Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:27]=[O:28].[Cl-].[NH4+]>O1CCCC1>[CH3:13][O:12][CH2:11][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:27]=[O:28])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: COCOCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCCc1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Next, to a mixture of bromo-4-(2-methoxymethoxyethyl)benzene (12.0 g, 49.0 mmol) and tetrahydrofuran (75 ml), a 1.58 mol/L n-butyllithium n-hexane solution (34 ml, 53.7 mmol) was added dropwise at −78° C. over 10 minutes. After stirring at −78° C. for 1 hour, a solution of N,N-dimethylformamide (11.4 mL, 147 mmol) in tetrahydrofuran (5 mL) was added and stirred at −78° C. for 1.5 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After concentration, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to give 4-(2-methoxymethoxyethyl)benzaldehyde (7.0 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCc3c(sc(N)c3C(=O)c3ccccc3)C2)cc1

Procedure:
To a well-stirred and ice-cooled solution of 2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.78 mmol, 0.2 g) in dichloromethane (20 ml) under an argon atmosphere, was added triethylamine (0.162 ml) and then p-toluenesulfonyl chloride (0.93 mmol, 177 mg) portionwise. The suspension was stirred at room temperature for 24 h and the precipitated solid was filtered. The organic solution was evaporated under vacuum to give a solid residue which was chromatographed on silica gel eluting with ethyl ether and petroleum ether mixture to afford 2-amino-3-benzoyl-6-(4-methylphenylsulphonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine. (m.p.165-167° C., 85 yield). 1 H-NMR (CDCl3): 1.95 (m, 2H); 2.43 (s, 3H); 3.07 (t, 2H); 3.51 (s, 2H); 6.76 (sb, 2H); 7.3-7.67 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([NH2:22])[CH3:21])=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:8](=[O:10])[CH:7]=[CH:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[CH3:21])=[CH:16][C:15]=1[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CC(N)c1ccc(F)c(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)C=Cc1ccc(F)cc1)c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 4-fluorocinnamic acid (3.16 g, 19.6 mmol), 1-(4-Fluoro-3-morpholin-4-yl-phenyl)-ethylamine (4.39 g, 19.1 mmol), EDC.HCl (7.53 g, 39.2 mmol), DMAP (2.39 g, 19.6 mmol) and Et3N (8.23 ml, 58.8 mmol) in CH2Cl2 (60 ml) was stirred at room temperature for 16 hours. Purification by flesh chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 6.9 g of the title compound. The enantiomer was separated by Chiralpak AD column (50×500 mm, 20um) eluted with 45% EtOH in hexane, RT=36.1 min.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([I:25])=[C:21]([O:26][CH3:27])[CH:20]=4)[N:16]=[N:15]3)[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C1COCC1.O>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([I:25])=[C:21]([O:26][CH3:27])[CH:20]=4)[N:16]=[N:15]3)[C:11](=[O:13])[N:12]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc(-c2cn(C3CCc4c(F)cccc4NC3=O)nn2)ccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)ccc1I
Temperature: 25 °C
Yield: 90.9 %

Procedure:
6-Fluoro-3-[4-(4-iodo-3-methoxy-phenyl)-1,2,3-triazol-1-yl]-1,3,4,5-tetrahydro-1-benzazepin-2-one (20 g, 41.8 mmol) was suspended in THF and stirred at room temperature. Cesium carbonate (24.53 g, 75 mmol) was added, followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (14.56 g, 62.7 mmol). The mixture was heated to gentle reflux for 2 h. The reaction was diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel, gradient to 100% EtOAc/hexanes. 6-Fluoro-3-[4-(4-iodo-3-methoxy-phenyl)-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoro-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (21.3 g) was obtained as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][OH:13].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OCCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCCO2)cn1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a solution of 6-bromopyridine-3-carbaldehyde (25 g, 134 mmol) in toluene (130 mL) were added 1,3-propanediol (20.45 g, 269 mmol) and 10-camphorsulfonic acid (3.12 g, 13.44 mmol). The reaction mixture was heated to reflux, with azeotropic removal of the evolved water, for 50 minutes, cooled down to r.t. and concentrated. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 solution (100 mL). Organic phase was collected and the aqueous phase was extracted with EtOAc (2×150 mL). Combined organic fractions were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to yield a brown solid which was triturated with Et2O and hexane (10/200 mL), to afford intermediate 316 (27.7 g, 84% yield) as a beige solid. MS (m/z): 244.1, 246.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.40 (d, J=2.4 Hz, 1H), 7.35 (dd, J=8.0, 2.4 Hz, 1H), 7.66 (dd, J=8.0, 0.4 Hz, 1H), 5.61 (s, 1H), 4.15 (ddd, J=11.8, 5.0, 1.2 Hz, 2H), 3.98-3.91 (m, 2H), 2.028-1.95 (m, 1H), 1.46 (d quint, J=13.2, 1.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@@:6]12[CH2:13][CH2:12][C@@H:11]1[CH2:10][CH2:9][C:8](Br)([Br:14])[C:7]2=[O:16])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@@:6]12[CH2:13][CH2:12][C@@H:11]1[CH2:10][CH:9]=[C:8]([Br:14])[C:7]2=[O:16])[CH3:2]
Reactant: CCOC(=O)C[C@@]12CC[C@@H]1CCC(Br)(Br)C2=O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@]12CC[C@@H]1CC=C(Br)C2=O
Temperature: 100 °C
Yield: 54.9 %

Procedure:
cis-3,3-Dibromo-2-oxobicyclo[4.2.0]-octane-1-acetic acid ethyl ester (14.16 g) lithium bromide (4.88 g, 56.21 mmol), and lithium carbonate (2.98 g, 14.4 mmol) were dissolved in 47.3 mL of DMF under nitrogen and heated to 100° C. for 5 minutes. The reaction mixture was then poured into 500 mL of water and extracted with 4×100 mL of toluene. The organic phase was washed with 4×100 mL of water, dried over MgSO4, and concentrated in vacuo affording 8.86 g (80%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(C(=CNC1C=CC(C)=CN=1)C(OCC)=O)#N>>[C:20]([C:14](=[CH:13][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:21]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCc1ccc(N)nc1
Agent: CCOC(=O)C(C#N)=CNc1ccc(C)cn1
Product: CCOC(=O)C(C#N)=CNc1ccc(CC)cn1
Yield: 25.4 %

Procedure:
The title compound (m.p. 155°-156°, 25.4% yield) was prepared from 2-amino-5-ethylpyridine and ethyl ethoxymethylenecyanoacetate in a manner similar to that described for the preparation of ethyl 2-cyano-3-(5-methyl-2-pyridylamino)acrylate in Preparation 6.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[CH3:27][C:24]([O:23][C:21]([N:17]1[CH2:16][C:15]2[CH:28]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=3)[CH:12]=[CH:13][C:14]=2[O:20][CH2:19][CH2:18]1)=[O:22])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)O)cc3)cc2C1
Temperature: 60 °C
Yield: 84.3 %

Procedure:
To a slurry of 1,1-dimethylethyl 7-{4-[(methyloxy)carbonyl]phenyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (9.8 g, 26 mmol) in tetrahydrofuran (40 mL) was added a solution of lithium hydroxide (3.1 g, 130 mmol) in water (15 mL). The resulting mixture was heated at 60° C. for 18 h then partitioned between ethyl acetate (100 mL) and 1M hydrochloric acid (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel column chromatography (5% methanol in dichloromethane) provided 4-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoic acid (8.1 g, 85% yield). MS (EI) for C21H23NO5: 370 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][CH2:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14])=[CH:5][CH:4]=1.[OH-:20].[Na+].S(O)(O)(=O)=O.[NH2:27]O>O>[CH3:16][C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[O:20][N:27]=1)([CH3:17])[CH2:9][O:8][CH2:7][C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: NO
Reactant: COc1ccc(COCC(C)(C)C(=O)CC#N)cc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(COCC(C)(C)c2cc(N)on2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a stirred solution of 2.0 g (7.65 mmol) of 5-(4-methoxy-benzyloxy)-4,4-dimethyl-3-oxo-pentanenitrile and 0.62 g (15.40 mmol) of sodium hydroxide in water (40 mL) are added 0.64 g (3.90 mmol) of hydroxylamine sulfate. The reaction is stirred at 100° C. for 18 h. After cooling to room temperature, the reaction is diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic extracts are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residual oil is purified by flash column chromatography using Biotage SP1 (silica, eluent hexanes, 5-50% ethyl acetate) to yield 0.873 g of 3-[1,1-dimethyl-2-(4-methoxybenzyl-oxy)-ethyl]-isoxazol-5-ylamine as a pale yellow solid. Yield 41%, m/z 277 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (6H, s), 3.44 (2H, s), 3.81 (3H, s), 4.35 (2H, br. s), 4.46 (2H, br. s), 5.06 (1H, s), 7.22-7.27 (2H, m), 6.86-6.89 (2H, m).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:5])=[O:4].[C:14]([O:17][CH2:18][CH2:19]Br)(=[O:16])[CH3:15].Cl>O.CN(C=O)C>[N+:3]([C:6]1([CH2:12][O:13][CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:5])=[O:4]
Reactant: CC(=O)OCCBr
Reactant: O=[N+]([O-])C1(CO)CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COCC1([N+](=O)[O-])CCCCC1
Reaction time: 0.33 h

Procedure:
Under the nitrogen gas atmosphere, NaH (2.32 g, 58 mmol) was added in the DMF (70 mL) solution of (1-nitro-cyclohexyl)-methanol (6.96 g, 35 mmol) which had been obtained in 1) while cooling the solution with ice, and the mixture was stirred for 20 minutes while making the temperature rise naturally. Bromoethyl acetate (9.96 g, 58.0 mmol) was dropped, and the mixture was stirred at room temperature over-night. The reaction mixture was diluted with water (200 mL), 2M hydrochloric acid (20 mL, 40 mmol) was added, and the mixture was extracted with ethyl acetate (50 mL) two times. The organic layer was washed with 5% sodium bicarbonate aqueous solution (20 mL) and water (50 mL), and then dried with anhydrous sodium sulfate. The solvents were removed by distillation under reduced pressure, the residue was refined with silica gel column chromatography (Highflash 4L, manufactured by Yamazen Corporation, the mixture of hexane and ethyl acetate of 5:1 in mixing ratio), and pale yellow oily ethyl (1-nitro-cyclohexylmethoxy)-acetate (5.47 g, 57%) was obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([Cl:28])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 180 °C
Yield: 232.2 %

Procedure:
A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 93 mg), 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 15, 135 mg) and DIPEA (0.26 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (435 mg). NMR: 10.64 (s, 1H), 8.91 (s, 3H), 8.30 (s, 1H), 5.97 (s, 1H), 5.17 (s, 1H), 1.83-1.97 (m, 1H), 1.56 (d, 3H), 0.93-1.09 (m, 2H), 0.63-0.77 (m, 2H). m/z 413.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:14][OH:15])[C:10]([NH:12][CH3:13])=[O:11].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.CC(C)=O>O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:14][O:15][CH3:16])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)C(=NO)c1ccccc1CO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: CNC(=O)C(=NOC)c1ccccc1CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
A mixture of 2-(2-hydroxymethylphenyl)-2-hydroxyimino-N-methylacetamide (521 mg, E/Z≠93/7), potassium carbonate (415 mg), 95% dimethyl sulfate (365 mg) and acetone (5.0 ml) was stirred at room temperature for 6 hours. A few pieces of ice were added, and the mixture was stirred for 30 minutes. Water (about 50 ml) was added, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product (E/Z≠9 97/3). The crude product was crystallized from ethyl acetate-hexane to obtain the title compound as crystals (389 mg) (E/Z=97/3, yield: 70.0%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[OH:30].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:30][C:22]3[CH:23]=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:21]=3[F:20])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(OCc3ccccc3)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)c(F)c1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of 7-(benzyloxy)-4-chloroquinoline (45 g, 0.17 mol) and 2-fluoro-4-nitrophenol (28.9 g, 0.18 mol) in toluene (42 mL) was added DIPEA (25.9 g, 0.2 mol). The suspension was heated to 115° C. for 12 hours and then concentrated in vacuo. The residue was diluted with EtOH (45 mL), stirred at 60° C. for 30 minutes, and then allowed to cool down to 0° C. in an ice bath. The solid was collected through filtration, dried in vacuo at 45° C. for 24 hours to afford the title compound as a light grey solid (59.1 g, 91%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].C(OC(=O)[CH2:23][C:24]#[N:25])(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:23][C:24]#[N:25])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCc1ccc([N+](=O)[O-])cn1
Reaction time: 20 h
Yield: 55.6 %

Procedure:
To a solution of 5-nitro-2-chloropyridine (18 g, 113.5 mmol) in THF (100 ml) at room temperature K2CO3 (39.2 g, 283.8 mmol), cyanoacetic acid tert-butyl ester (24 g, 170.30 mmol) and 4 Å molecular sieves were added. The mixture was heated to reflux and stirred for 20 h. After concentrating the mixture under reduced pressure the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The obtained oil was dissolved in toluene (300 ml), toluene-4-sulfonic acid (2 g, 11.6 mmol) was added, and the mixture was heated to reflux for 2 h. The mixture then was stirred at room temperature for 16 h. After which the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. Column chromatography (cyclohexane/dichloromethane, 4/1) gave the product as a colorless oil (10.3 g, 66%).
Reaction SMILES: C1(OC)C=CC=CC=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[C:22]2[NH:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[NH:26][C:27](=O)[C:21]=2[CH:20]=[CH:19][CH:18]=1.N>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(C)C>[Cl:16][C:17]1[C:22]2[NH:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[N:26]=[C:27]([N:13]3[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2Nc2c(Cl)cccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Solvent: CC(C)O
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Nc3c(Cl)cccc32)CC1
Temperature: 60 °C

Procedure:
To a stirred solution of anisole (0.40 mL, 3.68 mmol) in dry toluene (2.00 mL) was added titanium tetrachloride (0.24 mL, 2.18 mmol) at room temperature under argon. The mixture was then treated with 1-methylpiperazine (1.04 mL, 0.94 g, 9.40 mmol) and 4-chloro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (0.49 g, 2.00 mmol) (Giani et al, supra) and diluted with toluene (1.00 mL). After more 1-methylpiperazine (0.60 mL, 0.54 g, 5.40 mmol) was added, toluene (8.00 mL) was added and the resulting reaction mixture was heated at reflux for 6 h before it was cooled to 60° C. Isopropanol (0.80 mL), celite (0.40 g) and ammonia (30%, 0.50 mL) were added sequentially and the whole mixture was filtered hot. Upon cooling to room temperature, the filtrate was concentrated in vacuo to dryness. The purification was carried out either by acidic (3M HCl) extraction and basification (30% ammonia) or column chromatography using ethyl acetate/methanol (3/1) as the eluent. The title compound was obtained as a light yellow solid in 0.60 g (91%); m.p. 168°-170° C.; MS (EI) 326 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[O:20])[N:3]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Clc1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(Cl)c2ccccc21)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-Chloro-1H-indazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3) 7.64–7.70 (m, 1H), 7.38–7.48 (m, 2H), 7.18–7.26 (m, 2H), 6.94–7.0 (m, 2H), 6.82–6.88 (dd, 2H), 5.2 (s, 2H), 3.72–3.82 (m, 4H), 3.02–3.08 (m, 4H). 13C NMR (400 MHz, CDCl3): 165, 158.2, 142.8, 134.8, 128.8, 128.4, 122, 121.6, 118.8, 118.6, 115.4, 115.2, 110.6, 110.0, 51.8, 50.6, 50.2, 45.2, 42.
Reaction SMILES: C(Cl)(=[O:3])C.[CH3:5][CH2:6][O:7][CH2:8][CH3:9].[C:10]1([CH3:16])[CH:15]=C[CH:13]=[CH:12][CH:11]=1>[Ag]OC#N>[CH3:13][CH2:12][CH2:11][CH:10]([CH3:16])[CH3:15].[C:6]([O:7][CH2:8][CH3:9])(=[O:3])[CH3:5]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1
Reactant: CCOCC
Agent: N#CO[Ag]
Product: CCCC(C)C
Product: CCOC(C)=O
Reaction time: 0.5 h

Procedure:
Silver cyanate (13.5 g) suspended in anhydrous toluene (90 ml) under nitrogen was treated dropwise with acetyl chloride (5.34 ml) and stirred vigorously for 30 min. The product of step 1) (23 g) dissolved in anhydrous toluene (15 ml) was added and the mixture was stirred for 72 h. Ether (360 ml) was added and the insoluble material was filtered off and washed with a small volume of ether. The combined organic solutions were washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was treated with a solution of sodium methoxide in methanol (25 wt %, 64 ml) at room temperature for 72 h. The reaction was cooled in ice and treated with trimethylsilyl chloride (50.8 ml) and stirred at room temperature overnight. All volatiles were removed in vacuo and the residue partitioned between water and ethyl acetate. Drying and evaporation of the organic solution left a residue, which was chromatographed (SiO2/2:1 isohexane-ethyl acetate then 3:2 isohexane-ethyl acetate) to isolate the major component (12.2 g). This was taken in dry DMF (150 ml) with potassium carbonate (6.95 g) and methyl iodide (7.1 g) for 72 h at room temperature. The mixture was poured into water (2 L), acidified and extracted into ether. Washing with brine, drying and evaporation gave a solid which was boiled in isohexane (200 ml) containing ethyl acetate (3 ml). On cooling the precipitated pale yellow solid was collected and dried, to afford the title compound (10.5 g). δ 1HCDCl3 1.6 (6H, d), 2.44 (3H,s), 3.37 (3H, s), 3.95 (3H, s), 4.66 (1H, br) MS (APCI) (M++H) 297