Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:14][N:13]([C:15]3[N:16]4[C:20]([N:21]=[C:22]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C:23]=35)=[CH:19][CH:18]=[N:17]4)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH:11]2[CH2:12][N:13]([C:15]3[N:16]4[C:20]([N:21]=[C:22]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C:23]=35)=[CH:19][CH:18]=[N:17]4)[CH2:14]2)[OH:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 200 mg (0.53 mmol) (4-methoxy-phenyl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone in 3 mL MeOH was added 20 mg (0.53 mmol) sodium borohydride and the mixture was stirred at room temperature for 30 minutes. 1 mL saturated brine was added and the mixture extracted with DCM (2×5 mL), the organic layers were combined and dried over sodium sulphate. After filtration the solvent was evaporated to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]2=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:29]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:11](=[O:28])[N:12]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]2=[O:21]
Reactant: CCOC(=O)Cn1c(=O)c2cc(C)ccc2n(Cc2ccc(Cl)c(Cl)c2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cn1c(=O)c2cc(CBr)ccc2n(Cc2ccc(Cl)c(Cl)c2)c1=O
Yield: 48.1 %

Procedure:
In 30 ml of carbon tetrachloride were refluxed 3.5 g of ethyl 1-(3,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-6-methyl-3(2H)-quinazolineacetate, 1.66 g of N-bromosuccinimide and calalytic amount of benzoyl peroxide for 2 hours. The insolubles were filtered off and the filtrate was concentrated. Ether was added to the residue for crystallization and the crystals thus obtained were recrystallized from acetonitrile to obtain 2.0 g of ethyl 6-bromomethyl-1 -(3,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-3(2H)-quinazolineacetate. m.p. 128°-129° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][N:18]([CH2:31][CH3:32])[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20].[H-].[Na+].CCCCCC.C(OCC)(=O)C>CN(C=O)C>[CH:10]1[C:11]2[N:12]([CH2:15][CH2:16][CH2:17][N:18]([CH2:31][CH3:32])[S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:20])=[O:21])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCN(CCCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCN(CCCn1c2ccccc2c2ccccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 61.3 %

Procedure:
Carbazole (4.15 g, 24.8 mmol) and bromide 64 (9.7 g, 27.6 mmol) were dissolved in DMF (30 mL). NaH (2.0 g, 50.0 mmol, 2 eq) was added in portions, whereupon the temperature rose to 60° C. The reaction mixture was stirred for 1 h (TLC monitoring, hexane/ethyl acetate 3:2), poured into ice/water mixture, and extracted with ethyl acetate. The residue was triturated with ether. The yellow precipitate was filtered off and dried to afford 6.65 g (61%) of the product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:8].[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[Cl:9][C:6]1[C:7]([NH2:8])=[C:2]([NH:13][CH:10]2[CH2:12][CH2:11]2)[N:3]=[N:4][CH:5]=1
Reactant: Nc1c(Cl)cnnc1Cl
Reactant: NC1CC1
Product: Nc1c(Cl)cnnc1NC1CC1
Temperature: 120 °C
Yield: 73 %

Procedure:
3,5-Dichloro-4-aminopyridazine (5.12 g, 31.2 mmol) was added to cyclopropylamine (37.0 g, 650 mmol) in a stainless steel sealed container (100 mL capacity), to give a homogenous solution. The mixture was heated for 12 hours at 120° C. The reaction mixture was cooled to room temperature then evaporated in vacuo. The residue was dissolved in EtOAc (150 mL) with sonication and stirring. The EtOAc solution was washed with 10% aqueous potassium carbonate solution (2×200 mL), dried over anhydrous MgSO4, then filtered and evaporated in vacuo. The mixture was redissolved in CH2Cl2 and purified using silica gel column chromatography eluting with CH2Cl2 (100 mL), then EtOAc (150 mL) to give the title compound as a light orange solid in 73% yield, 4.2 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:10]2)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)[C:42]2C=CC=C[C:43]=2[C:48]2C=CC=C[C:49]=2[N:54](C)[CH3:55])CCCCC1.C(NC)CCC.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:49]([N:54]([CH3:55])[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:10]2)=[CH:4][CH:3]=1)[CH2:48][CH2:43][CH3:42]
Reactant: O=C(N[C@@H]1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccc(OC(F)(F)F)cc1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: CCCCNC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCN(C)c1ccc(C(c2ccc(Cl)cc2)N2CC[C@@H](NC(=O)c3ccc(OC(F)(F)F)cc3)C2)cc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
A mixture of the compound obtained in Example 1 (50 mg), tris(dibenzylideneacetone)dipalladium (0.9 mg), 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (1.5 mg), n-butylmethylamine (29 μL) and 1.0M lithium bis(trimethylsilyl)amide/tetrahydrofuran (0.35 mL) was stirred at 110° C. for 10 minutes by using Microwave Synthetic System (Discover; CEM Ltd.). The reaction mixture was diluted with ethyl acetate and thereto was added water. The organic layer was separated and evaporated in vacuo. The residue was purified by HPLC (XTerra Prep MS C18 column; Waters Inc., solvent; water/methanol=1:1→5:95), dissolved in tert-buthanol and lyophilized to give (3R)-1-[[4-(n-butylmethylamino)phenyl](4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (12.6 mg, yield: 23%; compound a) and (3R)-1-[bis-[4-(n-butylmethylamino)phenyl]methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (18.0 mg, yield: 30%; compound b) as a powder, respectively.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([F:12])=[CH:6][C:3]=1[CH2:4]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:24]([N:26](CC)CC)C.[C-]#N.[Na+]>ClCCl.O.CS(C)=O>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([F:12])=[CH:6][C:3]=1[CH2:4][C:24]#[N:26]
Reactant: COc1cc(F)cc(CO)c1F
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(F)cc(CC#N)c1F
Reaction time: 3.5 h
Yield: 68.1 %

Procedure:
To a stirred solution of 2,5-difluoro-3-methoxybenzyl alcohol (8.26 g, 47.4 mmol) in dichloromethane (100 ml) was added p-toluenesulfonyl chloride (9.95 g, 52.2 mmol) and triethylamine (7.30 ml, 52.2 mmol) at room temperature. After 3.5 hr, the mixture was poured into water (200 ml) and extracted with ether (200 ml). The extract was washed with brine (200 ml), dried (magnesium sulfate) and evaporated. To the residue was added DMSO (200 ml) and sodium cyanide (3.48 g, 71 mmol). The resulting mixture was stirred for 2 hr and then poured into water (200 ml) and extracted with ether (300 ml). The extract was washed with water (100 ml), brine (100 ml) and dried over magnesium sulfate. Removal of solvent gave 5.91 g (63%) of the titled compound as a red oil.
Reaction SMILES: [F:1][CH:2]([C:7]([O:9]C)=[O:8])[C:3]([O:5]C)=[O:4].C=O.FF.FC(C([O-])=O)[C:17]([O-])=[O:18].C1N2CN3CN(C2)CN1C3.O1COCOC1.C(=O)([O-])O.[K+].C(=O)([O-])O.[Na+]>>[OH:18][CH2:17][C:2]([F:1])([C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(F)C(=O)OC
Reactant: O=C([O-])C(F)C(=O)[O-]
Agent: C1N2CN3CN1CN(C2)C3
Agent: C1OCOCO1
Agent: C=O
Product: O=C(O)C(F)(CO)C(=O)O

Procedure:
In the first process step, dimethyl α-fluoromalonate is subjected to a hydroxymethylation with formaldehyde. (Dimethyl α-fluoromalonate is a known compound; see Journal of Fluorine Chemistry 25 (1984), 203-212.) The formaldehyde is preferably used in the form of an aqueous solution which has a formaldehyde content of 30 to 40 percent by weight. The formaldehyde is used in an amount of 1 to 10 moles, preferably 1.1 to 3 moles (based on 1 mole of dimethyl o,-fluoromalonate). Instead of formaldehyde, it is also possible to use paraformaldehyde, hexamethylenetetramine or 1,3,5-trioxane. It is advantageous to carry out the reaction in the presence of a basic catalyst which is then used in an amount of 2 to 50, preferably 5 to 15, mol % (based on dimethyl α-fluoromalonate). The catalyst used is in particular an alkali metal hydrogencarbonate, for example potassium hydrogencarbonate and sodium hydrogencarbonate. The reaction is carried out at a temperature of 5° to 40° C., preferably of 15 ° to 30° C. The resulting dimethyl ester of α-hydroxymethyl-α-fluoromalonic acid is then isolated out of the reaction mixture, preferably by salting out or extraction by means of a water-nonmiscible organic solvent. A suitable solvent is in particular an aliphatic chlorohydrocarbon having 1 to 4 carbon atoms, for example dichloromethane, trichloromethane, tetrarhloromethane, 1,1-dichloroethane, 1,2-dichloroethane. A combination of salting out and extraction is particularly advantageous; therein the reaction mixture has first added to it a saturated salt solution (ammonium sulfate, sodium chloride), and this mixture is then extracted. By evaporating the solvent, α-hydroxymethyl-α-fluoromalonic acid is obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][N:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([NH:11][CH2:12][CH3:13])=[O:10])=O>[OH-].[K+]>[C:14]([N:8]1[C:9](=[O:10])[N:11]([CH2:12][CH3:13])[C:5]([C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([Cl:1])[CH:3]=2)=[N:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCNC(=O)N(NC(=O)c1cccc(Cl)c1)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: CCn1c(-c2cccc(Cl)c2)nn(C(C)(C)C)c1=O
Temperature: 25 °C
Yield: 0 %

Procedure:
A solution of 1-(3-chloro-benzoyl)-2-t-butyl-4-ethyl semicarbazide (2.0 g, 0,067 mole) in 5% potassium hydroxide (40 mL) was refluxed for 20 hours, then cooled to room temperature and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried with sodium sulfate and filtered. The solvent was removed in vacuo to give a yellow liquid (1.2 g, 64% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].C(OC(C)C)(C)C>ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: COC(=O)Cc1ccc(Oc2ccc(N)cn2)cc1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: COC(=O)Cc1ccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[4-(5-aminopyridin-2-yloxy)phenyl]acetate (0.44 g, 1.7 mmol) in dichloromethane (7 mL) was added 3,4-dichlorophenylisocyanate (0.353 g, 1.9 mmol), and the resulting reaction solution was stirred for 1 hour at room temperature. To the reaction solution was added diisopropyl ether. Insoluble matter was removed by filtration, to thereby yield 0.60 g of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[O:38][CH3:39].[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:48](=[O:49])[CH2:47][N:44]3[C:45]([CH3:46])=[C:41]([Cl:40])[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43]3)[CH2:36][CH2:37]2)=[CH:28][C:27]=1[O:38][CH3:39]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-3-methoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.21 (d, 1H), 6.74 (s, 1H), 6.56 (d, 1H), 5.39 (s, 2H), 3.82 (s, 3H), 3.63 (m, 4H), 3.30 (m, 2H), 3.19 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=451.1, found 451.0.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31]1([N:41]=[C:42]=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>C(#N)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:42]([NH:41][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)=[O:43])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccc2ccccc12)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in acetonitrile (10 ml) were added triethylamine (0.089 ml, 0.64 mmol) and 1-naphthyl isocyanate (0.062 ml, 0.43 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (135 mg, 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>C(O)C.CO.[Cl-].[NH4+]>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH:9]=1
Reactant: COc1ccc(CNc2cc(F)cc(C=O)c2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Product: COc1ccc(CNc2cc(F)cc(CO)c2)cc1
Reaction time: 1 h
Yield: 39 %

Procedure:
3-Fluoro-5-(4-methoxy-benzylamino)-benzaldehyde (crude product) was dissolved in anhydrous ethanol (40 ml) and cooled in an ice bath. Sodium borohydride (800 mg, 21 mmol) was then added with stirring. After 1 hr., the mixture was diluted with methanol and excess ammonium chloride was added. After stirring for 1 hr. at room temperature, the mixture was evaporated in vacuo and coevaporated with methanol several times. The residue was purified by silica gel column chromatography (eluent, EA: hexane (from 1:4 to 1:1)) to afford 2.16 g (39%) of [3-fluoro-5-(4-methoxy-benzylamino)-phenyl]-methanol as a white solid. m.p. 93° C.
Reaction SMILES: [NH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[NH2:2].C(O)(=O)C.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:32])=[C:23]([C:25](=O)/[CH:26]=[CH:27]/N(C)C)[CH:24]=1>C(O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:32])=[C:23]([C:25]2[N:1]([CH:3]3[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]3)[N:2]=[CH:27][CH:26]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Reactant: CN(C)/C=C/C(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(Cl)ccc2O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Tert-butyl 3-hydrazinoazetidine-1-carboxylate, (Preparation 696, 88.37 g, 0.4247 mol) was dissloved in ethanol (883.7 mL) and the solution was cooled to 0° C. in an ice bath. Acetic acid (97.36 mL, 1.70 mol) was added followed by (2E)-1-(5-chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one, (Preparation 852, 95.86 g, 0.4247 mol) and the resulting slurry was allowed to warm to room temperature then stirred at room temperature for 2 days. The resulting suspension was cooled to 0° C. and the solid was filtered off, washed with cold ethanol (2×40 mL) and dried to give the title compound as a white granular solid, (83.23 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].C([Li])CCC.[P:15](Cl)([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1.CCCCCC>[CH2:1]([N:3]([CH2:8][CH3:9])[S:4]([CH2:7][P:15](=[O:16])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])(=[O:6])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCN(CC)S(C)(=O)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)N(CC)CC)OCC
Reaction time: 1.5 h

Procedure:
A solution of N,N diethyl methanesulfonamide (4.7 g) in tetrahydrofuran (50 ml) was stirred at 20° C and treated with butyllithium in hexane (2.6 N, 27.9 ml) and diethyl chlorophosphate (5.2 ml). The cooling bath was removed and the mixture was stirred for 1.5 hours and poured onto ice. The resulting mixture was saturated with sodium bicarbonate, extracted with methylene chloride and the organic phase was washed with water, dried with sodium sulfate and magnesium sulfate, filtered and concentrated in vacuo to give diethyl [[(diethylamino)sulfonyl]methyl]-phosphonate.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)=[CH:23][CH:22]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C1CCCc2cc(-c3ccc(Cl)cc3)ccc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 4-chlorophenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 257.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH:19]=1)[C:9]([O:11]CC1C=CC=CC=1)=[O:10]>O.C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH:19]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccccc1)c1cc(F)ccc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of lithium hydroxide (71.9 mg, 3.00 mmol) in water (12 ml) was added to a stirred solution of phenylmethyl 5-fluoro-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 19, 336 mg, 1 mmol) in THF (3 ml). The reaction mixture was stirred at room temperature overnight. The THF was removed, the mixture was adjusted to pH 7 with 2N HCl. The mixture was filtered and the residue was dried to yield the title compound as a white solid. 180 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.[S:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>O1CCCC1>[CH3:13][CH:12]([CH3:14])[CH2:11][O:10][C:9](=[O:15])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]2([OH:27])[CH2:25][CH2:26][S:21][CH2:22][CH2:23]2)=[CH:3][CH:4]=1
Reactant: CC(C)COC(=O)Nc1ccc(Br)cc1
Reactant: O=C1CCSCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1ccc(C2(O)CCSCC2)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-methylpropyl 4-bromophenylcarbamate (Step 1, 10.0 g, 36.7 mmol) in anhydrous tetrahydrofuran (184 mL) at −78° C. under N2 is treated n-butyllithium (1.6M in hexanes, 48.2 mL, 77.1 mmol) dropwise over 20 mins, and the mixture is stirred at −78° C. for 45 mins. The resulting slurry is then treated with a solution of tetrahydro-2H-thiopyran-4-one (4.48 g, 38.5 mmol) in anhydrous tetrahydrofuran (38 mL) dropwise over 5 mins to give an opaque mixture which is allowed to slowly warm to 0° C. with stirring over approximately 2.5 h. The mixture is then quenched by the slow addition of saturated aqueous ammonium chloride (75 mL), water (75 mL) is added, and the layers are separated. The organic phase is washed with water (50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the crude product is recrystallized from EtOAc/hexanes to give the title compound, mp 150–151° C.; MS (ESI−) for C16H23NO3S m/z 308 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1.[OH-].[Na+]>CO.C1COCC1>[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(CN)ccn3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(CN)ccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude ethyl 2-(6-(4-(aminomethyl)pyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified to pH 3 with 1N HCl and then concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (b, 1H), 9.20 (b, 1H), 8.33 (b, 2H), 8.18 (d, J=5.2 Hz, 1H), 7.17 (m, 2H), 7.11 (s, 1H), 7.00 (d, J=1.6 Hz, 1H), 5.50 (dd, J=10, 2.8 Hz, 1H), 4.10 (d, J=5.2 Hz, 2H), 3.07 (dd, J=15.2, 2.4 Hz, 1H), 2.29 (s, 3H), 2.12 (dd, J=15.6, 9.6 Hz, 1H). MS (ESI) m/z=329 [M+H]+.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([Br:27])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[CH2:20]([O:19][C:17]1[C:16]([Br:27])=[CH:15][N:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NC(=S)Nc1cc(OCc2ccccc2)c(Br)cn1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(OCc2ccccc2)c(Br)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
A flask was charged with 1-benzoyl-3-(4-(benzyloxy)-5-bromopyridin-2-yl)thiourea (9.8 g, 22.2 mmol) and THF (200 mL). 6N NaOH (100 mL) and NaOH (5 g) were added. The reaction was stirred at 60° C. for 3 hours, then concentrated and filtered to give the desired product (2.54 g, 33.9% yield) as off white solid.