Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:12]=2)C=CC=CC=1>[Pd].C1COCC1.C(OCC)(=O)C>[CH2:29]([O:28][C:13]1[CH:12]=[C:11]([NH2:10])[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OCc2ccccc2)cc(OCCCOc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCCCOc2ccccc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.6 %

Procedure:
A mixture of 10.9 g of 3-(octadecyloxy)-5-(3-phenoxypropoxy)phenylcarbamic acid phenylmethyl ester and 1.2 g of 10% palladium on carbon in 200 ml of THF and 50 ml of ethyl acetate was stirred under a hydrogen atmosphere at room temperature for 17 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was recrystallized from ethyl acetate-hexane to give 8.0 g (92% yield, mp 74°-76°) of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzenamine. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[H-].[Na+].[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][Br:23])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Reactant: BrCCOCCOCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ccc(OCCOCCOCCOCCBr)c(C(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.1 %

Procedure:
Under an argon atmosphere, 2 g of [(8-acetyl-7-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester was added to a suspension of 0.32 g of 60% sodium hydride in 30 ml of anhydrous dimethylformamide. The mixture was stirred at room temperature for 40 minutes and then 11.6 g of bis[2-[2-bromoethoxy)ethyl]ether was added and the mixture was stirred at room temperature for 20 hours. The resulting dark mixture was concentrated in vacuo to an oil which was dissolved in methylene chloride, washed with water and concentrated to give an oil. Purification by high pressure liquid chromatography (35% ethyl acetate-toluene) gave 3.0 g (80%) of [[8-acetyl-7-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[S:21])[CH2:14][CH2:13]1.ClC(Cl)Cl.BrBr.[OH-].[Na+]>ClC(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]2[S:21][C:24]3[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:23]=3[N:22]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(NC(=S)NCC2CCN(CC3COc4ccccc4O3)CC2)cc1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2nc(NCC3CCN(CC4COc5ccccc5O4)CC3)sc2c1
Yield: 21 %

Procedure:
To a stirred mixture of 8.3 parts of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea, 60 parts of trichloromethane and 240 parts of tetrachloromethane were added at once 3.1 parts of bromine. The whole was stirred and refluxed for 1 hour. After cooling, the reaction mixture was treated with a sodium hydroxide solution. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.7 parts (21.0%) of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-6-methoxy-2-benzothiazolamine; mp. 134.7° C. (compound 68).
Reaction SMILES: [CH3:1][N:2]1[C:6](SC)=[C:5]([N+:9]([O-:11])=[O:10])[S:4][C:3]1=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][N:15]=1>C(O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]([C:6]2[N:2]([CH3:1])[C:3](=[O:12])[S:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH3:22])=[CH:16][N:15]=1
Reactant: CNCc1ccc(Cl)nc1
Reactant: CSc1c([N+](=O)[O-])sc(=O)n1C
Solvent: CCO
Product: CN(Cc1ccc(Cl)nc1)c1c([N+](=O)[O-])sc(=O)n1C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A mixture consisting of 3-methyl-4-methylthio-5-nitro-2-thiazolone (1.0 g), N-(2-chloro-5-pyridylmethyl)-N-methylamine (0.9 g) and ethanol (30 ml) was heat-refluxed for five hours and then cooled to room temperature to obtain the desired 4-[N-(2-chloro-5-pyridylmethyl)-N-methylamino]-3-methyl-5-nitro-2-thiazolone (1.4 g) having a melting point in the range from 147° to 148° C. in a crystal form.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[C:15]([C:26]([F:29])([F:28])[F:27])[CH:14]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CCO.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[C:15]([C:26]([F:29])([F:28])[F:27])[CH:14]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C)cc3ccccc23)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)c(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
The saponification procedure described in Example 1 (Step 10) was followed. Ethyl (2E)-3-[4-[(3-methyl-2-phenyl-1-naphthalenyl)oxy]-2-(trifluoromethyl)phenyl]-2-propenoate (241) (0.070 g, 0.147 mmol) was dissolved in 1:1 THF:EtOH (6 mL). To the above mixture was added 1 N NaOH (1 mL, excess) at room temperature followed by heating at 70° C., with stirring, for 30 min. The reaction mixture was cooled at RT, subjected to standard work up and purification to afford 0.065 g (99%) of the title compound (242) as a white foam. IR (film) 3058, 1693, 1606, 1491, 1313, 1165, 1128 cm−1. 19F NMR (282.2 MHz, CD3OD): δ −60.98. 1H NMR (400 MHz, CD3OD): δ 7.91 (br d, J=8.0 Hz, 1H), 7.84 (d, J=16.0 Hz, 1H), 7.79 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.52 (dd, J1=7.2 Hz, J2=7.2 Hz, 1H), 7.43 (dd, J1=7.6 Hz, J2=7.6 Hz, 1H), 7.28 (m, 3H), 7.15 (br s, 1H), 7.14 (s, 1H), 6.90 (s, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.33 (d, J=16.0 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=O)=[CH:4][CH:3]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[BH4-].[Na+].CO>CC(O)C>[CH:27]1([NH:30][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: Cc1cc(Nc2nc(C(NC3CC3)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 140 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (100 mg, 0.28 mmol) in 2-propanol (3 mL) were added cyclopropylamine (0.1 mL) and 3A (8-12 mesh) molecular sieves, and the mixture was heated at 140° C. in a Biotage microwave reactor. Additional cyclopropylamine (0.15 mL) was added and the mixture in a sealed vial was heated conventionally at 90° C. for 4 d. Then a suspension of sodium borohydride (140 mg) in 2-propanol was added dropwise and the mixture was stirred at rt for 1 h. Then MeOH (0.1 mL), sodium borohydride (100 mg), and more MeOH (2 mL) were added, and the mixture was filtered and the filtrate was concentrated. To the residue were added THF (5 mL), MeOH (2 mL) and sodium borohydride (100 mg) and the mixture was stirred for 1 h at rt. AcOH (0.4 mL) was then added and the mixture was concentrated. DMSO (3 mL) was added and the mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O) followed by further purification by preparative HPLC (Phenomonex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O) to afford 2-((cyclopropylamino)(4-fluorophenyl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (5.5 mg, 9%). 1H NMR (300 MHz, DMSO-d6) δ 0.34 (m, 4 H) 1.24 (m, 1H) 2.03 (m, 1H) 2.26 (s, 3H) 4.91 (s, 1H) 6.41 (m, 1H) 7.11 (t, 2H) 7.4-7.6 (m, 3H) 7.76 (m, 2H) 8.56 (d, 1H) 10.38 (bs, 1H) 12.15 (bs, 1H); LC-MS (ESI) m/z 389 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[C:24]1(C)C=CC=C[CH:25]=1>C(O)C>[CH2:24]([O:2][C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:6][CH:5]=1)=[O:3])[CH3:25]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(-c2n[nH]c3ccccc23)o1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2n[nH]c3ccccc23)o1
Yield: 60 %

Procedure:
1.75 g (7.7 mmol) of 3-(5-carboxy-2-furyl)indazole together with 2.5 ml of concentrated sulfuric acid in 60 ml of toluene and 20 ml of ethanol were heated on a water separator. Customary work-up gave 1.2 g (60%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]#[N:19]>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:18]#[N:19]
Reactant: N#CCc1ccccc1Cl
Reactant: ClCCN1CCCCC1
Product: N#CC(CCN1CCCCC1)c1ccccc1Cl

Procedure:
The present invention relates to a novel process for the preparation of N-heterocyclealkanamide derivatives having the following formula: ##STR1## which comprises reacting 1-(2-chloroethyl)piperidine with 2-chlorobenzeneacetonitrile to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; alkylating the piperidenebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)piperidine-1-butanenitrile; hydrolyzing the resulting alkylated piperidinebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)piperidine-1-butanenitrile; reacting the resulting piperidinebutanenitrile with isopropylamine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)imino]ethyl]piperidine-1-butanenitrile; reducing the resulting imine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)amino]ethyl]-piperidine-1-butanenitrile; acetylating the resulting amine to form (±)-N-[3-(2-chlorophenyl)-3-cyano-5-(1-piperidinyl)pentyl]-N-(1-methylethyl)acetamide; hydrolyzing the resulting acetylated amino substituted piperidine butanenitrile to form (±)-α-[2-[acetyl(1-methylethyl)amino]ethyl]-α-(2-chlorophenyl)-1-piperidinebutanamide; and isolating the resulting piperidinebutanamide.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.S(O[CH2:22][CH2:23][O:24][C@H:25]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@:31]3([OH:49])[CH2:32][CH2:33][C@@H:34]2[C:44]2[CH:48]=[CH:47][O:46][CH:45]=2)[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[N:6]1([CH2:5][CH2:4][O:3][CH2:22][CH2:23][O:24][C@H:25]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]4[C@@H:39]3[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@:31]4([OH:49])[CH2:32][CH2:33][C@@H:34]3[C:44]3[CH:48]=[CH:47][O:46][CH:45]=3)[CH2:26]2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H](OCCOCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 86.7 %

Procedure:
To a suspension of 0.13 g of NaH (60% dispersion in mineral oil) in 15 ml of anhydrous dimethylformamide, 0.37 g of 1-(2-hydroxyethyl)pyrrolidine were added at room temperature in a nitrogen atmosphere. The mixture was kept at reflux for 2 hrs, then 0.90 g of 3β-(2-tosyloxy-ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as an intermediate in Ex. 7, were added. The mixture was kept at reflux temperature for 4 hrs; then 50 ml of water were added cautiously. The residue was extracted with methylene chloride, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using acetone/methanol 85/15 as eluant to give 0.70 g of the title compound (I-ah) as a light yellow solid.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+].O.Cl>O1CCCC1>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCN(C(=O)c2ccc(-c3ccccc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 50 °C
Yield: 85.5 %

Procedure:
A stirred mixture of methyl 1-(biphenyl-4-ylcarbonyl)piperidine-4-carboxylate (0.10 g, 0.31 mmol), sodium hydroxide (25 mg, 0.62 mmol), water (4 mL) and tetrahydrofuran (1 mL) is heated at 50° C. for 3 h. Solvents are removed under reduced pressure giving a residue. The residue is redissolved 1M aqueous HCl (4 mL) and extracted with EtOAc (3×4 mL). The organic layers are combined, dried (Na2SO4), filtered and concentrated under reduced pressure to give 82 mg (93%) of 1-(biphenyl-4-ylcarbonyl)piperidine-4-carboxylic acid. m/z=310 [M++H].
Reaction SMILES: C(O)(=O)C.O=[C:6]1[CH2:23][CH2:22][C: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)[CH2:8][CH2:7]1.[N:24]1[CH:25]=[N:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=12.[Na]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:24]1[CH:25]=[N:26][N:27]2[CH2:32][CH2:31][N:30]([CH:6]3[CH2:23][CH2:22][C:9]4([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]4)[CH2:8][CH2:7]3)[CH2:29][C:28]=12
Reactant: c1nc2n(n1)CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCn4ncnc4C3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Acetic acid (2.34 eq.) was added to a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.122 mmol, 1 eq.) and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (1.14 eq.) in methylene chloride (7 ml). Sodium triacetoxyborhydride (1.4 eq) was then added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and sat. NaHCO3 solution. The aqueous phase was washed with methylene chloride (2×20 ml), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica, ethyl acetate/ethanol 10:1) to obtain the desired product. Yield: 62%
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>>[F:19][C:20]1[CH:21]=[C:22]([NH:23][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(F)c1
Yield: 60.2 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 400 mg of 3,4-difluoroaniline in place of the 2,4-difluoroaniline. 210 mg of N-(3,4-difluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:18])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].[Li+].[OH-]>C1COCC1.O>[O:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:19])=[O:2])=[O:7])[C:9]1=[O:18]
Reactant: COC(=O)CNC(=O)c1cc2ccccc2oc1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)c1cc2ccccc2oc1=O
Temperature: 25 °C

Procedure:
A solution of coumarin-3-carbonylamino-acetic acid methyl ester (312 mg, 1.19 mmol), in THF (12 ml) under Ar atmosphere, at 0° C. (ice bath), a solution of LiOH in H2O (0.2 M) was added dropwise. The reaction mixture was stirred vigorously at room temperature until total conversion was observed by TLC (2 hours). The solution was partially concentrated and Et2O was added (10 ml). The organic layer was washed with NaHCO3 (10 ml, sat) and the combined aqueous layers were acidified with boo KHSO4 (pH=3-4) and extracted with ether (3×20 ml). The organic layer was concentrated at reduced pressure to afford 8G9C1 (280 mg, 95%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Se](=O)=[O:10]>O1CCOCC1>[Br:1][C:2]1[C:3]([CH:8]=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1Br
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ncccc1Br
Yield: 28.9 %

Procedure:
To a solution of 3-bromo-2-picoline (prepared as described by Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann, T. N.; Christensen, B. G. J. Med. Chem. 1987, 30, 871–880) (249 mg, 1.45 mmol) in dioxane (2 mL) was added selenium(IV) oxide (212 mg, 1.91 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ether, 3:1) to afford the title compound (78 mg, 29%) as a pale yellow solid. 1H NMR (CDCl3): δ 7.38 (dd, 1H, J=9, 6 Hz), 8.05 (d, 1H, J=9 Hz), 8.76 (d, 1H, J=3 Hz), 10.25 (s, 1H).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][Mg]Br>>[Br:9][C:10]1[CH:11]=[C:12]([CH2:13][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[OH:8])[CH:16]=[CH:17][CH:18]=1
Reactant: O=CC1CCCCC1
Reactant: Br[Mg]Cc1cccc(Br)c1
Product: OC(Cc1cccc(Br)c1)C1CCCCC1

Procedure:
Grignard reaction between cyclohexanecarbaldehyde and 3-bromobenzyl magnesium bromide (0.25M in ether) gave 2-(3-bromophenyl)-1-cyclohexylethanol as a white solid. Yield (1.62 g, 23%): 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J=0.8 Hz, 1H), 7.34-7.31 (m, 1H), 7.20-7.17 (m, 2H), 4.37 (d, J=6.0 Hz, 1H), 3.38-3.32 (m, 1H), 2.69 (dd, J=13.6, 3.6 Hz, 1H), 2.51-2.45 (dd, obs., 1H), 1.78-1.60 (m, 5H), 1.24-0.94 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C1COCC1.CO.[Pt](=O)=O>[F:27][C:2]([F:1])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(C(F)(F)c4ccccc4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: O=S1(=O)CCN2CCCC(c3ccc(C(F)(F)c4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
Platinum(IV) oxide (14 mg) was added to a solution of 9-{4-[difluoro(phenyl)methyl]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (49 mg) in THF (dry) (10 mL) and MeOH (10 ml). The mixture was stirred at room temperature under hydrogen for 4 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (18.8 mg) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][OH:16].O>O1CCOCC1>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:15][OH:16])=[O:5]
Reactant: NO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(O)cc1O
Solvent: C1COCCO1
Solvent: O
Product: O=C(NO)c1cc([N+](=O)[O-])c(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dihydroxy-5-nitrobenzoyl chloride (17.0 g, 78.1 mmol) in dioxane (70 mL) is added to an ice cold solution of 50% aqueous hydroxylamine (35 mL) and water (35 mL). After the addition is complete, the ice bath is removed and the mixture is stirred at room temperature for 30 min. The resulting thick precipitate is filtered, washed once with 1:1 water/dioxane and dried to obtain 2,4,N-trihydroxy-5-nitrobenzamide. After standing in the refrigerator for 18 h, the 1:1 water/dioxane solution affords additional 2,4,N-trihydroxy-5-nitrobenzamide: (M+H)+=215.1.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=2[CH3:21])[C:8](=[O:22])[CH:7]=1.[Cl:28]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:28][C:7]1[C:8](=[O:22])[N:9]([C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=2[CH3:21])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Solvent: ClCCl
Product: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared by a procedure similar to the one described for Example 481, except that the product from Step 2, Example 481 was chlorinated instead of being brominated. The procedure is as follows: 4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methyl-pyridin-2(1H)-one (from Step 2, Example 481 above) (7.0 g, 18.8 mmol) was refluxed with N-chlorosuccinimide (2.5 g, 18.8 mmol) in 50 ml of CH2Cl2 overnight. The reaction was evaporated on a rotary evaporator and the resulting solid was stirred in MeOH. The precipitate was collected on a filter pad, washed with MeOH and dried in vacuo to yield a white solid (1.6 g, 21%). 1H NMR (300 MHz, DMF-d7) δ 7.85 (app q, J=6.44 Hz, 1H), 7.43 (d, J=0.81, 1H), 7.42-7.23 (m, 3H), 6.84 (s, 1H), 5.48 (s, 2H), 4.67 (s, 2H), 2.05 (s, 3H), 2.03 (s, 3H); ES-MS m/z 406 (M+H). ES-HRMS m/z 406.1033 (M+H calcd for C21H16ClF2NO4 requires 406.1016).