Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:6][C:7]([CH:9]2[O:14][CH2:13][CH2:12][N:11](C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:10]2)=[O:8])[CH2:5][CH2:4]1>CO>[CH:3]1([NH:6][C:7]([CH:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(NC1CC1)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC1CC1)C1CNCCO1
Reaction time: 3 h

Procedure:
NaOH (1 mL, 2 M, 2.0 mmol) was slowly added to a solution of 9H-fluoren-9-ylmethyl 2-[(cyclopropylamino)carbonyl]morpholine-4-carboxylate (1.0 g, 2.6 mmol) in MeOH (70 mL) at ambient temperature. The reaction mixture was stirred for 3 h and the solvent was concentrated. The product was recovered in water (50 mL) and the mixture was neutralized to pH 7 using HCl solution. The product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound that was used for the next step without further purification. Yield: 0.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][O:11][CH3:12])[CH:4]=1.C([Li])CCC.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1Br.C(Cl)(Cl)Cl>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[N+:27]([C:25]1[CH:24]=[CH:23][C:22]([C:4]2[C:5]([O:9][CH2:10][O:11][CH3:12])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[C:21]([CH:26]=1)[C:20]([O:19][CH3:18])=[O:31])([O-:29])=[O:28]
Reactant: COCOc1cccc(OC)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COCOc1cccc(OC)c1-c1ccc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-methoxy-3-methoxymethoxy benzene (3.62 g., 21.55 mmole), prepared as described in J. Med. Chem. 1995, 38, 1437-1445, in THF (15 mL) at −30° C. was treated with n-butyllithium (8.28 ml. of 2.5M in hexane, 20.69 mmole), stirred for 1 hour at 25° C., cooled to 0° C., treated with anhydrous zinc chloride beads (3.5 g, 25.67 mmole), stirred for 2 hours at 25° C., treated with a solution of methyl-2-bromo-5-nitrobenzoate (5.0 g, 19.23 mmol) in THF (20 mL) and bis(triphenylphosphine)palladium dichloride (600 mg), stirred it 65° C. for 15 hours, cooled, and treated with chloroform and aqueous KHCO3. The precipitated zinc salts were filtered, and the water layer was removed, and the organic layer dried over (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 8% ethyl acetate in dichloromethane to provide the desired product. MS (ESI(−)Q1MS) m/z 346 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28](=O)[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:29])[CH2:27][C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc([N+](=O)[O-])c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 2,2-dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one (Example J12) according to the general procedure K. Obtained as a light yellow solid (1.01 g).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22](OCC)=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1C=CC=CC=1>[C:1]1([NH:7][C:8]2([CH2:22][OH:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: OCC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred and gently refluxing solution of 43 parts of ethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate in 288 parts of dry benzene is added dropwise a solution of 33.9 parts of sodium dihydro-bis(2-methoxyethoxy)aluminate 70% in 72 parts of dry benzene without heating. Upon completion, stirring is continued for 3 hours at reflux. The reaction mixture is allowed to cool to room temperature overnight and poured onto 1000 parts of ice-water. The resulting emulsion is decomposed by the addition of a concentrated sodium hydroxide solution. The organic layer is separated and filtered over hyflo. The filter-cake is washed thoroughly with benzene. The filtrate is dried, filtered and evaporated. The residue is crystallized from 385 parts of 2,2'-oxybispropane. The crude solid product is filtered off and recrystallized from 2-propanol, yielding 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinemethanol; mp. 96.7° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[C:8]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)=[N:7][O:6][CH:5]=2)[CH3:2].[N+](=[CH2:17])=[N-]>CCOCC>[CH2:1]([C:3]1[C:4]2[C:8]([C:9]([CH3:17])=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)=[N:7][O:6][CH:5]=2)[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCc1cc([N+](=O)[O-])cc2nocc12
Solvent: CCOCC
Product: CCc1cc([N+](=O)[O-])c(C)c2nocc12
Reaction time: 16 h

Procedure:
A solution of 4-ethyl-6-nitro-anthranil, (1.5 gm, 0.0577 mol.) in anhydrous ether (50 ml) was mixed with an ethereal solution of diazomethane (100 ml, conc. 1 gm CH2N2 /80 ml) and stirred for 16 hrs. The excess diazomethane was removed by pouring the reaction mixture over a short column of silica gel and eluting the column with ether. The ethereal solution was evaporated to give a yellow solid and this solid was purified by column chromatography (40% methylene chloride: pet. ether 30-60) to yield 4-ethyl-7-methyl-6-nitro-anthranil as a solid. The solid was recrystallized from 10% ether: pet ether 30-60, Yield: 1.145 gm. mp. 68°-69° C., IR (CHCl3): 2980, 1625, 1550, 1460 cm-1. H-NMR (CDCl3): 1.40 (t, 3H, CH3), 2.80 (s, 3H, CH3), 2.90 (q, 1H, CH2), 7.30 (br. s, 1H, H5), 9.30 (s, 1H, H3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol), dry pyridine (3 mL), and benzoyl chloride (35 μL, 0.3 mmol) were mixed, and the mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (methanol/chloroform=1/10) to give the title compound (36 mg, yield 91%) as white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1.[C:11]1([C:17]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:3]=1[N:10]=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:9]2
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1c(Br)ccc(Br)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1ccc(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc12

Procedure:
A solution of 5.3 g (20 mmol) of 3,6-dibromo-1,2-phenylenediamine 1,4 g (19 mmol) of benzil 2b, 4.2 g of sodium acetate and 150 ml of glacial acetic acid were refluxed for 4 hours. The precipitate was filtered off, washed with 100 ml of water and recrystallized twice from dioxane. Drying under reduced pressure at 50° C. gave the pure product in the form of colorless crystals, which according to HPLC had a purity of about 99.5%. The yield was 6.45 g (73%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(N2CCC(O)CC2)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (LXV) (5.0 g, 31.5 mmol) in DMF (50 mL) was added piperidin-4-ol (LXXXIX) (3.5 g, 34.65 mmol) and K2CO3 (8.7 g, 63.0 mmol). The reaction was headed at 85° C. overnight. The solution was poured into ice water, stirred for 15 min and then filtered. The solid was washed with cold water and dried under vacuum to produce 1-(5-aminopyridin-2-yl)piperidin-4-ol (XC) as a yellow solid (6.62 g, 29.67 mmol, 94.2% yield). 1H NMR (DMSO-d6) δ ppm 1.34-1.42 (m, 2H), 1.77-1.83 (m, 2H), 3.40-3.56 (m, 2H), 3.76-3.83 (m, 1H), 4.12 (brd, 2H), 4.81 (d, J=4 Hz, 1H), 6.94 (d, J=10 Hz, 1H), 8.17 (dd, J=10 Hz, J=3 Hz, 1H), 8.94 (d, J=3 Hz, 1H); ESIMS found for C10H13N3O3 m/z 224.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[N:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][Br:28])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cn1
Yield: 50.8 %

Procedure:
A mixture of 6-cyano-3-picoline (1.32 g, 11.19 mmol), benzoylperoxide (0.54 g, 2.24 mmol), and N-bromosuccinimide (2.8 g, 15.7 mmol) in carbontetrachloride (30 mL) was heated at reflux for 2 h. The resulting suspension was filtered and the filtrate diluted with dichloromethane (400 mL), washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:n-hexane, 1:9) to give the title compound as a yellow oil (1.12 g, 51%).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])C.Cl>C1COCC1.CCO.[Li+].[OH-]>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH:6]([CH3:16])[CH2:5][C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)CC(C)Cc1ccccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccccc1CC(C)CC(=O)O

Procedure:
A solution of 4-(2-methoxyphenyl)-3-methyl-butyric acid ethyl ester (24 mmol, crude from previous reaction) in THF (50 mL), EtOH (50 mL) and LiOH (1 M, 50 mL) was stirred at room temperature overnight. The reaction was acidified with 1 M HCl, and extracted with EtOAc. The combined extracts were washed with brine and dried over sodium sulfate. Concentration gave the desired product, which was used without further purification. LCMS-ESI+ (m/z): [M]+ calcd for C12H16O3: 208.11. Found: 208.86
Reaction SMILES: N1CCCCC1.C=O.[F:9][CH:10]([F:28])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH2:20])=[CH:14][CH:13]=1.O.[NH2:30][NH2:31]>C(O)C.CO.C(O)(=O)C>[F:9][CH:10]([F:28])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:20][NH:31][N:30]=2)=[CH:14][CH:13]=1
Reactant: NN
Reactant: C=C(C(=O)c1ccc(OC(F)F)cc1)c1ccccc1
Agent: C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: FC(F)Oc1ccc(C2=NNCC2c2ccccc2)cc1

Procedure:
17.5 g. of crude Compound No. 10 obtained by Example 3 was added to a mixture comprising 0.9 ml. of piperidine, 0.9 ml. of acetic acid, 25 ml. of 37% formaline and 180 ml. of methyl alcohol, and the mixture was refluxed and reacted for 3 hours. The reaction mixture was concentrated under reduced pressure, and then 150 ml. of water and 200 ml. of chloroform were added thereto for liquid phase separation, whereupon an organic phase was obtained. The organic phase was dried over anhydrous sodium sulfate and chloroform was distilled off to obtain 18.0 g. of 4'-difluoromethoxy-2-phenylacrylophenone (ND20 :1.5819). Then, 17.5 g. of this product and 8 ml. of hydrazine hydrate were refluxed in ethyl alcohol for reaction for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and 80 ml. of water and 100 ml. of chloroform were added, whereupon an organic phase was obtained. After drying the organic phase over anhydrous sodium sulfate, chloroform was distilled off, whereupon 17.5 g. of 3-(4-difluoromethoxyphenyl)-4-phenyl-2-pyrazoline (melting point: 65°-75° C.) was obtained. Then, 5.8 g. of the compound thus obtained and 3.1 g. of 4-chlorophenylisocyanate were added to dried ethyl ether and reacted for 6 hours under reflux. After cooling the reaction mixture, precipitated crystals were collected by filtration, whereby 5.3 g. of the product was obtained. This product was confirmed by the NMR spectrum to be 1-(4-chlorophenyl-carbamoyl)-3-(4-difluoromethoxyphenyl)-4-phenyl-2-pyrazoline. (Melting point: 147.0°-148.0° C.).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:36][CH:35]=1
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Br-]
Product: O=C(O)CCCCCCCCCCc1ccc(Cl)cc1

Procedure:
By the similar procedure of synthesis of B10, compound B2 (2.20 g, 4.28 mmol) and 4-chlorobenzaldehyde (401 mg, 2.85 mmole) were used as starting materials to afford B17 (526 mg, 1.77 mmol, 62%). mp: 93° C. 1H-NMR (CDCl3, 400 MHz) δ 7.21 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.33 (t, J=7.5 Hz, 2H), 1.53-1.63 (m, 4H), 1.26 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 179.90, 141.28, 131.21, 129.71, 128.27, 35.26, 34.00, 31.35, 29.69, 29.44, 29.39, 29.36, 29.19, 29.13, 29.01, 24.64. HRMS (ESI) calculated for C17H25ClO2Na [M+Na]+: 319.1441, found: 319.1435.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:2]=1.[C@@H:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH:25][C@@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)[CH:2]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Product: c1cncc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)c1

Procedure:
4-(3-Pyridinyl)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)CCC>[N:26]1([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH:3]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Solvent: CCCCO
Product: FC(F)(F)Oc1ccc(Nc2cc(N3CCOCC3)nc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of compound (6-chloro-2-phenyl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (39 g, 106 mmol) and morpholine (28 mL, 319 mmol) in n-butanol (400 mL) was refluxed for 24 hours under nitrogen atmosphere. Then the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The crude compound was passed through the silica gel by using 20% ethylacetate in petroleum ether to afford the compound (6-morpholin-4-yl-2-phenyl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (35.5 g, 80%) as off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[F:16]>CC(O)=O.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[F:16]
Reactant: Fc1cc(C(Cl)c2ccccn2)ccc1Br
Agent: [Zn]
Solvent: CC(=O)O
Product: Fc1cc(Cc2ccccn2)ccc1Br

Procedure:
To a solution of 2-[(4-bromo-3-fluoro-phenyl)-chloro-methyl]-pyridine (as described in Step C above) (0.29 g, 0.965 mmol) in HOAc (10 mL) was added zinc powder (0.315 g, 4.82 mmol) and the mixture was refluxed for 1 hr. The HOAc was removed in vacuo and the residue was partitioned with EtOAc and saturated NaHCO3. The EtOAc was washed with H2O, brine, dried with MgSO4, and evaporated in vacuo to obtain the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](O)=[N:6][CH:7]=1.P(Br)(Br)[Br:11]>>[Cl:9][C:4]1[C:5]([Br:11])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: Oc1ncc(Br)cc1Cl
Product: Clc1cc(Br)cnc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
36.0 g (172.7 mmol) of 5-bromo-3-chloro-2-hydroxypyridine are stirred at 160° C. for 6 hours in 320 ml of phosphorus tribromide. The reaction mixture is cooled to room temperature and poured carefully into ice water. After 2 hours, the mixture is extracted three times with 500 ml of dichloromethane in each case. The combined organic phases are washed with sodium bicarbonate solution until neutral, dried over Na2SO4 and filtered, and the filtrate is evaporated to dryness. Chromatographic purification (silica gel/dichloromethane) gives 20.53 g of 3-chloro-2,5-dibromopyridine. ##STR14## m.p.: 40°-41° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[S:15])[N:7]([CH3:14])[CH2:8][CH:9]([CH2:11][CH2:12]Cl)[O:10][C:4]=2[CH:3]=1.[CH3:18][NH:19][CH3:20]>C(O)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[S:15])[N:7]([CH3:14])[CH2:8][CH:9]([CH2:11][CH2:12][N:19]([CH3:20])[CH3:18])[O:10][C:4]=2[CH:3]=1
Reactant: CNC
Reactant: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=S
Agent: Cl
Solvent: CCO
Product: CN(C)CCC1CN(C)C(=S)c2ccc(Cl)cc2O1

Procedure:
A solution of 9.8 g (0.04 mole) of 8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione in 50 ml of absolute ethanol and 10 ml of a 40% aqueous solution of dimethylamine were mixed and heated in a steel bomb at 100° C. for 16 hr. The ethanol was evaporated under reduced pressure and the residue dissolved in chloroform and partitioned with 10% sodium hydroxide solution. The chloroform layer was evaporated under reduced pressure to give an amorphous solid. The solid was dissolved in 6N hydrochloric acid and the solution washed with ethyl acetate. The aqueous layer was basified with 50% sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was evaporated under reduced pressure to give a viscous oil comprised substantially of the free base of the title compound which was dissolved in absolute ethanol and reacted with ethereal hydrogen chloride. The hydrochloride salt was recrystallized from ethanol to give 30 g (25%) product, m.p. 196°-199° C.
Reaction SMILES: [CH3:1][N:2]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10](=[O:19])[C:4]([C:5]([O:7]CC)=[O:6])=[C:3]1[CH2:20][CH2:21][CH3:22].CO.O>[OH-].[Na+]>[CH3:1][N:2]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10](=[O:19])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(C(=O)OCC)c(=O)cc(-c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(C(=O)O)c(=O)cc(-c2ccccc2)n1C
Temperature: 85 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
4.5 g (0.015 mol) of ethyl 1-methyl-6-phenyl-2-propyl-4-oxonicotinate is suspended in 60 g of 5% sodium hydroxide in a 1:1 mixture of methanol and water. The mixture is heated at 85° C. and stirred for 21/2 hrs. The solution formed is acidified and the suspension formed is vacuum filtered. The filter cake is dried to afford 2.7 g of 1-methyl-6-phenyl-2-propyl-4-oxonicotinic acid, mp 150° C. (MDC/ether). An additional 0.5 g of 1-methyl-6-phenyl-2-propyl-4-oxonicotinic acid is obtained by extraction of the xylene solution with 30 ml of 1% sodium hydroxide and acidification of the basic extract.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[Br:12].[F:13][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([F:13])=[CH:4][C:3]=1[Br:12]
Reactant: COC(=O)c1ccc(Br)c(N)n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COC(=O)c1nc(N)c(Br)cc1F

Procedure:
A mixture of methyl 6-amino-5-bromopyridine-2-carboxylate (19.8 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (34.3 g) in acetonitrile (340 mL) under argon was heated to 40° C. for 1 hour, 60° C. for 1 hour and then 80° C. overnight. After partitioning between EtOAc and water (500 mL each) the aqueous fraction was re-extracted with EtOAc (300 mL) and the combined organic solution dried with MgSO4 and evaporated. Chromatography (20% then 30% EtOAc in hexane) separated various byproducts from the required ester (2.09 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(F)c(N)cc1Br
Temperature: 0 °C
Yield: 31.9 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0 g) in ethanol (300 mL) was added SnCl2.2H2O (51.8 g, 0.230 mol) at room temperature. The mixture was heated at reflux for 3 h. The solvent was evaporated under reduced pressure to give a residue, which was poured into ice water. The aqueous phase was basified with sat. NaHCO3 to pH 7. The solid was filtered off and the filtrate was extracted with dichloromethane (200 mL×3). The combined organics were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=10/1) to afford 5-bromo-2-fluoro-4-methylaniline (5.0 g, 30% yield for two steps). 1NMR (400 MHz, CDCl3) δ 6.96 (d, J=8.8 Hz, 1H), 6.86 (d, J=11.6 Hz, 1H), 3.64 (br, 2H), 2.26 (s, 3H). MS (ESI) m/z (M+H+) 204.0.