Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>C1COCC1>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccncn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccncn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
To 4-aminopyrimidine (1.0 g, 10.52 mmol) in THF (40 ml) at 0° C. under nitrogen was added potassium tert-butoxide (2.46 g, 22 mmol). After stirring for 5 min 2,4-difluoronitrobenzene (1.672 g, 10.52 mmol) was added dropwise. The reaction was stirred for 1 h at 0° C. then at 20° C. for 1 h, then quenched with 5% citric acid to give a pH of 5. The mixture was extracted with EtOAc (150 mL), dried (Na2SO4) and evaporated to an orange gum. This was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM to give the title compound as a yellow solid, (0.31 g, 12%). LCMS (Method B): RT=2.16 min, [M+H]+=234.91
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21].[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21])[C:30](=[O:31])[C:29]1[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=1
Reactant: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) and using a gradient of n-heptane:EtOAc (100:0 to 0:80) for the chromatographic purification. Colorless solid (30%). MS (ESI): m/z=559.096 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:13][CH:10]2[CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH2:9]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2COC(c3ccccc3)OC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a 2 liter round bottom flask was added 2-phenyl-1,3-dioxan-5-ol (50 g, 277 mmol), triethyl amine (42.1 g, 416 mmol), DMAP (3.39 g, 27.7 mmol) and dichloromethane (1 L). The reaction was cooled to 0° C. To this solution was added tosyl chloride (58.2 g, 305 mmol) and the reaction was stirred overnight at RT. The reaction was poured onto water (800 mL) and extracted into DCM. The organic layers were combined and concentrated to dryness. The crude mixture was recrystallized from EtOAc:Hex to afford 88 g (96% yield) of a white solid. 1H NMR (CDCl3, 400 MHz), δ: 2.44 (3H, s), 4.09 (2H, dd, J=13.6, 2 Hz), 4.27 (2H, dd, J=13.6, 1.6 Hz), 4.51 (2H, pseudo t, J=1.6 Hz), 7.33-7.36 (5H, m), 7.44-7.45 (2H, m), 7.85 (2H, d, J=8.39 Hz). Mass Spec (lo-res): Calc'd for C17H18O5S: 334.09; found: 335.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9](I)[CH3:10]>N>[CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)([CH2:9][CH3:10])[CH3:2]
Reactant: CCI
Reactant: CCc1ccncc1
Agent: N
Product: CCC(C)c1ccncc1

Procedure:
A method similar to that of Brown and Murphey is employed.4Approximately 500 ml of NH3 was condensed in a 1-liter flask; 1 mole of sodium amine (Fisher) followed by 1.0 mole of 4-ethylpyridine is added to the flask. After stirring under NH3 reflux for 30 minutes, 1.1 mole of ethyl iodide is added via an addition funnel to the orange-red suspension over a 1.5 hour period. Stirring is continued after the ethyliodide addition is complete and the solvent is allowed to evaporate slowly. Water (50 ml) is added to the residue and the layers are separated. The aqueous layer is extracted with ether and the combined organic layers are dried over Na2CO3, concentrated, and distilled. A colorless oil, 117.2 gm (87%), bp 120-25/90mm (lit.5 128°-30°/100 mm) is collected. The oil exhibits an nmr signal typical for a sec-butyl group in addition to the usual pattern for 4-substituted pyridine.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([C:5]1[CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]>Cl>[C:3]([C:5]1[CH:6]=[C:7]([S:12]([NH2:2])(=[O:14])=[O:13])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: N#Cc1cc(S(N)(=O)=O)ccc1F

Procedure:
Concentrated ammonium hydroxide (28% solution in water, 3.17 mL) was cooled to 0° C. and 3-cyano-4-fluorobenzene-1-sulfonyl chloride (1.00 g) was added. The solution was mixed at 0° C. for four minutes. 4M HCl (10 mL) was added slowly and the solution was extracted with ethyl acetate. The extract was dried on brine and anhydrous sodium sulfate and the solvent removed under vacuum.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[C:4]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.[Mg]>CO>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][C@H:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[C:4]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:3]=1
Reactant: CCOC(=O)C1=C(c2cc(OCc3ccccc3)nc(C)c2C)CCN(C(=O)OC(C)(C)C)C1
Agent: [Mg]
Solvent: CO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc(OCc2ccccc2)nc(C)c1C

Procedure:
To a MeOH solution (0.09 M) of 1-(1,1-dimethylethyl) 3-ethyl 2′,3′-dimethyl-6′-[(phenylmethyl)oxy]-5,6-dihydro-4,4′-bipyridine-1,3(2H)-dicarboxylate (1 eq.) from the previous step was added magnesium turnings (3.3 eq.). The suspension was evacuated and back-filled with N2. Finally, the reaction mixture was sonicated at RT for 3 h during which the magnesium turnings disappeared. The reaction was then quenched with the addition of diethyl ether and sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 95:5 (v/v) Hex:EtOAc→1:1 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CC(F)(F)C4)C3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and N-methylpiperazine. White solid (81%). MS (EI): 570.2 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:22][C:23]([O:25]C)=[O:24])[CH:20]=3)[N:13]3[CH:32]=[CH:33][N:34]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1>O.CO>[CH3:4][N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][C:23]([OH:25])=[O:24])[CH:20]=3)[N:13]3[CH:32]=[CH:33][N:34]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1
Reactant: COC(=O)CC(CC(=O)OC)n1cc(-c2nc(-c3cnn(C)c3)cc3nccn23)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC(=O)O)CC(=O)O)c3)n2)cn1
Reaction time: 72 h
Yield: 65.3 %

Procedure:
Lithium hydroxide hydrate (0.0813 g, 1.94 mmol) was dissolved in water (2 mL) and was added to a solution of dimethyl 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanedioate (0.205 g, 0.484 mmol) in MeOH (4 mL). After stirring 3 days the reaction was concentrated to remove the MeOH and was then acidified to pH 4 with 1 N HCl (approximately 2 mL). Cooling resulted in a solid which was filtered and washed with MeOH. The filtrate was slightly concentrated to provide a second crop of product which was combined to provide 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanedioic acid (125 mg, 65% yield). MS (apci) m/z=396.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[C:3]=1[C:4]#[N:5].[S:22](Cl)(=[O:25])(=[O:24])[NH2:23]>C(#N)C>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH2:11][C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:22](=[O:25])(=[O:24])[N:23]=1
Reactant: NS(=O)(=O)Cl
Reactant: CCCC(=O)N1CCC[C@@H]1COc1cccc(N)c1C#N
Solvent: CC#N
Product: CCCC(=O)N1CCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.8 %

Procedure:
To a solution of (R)-2-amino-6-((1-butyrylpyrrolidin-2-yl)methoxy)benzonitrile (84 mg, 0.29 mmol) (Example 165a) in acetonitrile (9 mL), was added sulfamoyl chloride (70 mg, 0.60 mmol). The reaction was stirred at rt for 20 h, and upon completion was concentrated in vacuo. The resulting residue was dissolved in EtOH (1 mL), and 2N aqueous NaOH (4 mL) was added. The mixture was refluxed for 2 h, and upon completion was cooled to rt, neutralized with 1N HCl and stirred at 0° C. The resulting precipitate was collected by vacuum filtration to provide the desired product (38 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.89 (t, J=7.3 Hz, 3H), 1.54 (sext, J=7.3 Hz, 2H), 1.94 (m, 4H), 2.26 (t, J=7.3 Hz, 2H), 3.49 (m, 2H), 4.10 (m, 1H), 4.25 (m, 1H), 4.43 (m, 1H), 6.62 (d, J=8.2 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 8.08 (br s, 1H), 8.34 (br s, 1H), 10.93 (br s, 1H). MS 367 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH2:16][CH2:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1.P([O-])([O-])([O-])=O.Cl>C(#N)C>[Cl:26][C:22]1[CH:21]=[C:20]([CH2:19][C:18](=[O:27])/[CH:17]=[CH:16]/[C@H:11]2[CH2:12][CH2:13][C:14](=[O:15])[N:10]2[CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]([OH:28])=[O:2])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)COCCCCN1C(=O)CC[C@H]1CCC(=O)Cc1cccc(Cl)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: O=C(O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 20.3 %

Procedure:
A mixture of (4-{(R)-2-[4-(3-chlorophenyl)-3-oxo-butyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester (8.1 mg, 0.02 mmol), rabbit liver esterase (1 mg, 134 units/mg), pH 7.2 phosphate buffer (3 mL) and acetonitrile (0.1 mL) was stirred together at rt for 16.5 h. Aqueous HCl (0.5 M, 5 mL) was added and the mixture was extracted with CH2Cl2 (3×5 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 1.6 mg (20%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid.
Reaction SMILES: CS[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1>C(#N)C>[CH2:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:3]2[O:4][C:5]3[CH:11]=[CH:10][C:9]([S:12](=[O:14])(=[O:13])[NH2:15])=[CH:8][C:6]=3[N:7]=2)[CH2:22][CH2:21]1)=[O:24])[CH3:27]
Reactant: CSc1nc2cc(S(N)(=O)=O)ccc2o1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CC#N
Product: CCOC(=O)N1CCC(Nc2nc3cc(S(N)(=O)=O)ccc3o2)CC1
Temperature: 190 °C
Yield: 22.8 %

Procedure:
A mixture of 2-methylsulfanyl-benzooxazole-5-sulfonic acid amide (5.00 g, 20.5 mmol, 1.0 equiv) and ethyl 4-amino-1-piperidine carboxylate (3.53 g, 20.5 mmol, 1.0 equiv) in anhydrous acetonitrile (25 mL) was heated to 190° C. under microwave irradiation for 1 h. The crude reaction mixture was concentrated by evaporation under reduced pressure, the organic phase filtered over silica with ethyl acetate and purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water to afford 1.72 g (23%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.19 (t, J=7.1 Hz, 3H), 1.37-1.49 (m, 2H), 1.94-1.99 (m, 2H), 2.94-3.02 (m, 2H), 3.80-3.83 (m, 1H), 3.91-3.95 (m, 2H), 4.04 (q, J=7.1 Hz, 2H), 7.26 (br s, 2H), 7.49 (d, J=0.9 Hz, 2H), 7.63 (d, J=0.8 Hz, 1H), 8.28 (d, J=7.6 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 14.56, 31.10, 42.05, 49.60, 60.65, 108.39, 112.71, 118.35, 140.08, 143.52, 149.76, 154.59, 162.67. MS (ISP): 368.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:13][OH:14])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Commercially available (S)-2-benzyloxycarbonylamino-6-tert-butoxycarbonylamino-hexanoic acid (1) (14.89 g) was dissolved in 120 mL dry THF. This solution was cooled to −10° C. BH3 (80 mL, 1M in THF) was slowly added and the resulting solution was stirred for 1 hour below −5° C. and was allowed to warm to room temperature overnight. The reaction was quenched with MeOH, evaporated to dryness and use as such in the next reaction.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(O)CCCl
Reactant: COc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(OCCC(=O)O)cc1
Yield: 18.1 %

Procedure:
Solid KOH 6.80 g, (0.122 mol) and H2O (10 ml) are added to para-methoxyphenol 7.0 g (0.0564 mol), the resultant mixture is stirred at the room temperature while 3-chloropropanoic acid (6.12 g, 0.0564 mol) is added to thereof. Then the mixture is stirred and heated to reflux for 3 h. The reaction solution is acidified to pH 2 by adding concentrated aqueous HCl and extracted with ether. The combined ether extracts is then washed with 10% aqueous NaHCO3 and acidified to pH 3-4 by adding concentrated aqueous HCl, and precipitate is formed. The residue is filtered and recrystallized by benzene to provide needle crystal 2.0 g. m.p.: 102-103° C., yield: 18.1%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=O)[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([Cl:25])=[O:21])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
Heated for refluxing were 2-benzyloxy-6-naphthoic acid of 27.8 g and oxalyl chloride of 15.2 g in toluene of 200 g for 3 hours, and then excess oxalyl chloride and toluene were distilled off under reduced pressure to obtain 2-benzyloxy-6-naphthoyl chloride. This acid chloride was dissolved in toluene of 120 g, and pyridine of 9.5 g and 2-propanol of 6.6 g were added thereto, followed by stirring the solution at 80° C. for 3 hours. Then, after filtering off deposited pyridine hydrochloride, an organic layer was washed with 1N-hydrochloric acid and further washed with water to neutral. The organic layer was separated, and toluene was distilled off under reduced pressure to obtain a crude product. The product was recrystallized from ethanol, whereby 1'-methylethyl 2-benzyloxy-6-naphthoate of 27.2 g was obtained in the form of colorless crystal.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].Cl.[CH3:7][CH:8]1[CH2:10][NH:9]1>O>[NH2:5][CH:3]([CH3:4])[CH2:2][NH:1][CH2:7][CH:8]([NH2:9])[CH3:10]
Reactant: CC(N)CN
Reactant: CC1CN1
Agent: Cl
Solvent: O
Product: CC(N)CNCC(C)N
Temperature: 110 °C
Yield: 24 %

Procedure:
Into a 500 mL flask, 180 mL of de-ionized water was placed. To this, 120 mL of 1,2-diaminopropane (1.39 mol) was added and a condenser was fitted to the flask. 50 mL (0.507 mol) of hydrogen chloride (37%) was added dropwise and the reaction allowed to subside before adding 10 mL of 2-methylaziridine (0.142 mol). The solution was then heated to 110° C. for 25 hours. The solvent and excess 1,2-diaminopropane were then removed by vacuum distillation. The crude product was then distilled under vacuum (approximately 40 torr) with a boiling point of 110° C. The yield was 24% with 4.541 g obtained. The purity was determined by NMR, showing multiplets at 2.71, 2.35 and 0.91 ppm which corresponded to those in a commercial sample. There was an additional peak at 2.11 ppm which may be due to a structural isomer of the product.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([C:16]1[S:17][C:18]2[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][C:19]=2[N:20]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[S:17][C:18]2[CH2:24][CH2:23][CH:22]([CH2:25][O:26][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:21][C:19]=2[N:20]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCc1nc2c(s1)CCC(CO)C2
Product: CCCCc1nc2c(s1)CCC(COS(=O)(=O)c1ccc(C)cc1)C2

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. It is obtained as an undistillable oil which is used crude for the subsequent reactions.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:17]([C:18](=[O:21])[C:19]=3[OH:20])=[CH:16][C:15]([Cl:22])=[CH:14][CH:13]=4)=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:22][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]([OH:1])=[C:4]([OH:3])[CH:9]=1)=[C:19]([OH:20])[C:18]2=[O:21]
Reactant: O=c1c(O)c(-c2ccc3c(c2)OCO3)oc2ccc(Cl)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1c(O)c(-c2ccc(O)c(O)c2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72704984 %

Procedure:
10 mg (31.6 pmol) of the compound obtained in Example 12 was dissolved in 2 ml of methylenechloride, 3 molar equivalents of boron tribromide (BBr3) was added thereto, and then the mixture was stirred at room temperature for 2 hours. The remained boron tribromide (BBr3) was decomposed with methanol. The residue was concentrated under reduced pressure, and purified by preparative TLC to give 7 mg of the title compound in a yield of 72%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2C)=[CH:4][CH:3]=1.[NH2:30][C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33](Cl)[N:32]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:33]5[N:32]=[C:31]([NH2:30])[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ncnc(N2CCOc3ccc(B(O)O)cc3C2)c1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(-c2ccc3c(c2)CN(c2ncncc2Cc2ccc(F)cc2)CCO3)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 102.7 %

Procedure:
To a solution of (4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 8, step 2) (0.200 g, 0.509 mmol) and 2-amino-6-chloro-3-nitropyridine (0.106 g, 0.610 mmol) in dioxane (3 mL) and water (0.4 ml) was added potassium carbonate (0.211 g, 1.53 mmol). The solution was sparged with N2 (g) for five minutes before the addition of dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.042 g, 10 mol %). The resulting suspension was heated at 90° C. for 20 h in a sealed tube vessel. On cooling to room temperature the mixture was diluted with acetonitrile (25 mL) then filtered and concentrated to afford 6-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3-nitropyridin-2-amine (0.247 g, 100% yield) as an oil that was used without further purification. MS (EI) for C26H23FN6O3: 487 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:35])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1>>[CH3:22][O:23][C:24](=[O:35])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])=[CH:31][CH:32]=1
Reactant: COC(=O)CCc1ccc(CBr)cc1
Reactant: CC1(C)CCNC(=O)[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C1
Product: COC(=O)CCc1ccc(CN([C@@H]2CC(C)(C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
4-Chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 3-(4-bromomethyl-phenyl)-propionic acid methyl ester analogous to Example 2c to yield 3-(4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-propionic acid methyl ester: MS: m/e=507.6 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6](OC)=[O:7])#[N:2].[BH4-].[Na+]>CO.C1COCC1>[OH:7][CH2:6][C:5]1[CH:10]=[C:11]([CH3:13])[N:12]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: COC(=O)c1cc(C)nc(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(C#N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a stirring solution of 1.3 g (7.33 mmol) of methyl 2-cyano-6-methylisonicotinate in 25 mL of MeOH and 5 mL of THF at 0° C. was added 823 mg (21.7 mmol) of NaBH4. After 2 h the ice bath was removed and stirring was continued with warming to r.t. and after a further 15 min. 1.06 g of NaBH4 was added. After another 15 min., the solution was concentrated, and EtOAc was added. The pH was adjusted to 7 with 1N HCl, and the layers were separated. The aqueous layer was extracted with EtOAc (2×), and the combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (2-3) % MeOH/CHCl3 provided 440 mg of 4-(hydroxymethyl)-6-methylpicolinonitrile in 40% yield as a colorless solid.