Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([O:31][CH2:32][CH2:33]O)=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccnc2ccccc12
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccnc3ccccc23)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(4-quinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 3 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate-methanol; 20: 1) and crystallized from dichloromethane-hexane to provide 1.2 g of alpha-oxo-4-[[2-(4-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 135°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:5]([NH:7][C:8]1[CH:38]=[CH:37][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:15][C:14]=2[CH2:27][NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=2)=[CH:10][CH:9]=1)=[O:6]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:5]([NH:7][C:8]1[CH:38]=[CH:37][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[CH2:27][NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNC(=O)c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNC(=O)c2cccnc2)c1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
The product of step D (44 mg, 0.073 mmol) was diluted with methylene chloride:TFA (1:1) and stirred for 3 hours. The reaction mixture was concentrated, taken up in ether and sonicated. The solid was filtered, rinsed with ether and dried under vacuum to yield the title compound (35 mg, 88% yield) as white solid. 1H NMR (400 MHz, CDCl3/CD3OD) 8.75 (m, 1H), 8.65 (m, 1H), 8.15 (m, 1H), 8.10 (m, 1H), 8.0 (m, 1H), 7.60 (m, 3H), 7.45 (m, 1H), 7.20 (m, 1H), 6.95 (d, 2H), 6.90 (d, 1H), 4.65 (m, 2H), 3.62 (s, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[CH:28]1[O:30][CH2:29]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=2)[CH2:29][CH:28]([OH:30])[C:27]([F:32])([F:31])[F:26])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Reactant: FC(F)(F)C1CO1
Product: CC(C)Oc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Yield: 27.8 %

Procedure:
The N-(3-phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine (0.528 g, 1.59 mmol) product from EX-645B and 1,1,1-trifluoro-2,3-epoxypropane (0.506 g, 4.51 mmol) were heated to 90° C. in a sealed container for 2 d under an argon atmosphere. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (0-10% ethyl acetate) and fractions were pooled after TLC analysis to give 197 mg (28%) of the desired 3-[(3-phenoxyphenyl)[[3-(isopro-poxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as clear, colorless oil. HRMS calcd. for C25H26F3NO3:446.1943 [M+H]+, found: 446.1936. 1H NMR (C6D6) δ 6.9-7.1 (m, 6H), 6.84 (tt, 1H), 6.74 (s, 1H), 6.66 (dd, 1H), 6.61 (d, 1H), 6.56 (t, 1H), 6.41 (td, 2H), 4.33 (s, 2H), 4.17 (septet, 1H), 3.91 (br s, 1H), 3.56 (dd, 1H), 3.31 (m, 1H,), 2.8 (br s, 1H). 1.06 (s, 6H). 19F NMR (C6D6) δ −78.85 (d, 3F).
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9](C(=O)C(F)(F)F)[CH2:10]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].O>CO>[N+:15]([C:14]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]2[CH:7]3[CH2:18][CH:11]([CH2:10][NH:9][CH2:8]3)[C:12]=2[CH:13]=1)([O-:17])=[O:16]
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])C1CNCC2C1
Yield: 71.2 %

Procedure:
1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (3.7 g, 10.7 mmol) and Na2CO3 (2.3 g, 21.4 mmol) were combined in MeOH (50 mL) and H2O (20 mL) then warmed to reflux for 18 hours. The reaction was cooled, concentrated, treated with H2O and extracted with CH2Cl2 (3×50 mL) then dried through a cotton plug. After concentration, the residue was chromatographed to provide brown solids (1.9 g, 71%) (TLC 5% MeOH/CH2Cl2 (NH3) Rf 0.36). 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 3.17 (br s, 2H), 3.11 (d, J=12.6 Hz, 2H), 2.53 (m, 1H), 2.07 (d, J=11.0 Hz, 1H). GCMS m/e 249 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][S:13]([OH:16])(=O)=[O:14].[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][S:13]([Cl:19])(=[O:16])=[O:14]
Reactant: O=S(=O)(O)Cc1cc(C(F)(F)F)ccc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Product: O=S(=O)(Cl)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 85 °C
Yield: 91.6 %

Procedure:
A mixture of sodium (2-chloro-5-trifluoromethyl-phenyl)-methanesulfonic acid (Example 1.1) (9.4 g) and phosphorous pentachloride (13.5 g) was heated to 80-90° C. for 4 hours. The reaction mixture was concentrated. The residue was poured onto a mixture of ice and water and the mixture extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated to give (2-chloro-5-trifluoromethyl-phenyl)-methanesulfonyl chloride as an off-white solid (8.480 g). 1H-NMR (400 MHz, CDCl3): 7.87 (m, 1H), 7.68 (m, 2H), 5.15 (s, 2H) ppm.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:11][O:10][C:9](=[O:12])[N:8]1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=O)=O.O[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH:7]([CH2:6][O:5][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[CH2:11][O:10][C:9]2=[O:12])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)OCC1COC(=O)N1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2COC(=O)N2c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 1.50 g of 3-(4-chlorophenyl)-2-oxooxazolidin-4-ylmethyl methanesulfonate and 0.80 g of methyl 4-hydroxybenzoate. To the solution was added 0.80 g of anhydrous potassium carbonate, and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and water was added thereto. The obtained residue was recrystallized from methanol to give 1.60 g of the title compound (compound 176) in a yield of 90%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[CH:22].C(N(CC)CC)C>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:22]#[C:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: C#Cc1ccccc1
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3)c2)ccc1O
Temperature: 50 °C
Yield: 77.2 %

Procedure:
A mixture of Intermediate 1 (2.5 g), ethynylbenzene (800 mg), copper (I) iodide (124 mg), bis(triphenylphosphine)palladium (II) dichloride (1.37 g), triethylamine (19.0 g) and acetonitrile (20 ml) is heated with stirring at 50° C. under argon atmosphere. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (1.8 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[C:11]1([CH2:17]/[CH:18]=[CH:19]/[C:20](OCC)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([CH2:17]/[CH:18]=[CH:19]/[CH2:20][OH:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)/C=C/Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: OC/C=C/Cc1ccccc1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a stirred suspension of LiAlH4 (2.4 g, 63.1 mmol) in dry Et2O (60 mL) at 0° C. under nitrogen atmosphere was added dropwise a solution of anhydrous AlCl3 (1.7 g, 12.6 mmol) in dry Et2O (30 mL). The reaction mixture was stirred at the same temperature for 30 min. To this stirred suspension, ester obtained in example 1 (8.0 g, 42.1 mmol) in dry Et2O (30 mL) was added dropwise over a period of 15 min and the resulting mixture stirred at 0° C. for 1 h. Then it was quenched with ice-water and filtered through celite and the residue was washed with ethyl acetate (3×30 mL). The combined organic layer was dried over anhydrous Na2SO4, concentrated, and the crude product was purified by column chromatography using petroleum ether/EtOAc (4:1) to afford the pure allylic alcohol 7 (5.4 g, 87%) as a colorless oil. IR: (CHCl3, cm−1): νmax 694, 744, 966, 1049, 1107, 1364, 1454, 2857, 2932, 3385; 1H NMR (200 MHz, CDCl3): δ 1.22 (br s, 1H), 3.38 (d, J=6.4 Hz, 2H), 4.12 (t, J=4.8 Hz, 2H), 5.62-5.93 (m, 2H), 7.15-7.32 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 36.4, 61.9, 126.0, 126.3, 127.2, 128.5, 132.7, 137.2; Anal. Calcd for C10H12O: C, 81.04; H, 8.16. Found: C, 81.02; H, 8.15%.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.O1CCCNCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:28][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CNCCOC1
Agent: Cl
Product: CC(C)(C)c1nc(N2CCCOCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1,4-oxazepane hydrochloride and isolated as white gum (12.0 mg, 63%). MS(m/e): 401.5 (MH+).
Reaction SMILES: B.CSC.[CH2:5]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:22]([N:24]([CH3:26])[CH3:25])=O)[C:13]1=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C[O:31][CH2:30][CH2:29]1>>[C:30]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][CH:14]1[CH2:22][N:24]([CH3:26])[CH3:25])(=[O:31])[CH3:29]
Reactant: CN(C)C(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Reactant: C1CCOC1
Agent: B
Solvent: CSC
Product: CC(=O)N1c2ccccc2N(Cc2ccccc2)CC1CN(C)C
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Borane-dimethylsulfide complex (10M-THF solution; 5 ml) was added to a THF (20 ml) solution of 4-benzyl-N,N-dimethyl-3-oxo-3,4-dihydro-2-quinoxalinecarboxamide (1.5 g). The reaction mixture was stirred at room temperature for one hour, further at 50° C. for 18 hours, then concentrated. The residue was dissolved in methanol (30 ml) and the mixture was stirred at 50° C. for 20 hours together with 6N hydrochloric acid (10 ml). The reaction mixture was concentrated, and the residue was dissolved in pyridine (10 ml). Acetic anhydride (0.5 ml) was added to the reaction mixture, which was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/3) to obtain the entitled compound (0.6 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11]C)=[O:9])=[C:6]([C:13]([O:15][CH2:16]C)=[O:14])[C:5]([N+:18]([O-:20])=[O:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.C[O-].[Na+].[C:30](O)(=[O:32])C>CO>[CH3:11][O:10][C:8]([C:7]1[C:2]([O:32][CH3:30])=[N:3][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:18]([O-:20])=[O:19])[C:6]=1[C:13]([O:15][CH3:16])=[O:14])=[O:9]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(OC)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 25 ml of methanol was dissolved 1.2 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine as obtained in Reference Example 18. To the solution was added 6.34 ml (2.0 eq.) of a solution of 1N sodium methoxide in methanol, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 0.2 ml (1.1 eq.) of acetic acid, and the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (eluent:ethyl acetate). The resulting crystals were collected by filtration with hexane.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:46])[NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[N:19]=[C:18]([N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:17]=1[N+:43]([O-])=O)([CH3:6])([CH3:5])[CH3:4]>CO.ClCCl.O.[Ni](Cl)Cl>[C:3]([O:7][C:8](=[O:46])[NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[N:19]=[C:18]([N:24]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:17]=1[NH2:43])([CH3:4])([CH3:6])[CH3:5]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(Cl)c(C)c(NCCOCCNC(=O)OC(C)(C)C)c2[N+](=O)[O-])cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(Cl)c(C)c(NCCOCCNC(=O)OC(C)(C)C)c2N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, sodium borohydride (0.76 g, 20.0 mmol) was added in two portions to a solution of nickel (II) chloride hydrate (1.57 g, 6.62 mmol) in methanol (160 mL), and the mixture was stirred at room temperature for 15 minutes. A solution of {2-[2-(2-[bis{4-methoxybenzyl}amino]-6-chloro-5-methyl-3-nitropyridin-4-ylamino)ethoxy]ethyl}carbamic acid tert-butyl ester (8.37 g, 13.3 mmol) in methanol (10 mL) and dichloromethane (10 mL) was then added, and the addition funnel was rinsed with a mixture of methanol (10 mL) and dichloromethane (10 mL). The reaction was stirred for two hours, during which time additional sodium borohydride was added three times (0.5 g, 0.5, g and 1.0 g). Water (200 mL) was then added, and the methanol was removed under reduced pressure. The remaining solution was extracted with diethyl ether (700 mL, 300 mL), and the combined extracts were washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to product the crude product contaminated with water. Toluene (300 mL) was added and then removed by distillation to provide [2-(2-{3-amino-2-[bis-(4-methoxybenzyl)amino]-6-chloro-5-methylpyridin-4-ylamino}ethoxy)ethyl]carbamic acid tert-butyl ester, which was used in Part F without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C.CCOCC>C(O)C>[CH2:9]([C:7]1[CH:8]=[C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)[CH:4]=[N:5][CH:6]=1)[CH3:10]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1cncc(CBr)c1
Solvent: CCOCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cncc(CSc2nc(C)cc(O)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(bromomethyl)-5-ethylpyridine (4.82 g, 24.08 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (2.22 g, 15.65 mmol) in anhydrous ethanol (100 mL) at 0° C. was added triethylamine (9.74 g, 13.41 mL, 96.35 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated to provide a crude residue. Ether was added to precipitate the triethylamine hydrobromide salt. The solid was filtered and was washed with ether several times. The solvent was evaporated to provide a crude residue, which was purified by combiflash using 0-10% MeOH:dichloromethane. 2-{[(5-ethylpyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol was obtained as a white solid (2.83 g, 45% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.14 (t, 3H), 2.21 (s, 3H), 2.61 (q, 2H), 4.35 (s, 2H), 6.00 (bs, 1H), 7.69 (s, 1H), 8.31 (s, 1H), 8.45 (s, 1H); M+261.5.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[H][H].CCCCCC.C(OCC)(=O)C>CO.[Pd]>[NH2:29][C:25]1[CH:24]=[C:23]([NH:22][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:11][CH:10]=3)[N:4]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: [H][H]
Reactant: COCCOCOc1ccc(Nc2ncc(F)c(Nc3cccc([N+](=O)[O-])c3)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCCOCOc1ccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a suspension of Pd/C (0.2 g) in methanol (20 mL), 5-fluoro-N2-(4-((2-methoxyethoxy)methoxy)phenyl)-N4-(3-nitrophenyl)pyrimidine-2,4-diamine (0.40 g) was added under nitrogen atmosphere into the autoclave at room temperature. Hydrogen pressure (70 psi) was applied and the reaction mixture was stirred overnight at room temperature. The reaction was monitored on TLC using hexane:ethyl acetate (4:6) as mobile phase. After completion, the reaction mixture was filtered using Celite and the filter cake was washed with methanol. The combined filtrate was concentrated under reduced pressure at 40° C. to give 0.3 g of N4-(3-aminophenyl)-5-fluoro-N2-(4-((2-methoxyethoxy)methoxy)phenyl)pyrimidine-2,4-diamine as a solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:18])[CH2:12][NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:5][C:4]=1[C:19]#[N:20]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:18])[CH2:12][NH:13][CH:14]2[CH2:15][CH2:16][CH2:17]2)=[CH:5][C:4]=1[C:19]#[N:20]
Reactant: N#Cc1cc(C(=O)CNC2CCC2)cc(C#N)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CCC2)cc(C#N)c1N

Procedure:
m.p. of the hydrochloride: 258° C. (decomp.), was prepared from 4'-amino-2-cyclobutylamino-3',5'-dicyano-acetophenone analogous to Example 48.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:23]=[C:22]([NH2:24])[NH:21][N:20]=2)[CH2:15][CH2:14]1.[Cl:25][C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=1.O>CS(C)=O>[Cl:25][C:26]1[N:27]=[N:28][C:29]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:23]=[C:22]([NH2:24])[NH:21][N:20]=3)[CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: Nc1cc(C2CCNCC2)n[nH]1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(C2CCN(c3ccc(Cl)nn3)CC2)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
1,8-Diazabicyclo[5.4.0]-7-undecene (0.750 mL, 5.02 mmol) was added to a suspension of 3-(piperidin-4-yl)-1H-pyrazol-5-amine hydrochloride (0.400 g, 1.67 mmol) produced in Reference Example 33 in dimethyl sulfoxide (4 mL), and the mixture was stirred at room temperature for 10 minutes. Then, 3,6-dichloropyridazine (0.249 g, 1.67 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour and at 60° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: ethyl acetate/methanol=95/5-90/10 (gradient)] to obtain the title compound (0.330 g, yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10](OS(C)(=O)=O)[CH3:11])=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH:10]([CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane (Step F, 12 g, 34 mmol) in DMF (50 mL) was added sodium azide (11 g, 0.17 mol). After stirring at 120° C. for 1 h, the reaction mixture was poured into water (200 mL), and the product was extracted with ether (2×100 mL). The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated to dryness, and the residue was purified on a silica gel column eluting with hexane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH:10]([OH:19])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+]>O>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH:10]([OH:19])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2ncccc2Cl)CC1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CCN(c2ncccc2Cl)CC1O
Reaction time: 2 h

Procedure:
Ethyl 1-(3-chloro-2-pyridinyl)-3-hydroxy-4-piperidinecarboxylate in water (55 mL) was treated with sodium methoxide (0.5 M, 8 mL, 4.0 mmol) at room temperature. After 2 hours, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to provide the title compound. MS (EI, M+H)+257.