Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:7][CH2:8][CH:9]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][CH2:13][C@@H:12]([C:22]([OH:24])=[O:23])[NH:11][C:10]1=[O:25])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[C:1]([S:7][CH2:8][CH:9]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][CH2:13][C@@H:12]([C:22]([O:24][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:23])[NH:11][C:10]1=[O:25])(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)C(=O)SCC1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)SCC1CCCCCCCSC[C@@H](C(=O)OCc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R)-6-(Pivaloylthiomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid (0.25 g, 0.64 mmol) is dissolved in dimethylformamide (5 ml) and cesium carbonate (0.23 g, 0.71 mmol) is added, followed by benzyl bromide (0.11 g, 0.64 mmol). The mixture is stirred overnight at room temperature, poured into water (300 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers are washed with water (2×100 ml), brine (1×200 ml), dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (3% ethyl acetate/hexane) gives benzyl (3R)-6-(pivaloylthiomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylate, m.p. 135°-137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21].N1C=CC=CC=1>O>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])=[CH:3][C:4]=2[C:16]([F:19])([F:17])[F:18])=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 10.8 %

Procedure:
5-[4-amino-2-(trifluoromethyl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile (0.33 g, 1.25 mmol) was dissolved in isopropyl sulfonyl chloride (1.0 mL, 9.0 mmol), pyridine (0.5 mL) was added, and the mixture was heated to 100° C. for 6 hours. The mixture was cooled and diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)phenyl]-propane-2-sulfonamide (50 mg).
Reaction SMILES: N[C:2]1[C:3]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.N([O-])=[O:15].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[OH:15][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CCCC#N)c(N)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc(CCCC#N)c(O)c1
Yield: 50.7 %

Procedure:
A solution of 3-amino-2-(3-cyanopropyl)-5-methylpyridine [from Example 1(c)] (1 g) in diluted sulphuric acid (0.78 ml conc. and 6.5 ml water) was reacted with sodium nitrite (0.59 g in 3 ml water) between 6°-10° C. The pH was brought to 6.5 with sodium hydroxide and the product was extracted with chloroform, chromatographed on silica in chloroform-methanol giving 3-hydroxy-2-(3-cyanopropyl)-5-methylpyridine (0.51 g) m.p. 132.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1cccnc1)c1cc(-c2ccncc2)ccc1OCc1ccc(F)c(F)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-([(3,4-difluorophenyl)methyl]oxy)-N-3-pyridinylbenzamide (may be prepared as described in Example 60; 120 mg, 0.29 mmol), 4-pyridinylboronic acid (52.8 mg, 0.43 mmol), tetrakis(triphenylphosphine)palladium(0) (19.85 mg, 0.02 mmol), sodium carbonate (0.57 ml, 0.57 mmol) and 1,2-dimethoxyethane (3 ml). The mixture was sealed and heated to 120° C. for 1 hr under microwave conditions. The 1,2-dimethoxyethane was evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 23.5 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH:8]([F:10])[F:9])[CH:7]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:4]1[C:5](=[O:11])[N:6]([CH:8]([F:9])[F:10])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=c1ccc(Br)cn1C(F)F
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1c(Br)cc(Br)cn1C(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
To a stirred solution of 5-Bromo-1-difluoromethyl-1H-pyridin-2-one (1 g, 4.46 mmol) in 7 ml acetic acid was added bromine (0.24 ml, 4.46 mmol) drop wise at 0° C. and then the reaction mixture was stirred at rt for 12 hrs. Acetic acid was removed under reduced pressure. To this was added ethylacetate and washed with aq NaHCO3 solution. Organic layer was dried over anhy sodium sulphate and concentrated under reduced pressure. It was purified by column chromatography using 5% ethyl acetate in hexane to afford 3,5-Dibromo-1-difluoromethyl-1H-pyridin-2-one (900 mg, 66.5%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:8]=2[CH:9]=1.[BH4-].[Na+]>[Pd].ClCCl.O>[NH2:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:4][CH2:3][C:2]([F:18])([F:1])[F:17])=[CH:9][C:8]=2[CH:10]=1
Reactant: O=[N+]([O-])c1ccc2oc(CCC(F)(F)F)cc2c1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ccc2oc(CCC(F)(F)F)cc2c1
Reaction time: 5 h

Procedure:
A mixture of 2.4 g (9.2 mmol) of 2-(3,3,3-trifluoropropyl)-5-nitrobenzofuran, 0.65 g (17 mmol) of sodium borohydride, 45 mg of Adogen® 464 (methyl trialkylammonium chloride) and 0.38 g of 5% palladium on carbon containing 50% of water in 95 ml of dichloromethane and 48 ml of water is stirred for 5 hours, then it is filtered on silica and the silica is rinsed with ethanol. The filtrate is then concentrated under reduced pressure and coevaporated with toluene. By chromatography of the residue on a silica column using a 0-30% mixture of ethyl acetate in cyclohexane, 2.0 g of product are obtained. Melting point: 74° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[OH:16][C@@H:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18](=[CH2:22])[C:19](O)=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:19](=[O:20])[C:18](=[CH2:22])[C@@H:17]([OH:16])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:10]
Reactant: C=C(C(=O)O)[C@@H](O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)NCC(=O)OCC)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (3.75 mL, 0.027 mol, 1.2 eq) was added to a suspension of glycine ethyl ester hydrochloride (3.44 g, 0.024 mol, 1.1 eq) in anhydrous dichloromethane (60 mL) (see FIG. 4). The mixture was stirred for 15 min at room temperature and then cooled to 0° C. (ice bath). Compound 9a (4 g, 0.022 mol, 1 eq) and dicyclohexylcarbodiimide (5.09 g, 0.02469 mol, 1.1 eq) were added successively to the reaction mixture which was stirred at room temperature for 17 h. The precipitate (dicyclohexylurea and triethylamine hydrochloride) was collected by filtration. The filtrate was washed with a 1N aqueous solution of HCl (50 mL), brine (50 mL) and dried over sodium sulfate. Evaporation of the solvent afforded an oil which was purified by column chromatography (eluent: hexane/EtOAc=6:4). The desired product 10a was obtained as a yellow oil (3.51 g, 60%). Rf0.25 (hexane/EtOAc=4:6). 1H NMR δ (CDCl3) 1.25 (t, 3H), 3.63 (s, 1H), 4.02 (m, 2H), 4.17 (q, 2H), 5.49 (s, 1H), 5.58 (d, 1H), 5.96 (s, 1H), 6.86 (s, 1H), 7.65 (m, 5H).[M+H]+ 264.1,: tR=2.55 min; purity: 96%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:18]=[C:19]([Cl:23])[CH:20]=[N:21][CH:22]=1.N1C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([CH3:39])=[CH:34][C:33]=1[S:40](Cl)(=[O:42])=[O:41].Cl>C1COCC1.C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([NH:15][S:40]([C:33]2[CH:34]=[C:35]([CH3:39])[C:36]([Cl:38])=[CH:37][C:32]=2[Cl:31])(=[O:42])=[O:41])[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:18]=[C:19]([Cl:23])[CH:20]=[N:21][CH:22]=1
Reactant: Nc1ccc(Oc2cncc(Cl)c2)c(C(=O)NCc2ccco2)c1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(=O)NCc3ccco3)c2)c(Cl)cc1Cl
Reaction time: 21 h
Yield: 89.6 %

Procedure:
To a 0.2M solution of N-(2-furanylmethyl) 5-amino-2-(3-chloro-5-pyridyloxy)benzamide (2.6 g, 7.6 mmol, prepared in Example 35.3) in a 1:1 THF/CH2Cl2 solution was added pyridine (0.67 mL, 8.3 mmol) followed by 2,4-dichloro-5-methylbenzenesulfonyl chloride (2.16 g, 8.3 mmol). The resulting mixture was stirred for 21 hr. A 1M aqueous solution of HCl (100 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (100 mL). The organic layers were combined and washed once with a brine solution (200 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was purified by chromatography (10-40% EtOAc in hexane) to yield 3.86 g (90%) of product as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:29])=[O:10])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([S:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:35])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:29])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nn1nc(Sc2ccccc2)c2ccccc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(S(=O)c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
A mixture of the product from Example 58 (0.0200 g, 0.047 mmol) and 3-chlorobenzoperoxoic acid (0.0125 g, 0.051 mmol) in DCM (0.5 mL) was stirred at room temperature for 1 hour, diluted with EtOAc, washed with sat NaHCO3 and brine, dried (Na2SO4), filtered, and chromatographed (8-10% EtOAc/DCM) to give 4.5 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 8.44-8.48 (m, 1H), 8.30-8.34 (m, 1H), 7.86-7.96 (m, 2H), 7.70-7.76 (m, 2H), 7.50-7.61 (m, 3H), 7.38-7.46 (m, 4H), 3.76 (s, 2H); MS (ESI−) M/Z 436 (M−H)−.
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].[Cl:19]CCl.CS(Cl)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(N(CC)CC)C>[Cl:19][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: ClCCl
Reactant: CC(=O)Nc1ccc(C(O)C(C)C)cc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc(C(Cl)C(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a stirred solution of 36 parts of intermediate 15, namely N-[4-(1-hydroxy-2-methylpropyl)-2-nitrophenyl]acetamide and 390 parts of dichloromethane were added 35.0 parts of N,N-diethylethanamine. After cooling to 0° C., 20.0 parts of methane-sulfonyl chloride were added dropwise to the previous mixture. Upon completion, stirring was continued for 12 hours at room temperature. The whole was poured into water and sodium carbonate was added while stirring. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 39 parts (100%) of N-[4-(1-chloro-2-methylpropyl)-2-nitrophenyl]acetamide (interm. 16).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([Br:24])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([Br:24])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2C=Cc3cc(F)cc(Br)c3O2)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCC2CCc3cc(F)cc(Br)c3O2)cc1
Yield: 48.8 %

Procedure:
A solution of (8-bromo-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (300 mg, 0.73 mmol) in absolute ethanol was added to 5% sulfided platinum on carbon (50 mg) and the mixture hydrogenated at 55 psi of hydrogen for 1 hour. The mixture was then filtered through celite and the filtrate concentrated under reduced pressure to afford a white semi-solid. Purification by flash chromatography using a solvent gradient of 5 to 25% ethyl acetate in hexane gave 148 mg (49%) of (8-bromo-6-fluoro-3,4-dihydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a white solid.
Reaction SMILES: [NH2:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[N:4]=[N:3]1.[Br:12][CH2:13][CH2:14][C:15](Cl)=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[Br:12][CH2:13][CH2:14][C:15]([NH:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[N:4]=[N:3]1)=[O:16]
Reactant: Cc1ccc2c(c1)nnn2N
Reactant: O=C(Cl)CCBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)nnn2NC(=O)CCBr
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 14.8 g (0.1 mol of 1-amino-5-methyl benztriazole in 200 ml of anhydrous benzene was placed under a nitrogen atmosphere and, over a period of 30 minutes, a solution of 18.9 g (0.11 mol) of β-bromopropionyl chloride in 25 ml of anhydrous benzene and 10.1 g (0.10 mol) of triethylamine were simultaneously added to the solution while stirring the latter. The addition was so made that the amount of acid chloride added was always greater than the amount of amine. The temperature of the mixture rose to above 40° C. Stirring was then continued for 1 hour without application of heat and was continued for a further hour with heating to 60° C. following by stirring for two further hours without application of heat. The organic phase was then poured off from a greasy deposit in the reaction vessel and was washed with water. The deposit was taken up in chloroform and was also washed with water. The organic phases obtained were dried over sodium sulphate, combined and completely concentrated by evaporation. 24 G of the intermediate product, 1-(β-bromopropionylamino)-5-methyl benztriazole were obtained as residue in the form of a frothy resin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][NH:6][C:7](=[O:15])OC1C=CC=CC=1.[C:20]([NH2:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][NH:6][C:7]([NH:29][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21])=[O:15]
Reactant: O=C(NOc1cc(Cl)cc(Br)c1)Oc1ccccc1
Reactant: CC(C)(N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)NOc1cc(Cl)cc(Br)c1)c1ccccc1
Reaction time: 5 h
Yield: 86 %

Procedure:
3.00 g of phenyl 3-bromo-5-chlorophenoxycarbamate was dissolved in 50 ml of tetrahydrofuran. The resulting solution was added to a mixture of 1.54 g of cumylamine and 1.15 g of triethylamine, followed by stirring for 5 hours, while being heated to reflux. The reaction solvent was then distilled off under reduced pressure. The resulting residue was partially purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1). The resulting crude crystal was washed with hexane to obtain 1-(3-Bromo-5-chlorophenoxy)-3-(2-phenylpropan-2-yl)urea (2.89 g, yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]1([N:69]([CH2:71][CH:72]2[CH2:77][CH2:76][CH2:75][CH2:74][NH:73]2)[CH3:70])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:73]1[CH2:74][CH2:75][CH2:76][CH2:77][CH:72]1[CH2:71][N:69]([CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[CH3:70])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(CC1CCCCN1)C1CCCCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN(C)C3CCCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-cyclohexyl-N-methyl-piperidin-2-ylmethyl-amine in DMSO at ambient temperature.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:9]=[CH:10][N:11]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[Cl:8][C:5]1[N:4]2[N:9]=[CH:10][N:11]=[C:3]2[C:2]([NH:12][C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(Br)c2ncnn12
Reactant: Nc1ccc(C(=O)NCc2cccnc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(NCc1cccnc1)c1ccc(Nc2ccc(Cl)n3ncnc23)cc1
Yield: 71.8 %

Procedure:
A solution of 8-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.43 mmol), 4-Amino-N-pyridin-3-ylmethyl-benzamide (108 mg, 0.48 mmol), sodium-tert-butoxide (58 mg, 0.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (39 mg, 40 μmol) and Xantphos (50 mg, 90 μmol) in dioxane is degassed for one minute by nitrogen bubbling and then irradiated in a sealed tube in a microwave (CEM Explorer) under a nitrogen atmosphere for 30 minutes at 110° C. The solvent is evaporated and the crude is dissolved in dichloromethane and filtered in order to remove the palladium catalyst. The residue is purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 95:5) affording the title compound (117 mg) as a solid.
Reaction SMILES: OC(C1N=CC(C2N=C3[N:17]([C@H:22]4[CH2:27][CH2:26][C@H:25]([O:28][CH3:29])[CH2:24][CH2:23]4)C(=O)CNC3=NC=2)=CC=1)(C)C.Br[C:31]1[C:32]([NH:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:33][CH:34]=[C:35]([Br:37])[N:36]=1.Cl.CO[C@H]1CC[C@H](N)CC1.CCN(C(C)C)C(C)C>[Cl-].[Na+].O.C(OCC)(=O)C.CN1C(=O)CCC1>[Br:37][C:35]1[N:36]=[C:31]([NH:17][C@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][CH3:29])[CH2:24][CH2:23]2)[C:32]([NH:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:33][CH:34]=1
Reactant: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(-c4ccc(C(C)(C)O)nc4)nc32)CC1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Agent: CO[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Temperature: 127 °C

Procedure:
7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (alternate approach). Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4-methoxycyclohexanamine.hydrochloride (1.5 equiv), NMP and DIEA were combined and heated to 127° C. and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to 35° C. over 4 h. The batch was transferred to a mixture of ethyl acetate and 5% brine. The aqueous layer was removed and the organic layer containing the batch was washed successively with 5% brine and water. The organic layer containing the batch was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected by vacuum filtration. The filter cake was washed with MTBE and the product was dried in a vacuum to give 41% yield of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate (1 equiv), water and 85% phosphoric acid (3:1) was heated to 80° C. over 1 h. Heating was maintained for 18 h to effect reaction completion. Upon reaction completion, the mixture was cooled to 25° C. and filtered to give a crude product as tan solid. The resulting solids were washed with water, slurried in water and filtered. The filter cake was washed with water until the pH of the filtrate was between 4 and 8. The resulting material was dried under vacuum to give 89% yield of 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyloxy)propan-2-yl)pyridine (1 equiv), sodium carbonate (3 equiv) and PdCl2(AmPhos)2 (0.003 equiv) were combined in isopropanol and heated at 70° C. for 1.5 h. Standard work-up and purification afforded the protected compound in 93% yield. Deprotection using standard conditions for removal of a trimethylsilyl-group and isolation gave the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7](NN)[N:6]=[C:5]([F:12])[C:4]=1[F:13].C(OCC)C.CCCCCC.C(OCC)C>O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:1][CH2:2][C:3]1[C:8]([F:9])=[CH:7][N:6]=[C:5]([F:12])[C:4]=1[F:13]
Reactant: NNc1nc(F)c(F)c(CO)c1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: OCc1c(F)cnc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To a suspension of 0.7 g (0.0036 mole) of (4-hydroxymethyl-2,3,5-trifluoropyridin-6-yl)hydrazine (from Example 6) in 25 ml of distilled water was added a solution of 2.5 g (0.016 mole) of copper (II) sulfate during a 1.5 hour period. Nitrogen evolution continued while the reaction mixture was stirred at ambient temperature for two hours and while it refluxed for an additional two hours. After being cooled, the reaction mixture was extracted with diethyl ether. This extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving a brown oil. This oil was passed through a short column of silica gel using a mixture of diethyl ether and hexane (50/50) as eluant. The appropriate fractions were combined and the solvent evaporated under reduced pressure, yielding 0.3 g of 4-hydroxymethyl-2,3,5-trifluoropyridine as a yellow oil. The structure and nmr spectra for this compound are set forth in Table 1C.