Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([I:11])[C:3]=12.[H-].[Na+].[CH:14](Br)([CH3:16])[CH3:15]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1nc[nH]c2ncc(I)c1-2
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-5-iodopyrrolo[2,3-d]pyrimidine (10.0 g, see Example 17) was added in portions with stirring under nitrogen at 0° C. to a suspension of sodium hydride (1.6 g of a 60% dispersion in mineral oil) in N,N-dimethylformamide (250 ml). When the addition was complete the mixture was allowed to warm up to ambient temperature and when no more gas evolution was observed, a solution of isopropyl bromide (34.0 ml) in N,N-dimethylformamide (20 ml) was added dropwise. The mixture was stirred at ambient temperature overnight then quenched by the dropwise addition of water (300 ml) with external ice-cooling. The mixture was then washed with ethyl acetate (3×300 ml), the combined organic layers were washed with water, dried, filtered and evaporated to give 4-chloro-5-iodo-7-isopropylpyrrolo-[2,3-d]pyrimidine as a yellow solid, m.p. 116-118° C. The structure was confirmed by 1H nmr.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:26][C@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:28][C:29](O)=[O:30])(=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@@H:10]([CH2:12][OH:13])[NH:11][C:29](=[O:30])[CH2:28][C@H:27]([O:26][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Reactant: N[C@H](CO)C(=O)OCc1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CI
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCCCCC
Yield: 91.2 %

Procedure:
In the same manner as described in Example 2-(5), D-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (875 mg, 2.2 mmol) in the presence of EDC MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 1.05 g (91%) of N-[(R)-3-decanoyloxytetradecanoyl]-D-serine benzyl ester: mp 51-52° C.: 1H NMR (CDCl3) δ 0.88 (m, 6 H), 1.1-1.7 (m, 34 H), 2.30 (t, 2 H, J=7.7 Hz), 2.50 (m, 2 H), 3.68 (s, 1 H), 3.93 (d, 2 H, J=3.1 Hz), 4.62 (m, 1 H), 5.22 (m, 3 H), 6.63 (d, 1 H, J=6.9 Hz), 7.35 (br s, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]3[O:33][CH2:32][C@H:31]([CH2:34]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:30][C:26]3=2)[N:21]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][N:16]([CH2:34][C@@H:31]3[O:30][C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=[C:25]4[O:33][CH2:32]3)[N:21]=[C:20]([CH3:19])[CH:29]=[CH:28]5)[CH2:15][CH2:14]1)[CH:7]=[CH:6]2
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: COc1ccc2nc(N3CCNCC3)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2nc(N3CCN(C[C@H]4COc5ccc6nc(C)ccc6c5O4)CC3)ccc2c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
A mixture of 6-methoxy-2-piperazin-1-yl-quinoline of Step D (1.05 g, 4.31 mmol) in dimethylsulfoxide (15 mL) and [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromobenzene sulfonate (1.62 g) is heated at 80° C. under nitrogen for 3 hours and at 90° C. for 1 additional hour. The solution is poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (0.5–3%) in dichloromethane-hexane (1:1) containing 0.1% ammonium hydroxide to provide the title compound (0.790 g). The pure material is charcoalized (in ethyl acetate), filtered, evaporated and induced to crystallize from hexane by sonication. The off-white solid melts at 158–160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Li+].CC([N-]C(C)C)C.[C:19](=[O:21])=[O:20]>C1COCC1.C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:19]([OH:21])=[O:20]
Reactant: COc1cncc(OC)c1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cncc(OC)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
A solution of 3,5-dimethoxypyridine (600 mg, 4.3 mmol) (prepared according to the method of Testaferri, L. et al Tetrahedron, 1985, 41, 1373) in THF (2.6 ml) was added to a solution of LDA [generated from n-BuLi (1.9 ml, 2.5 M in hexane, 4.73 mmol) and diisopropylamine (0.6 ml, 5.16 mmol)] in THF (2.6 ml) at −78° C. under nitrogen. The reaction mixture was stirred for 30 minutes at −78° C., transferred via cannula to a suspension of crushed solid CO2 (30 g) in toluene (100 ml) under vigorous stirring and warmed to room temperature. The reaction is quenched by addition of water (20 ml) to and 1M NaOH (10 ml) and the aqueous layer separated, acidified to pH 4 with glacial acetic acid and extracted with 10% MeOH in dichloromethane (3×50 ml). The combined organic layers were dried (MgSO4) and the solvent removed under vacuum to give the title compound (502 mg, 63%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(F)c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of ethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(cycloheptylidene)methyl]phenyl}-2-propenoate (134) (0.22 g, 0.56 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration, light brown foam was obtained. It was triturated with hexanes (contains 1% MeOH) to give compound 135 as a pale yellow solid (0.171 g, 84%). mp 164-165° C. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (br s, 8H), 2.10-2.30 (m, 4H), 6.45 (d, J=15.9 Hz, 1H), 6.70-6.78 (m, 1H), 6.80-6.90 (m, 1H), 7.14 (d, J=8.2 Hz, 2H), 7.53 (d, J=16.2 Hz, 1H), 7.59 (d, J=8.0 Hz, 2H), 9.74 (s, 1H), 12.35 (s, 1H). LCMS (ES): m/z 367 (M+H)+, m/z 365 (M−H)−. Anal. Calcd for C23H23FO3. 0.1H2O: C, 75.02; H, 6.35; Found: C, 74.93; H, 6.44.
Reaction SMILES: [H-].[Na+].C(N(CC)[CH:6]=[C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=O)C.[C:25]([CH2:27][C:28]([NH2:30])=[O:29])#[N:26].Cl>CN(C=O)C.CO>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[NH:30][C:28](=[O:29])[C:27]([C:25]#[N:26])=[CH:6][C:7]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:14]=1
Reactant: CCN(C=C(C(=O)c1ccc(C)cc1)c1ccccc1)CC
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2[nH]c(=O)c(C#N)cc2-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a slurry of NaH (1.38 g, 60% in mineral oil, 34.41 mmol) in DMF (20 mL) at 0° C. was added a solution of 3-dimethylamino)-1-(4-methylphenyl)-2-phenylprop-2-en-1-one (2-2; 4.15 g, 15.64 mmol) and 2-cyanoacetamide (1.45 g, 17.2 mmol) in MeOH (1.5 mL) and DMF (40 mL) dropwise over 40 min. The resulting mixture was stirred at 90° C. for 4 h and cooled to rt. The mixture was poured into dilute HCl aqueous solution (240 mL, 0.25 M) and filtered, washed with water (40 mL) and dried in vacuo to afford 6-(4-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (2-3). 1H-NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.15-7.28 (m, 7H), 7.05-7.07 (m, 2H), 2.36 (s, 3H). LRMS m/z (M+H) Calcd: 287.3, found: 287.1.
Reaction SMILES: F[C:2]1[C:3]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([CH3:16])[N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O.[Cu]I>[CH3:25][O:24][C:21]1[N:22]=[CH:23][C:18]([NH:17][C:2]2[C:3]([C:8]3[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([CH3:16])[N:9]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(N)cn1
Reactant: CSc1cc(-c2nccnc2F)nc(C)n1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nccnc2-c2cc(SC)nc(C)n2)cn1
Temperature: 100 °C
Yield: 46.1 %

Procedure:
A glass microwave reaction vessel was charged with 4-(3-fluoropyrazin-2-yl)-2-methyl-6-(methylthio)pyrimidine (21 mg, 0.089 mmol), 5-amino-2-methoxypyridine (0.022 mL, 0.178 mmol), copper(I) iodide (2 mg, 8.89 μmol) and N-ethyl-N-isopropylpropan-2-amine (22.97 mg, 0.178 mmol) in dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 24 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow solid. The crude product was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (14 mg, 0.041 mmol, 46.3% yield). 1H NMR (300 MHz, CDCl3) δ 12.20 (s, 1H); 8.42 (d, J=2.05 Hz, 1H); 8.22 (s, 1H); 8.18 (s, 1H); 8.09 (dd, J=8.92, 2.63 Hz, 1H); 8.02 (d, J=1.90 Hz, 1H); 6.79 (d, J=8.77 Hz, 1H); 3.95 (s, 3H); 2.78 (s, 3H); 2.63 (s, 3H). m/z (ESI, +ve ion) 341.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:30]=[CH:31][CH:32]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[N:21][N:22](CC(OCC)=O)[N:23]=2)[CH:16]=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[Na+].Cl>CO>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:30]=[CH:31][CH:32]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[N:21][NH:22][N:23]=2)[CH:16]=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(OCc2cccc(-c3nnn(CC(=O)OCC)n3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(O)c1cccc(OCc2cccc(-c3nn[nH]n3)c2)c1
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To 1.5 g of 5[3-[3-(1-hydroxyhexyl)phenoxymethyl]-phenyl]2-carbethoxymethyl-2H-tetrazole in 5 ml of methanol was added 6.0 ml of 2N sodium hydroxide. The mixture was stirred for 3 hours. The mixture was acidified with hydrochloric acid and extracted with ether. On evaporation of the ether layer there was obtained 1.3 g of crude product. This was passed through a silica gel column and eluted with chloroform:methanol (4:1) to give 0.9 g of product as a light amber liquid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH2:15][CH2:14][CH2:13][C:12](=O)[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[N:18][OH:19])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C#CC2=CC(=O)CCC2)n1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(C#CC2=CC(=NO)CCC2)n1
Yield: 42.4 %

Procedure:
A solution of 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone (422 mg, 2 mmol) and hydroxylamine hydrochloride (278 mg, 4 mmol) in pyridine (20 ml) is stirred for 17 h at RT. After that time the solvent is evaporated in vacuo. The residue is dissolved in ethyl acetate (300 ml) and washed with sat NaHCO3 (1×50 ml). The water phase is extracted with ethyl acetate (1×50 ml). The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo. The residue (0.45 g) is purified on column chromatography (Silica gel, eluent hexane/ethyl acetate 2:1 v/v) and the fractions containing the desired compound are collected and concentrated in vacuo to yield 0.192 g (yield=42%) of the title compound as light yellow crystals, m.p. 166-168° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][CH2:14][CH:13]=[CH2:12])[CH:2]=[O:1]
Reactant: C=CCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C=O)cc1OC

Procedure:
Vanillin (20.0 g, 0.130 mol) and allyl bromide (19.9 g, 0.160 mol) were heated under reflux together with potassium carbonate (27.3 g, 0.200 mol) in 150 ml acetone (abs.) for 8 hours. After cooling, the solid was filtered off and washed with acetone. A yellow oil was obtained after a thorough concentration of the organic phases.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5]([O:6][CH2:7][CH3:8])[CH:4]=1.[CH2:13]([C:16]1[CH:17]=[C:18]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:19]=[CH:20][C:21]=1[O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH:14]=[CH2:15]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][C:18]1[CH:19]=[CH:20][C:21]([O:22][S:23]([C:26]([F:27])([F:28])[F:29])(=[O:25])=[O:24])=[C:16]([CH2:13][CH:14]=[CH2:15])[CH:17]=1)[CH3:36].[CH2:7]([O:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:9]=1[O:10][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])[CH:2]=[O:1])[CH3:8]
Reactant: CCOc1cc(C=O)ccc1O
Agent: C=CCc1cc(CCC(=O)OCC)ccc1OS(=O)(=O)C(F)(F)F
Product: CCOc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F

Procedure:
Ethyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate was prepared from ethyl vanillin using the procedure described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate. Thus there was obtained 3-ethoxy-4-trifluoromethylsulphonyloxybenzaldehyde as an oil; NMR (CDCl3): 1.50(3H, t), 4.22(2H, q), 7.36-7.58(3H, m), 9.97(1H, s); m/Z 299 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:2]([CH3:1])[C:31]([NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: O=C=Nc1ccccc1
Reactant: CNCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Product: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)Nc1ccccc1
Yield: 112.7 %

Procedure:
In a manner similar to that of Example 9(a) by reacting 300 mg (0.9 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethylene)thiazolidine-2,4-dione with 190 μl (1.8 mmol) of phenyl isocyanate, 450 mg (98%) of the expected product are obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].ClC(Cl)CCCCCN=C=N.O>C(Cl)Cl>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: N=C=NCCCCCC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 1 h
Yield: 143.9 %

Procedure:
A portion (200 mg) of the compound obtained in Example 81 and N-t-butoxycarbonylglycine (170 mg) were suspended in methylene chloride (15 ml) and to the suspension was added dichlorohexylcarbodiimide (216 mg) under cooling with ice. The mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield the titled compound (470 mg) as a crude yellow solid. The compound was used in the subsequent reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH2:23].C([O-])(O)=O.[Na+]>C(O)C>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH3:16])[N:5]=[CH:4][C:3]([C:17]#[N:18])=[C:2]2[NH:23][C:22]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:20]([OH:19])[CH:21]=1)[CH3:14]
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2cc1OC
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OC
Yield: 47.4 %

Procedure:
A mixture of 1.00 g (3.82 mmol) of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile and 0.563 g (4.58 mmol) of 3-hydroxy-4-methylaniline in 20 mL of ethanol was refluxed under N2 for 8 h. Saturated NaHCO3 was added, volatile material was removed and the residue was azeotroped with ethanol. The crude product was slurried with hexane, filtered, washed with water and cold ethanol and dried. Recrystallization from ethanol gave 0.632 g of 6-ethoxy-4-(3-hydroxy-4-methylphenylamino)-7-methoxyquinoline-3-carbonitrile as light yellow crystals: mass spectrum (electrospray, m/e): M+H 349.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.C([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(OC(C)(C)C)=O.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:3][C:4]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Oc1cc(Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)Oc1cc(N2CCNCC2)ccc1Cl
Temperature: 85 °C

Procedure:
1-Bromo-3-isopropoxy-4-chlorobenzene (preparation described elsewhere) was combined with 1.11 g (6 mmol) of 1-Bocpiperazine, 672 mg (7.0 mmol) of sodium tert-butoxide, 93 mg (0.15 mmol) of rac-2,2′-Bis(diphenylphosphine)-1,1′-binaphthyl, and 45 mg (0.05 mmol) Tris(dibenzylideneacetone)dipalladium (0) in a flask under an N2 atmosphere, and the mixture was heated at 85° C. for 3.5 hours. The resulting residue was partitioned between a 1/1 mixture of ether and ethyl acetate and water, and the phases were separated. The ether/ethyl acetate phase was diluted with one volume of hexanes, washed twice with 0.5M pH=7 phosphate buffer, and once each with 1M NaOH and brine. The final organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to an oil. The oil was dissolved in ethyl acetate, 10 mL each of 2M HCl in ether and methanol were added, and the product was isolated by filtration after crystallization. 1H NMR (D2O, 400 MHz): 7.23 (d, 1H), 6.69 (s, 1H), 6.59 (d, 1H), 4.53 (m, 1H), 3.28 (m, 8H), 1.20 (d, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[Br:13]N1C(=O)CCC1=O>ClCCCl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH3:10])[C:6]=2[C:11]=1[Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nsc2cc(F)c(N)cc12
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClCCCl
Product: Cc1nsc2cc(F)c(N)c(Br)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 5-amino-6-fluoro-3-methyl-1,2-benzisothiazole (0.600 g, 0.00329 mol) in 1,2-dichloroethane is added N-bromosuccinimide (0.586 g, 0.00329 mol) followed by 1,1′-azobis(cyclohexanecarbo-nitrile) (0.0200 g). The mixture is stirred two hours at 70° C., additional N-bromosuccinimide (0.240 g, 0.00135 mol) is added, and the mixture is stirred 40 minutes at 70° C. The mixture is then cooled to room temperature, filtered and concentrated in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound (0.870 g, 100w) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][NH2:12]>O1CCOCC1>[NH:11]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1COCCO1
Product: NNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
2-Chloro-5-nitropyridine (5 g, 31.5 mmol) and hydrazine (1.74 g, 34.7 mmol) were dissolved in 60 ml of dioxane, and the solution was stirred at room temperature for 16 hours. The precipitated yellow powder (m.p.: 198°-208°0 C.) was collected by filtration to obtain 502 mg of the intended product as a hydrochloride salt.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C@@H:9]([OH:27])[CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].Cl>C(OCC)(=O)C>[OH:27][C@@H:9]([CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1)[CH2:8][O:7][C:6]1[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC[C@@H](O)CN2CC3CNCC(C2)O3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
A solution of tert-butyl 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (ii) above; 1.0 g, 2.47 mmol) in ethyl acetate (13 mL) was cooled to 0° C. Ethyl acetate (26 mL) saturated with gaseous HCl was added, and the mixture stirred for 4 h at rt. The solvent was removed in vacuo before MeCN (25 mL), water (1.3 mL) and K2CO3 (2.0 g) were added. The resulting mixture was stirred overnight before CHCl3 was added, and the mixture filtered through Celite®. The filtrate was concentrated in vacuo to give 682 mg (91%) of the title compound.