Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22].[BH4-].[Na+].C(O)(=O)C>C(O)CC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([OH:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22]
Reactant: COc1ccc(CCC(=O)c2cc(OC)ccc2O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCO
Solvent: CC(=O)O
Product: COc1ccc(CCC(O)c2cc(OC)ccc2O)c(OC)c1

Procedure:
1-(2-hydroxy-5-methoxyphenyl)-3-(2′,4′-dimethoxyphenyl)-1-propanone (6) (5 mg) was dissolved in 1-propanol (1 ml), followed by the addition of sodium borohydride (2 mg) and the mixture was allowed to react at room temperature for 5 hours. Upon completion of the reaction, 20% acetic acid (0.2 ml) was added to neutralize the excess sodium borohydride. The reaction mixture was then separated on a pre-packed C18 column eluting with a MeOH/H2O gradient to provide 1-(2-hydroxy-5-methoxyphenyl)-3-(2′,4′-dimethoxyphenyl)-1-propanol (7).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:18]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To an ice-cooled solution of 3-(p-hydroxyphenyl)-propionic acid (8.3 g, 50.0 mmol) in ethanol (100 mL) was dropwise added thionyl chloride (3.7 mL, 50.7 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and the residue purified by kugelrohr distillation, to give 9.6 g (99%) of 3-(4-hydroxy-phenyl)-propionic acid ethyl ester as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Cl.[CH:18](OCC)=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:18][OH:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(F)cc(F)c1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(=CO)c1cc(F)cc(F)c1

Procedure:
5.0 g of ethyl 3,5-difluorophenylacetate are dissolved in 50 ml of ethyl formate. 2.0 g of 60% NaH are added portionwise. The mixture is poured onto a 1N HCl solution and then extraction is carried out with AcOEt. The residue is triturated in petroleum ether, the remaining white precipitate is filtered off and then the filtrate is evaporated to produce 3.3 g of the expected compound in the form of a liquid.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:4][CH3:5].[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>CC(C)=O.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCC(CC)S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCC(CC)S(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The general method of procedure A was followed with 3-pentanesulfonamide (10 g), acetone (300 ml), 1N sodium hydroxide (56 ml), and 4-chlorophenyl isocyanate (9.6 g) dissolved in 70 ml of acetone. After two hours of stirring, 1N HCl (66 ml) was added followed by more water. The acetone was stripped off, and the resulting solid collected, to give, after drying at 65° C. under vacuum, 13.1 g of product.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[CH2:3][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:1])[CH3:5]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Reactant: CNC
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN(C)C)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with dimethylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 26.1, 26.2, 35.9, 43.2, 47.9, 53.1, 59.3, 69.9, 102.9, 105.4, 112.4, 112.6, 131.7, 137.5, 169.2; MS m/z 436.2 (M+1),
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([S:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:18])[CH3:17])[CH3:16]
Reactant: SC1CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC1CCCCC1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a solution of 2.5 g (21.5 mmol) of cyclohexyl thiol in ethanol (75 mL) were added 1.2 g (21.5 mmol) of KOH pellets, followed by 4.2 g (21.5 mmol) of ethyl α-bromoisobutyrate. The reaction was heated to reflux for 18 h and then cooled to room temperature. The solid (KBr) was separated by filtration and rinsed with ethanol (20 mL). The filtrate was concentrated under reduced pressure and the residue dissolved in DCM (50 mL). The organic layer was washed with water (2×20 mL). The aqueous washes were back-extracted with DCM (10 mL). The combined organics were washed with brine, dried over Na2SO4. Filtration and concentration under reduced pressure afforded 4.15 g of 2-cyclohexylsulfanyl-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].[S:44]1[CH:48]=[CH:47][C:46]([CH2:49]O)=[CH:45]1>O1CCCC1.ClCCl>[F:34][C:35]1[CH:42]=[C:41]([O:43][CH2:49][C:46]2[CH:47]=[CH:48][S:44][CH:45]=2)[CH:40]=[CH:39][C:36]=1[C:37]#[N:38]
Reactant: N#Cc1ccc(O)cc1F
Reactant: OCc1ccsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(OCc2ccsc2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
A solution of triphenylphosphine (20 g) in tetrahydrofuran (300 mL) cooled at 0° C. is treated dropwise during 5 minutes with diisopropyl azodicarboxylate (15 mL) and stirred for 15 minutes at 0° C. It is then treated, dropwise, with a solution of 2-fluoro-4-hydroxybenzonitrile (7 g) and 3-thienylmethanol (7 g) in tetrahydrofuran (200 mL) during 2 hours, and stirring is continued at ambient temperature for 18 hours. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate (500 mL). This solution is washed with water (200 mL) and aqueous sodium hydroxide solution (1 N), dried over magnesium sulphate and concentrated in vacuo, to give an oil, which is passed through a pad of silica gel (thickness 5 cm) with the aid of dichloromethane. The resulting filtrate is concentrated in vacuo, to give an oil which crystallizes on standing. Recrystallization from isopropyl ether gives 2-fluoro-4-(3-thienyl-methoxy)benzonitrile (6 g), in the form of a white solid, m.p. 63-65° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:6]=[CH:5][N:4]=1.[H][H]>[Pd].CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=2)=[CH:17][CH:18]=1
Reactant: CNc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNc1nccc(-c2ccccc2Oc2ccc(N)cc2)n1
Reaction time: 24 h

Procedure:
To N-methyl-4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine (0.667 g, 2.1 mmol) and palladium, 10 wt. % on activated carbon, wet (0.44 g, 0.41 mmol) in a 100 mL round bottom flask was added MeOH under nitrogen via syringe. The atmosphere was replaced with hydrogen from a balloon and the mixture stirred rapidly for 24 h. The reaction was flushed with nitrogen, and filtered through celite rinsing with 100 mL MeOH. The filtrate was concentrated in vacuo to give 4-(2-(4-aminophenoxy)phenyl)-N-methylpyrimidin-2-amine as a light yellow solid. MS m/z=293 [M+1]+. Calc'd for C17H16N4O: 292.34.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]>C1COCC1.[Cl-].[Na+].O>[C:3]([CH:2]([CH2:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC(=O)C(F)(F)F)C(C)=O
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl acetoacetate (3.98 mL) in THF (dry) (50 mL) was added NaH (1.571 g) at 0° C., and the mixture was stirred for 30 min at the same temperature. To the mixture was added 3-bromo-1,1,1-trifluoroacetone (5 g) 0° C., and the mixture was stirred for 3 h. The mixture was poured into brine at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.570 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:2].[H-].[Na+].I[CH3:19].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:19])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)Cc1ccc(OC)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)c1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of (3-bromo-4-methoxy-phenyl)-acetic acid ethyl ester (1.45 g, 5.12 mmol, 1.00 eq.) in THF (18 mL), sodium hydride (60% dispersion in mineral oil, 225 mg, 5.63 mmol, 1.10 eq.) was added. The reaction mixture was stirred at r.t. for 30 min. Iodomethane (0.34 mL, 5.38 mmol, 1.05 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. Water was carefully added. THF was removed in vacuo. The residue was extracted with AcOEt (2×). The org. layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 25 fractions of 40 mL, Heptane 100% to Heptane+15% AcOEt) to yield the title compound as a yellow oil.
Reaction SMILES: CO[C:3](=[O:11])[C@@H:4]([CH2:9][OH:10])[NH:5][C:6](=[O:8])[CH3:7].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(OC)(C)(C)C>[C:6]([NH:5][C@H:4]([CH2:9][OH:10])[C:3]([NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:8])[CH3:7]
Reactant: COC(=O)[C@@H](CO)NC(C)=O
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 68.4 %

Procedure:
N-Acetyl-D-serine methyl ester (1.0 g, 0.0062 mole) was dissolved in benzylamine (1.32 g, 0.0124 mole) at 0-5° C. To this was added triethylamine (0.125 g, 0.00124 mole) at 0-5° C. The reaction mixture was heated and stirred at 60° C. for 12 hr, cooled to room temperature, 20 ml methyl tert-butyl ether added and stirred for 3 hr. The product was filtered and dried under vacuum to obtain (R)-2-acetamido-N-benzyl-3-hydroxy-propionamide. (1.0 g, Yield: 68.4%, HPLC:94.8%, Chiral HPLC: 81.2%),
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[O:25][CH:26]1[CH2:27][CH2:28][N:29]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[O:14][N:13]=3)[CH:7]=2)[CH2:30][CH2:31]1
Reactant: Clc1cccc(OC2CCNCC2)c1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCC(Oc2cccc(Cl)c2)CC1
Yield: 49.7 %

Procedure:
Dilute a 0.370 M solution (in dimethylformamide) of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine (140 mg, 0.522 mmol) with ethanol (3.0 mL) and add solution of 4-(3-chlorophenoxy)-piperidine (121.5 mg, 0.574 mmol, 1.1 equivalents) (Table No.1, SM 7) dissolved in ethanol (0.200 M solution). Under a vented argon atmosphere, reflux the reaction mixture overnight. Concentrate the reaction mixture and purify with a Waters Sep-Pak 5 g silica gel cartridge and elute with a graded solvent mixture from 1% methanol in dichloromethane to 5% methanol in dichloromethane to give the title compound (124.6 mg, 50% Yield). Purity by LC/MS=100%, [M+H]+=480
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CN=C1.[C:20](O)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[OH:23][C:22]1[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=1[C:20]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:28]
Reactant: O=C(O)c1ccccc1O
Reactant: NCCNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: O=C(NCCNC(=O)c1ccccc1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a mixture of benzyl 2-aminoethylcarbamate (1.65 g, 8.5 mmol), imidazole (0.58 g, 8.5 mmol), salicylic acid (1.73 g, 8.5 mmol) in ethyl acetate (30 mL) was added a solution of DCC (1.75 g, 8.5 mmol) in ethyl acetate (50 mL). The mixture was stirred (RT, 16 h) and filtered. The solution was concentrated under reduced pressure and the crude product was purified by silica chromatography (EtOAc:PE, 0-50%) to afford benzyl 2-(2-hydroxybenzamido)ethylcarbamate as a white solid (1.84 g, 66%). Mass calculated for C17H18N2O4=314.34. found: [M+H]+=315.2.
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C4CCCCO4)[CH:18]=3)[CH:12]=[C:13]2[NH2:16])=[N:8]1.CCN(C(C)C)C(C)C.[CH:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.[OH-].[Na+]>C(Cl)Cl>[OH:23][C:19]1[CH:18]=[C:17]([C:11]2[CH:12]=[C:13]3[C:14]([CH:15]=[N:7][NH:16]3)=[C:9]([NH:8][C:45]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:46])[CH:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cc(-c2cccc(OC3CCCCO3)c2)cc2nn(C3CCCCO3)cc12
Reactant: O=C(Cl)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc(O)c2)cc2[nH]ncc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Tetrahydro-2H-pyran-2-yl)-6-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazol-4-amine (50 mg, 0.127 mmol) was dissolved in DCM (1 ml) and DIPEA (0.111 ml, 0.635 mmol) and cyclohexanecarbonyl chloride (45 mg, 0.254 mmol) were added. The reaction was stirred at RT for 1 h. 2 M Sodium hydroxide (aq) (2 ml) was added and the reaction stirred at RT for 1 h, before the organic layer was passed through a hydrophobic frit. The aqueous layer was washed several times with DCM, which was passed through a hydrophobic frit. The combined organic layers were evaporated under a stream of nitrogen. The residue was dissolved in MeOH (2 ml) and 4 M HCl in dioxane was added (2 ml). The reaction was stirred at RT for 1 h. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO:MeOH (1:1, v/v) and purified by MDAP (Method B). The residue was dissolved in 1,4-dioxane:water and freeze dried to produce the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N+:16]([O-])([O-:18])=[O:17].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:16]([C:15]1[CH:14]=[CH:13][C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])=[CH:3][C:2]=1[OH:1])([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 30 %

Procedure:
3-Hydroxybenzophenone (3.00 g, 15.1 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.42 g, 16.7 mmol). The addition of sulfuric acid (25 mL/3 M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(1.10 g, 30%). 1H NMR (CD3COCD3): δ 8.25 (d,1H), 7.86 (d,1H), 7.71 (m, 1H), 7.59 (d, 1H), 7.48 (s, 1H), 7.39 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:15])[NH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24]Br>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:15])[N:4]2[CH2:23][CH2:24][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[N:6][CH:7]=1
Reactant: BrCCBr
Reactant: O=c1[nH]c(Nc2ccccc2)ncc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Br)cnc2n1CCN2c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-(phenylamino)pyrimidin-4(3H)-one (0.082 g, 0.308 mmol) in DMF (8 mL) was added K2CO3 (0.043 g, 0.308 mmol) and 1,2-dibromoethane (0.029 ml, 0.339 mmol). The reaction was stirred at 60° C. overnight, cooled to room temperature and then partitioned between EtOAc and saturated NaCl. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by trituration with Et2O/CH2Cl2. The resulting solid was washed with Et2O, and the filtrate discarded. The solid was then dissolved with CH2Cl2/MeOH, concentrated and dried under vacuum. The product was obtained (75 mg; 83%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.75 (m, 2H), 7.42 (m, 2H), 7.15 (m, 1H), 4.18 (m, 4H). LRMS (ESI pos) m/e 292, 294 (M+, Br pattern).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[N:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)sc2ccc(F)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A suspension of 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.5 g) and 4-pyridineboronic acid (0.197 g) in 1,2-dimethoxyethane (6 ml), ethanol (2 ml) and 2 M aqueous sodium carbonate solution (4.0 ml) was degassed 3-4 times to remove oxygen, then tetrakis(triphenylphosphine)palladium (0.065 g) was added. The reaction mixture was stirred at 80° C. for 3 h, quenched with ice/water, and extracted with ethyl acetate. The organic layers were washed, dried and concentrated. The residue was chromatographed over silica gel using heptane/ethyl acetate as eluent to obtain the title compound (0.35 g) as a yellowish solid. MS (ISP): 467.3 (M+H)+
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[O:7][CH2:8][CH:9]([OH:24])[CH2:10][NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][NH:20][C:19]2=[O:23])[CH2:14][CH2:13]1)[CH:2]=[CH2:3].C=O.[CH:31](O)=O.Cl>C(O)(C)C>[CH2:1]([O:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[O:7][CH2:8][CH:9]([OH:24])[CH2:10][N:11]([C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][NH:20][C:19]2=[O:23])[CH2:14][CH2:13]1)[CH3:31])[CH:2]=[CH2:3]
Reactant: O=CO
Reactant: C=CCOc1ccccc1OCC(O)CN[C@H]1CC[C@@H](N2CCNC2=O)CC1
Agent: C=O
Agent: Cl
Solvent: CC(C)O
Product: C=CCOc1ccccc1OCC(O)CN(C)[C@H]1CC[C@@H](N2CCNC2=O)CC1
Temperature: 25 °C

Procedure:
A mixture of cis-1-(4-[3-(o-allyloxyphenoxy)-2-hydroxypropylamino]-cyclohexyl)-2-imidazolidinone (4.4 g) in 15 ml isopropanol, 37.5% aqueous formaldehyde (0.671 g), and formic acid (2.6 g) is stirred at reflux for 19 hours. The solution is cooled to room temperature, 1 ml concentrated hydrochloric acid is added and the mixture concentrated to dryness. The glassy residue is dissolved in 100 ml of water, made alkaline with excess of 25% aqueous sodium hydroxide and extracted with methylene chloride (1×50 ml, 1×25 ml). The extract is dried, filtered and concentrated to give a residue which is purified by preparative thin layer chromatography on silica gel, using ethyl acetate-methanol-ammonium hydroxide (90:5:5) as the eluent, to yield the cis-1-{4-[3-(o-allyloxyphenoxy)-2-hydroxy-N-methyl-propylamino]cyclohexyl}-2imidazolidinone as an oil. The hydrochloride salt, m.p. 80° dec., is prepared by dissolving 2.3 g of the base in 50 ml ethyl acetate, adding a saturated solution of hydrogen chloride gas in ethyl acetate, and collecting the resulting salt.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([NH2:29])[CH:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[CH:20]=4)[C:9]3=[N:10][CH:11]=2)[N:3]=[N:2]1.N1C=CC=CC=1.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([NH:29][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[CH:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[CH:20]=4)[C:9]3=[N:10][CH:11]=2)[N:3]=[N:2]1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4c[nH]nn4)cnc32)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4c[nH]nn4)cnc32)c1
Yield: 9.3 %

Procedure:
To a solution of 5-(6-(1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (70 mg, 0.179 mmol) in DCM was added pyridine (42 mg, 0.53 mmol, 3.0 eq.) followed by ethanesulfonyl chloride (20 mg, 0.179 mmol, 1.0 eq.). The reaction was monitored by LCMS. After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 9.3% yield (8 mg). 1H NMR (300 MHz, DMSO): δ 10.4 (s, 1H) 9.0-8.97 (m, 2H), 8.64 (d, 1H), 7.92 (s, 1H), 7.75-7.64 (m, 3H), 7.47-7.43 (m, 3H), 3.31-3.24 (q, 2H), 1.39-1.34 (t, 3H); LC-MS (ESI): Calculated mass: 481.4; Observed mass: 481.8 [M+H]+ (rt: 1.36 min).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C1(C=CC(O)=CC=1)O.[OH-].[K+]>>[C:10]([CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])#[N:11]
Reactant: C=CC(=O)OCC
Reactant: N#CCc1cccc(F)c1F
Agent: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)CCC(C#N)c1cccc(F)c1F
Temperature: 160 °C

Procedure:
To a mixture of (2,3-difluorophenyl)acetonitrile (40.5 g, 265 mmol), ethyl acrylate (24 mL, 220 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160° C. for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=207.9 (M-OEt).