Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42]O)[CH3:39].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]4([C:9]([NH:8][C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[O:10])[CH2:12][CH2:13]4)=[O:15])=[CH:18][C:19]=3[F:37])=[CH:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35])[CH3:39]
Reactant: CCN(CC)CCO
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCOc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (186 mg, 0.36 mmol) in CH2Cl2 (10 mL) was added 2-(diethylamino)ethanol (63 mg, 0.54 mmol), and PPh3 (141 mg, 0.54 mmol). DIAD (109 mg, 0.54 mmol) was then added as a CH2Cl2 (1 mL) solution. The resulted solution was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. To the residue was added 1 N HCl (50 mL), and it was washed with EtOAc (50 mL×2). The aqueous phase was basified by adding 15% NaOH aqueous solution until pH=11-13, and then extracted with ether (50 mL×2). The combined organic layer was dried (MgSO4), and concentrated in vacuo. The residue was purified on preparative HPLC to give N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamide (74 mg, 34%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (br s, 1 H), 10.02 (br s, 1 H), 8.47 (d, J=5.2 Hz, 1 H), 7.91 (br d, J=13.9 Hz, 1 H), 7.54-7.52 (m, 2 H), 7.55-7.50 (m, 1 H), 7.52 (s, 1 H), 7.50-7.40 (m, 1 H), 7.41 (s, 1 H), 7.16 (br t, J=8.7 Hz, 2 H), 6.41 (br d, J=4.7 Hz, 1 H), 4.18 (t, J=6.0 Hz, 2 H), 3.94 (s, 3 H), 2.87 (br t, J=6.3 Hz, 2 H), 2.59 (q, J=7.1 Hz, 4 H), 1.47 (br s, 4 H), 1.00 (t, J=7.0 Hz, 6 H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([C:15]([F:18])([F:17])[F:16])[C:8]=1[F:19].[C:20](=[O:22])=[O:21].C(O)(C(F)(F)F)=O>CCOCC>[F:19][C:8]1[C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=1[C:20]([OH:22])=[O:21]
Reactant: Fc1cc(Br)c(F)c(C(F)(F)F)c1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(F)c(F)c(C(F)(F)F)c1F
Temperature: -78 °C
Yield: 69 %

Procedure:
A solution of n-butyl lithium (2.6M in hexanes, 9.6 ml, 25 mmol) was added dropwise through an addition funnel over 15 minutes to a solution of 1-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene (7.00 g, 25 mmol) in ether (100 ml) stirred under N2 at -78° C. After 5 minutes the mixture was rapidly blown by catheter onto a suspension of dry ice (100 g) in ether (100 ml). After 5 minutes TFA (2 ml) was added to this. When the solution had warmed up to 20° C., it was washed with diluted HCl (0.5M, 20 ml), and extracted with dilute base (0.5N, 2×50 ml). The combined basic extracts were washed with ether (25 ml), made acidic with concentrated HCl (~4 ml), and extracted with ether (3×50 ml). The combined ethereal extracts were washed with water (50 ml), saturated brine (50 ml), and dried (MgSO 4). The solvent was removed under reduced pressure to give 2,4,5-trifluoro-3-(trifluoromethyl)benzoic acid (4.21 g, 69%) as white microscopic needles; mp 87°-90° C. Nmr (CDC3) δ 11.80 (1H, br s, OH), 8.05 (1H, d of t, Jd =6 Hz, aromatic).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]([N:15]=[C:16]=S)([CH3:14])([CH3:13])[CH3:12].C1(N=C=NCCN2CCOCC2)CCCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>N1C=CC=CC=1>[C:11]([NH:15][C:16]1[NH:9][C:5]2[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[CH:3][C:4]=2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)N=C=S
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)(C)Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 80 °C
Yield: 26.8 %

Procedure:
4,5-Dichlorophenylene diamine (8.0 g, 45.2 mmol) (Aldrich, Milwaukee, Wis.) was combined with tert-butyl isothiocyanate (6.3 mL, 49.7 mmol) (Aldrich, Milwaukee, Wis.) in anhydrous pyridine (100 mL). The solution was heated at 80° C. for 1 h under nitrogen. 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-ρ-toluene-sulphonate (24.9 g, 58.8 mmol) (Fluka Chemika) was added along with anhydrous pyridine (90 mL). This solution was heated at 90° C. for 2.5 h. The pyridine. was removed by rotoevaporation, and the residue was dissolved in ethyl acetate (300 μM) and extracted with water (4×100 mL). The ethyl acetate layer was treated with decolorizing carbon and washed through a silica gel filter pad (4×8 cm, 230-400 mesh) using ethyl acetate. The crude product was purifed on a silica gel column (5×16 cm, 230-400 mesh) using (1:4) ethyl acetate:hexane. Crude fractions were repurified on a second identical column using (1:3) ethyl acetate: hexane. Pure fractions from the two columns were combined to give a tan solid (3.13 g, 12.1 mmol, 27%); m.p. 219-221° C.; MS (API+): m/z (rel. intensity) 258 (100, M+1); 1H NMR (DMSO-d6) d 10.31 (s, 1H, NH), 7.31 (s, 2H, Ar-H), 6.61 (s, 1H, NH), 1.38 (s, 9H, t-butyl).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]1)[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1C[C@@H](C)O[C@@H](C)C1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
cis-2,6-Dimethylmorpholine (2.0 g) was dissolved in acetonitrile (70 ml). Ethyl bromoacetate (2.5 ml) and potassium carbonate (3.1 g) were added and the mixture was heated with stirring at 60° C. for 12 hours. The solvent was evaporated and then ethyl acetate was added to the residue. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (2.9 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=O)([O-])=O.C(O)C.[H][H]>C(O)(C)C.[Pd]>[CH:13]1[CH:12]=[C:11]([NH2:15])[CH:10]=[C:9]([CH2:7][C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([NH2:1])[CH:5]=2)[CH:14]=1
Reactant: [H][H]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCO
Product: Nc1cccc(Cc2cccc(N)c2)c1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
30.7 g (0.1 mol) of 3,3'-dinitro-4-chlorobenzophenone, 1.5 g of 5% Pd/C and 100 ml of ethanol were charged in a closed glass vessel equipped with a thermometer and a stirrer. While stirring the mixture at a temperature of 65° to 70° C., hydrogen was introduced thereto and 20.1 l (0.9 mol) of hydrogen was absorbed in 6 hours. Since no more absorption of hydrogen was observed, the reaction was terminated at this point. The reaction mixture was cooled to room temperature and filtered to obtain a black filter cake. This filter cake was dissolved in 100 ml of a 90% aqueous isopropyl alcohol solution with heating. The catalyst was removed by filtration with heating. The filtrate was cooled to precipitate 3,3'-diaminodiphenylmethane hydrochloride as a crystal. This crystal was recovered by filtration, washed with 10 ml of isopropanol and neutralized with dilute aqueous ammonia to precipitate a white crystal. The crystal was recovered by filtration and dried in vacuo to give 16.3 g (yield 82.2%) of 3,3'-diaminodiphenylmethane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17](OB(O)O)=[CH:16][CH:15]=1)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>COCCOC>[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:16][CH:15]=1)[CH3:12]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Under an argon atmosphere, tetrakistriphenylphosphine palladium (69 mg) was added to 5 ml of 1,2-dimethoxyethane. A mixture resulting from dissolving 5-bromo-2-fluorobenzaldehyde (406 mg) in 5 ml of 1,2-dimethoxyethane was added. A mixture resulting from dissolving 4-ethoxyphenylboric acid (398 mg) in 1.5 ml of 1,2-dimethoxyethane was added. Two milliliter of 2M sodium carbonate solution was added. Stirring was conducted for one hour and ten minutes under reflux. After cooling to room temperature, 20 ml of toluene was added and was washed with 10 ml of water twice, 10 ml of a 2N sodium hydroxide solution twice and 10 ml of water twice. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was purified by silica gel chromatography (hexane/ethyl acetate=4/1). The resulting effective fractions were concentrated to yield 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde (369 mg, Yield 76%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[NH:6][N:5]=1.[Br:14][C:15]1[C:22]([O:23][CH2:24][CH3:25])=[C:21]([CH:26](Cl)[CH3:27])[CH:20]=[C:19]([Cl:29])[C:16]=1[C:17]#[N:18]>CN(C)C=O.C(Cl)Cl>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:26]([C:21]3[CH:20]=[C:19]([Cl:29])[C:16]([C:17]#[N:18])=[C:15]([Br:14])[C:22]=3[O:23][CH2:24][CH3:25])[CH3:27])[N:5]=[C:4]([CH3:3])[C:12]=12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1Br
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1Br
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
Sodium hydride (16 mg, 0.41 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (33 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL, 40 mmol) and was stirred for 10 minutes. 2-bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (60 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) was added and the reaction was stirred at 50° C. overnight. The mixture was diluted with methylene chloride, washed with sat'd NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by flash column chromatography eluting with CH2Cl2/MeOH 0-10%, to give 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (0.05 gm, 60%) as a solid, LCMS calculated for C17H16BrClN6O (M+H)+: m/z=437.0, 435.0; found: 436.9, 434.7.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[I:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([C:20](=[CH:23]NC1C=CC=CC=1)[C:21]#[N:22])=[O:19]>C(O)C.CO>[NH2:22][C:21]1[N:2]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[CH3:13])[C:7]([OH:9])=[O:8])[N:3]=[CH:23][C:20]=1[C:18](=[O:19])[C:17]1[CH:31]=[CH:32][CH:33]=[C:15]([I:14])[CH:16]=1
Reactant: Cc1ccc(C(=O)O)cc1NN
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Temperature: 75 °C
Yield: 22 %

Procedure:
To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride 1 (Example 3A, 314 mg, 1.54 mmol, 1.0 eq) in 50 mL of ethanol and 5 mL of methanol was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 2 (579 mg, 1.54 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84). The mixture was heated to 75° C. for 18 h. The precipitated solids were collected on a fritted filter and were washed with ethanol to provide 3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-4-methyl-benzoic acid 3 (153 mg, 22%) as a white solid. MS m/z 448 [M+H]+; 1H NMR (300 MHz, DMSO-d6)<2.18 (s, 3H), 7.05 (bs, 2H), 7.34 (dd, J1=J2=7.7 Hz), 7.58 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.81 (m, 2H), 7.94 (m, 1H), 7.98 (m, 1H), 8.03 (m, 1H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25]>>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:27](/[S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)(=[O:26])=[O:25])\[C:28]#[N:29])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: N#CCS(=O)(=O)c1ccccn1
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccn2)cc(C(C)(C)C)c1O

Procedure:
M34 was prepared with 3,5-di-t-butyl-4-hydroxybenzaldehyde and (pyrid-2-yl)sulfonly acetonitrile under similar conditions as described for M26.
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH:18]([Sn](CCCC)(CCCC)CCCC)=[CH2:19]>C1(C)C=CC=CC=1.CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl:1][C:2]1[C:12]([CH:18]=[CH2:19])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=Cc1ccc([Si](C)(C)C)c(C(=O)NCC)c1Cl
Reaction time: 24 h
Yield: 21.3 %

Procedure:
To a solution of the compound of Example 239 (0.382 g, 1.0 mmol), tetrakis(triphenylphosphine)palladium(O) (23 mg, 0.02 mmol) and 2,6-di-t-butyl-4-methylphenol (1.5 mg) in toluene (10 mL) was added vinyltributyltin (0.349 g, 1.1 mmol). The light yellow solution was heated at reflux for 24 h, additional tetrakis(triphenylphosphine)palladium(O) (15 mg) was added, and reflux was continued for 24 h. The cool mixture was diluted with ether, filtered through Celite, concentrated and purified by RC (ethyl acetate/hexanes). The product was further purified by recrystallization from pentane to afford the title compound as white needles (0.060 g, 21%). m.p. 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=[O:9])=[CH:4][CH:3]=1.[C:12]([OH:17])(=[O:16])[CH:13]([CH3:15])O.B(F)(F)F.CCOCC>CCOCC.O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]2[O:17][C:12](=[O:16])[CH:13]([CH3:15])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(O)C(=O)O
Reactant: O=CCOc1ccc(Cl)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1OC(COc2ccc(Cl)cc2)OC1=O
Reaction time: 24 h

Procedure:
To a solution of 17.05 g (0.07 mole) of 4-chlorophenoxyacetaldehyde in 100 ml of ether was added 9.0 g (0.1 mole) of lactic acid dissolved in 50 ml of tetrahydrofuran. To the clear solution was added 15 g (0.105 mole) of boron trifluoride etherate. After 24 hours at ambient temperature, the reaction mixture was washed with aqueous sodium bicarbonate, dried, concentrated, and purified by silica chromatography. The first fraction that emerged from the column was 2-(4-chlorophenoxymethyl-10-5-methyl-1,3-dioxolan-4-one, the transisomer, having a melting point of 37°-40°. The second fraction was the cis isomer which melted at 53°-55°.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)[N:6]=[CH:5][C:4]=1[C:16](=O)[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:21][CH2:20]1.C(O)C.B.[Na].Cl.C(O)C>O1CCCC1>[ClH:31].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:16]=[CH:17]/[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:23][CH2:24]1
Reactant: Cc1cc(C)nc(-n2ncc(C(=O)CCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)c2C)n1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C)nc(-n2ncc(/C=C/CN3CCN(c4ccc(Cl)c(Cl)c4)CC3)c2C)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 115.6 %

Procedure:
1.0 g of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3,4-dichlorophenyl)-1-piperazinyl]-1-propanone hydrochloride was dissolved in a solvent mixture comprising 50 ml of ethanol and 50 ml of tetrahydrofuran. After cooling with ice to 0° C., 500 mg of sodium boron hydride was added and the mixture was stirred at the same temperature for 45 minutes. Further, 50 mg of sodium boron hydride was added and the mixture was stirred for additional 2 hours. Then it was neutralized by adding a 1N hydrochloric acid/ethanol solution. After evaporating the ethanol, chloroform was added to the concentrated residue. Then it was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, 50 ml of dioxane, 50 ml of tetrahydrofuran and 220 mg of p-toluenesulfonic acid monohydrate were added to the obtained residue. Then the resulting mixture was heated under reflux for 5 hours. After evaporating the solvent, chloroform was added to the residue. Then it was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform:methanol=30:1), converted into hydrochloride by adding a 1N hydrochloric acid/ethanol solution and recrystallized from ethanol to thereby give 560 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[Br:14].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5]([Br:14])=[CH:6][CH:7]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(=O)c1cc(NC(C)=O)ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of 5-acetylamino-2-bromo-benzoic acid methyl ester (ii, 5.44 g, 20.0 mmol) in H2SO4 (50 mL) at 0° C. was added HNO3 (50 mL). The reaction mixture was stirred at 0° C. for 20 min and poured into ice water (200 mL). The mixture was then extracted with EtOAc (3×200 mL). The combined extracts were washed with saturated aqueous NaHCO3 (3×200 mL), H2O (3×200 mL), brine (1×200 mL), and dried with Na2SO4. Flash column chromatography gave the desired product iii as a yellow solid (3.60 g, 57%). 1H NMR (acetone-d6): δ 9.47 (br s, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.89 (d, J=9.0, 1H), 3.84 (s, 3H), 2.10 (s, 3H). Anal. Calcd for C10H9BrN2O5: C, 37.88; H, 2.86; N, 8.83. Found: C, 38.02; H, 2.74; N, 8.74.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]2.C(N(CC)CC)C.[C:24](Cl)(=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>ClCCl>[Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])[CH:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C(=O)Cl
Reactant: COC(=O)CC1CCc2cc(Br)ccc2N1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1CC(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 6-bromo-2-methoxycarbonylmethyltetrahydroquinoline (43.8 g, 0.153 mol) and triethylamine (37.5 g, 0.371 mol) in dichloromethane (700 mL) was added slowly ethyl chlorooxalate (25.5 g, 0.187 mol) at 0° C. The mixture was stirred for 3 h at 0° C., poured into 0.3N hydrochloric acid (750 mL) and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 4:1 to 3:1 hexane/ethyl acetate to give 56.9 g of the title compound (97%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23]([OH:28])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:24]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Brc1ccccn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccccn1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
n-Butyl lithium (2.5 M, 2.4 mL, 6.0 mmol) was added dropwise to a solution of 2-bromopyridine (0.57 mL, 6.0 mmol) in THF (10 mL) at −78° C. under nitrogen and stirred for 30 minutes. A solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.3 g, 5.78 mmol) in THF (10 mL) was added dropwise and the mixture stirred at −78° C. for 1 hour. The reaction mixture was warmed to room temperature then saturated aqueous sodium hydrogen carbonate and ethyl acetate were added, the organics separated, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20-50% ethyl acetate/pentane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.62 g). LCMS m/z 305.3 [M+H]+. R.T.=2.50 min (Analytical Method 3).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:9]([N:6]1[CH2:7][CH:8]=[C:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: OCC1=CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxymethylpyridine (20 g, 0.183 mol) in anhydrous dimethylformamide (70 ml) was treated with benzyl bromide (24 ml, 0.202 mol) and the mixture was stirred at 100° C. for two hours. The reaction was cooled to room temperature and diluted with absolute ethanol (250 ml). Sodium borohydride (8.7 g, 0.229 mol) was added portionwise and the mixture stirred at reflux for 3 hours. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed with 1:1 hexane/ethyl acetate as eluant to the title compound (13 g, 35%) as a lemon yellow solid; δH (CDCl3) 2.12-2.20 (2H, m, tetrahydropyridinyl CH2), 2.60 (2H, t, J 7.5 Hz, tetrahydropyridinyl CH2), 2.96-3.04 (2H, m, tetrahydropyridyl CH2), 3.60 (2H, s, PhCH2N), 4.00-4.04 (2H, m, CH2OH), 5.60-5.66 (1H, m, tetrahydropyridinyl 5-H), and 7.20-7.40 (5H, m, ArH). m/z (CI+, NH3) 204 (M+1)+.