 %

Procedure:
To a solution of thieno[2,3-b]pyridine (0.50 g, 3.7 mmol) in THF (25 mL) at about −78° C. was added n-BuLi (1.6 M in hexane, 2.5 mL, 4.1 mmol) dropwise over about 10 min. After about 45 min, added triisopropyl borate (0.93 mL, 4.1 mol). Stirred for about 1 hour at about −78° C. then at about 0° C. for about 30 min. 10% aqueous HCl (10 mL) was added and the ice bath was removed. After about 30 min, EtOAc (30 mL) was added. The reaction mixture was filtered to remove a precipitate that was washed with additional water and EtOAc. The combined layers were separated and the aqueous layer was extracted with additional EtOAc (2×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, decanted, and concentrated to get a solid that was triturated with EtOAc and heptane then filtered to give thieno[2,3-b]pyridin-2-ylboronic acid (0.043 g, 6%); RP-HPLC (Table 1, Method g) Rt 1.67 min, m/z (ESI+) 180.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-difluoronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)=[CH:24][CH:23]=1.O>O1CCOCC1>[CH3:33][C:28]1([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][O:16][N:15]=[CH:14][C:5]3[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=3[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:23][CH:24]=2)[O:29][CH2:30][CH2:31][O:32]1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Reactant: CC1(c2ccc(CBr)cc2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOCc1ccc(C2(C)OCCO2)cc1
Yield: 74.2 %

Procedure:
1.0 Gram (0.0043 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dioxane, and 0.14 g (0.0058 mole) of sodium hydride was added. Thereafter, 1.1 g (0.0043 mole) of 2-(4-bromomethylphenyl)-2-methyl-1,3-dioxolane was added to this solution which was then heated under reflux for 3 hours. After completion of the reaction, the reaction solution was poured into 200 ml of cold water and extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.3 g of the desired compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[OH:5].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.C([O-])(O)=O.[Na+].O>O1CCOCC1>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([NH:2][CH2:3][C@@H:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[OH:5])[CH:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NC[C@H](O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O[C@@H](CNc1cc(Cl)ncn1)c1ccc(F)cc1
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A suspension of (R)-2-amino-1-(4-fluoro-phenyl)-ethanol hydrochloride (500 mg, 2.61 mmol), 4,6-dichloropyrimidine (353 mg, 2.37 mmol), and NaHCO3 (1.39 g, 16.6 mmol) in dioxane (10 mL) was heated in a 100° C. bath for 19 h and cooled to rt. Water (10 mL) was added, and the mixture, containing solid, was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The residue was purified (FCC) to give the title compound as a white solid (415 mg, 59%) in 90% enantiomeric excess (Chiralcel AD-H column, supercritical CO2).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].Cl[C:17]1[CH:18]=[C:19]([N:26]([C:31]2[C:50]([CH:51]3[CH2:53][CH2:52]3)=[CH:49][C:34]3[C:35]([C:45]([NH:47][CH3:48])=[O:46])=[C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[O:37][C:33]=3[CH:32]=2)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]>CN(C=O)C.O>[CH:51]1([C:50]2[C:31]([N:26]([C:19]3[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:18]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:32][C:33]3[O:37][C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)=[C:35]([C:45](=[O:46])[NH:47][CH3:48])[C:34]=3[CH:49]=2)[CH2:53][CH2:52]1
Reactant: COC(=O)CC(=O)OC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(C(=O)OC)C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
To a stirred suspension of Cs2CO3 (17.5 g, 53.8 mmol) in DMF (20 ml) under a nitrogen atmosphere was added dimethyl malonate (2.57 mL, 22.4 mmol) at room temperature. This was followed by the addition of a sonicated solution of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (10.0 g, 17.9 mmol) in DMF (50 mL) at room temperature by dropwise addition. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted with EtOAc (3×40 mL). The organic layer was washed with water (3×50 mL), dried over sodium sulfate and evaporated to dryness. The crude product triturated with ether and the solid collected by filtration to afford the title compound in 68% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (d, J=4.7 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 8.04 (s, 1H), 7.90-8.00 (m, 2H), 7.36-7.51 (m, 3H), 7.26-7.31 (m, 1H), 7.14-7.20 (m, 1H), 5.45-5.56 (m, 1H), 3.52-3.64 (m, 9H), 2.84 (d, J=4.5 Hz, 3H), 1.88-2.03 (m, 1H), 0.82-1.00 (m, 2H), 0.69 (d, J=3.1 Hz, 1H), 0.29-0.50 (m, 1H). LCMS (m/z, ES+)=654 (M+H+).