Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH:2]([NH:1][C:37]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12)=[O:38])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol (125 mg, 0.35 mmol) in acetonitrile (30 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (66 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg, 0.52 mmol) and 1-hydroxybenzotriazole hydrate (53 mg, 0.35 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from chloroform-hexane to give the objective substance (162 mg, 88%).
Reaction SMILES: ClC1C=CC=C([C:8](OO)=[O:9])C=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([S:27][CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].C(OCC)(=[O:36])C>ClCCl>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([S:27]([CH2:28][CH2:29][C:30]2[O:31][C:8](=[O:9])[NH:33][N:32]=2)=[O:36])[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(S(=O)CCc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 2.25 h

Procedure:
m-Chloroperbenzoic acid (1.30 g, 6.0 mmol) is added in eight portions at 5-minute intervals to a 0° C. solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (2.25 g, 6.4 mmol) in dichloromethane (64 mL). The reaction mixture is stirred at 0° C. for 2.25 hours, then diluted with ethyl acetate and washed three times with a saturated solution of sodium bicarbonate, then with water and brine. Drying the organic phase over magnesium sulfate and evaporation gives a crude product which is chromatographed on a column of silica with ethyl acetate/hexane (3/1) to afford 1.92 g of a glassy solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2C=C[C:44]([O:47][CH2:48]CCN(C)C)=[C:43]3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:43][CH2:44][O:47][CH3:48])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCOC)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H) 8.19 (s, 1H) 8.14 (m, 1H) 8.06 (m, 1H) 7.91 (m, 1H) 7.81 (m, 1H) 7.28 (d, J=8.32 Hz, 1H) 7.22 (d, J=8.32 Hz, 1H) 4.44 (m, 2H) 3.95 (m, 2H) 3.58 (s, 3H) 3.23 (q, J=7.32 Hz, 2H) 2.49 (s, 3H) 1.37 (t, J=7.32 Hz, 3H). [M+H] calc'd for C23H25N2O4S, 425; found, 425.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=O.[OH:9][C:10]1[C:17]([OH:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>C(O)C>[OH:9][C:10]1[C:17]([OH:18])=[C:16]([OH:19])[C:15]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: C1CCNCC1
Reactant: C=O
Reactant: O=Cc1ccc(O)c(O)c1O
Solvent: CCO
Product: O=Cc1cc(CN2CCCCC2)c(O)c(O)c1O

Procedure:
20.4 g (0.24 mol) of piperidine were added to 19.2 g (0.24 mol) of a 37% aqueous formaldehyde solution in 140 ml of ethanol. Then 25.0 g (0.16 mol) of 2,3,4-trihydroxybenzaldehyde were added thereto. The reaction mixture was refluxed for one hour, developing a dark brown color. After cooling, a beige-brown solid precipitated out, which was filtered out and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:20])[NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCO
Reactant: Fc1cc(F)cc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cc(F)cc(F)c2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To the suspension of 4-(3,5-difluoro-phenyl)-1H-indole (13.52 g, 59 mmol) in t-BuOH:ethanol:acetic acid (375 mL:225 mL:115 mL) was added pyridinium tribromide (57 g, 177 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (286 mL). Zinc dust (19.25 g, 295 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), neutralized with 1N HCl, washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 9.88 g (68%) of 4-(3,5-difluoro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]#[CH:10])SC)#[N:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>>[C:1]([NH:3][C:4]([NH:7][CH2:8][C:9]#[CH:10])=[N:21][CH2:20][CH2:19][S:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)#[N:2]
Reactant: C#CCN=C(NC#N)SC
Reactant: NCCSCc1ccccn1
Product: C#CCNC(=NCCSCc1ccccn1)NC#N

Procedure:
The product of Step A is reacted with about an equimolar amount of 2-[(2-pyridyl)methylthio]ethylamine in a non-reactive solvent to give after workup, the title product.
Reaction SMILES: [O:1]=[C:2]([C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:4]#[N:5].[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1(C)C(C)=CC=CC=1>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([O:1]/[C:2](/[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])=[C:3](\[C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][CH:11]=1)/[C:4]#[N:5])=[O:29]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Solvent: Cc1ccccc1C
Product: Cc1nn(C)c(/C(OC(=O)C(C)(C)C)=C(\C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 70 °C
Yield: 95.9 %

Procedure:
In a 10 L-reaction flask, 456 g (1.47 mol) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl)propionitrile and 2738 g of xylene were added, the temperature was raised to 70° C., and 534 g (4.43 mol) of pivaloyl chloride was added dropwise under reflux over 10 hours while removing hydrogen chloride under a reduced pressure at 68 to 71° C./10 to 13 kPa. After reacting as such for 3 hours, 2181 g of a mixture of pivaloyl chloride and xylene was distilled off at 70° C. under a reduced pressure in order to remove excess pivaloyl chloride. After adding 456 g of warm water of 70° C., 228 g of 2.7% sodium hydrogen carbonate aqueous solution was added dropwise. After separating the resulting aqueous phase, the resulting organic phase was washed with 456 g of warm water of 70° C., the resulting aqueous phase was separated to obtain a xylene solution. A quantitative analysis with liquid chromatography showed that the xylene solution contained 555 g (yield 95.6%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl)acrylonitrile. After distilling off xylene at 90° C., 1141 g of heptane was added, and crystallization was carried out by gradually cooling from 70° C. After aging at 0° C. for 1 hour, the resulting crystal was filtered, and dried to obtain 533 g (yield 91.9%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl)acrylonitrile (melting point: 110° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]=O>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:19])[O:18][CH2:20]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Tert-butoxycarbonyl-L-phenylalanine (20.00 g), paraformaldehyde (6.04 g) and pyridinium p-toluenesulfonate (0.95 g) were added to toluene (200 ml), and they were stirred under heating and reflux for 30 minutes. The reaction mixture was cooled to room temperature and washed with a saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The obtained toluene layer was dried over anhydrous sodium sulfate and then sodium sulfate was removed. The solvent was evaporated under reduced pressure. The concentrated solution was cooled to room temperature to crystallize the product. The crystals were separated and dried to obtain intended (4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (15.10 g) (yield: 72%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH3:10].[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][C:17]2[NH:18][C:19](=[O:33])[C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)[O:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1.CCCCCCC>CN(C)C=O.CCCCCCC.C(OCC)(=O)C>[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][C:17]2[N:18]=[C:19]([O:33][CH2:8][CH2:9][CH3:10])[C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)[O:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1
Reactant: CCCBr
Reactant: O=c1[nH]c(Cc2ccc(Cl)cc2)nc2oc(-c3cccc(F)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cccc(F)c3)nc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
28 mg of potassium carbonate and 21 mg of 1-bromo-propane were added to a solution of 60 mg of 5-(4-chloro-benzyl)-2-(3-fluoro-phenyl)-6H-oxazolo[5,4-d]pyrimidin-7-one in 3 ml of dimethylformamide, and the reaction mixture was stirred at 60° C. for 16 h. After cooling, the mixture was subjected to chromatography (silica gel, gradient from heptane to heptane/ethyl acetate 3:1). 15 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C:17]1[CH:22]=[CH:21][C:20]([O:23]B(O)O)=[CH:19][CH:18]=1)(C)C.N1C=C[CH:30]=[CH:29][CH:28]=1>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH:29]([CH3:30])[CH3:28])=[CH:21][CH:22]=2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccnn1Cc1ccccc1
Reactant: CC(C)c1ccc(OB(O)O)cc1
Reactant: c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Nc2ccnn2Cc2ccccc2)cc1
Reaction time: 15 h
Yield: 26 %

Procedure:
A suspension of 1-benzyl-1H-pyrazol-5-amine (1.7 g), 4-isopropylphenylboric acid (2.0 g), copper acetate (1.8 g), pyridine (4.0 mL) and molecular sieves 4A (4 g) in tetrahydrofuran (50 mL) was stirred for 15 hr. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.80 g, 26%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)c(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred mixture of phenylboronic acid (1.20 g, 9.85 mmol) and 4-bromo-3-trifluoromethyl-phenol (1.18 g, 4.92 mmol) in DCM (50.00 mL) was added cupric acetate (1.34 g, 7.39 mmol), powdered 4 A molecular sieves and TEA (3.43 mL, 24.6 mmol) at rt. The resulting mixture was then stirred at rt for 24 h at ambient atmosphere. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[N+:13]([O-:15])=[O:14].[CH3:16][C:17]1[N:21]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[N:19][N:18]=1.C(=O)=O.CC(C)=O.C([Li])CCC.CCCCCC>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH:11]([CH2:12][N+:13]([O-:15])=[O:14])[CH2:16][C:17]1[N:21]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[N:19][N:18]=1
Reactant: Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])cc1/C=C/[N+](=O)[O-]
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc([N+](=O)[O-])cc1C(Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C[N+](=O)[O-]

Procedure:
Adapting literature known protocols (Huff et al., Tetrahedron Lett., 1996, 37(12), 3655-3658; Baylis, Tetrahedron Lett., 1995, 36(51), 9385-9388; and Xu, et al., U.S. Pat. No. 8,344,028 (2013)), 5-[2-(2-methyl-5-nitro-phenyl)-3-nitro-propyl]-1-trityl-tetrazole (20b) is prepared from 1-methyl-4-nitro-2-[(E)-2-nitrovinyl]benzene (19a) through 1,4-conjugate addition of lithiated 5-methyl-1-trityl-tetrazole (Huff et al., Tetrahedron Lett., 1996, 37(12), 3655-3658). 5-Methyl-1-trityl-tetrazole (3.92 g, 12.0 mmol) in anhydrous tetrahydrofuran (THF) (15 mL) is lithiated under a nitrogen atmosphere and at a temperature of about −78° C. (dry ice/acetone bath) with n-butyllithium (nBuLi) in hexane (12.0 mL, 12.0 mmol) and added via a cannula to a cooled solution (−78° C.; dry ice/acetone bath, nitrogen atmosphere) of (19a) (2.08 g, 10.0 mmol) in anhydrous tetrahydrofuran (THF) (15 mL). Aqueous work-up and purification by silica gel column chromatography using ethyl acetate (EtOAc) and hexanes mixtures afford the title compound (20b).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([C:14](O)=[O:15])[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)=[N:10]2)[CH:6]=[CH:7][CH:8]=1.CO>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]3[C:14](=[O:15])[NH:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:11]3=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2cc(C(=O)O)c(-c3ccccc3[N+](=O)[O-])n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(-n2cc3c(=O)[nH]c4ccccc4c3n2)c1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 1-(3-methoxyphenyl)-3-(2-nitrophenyl)-1H-pyrazole-4-carboxylic acid (500 mg), 10% palladium/active carbon (50% water, 50 mg), tetrahydrofuran (30 ml) and methanol (50 ml) was stirred under hydrogen atmosphere, at room temperature for one night. To the reaction mixture was added tetrahydrofuran to dissolve the precipitated solid and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. To the residue was added ethanol-ethyl acetate, and the solid was collected by filtration. The solid was washed with ethyl acetate and dried to obtain the target compound (353 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27].C([O-])(O)=O.[Na+]>CC(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:17]3=[N:18][CH:19]=[C:20]([F:24])[CH:21]=[C:22]3[NH:27][N:26]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Fc1cnc2c(-c3ccc(OCc4ccccc4)cc3)n[nH]c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 79.5 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (41 mg), hydrazine hydrate (31.5 mg) and 2-propanol (10 mL) was stirred at 90° C. for 12 h, treated with saturated NaHCO3 aqueous solution, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (32.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.C([BH3-])#N.[Na+].[CH3:30][C:31]([CH3:33])=O>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:31]([CH3:33])[CH3:30])[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(NCC2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]-5-methylbenzamide from Example 204 (1.0 g, 2.78 mmol) in 20 mL of acetone and 6 mL of 95:5 methanol-acetic acid was treated with sodium cyanoborohydride (0.70 g, 11.1 mmol). After stirring at room temperature for 24 h, the reaction mixture was applied to a 10 g SCX column, washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo, affording 0.76 g (69%) of the title compound as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].CN(C)C=O.[N+:12]([CH3:15])([O-:14])=[O:13].[Cl:16][C:17]1[CH:38]=[CH:37][C:20]2[N:21]=[C:22](NCN=O)[CH2:23][C:24](=[O:32])[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]=2[CH:18]=1>O.C(O)(=O)C>[Cl:16][C:17]1[CH:38]=[CH:37][C:20]2[NH:21][C:22](=[CH:15][N+:12]([O-:14])=[O:13])[CH2:23][C:24](=[O:32])[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]=2[CH:18]=1
Reactant: O=NCNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1CC(=C[N+](=O)[O-])Nc2ccc(Cl)cc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium t-butoxide, 10.24 g (.092 moles) was added to a mixture of 250 ml of dimethylformamide and 50 ml of nitromethane. After stirring at room temperature for 15 min under nitrogen, 25 g (0.076 m) of 7-chloro-3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one was added and stirring was continued for an additional 19 hours. The mixture was acidified with acetic acid and diluted with water. The precipitate was filtered off, washed with water and recrystallized from methylene chloride/ethanol to give pale yellow crystals with mp 259°-261°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(Nc2ncnc3cnc(NCCN4CCNCC4)nc23)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCN(CCNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(1-piperazinyl)ethylamino]pyrimido[5,4-d]pyrimidine by reaction with acetic anhydride. Melting point: 196°-198° C.; Rf : 0.59 (alumina; methylene chloride/methanol=10:0.4)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:9]=1[OH:16].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:16][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[C:13]([F:14])[C:8]=1[F:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccc(F)c(F)c1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Fc1ccc(OCc2ccccc2)c(F)c1F
Temperature: 50 °C
Yield: 90.7 %

Procedure:
Sodium carbonate (19.50 g, 183.96 mmol) was dispersed into a solution of 2,3,4-trifluorophenol (13.64 g, 92.10 mmol) in acetone (300 mL). To the stirred suspension was added benzyl bromide (17.31 g, 101.21 mmol) dropwisely. The mixture was heated under reflux at 50° C. for 24 h. The acetone was removed under reduced pressure and the residue was dissolved in water (300 mL). The solution was extracted with ethyl acetate (100 mL×2). The combined organic extracts were washed with 5% sodium hydroxide (100 mL) and brine (100 mL) sequentially and dried over Na2SO4. The solvent was removed in vacuo to yield a pale yellow solid (19.89 g, 90.7% yield). 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 5H), 6.85 (m, 1H), 6.64 (m, 1H), 5.15 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:3]=1[CH3:22].[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:28]([C:27]1[CH:30]=[CH:31][C:24]([O:23][C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[C:3]=2[CH3:22])=[CH:25][CH:26]=1)=[O:29]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(C=O)cc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 39.6 %

Procedure:
To a solution of t-butyl 4-((6-chloro-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (2.0 gm, 0.00610 mole) and 4-hydroxybenzaldehyde (1.34 gm, 0.00610 mole) in dimethyl formamide (50 mL), Cesium carbonate (4 gm, 0.0122 mole) was added and reaction mixture was stirred for 24 hours at 70° C. Then reaction mixture was cooled, poured into ice cold water and extracted with ethyl acetate. organic extract was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to yield crude product. The crude product so obtained was purified through column chromatography using 15-20% ethyl acetate in hexane to yield 1 gm product as oil.