Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:15][C@@H:14]3[C@@H:10]([CH2:11][NH:12][CH2:13]3)[CH2:9]2)=[C:4]([F:16])[CH:3]=1.O.[C:18](=[O:21])([O-:20])[O-].[K+].[K+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CC(C)=O>[C:18]([N:12]1[CH2:11][C@@H:10]2[C@@H:14]([CH2:15][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[CH:3][C:4]=3[F:16])[CH2:9]2)[CH2:13]1)([O:20][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:21]
Reactant: Nc1ccc(N2C[C@H]3CNC[C@H]3C2)c(F)c1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(N2C[C@H]3CN(C(=O)OCc4ccccc4)C[C@H]3C2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
cis-3-Benzyl-7-(2-fluoro-4-nitrophenyl)-3,7-diazabicyclo[3.3.0]octane (9.11 g, 26.71 mmol), THF (100 mL), and methanol (50 mL) are combined with 10% palladium on carbon (6.67 g) and ammonium formate (16.83 g, 266.90 mmol) under nitrogen, heated to reflux for 2.5 hours, cooled to ambient temperature, stirred 15 hours, filtered through celite and concentrated in vacuo to give crude cis-3-(4-amino-2-fluorophenyl]-3,7-diazabicyclo[3.3.0]octane. cis-3-(4-Amino-2-fluorophenyl]-3,7-diazabicyclo[3.3.0]octane, water (100 mL), acetone (100 mL), and potassium carbonate (7.75 g, 56.07 mmol) are combined, cooled to 0° C., and benzyl chloroformate is added slowly. The reaction is warmed to ambient temperature, stirred 15 hours, concentrated in vacuo, and diluted with ethyl acetate. The organic phase is washed with water (2×150 mL) and saline (150 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with hexane/ethyl acetate (80/20). The appropriate fractions are combined (Rf =0.41, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 121-122° C.
Reaction SMILES: [Na].Cl[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1.[CH3:15][OH:16]>C(OCC)C>[CH3:15][O:16][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1
Reactant: CO
Reactant: CCc1cc([N+](=O)[O-])c(Cl)nc1C
Agent: [Na]
Solvent: CCOCC
Product: CCc1cc([N+](=O)[O-])c(OC)nc1C
Temperature: 50 °C
Yield: 80 %

Procedure:
Sodium metal (100 mg, 4.3 mmol) was dissolved in methanol (5 mL) under a nitrogen atmosphere. A solution of 2-chloro-3-nitro-5-ethyl-6-methylpyridine (677 mg, 3.37 mmol) in methanol (5 mL) was added dropwise. The reaction was warmed at 50° C. for four hours. The reaction was cooled, diluted with diethyl ether, the ether layer washed with water, dried (Na2SO4), filtered through a pad of charcoal and evaporated to yield 535 mg (80%) of product.
Reaction SMILES: Br[C:2]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19](Br)([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4].[OH-:28].[Na+].[OH2:30]>ClCCl.CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-]>[CH2:24]([C:2]([OH:30])([CH2:26][CH3:27])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([OH:28])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4])[CH3:25]
Reactant: O
Reactant: CCC(Br)(CC)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)Br)cc2)cc1
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(O)(CC)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)O)cc2)cc1

Procedure:
To a solution of 29.15 g (0.0587 mol) of 2-bromo-1-{4-[4-(2-bromo-2-methyl-propionyl)-phenoxy]-phenyl}-2-ethyl-butane-1-one dissolved in 60 ml of dichloromethane, 16.88 g (0.211 mol) of 50% NaOH and 291.5 mg of 50% BTEAC were added. The reaction was refluxed for 3 h, adding every 30′, 291.5 mg of BTEAC, then diluted with water and dichloromethane.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[F:12][C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][O:3][CH2:2][N:17]2[CH:18]=[C:13]([F:12])[CH:14]=[N:15][C:16]2=[O:19])=[CH:6][CH:7]=1
Reactant: ClCOCc1ccc(Cl)cc1
Reactant: O=c1ncc(F)c[nH]1
Product: O=c1ncc(F)cn1COCc1ccc(Cl)cc1
Reaction time: 6 h
Yield: 70 %

Procedure:
was prepared as described in Example 3 from 4-chlorobenzyl chloromethyl ether (see Preparation 5a and 5b) (4 mmol) and 5-fluoropyrimidin-2-one (4 mmol) by allowing the reaction to proceed for 6 hours at room temperature; yield 70% (0.75 g), m.p. 103° C. 1H NMR (CDCl3): δ4.62 (CH2Ph), 5.30 (CH2N), 7.17 (Ph), 7.63 and 8.53 (H-4, H-6). IR(KBr): 1670 cm-1 (CO).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([Cl:17])[N:3]=1.[NH3:18]>[Cu].CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:18])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([Cl:17])[N:3]=1
Reactant: Nc1nc(Cl)c(-c2ccc(Cl)cc2Cl)c(Cl)n1
Reactant: N
Agent: [Cu]
Solvent: CCO
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(Cl)n1
Temperature: 180 °C
Yield: 25 %

Procedure:
A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dichloropyrimidine (0.5 g) (Example 32) EtOH saturated with ammonia (20 ml) and copper powder (0.05 g) was heated in an autoclave at 180° C. for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.12, 25%), mp. 219° C. Microanalysis:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]2[NH:1][C:32](=[O:34])[N:9]([C@@H:10]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[C:3]2=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(Cl)cc2N)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(=O)[nH]c3cc(Cl)cnc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 189 %

Procedure:
A stirred solution of (R)-tert-butyl 3-(3-amino-5-chloropyridin-2-ylamino)pyrrolidine-1-carboxylate (680 mg, 2.2 mmol) and i-Pr2NEt (1.2 mL, 6.6 mmol0 in CH2Cl2 (50 mL) was cooled in an ice bath and solid triphosgene (213 mg, 0.72 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was concentrated to leave a black solid which was purified by chromatography on a 12-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(6-chloro-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (461 mg, 62%) as a black solid. LC-MS Method 1 tR=1.65 min, m/z=339, 283.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:12](=O)[CH3:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:21](OCC)(=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(O)(=O)C.O.[NH2:36][NH2:37]>O1CCCC1>[CH2:25]([O:24][C:22]([C:21]1[NH:36][N:37]=[C:12]([C:9]2[S:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:11][CH:10]=2)[CH:13]=1)=[O:23])[CH3:26]
Reactant: CC(=O)c1cnc(-c2ccccc2)s1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cnc(-c3ccccc3)s2)n[nH]1
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of 0.10 g (0.49 mmol) of the above-prepared 1-(2-phenyl-thiazol-5-yl)-ethanone was added 0.11 g (0.98 mmol) of 1M potassium tert-butoxide in tetrahydrofuran. The solution was allowed to stir for 0.5 hours. 0.15 g (0.98 mmol) of diethyl oxalate was added and the solution was allowed to stir for 2 hours. The reaction was quenched with aqueous ammonium chloride and partitioned with ethyl acetate. The organic phase was twice washed with aqueous ammonium chloride, once with water, once with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in ethanol (10 ml). To the ethanolic solution was added 0.04 g (0.64 mmol)of glacial acetic acid followed by 0.03 g (0.64 mmol) of hydrazine monohydrate. The solution was allowed to stir for 3 hours at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 9:1 hexanes:ethyl acetate as eluant to give 75 mg of the title compound (51%). 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H) 7.98 (m, 2H) 7.47 (m, 3H) 7.10 (s, 1H) 4.42 (q, 2H) 1.42 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:13])[C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=O)[C:19]([CH3:26])=[N:18]2.P(Br)(Br)([Br:29])=O.[OH-].[NH4+]>CN(C)C=O>[Br:29][C:8]1[C:7]([CH3:13])=[N:6][C:5]2[C:10]([N:9]=1)=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2.[Br:29][C:20]1[C:19]([CH3:26])=[N:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([Cl:14])[CH:16]=2)[N:21]=1
Reactant: Cc1nc2ccc(Cl)cc2[nH]c1=O
Reactant: Cc1nc2cc(Cl)ccc2[nH]c1=O
Reactant: O=P(Br)(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Cl)ccc2nc1Br
Product: Cc1nc2ccc(Cl)cc2nc1Br
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 20.1 %

Procedure:
6-Chloro-3-methylquinoxalin-2(1H)-one compound with 7-chloro-3-methylquinoxalin-2(1H)-one (300 mg, 771 μmol, Eq: 1.00) was stirred neat in phosphoryl tribromide (1.6 g, 5.58 mmol, Eq: 7.24). N,N-Dimethylformamide (1 drop) (771 μmol, Eq: 1.00) was added and the mixture was stirred at 105° C. for 1.5 h. The mixture was added to ice water and neutralized with aqueous 25% ammonium hydroxide. The precipitated solid was filtered and dried under high vacuum followed by preparative HPLC to give 3-Bromo-6-chloro-2-methyl-quinoxaline with 2-bromo-6-chloro-3-methyl-quinoxaline (40 mg, 10.1%) as a light brown solid. MS: m/z=195.03 (M+H+)
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C1(C)C=CC(S(O[CH2:32][CH2:33][CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)(=O)=O)=CC=1>>[CH:36]1([O:35][CH2:34][CH2:33][CH2:32][O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Cc1ccc(S(=O)(=O)OCCCOC2CCCCC2)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOC3CCCCC3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.795 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 1.07 g of 3-cyclohexyloxypropyl toluene-4-sulphonate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.39 (1:1 EtOAc-heptane); Rt=5.43.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:17][C:7]1[C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4](=[O:8])[NH:5][CH:6]=1
Reactant: BrBr
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(Br)c[nH]c(=O)c1[N+](=O)[O-]
Reaction time: 5.5 h
Yield: 90 %

Procedure:
To a stirred solution of 4-methyl-3-nitro-2-pyridone (0.45 g, 2.9 mmol) in glacial acetic acid (3 mL) was added sodium acetate (0.24 g) followed by bromine (0.15 mL) dropwise. After 5.5 hours, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and concentrated to give 5-bromo-4-methyl-3-nitro-2-pyridone (0.62 g, 2.6 mmol, 90%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].Br[CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH2:9][NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:11][CH:12]=1)#[N:15]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
Prepared using General Procedure 13. To a stirred solution of methyl 2-aminoacetate hydrochloride (5.07 g, 40.4 mmol) and 4-(bromomethyl)benzonitrile (7.20 g, 36.7 mmol) in DMF (40 mL) was added potassium carbonate (11.2 g, 81 mmol). After stirring at room temperature for 3 h the reaction mixture was diluted with water (300 mL) and the product extracted into EA (200 mL). The organics were washed with water (200 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (MeOH/DCM) to afford 1.6 g (21%) of methyl 2-((4-cyanobenzyl)amino)acetate INT-73 as a clear oil. LCMS-ESI (m/z) calculated for C11H12N2O2: 204; found 205 [M+H]+, tR=0.4 min (Method 10).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[N:4][C:5](Cl)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[K+].[CH2:24]([OH:26])[CH3:25]>>[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[N:4][C:5]([O:26][CH2:24][CH3:25])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COc1cc(-c2nc(Cl)c(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOc1nc(-c2ccc(Cl)c(OC)c2)c(Cl)cc1C(F)(F)F

Procedure:
6.5 g (18 mmol) of 3,6-dichloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine and 6.1 g (109 mmol) of potassium hydroxide in 100 ml of ethanol were stirred at 23° C. for 41 h. The solvent was then removed by distillation and the residue was taken up in 100 ml of dilute hydrochloric acid. Extraction was carried out three times with 100 ml of methylene chloride each time. The combined extracts were dried over sodium sulfate and then concentrated. Yield: 6.3 g (85%) of a colorless oil (purity about 90%).
Reaction SMILES: [SH2:1].O(C)[Na].[NH2:5][C:6]1[C:7]2[C:14]([C:15]#[N:16])=[CH:13][N:12]([CH2:17][O:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[C:8]=2[N:9]=[CH:10][N:11]=1>>[NH2:5][C:6]1[C:7]2[C:14]([C:15](=[S:1])[NH2:16])=[CH:13][N:12]([CH2:17][O:18][CH:19]([CH2:20][OH:21])[CH2:22][OH:23])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: N#Cc1cn(COC(CO)CO)c2ncnc(N)c12
Reactant: S
Agent: CO[Na]
Product: NC(=S)c1cn(COC(CO)CO)c2ncnc(N)c12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Dry H2S was passed through a NaOCH3 solution (1 M) (6 mL) with magnetic stirring and cooling at 0° C. for 10 minutes. Compound 18a (0.13 g; 0.5 mmole) was then added in one portion to the stirred solution of NaSH which had been generated in situ as described above. The mixture was stirred at room temperature for 4 hours and then allowed to stand at 0° C. for an additional 12 hours. The mixture was filtered and the filtrate conc. in vacuo. The residue was purified by a column (2×40 cm; prepacked in CH2Cl2) of silica gel (20 g; 70-230 mesh). Elution of the column with CH2Cl2 :CH3OH (94:6) gave the title compound, which was crystallized from H2O to afford pure 18c (0.04 g; yield 28%); m.p. 180°-181° C.; IR (KBr) γ3400 and 3180 (NH2, OH), 1640 cm-1 ; UVλmax nm: (pH 1), 241 (2750) 301 (1220); MeOH, 283 (5387); pH 11, 216 (26200) 278 (5806); 1H NMR (DMSO-d6): δ3.3-3.45 (m, 4H, H-3', H-4'), 3.60 (m, 1H, H-4'), 4.62 (t, 2H, OH), 5.65 (s, 2H, H-1'), 7.9 (s, 1H, C6 --H), 7.98 (brs, 2H, D2O exchangeable, NH2), 8.15 (s, 1H, C2 --H), 9.45 and 9.60 (brs, 1 each, D2O exchangeable, CSNH2). Anal. (C11H15N5O3S.H2O). (C,H,N).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:11](=[O:12])[CH:10]([C:13](=[O:22])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:8](=[O:9])[N:7]([CH3:23])[C:5]1=[O:6].Cl[C:25]1[N:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1.Cl>C1(C)C=CC=CC=1.CS(C)=O.O>[CH3:23][N:7]1[C:8](=[O:9])[CH:10]([C:13](=[O:22])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:25]3[N:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[CH:17][CH:16]=2)[C:11](=[O:12])[N:4]([CH3:3])[C:5]1=[O:6]
Reactant: COc1ccc(Cl)nn1
Reactant: CN1C(=O)C(C(=O)Nc2ccc(O)cc2)C(=O)N(C)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccc(NC(=O)C3C(=O)N(C)C(=O)N(C)C3=O)cc2)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4.0 g (0.06 mole) of 85% KOH are added to 8.7 g (0.03 mole) of 1,3-dimethyl-5-(4-hydroxyphenylcarbamoyl)barbituric acid in 70 ml of toluene and 50 ml of dimethyl sulfoxide. The mixture is dewatered with a water separator at reflux temperature. After the toluene has been distilled off, 4.3 g (0.03 mole) of 3-chloro-6-methoxypyridazine are added. The bath temperature is increased gradually until a temperature in the range from 120° to 140° C. is reached, and the mixture is kept at this temperature for 2 hours. The mixture is then cooled to 80° C., neutralised with dilute hydrochloric acid, cooled to room temperature and diluted with water. The precipitate is isolated by filtration, washed with water and dried.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][CH2:12][O-].[Na+].O1CCOCC1.S(OCC)(OCC)(=O)=O>O>[O:1]([CH2:8][CH2:9][O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: OCCOc1ccccc1
Agent: CCOS(=O)(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOCCOc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
143.0 g (1.04 mol) of 2-phenoxyethanol, 81.0 g (1.19 mol) of sodium ethylate and 291 g of 1,4-dioxane are placed in a 1-liter four-necked flask equipped with a stirrer, a thermometer, a distillating column and a nitrogen-inlet tube. The solution is heated to 90° to 105° C., and then 200 g of the solvent is removed in a period of 2 hours. The distillating column is then replaced by a dropping funnel, and 183.5 g (1.19 mol) of diethyl sulfate is added thereto dropwise at 45° C. over a period of 30 minutes. After stirring the reaction mixture at 60° C. for 1 hour, the reaction product is placed in water and extracted with ether. The solvent is removed using an evaporator, and further distilled under reduced pressure to yield 160 g of ethyl 2-phenoxyethyl ether.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>C(Cl)Cl>[Si:46]([O:45][CH2:44][CH2:43][NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 75 °C

Procedure:
To a scintillation vial containing N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine (17 mg, 0.040 mmol) and K2CO3 (22.06 mg, 0.160 mmol) was added DMF (0.3 ml) and (2-bromoethoxy)(tert-butyl)dimethylsilane (9.55 mg, 0.040 mmol). The reaction mixture was capped and heated to 75° C. for 7 hr. The reaction mixture was diluted with DCM and washed with H2O, sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude solid was purified by reverse phase preparative HPLC. Collected fractions were combined, neutralized with Saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and used directly in next step. LCMS (m/z): 584.3 (MH+), retention time=0.87 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[OH:23]>CN(C=O)C.O>[Br:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
18.2 g (0.13 mol.) of potassium carbonate and 18.74 g (13.03 ml, 0.11 mol.) benzyl bromide is added to 2-bromo-4-chlorophenol (1) (25 g, 0. 12mol) in DMF (25 ml) under nitrogen. The reaction mixture is heated (oil bath temperature 115° C.) for 1.5 hours and then allowed to cool and left to stand overnight at RT. The reaction mixture is diluted with distilled water (100 ml) and then extracted with Et2O (2×100 ml). The organic extracts are combined, washed with 1M sodium hydroxide (100 ml) and concentrated in vacuo to leave a colorless oil. This oil is purified by flash chromatography (SiO2, pentane) to yield a colorless oil which crystallised on standing to give the title compound as a colorless solid, (29.14 g, 81%), m.p. 49-50.5° C. δH (250 MHz, CDCl3), 7.55 (d, J=2.6 Hz, 1H), 7.46 (m, 5H), 7.19 (dd, J=8.9, 2.5 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.13 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[CH:24]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27][CH2:26][CH2:25]1.[O-]CC.[Na+]>C(O)C.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:32]=[C:30]([NH:29][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:31]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2ccc(OC)cc2)nn2c(Cl)cccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a mixture of 1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (1.57 g, 5.0 mmol) and N-cyclopentylguanidine hydrochloride (1.07 g, 6.6 mmol) in ethanol (50 mL) was added sodium ethoxide (2.5 mL, 21 wt % in ethanol, 6.6 mmol). The resulting suspension was stirred overnight at room temperature, then diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (7:3 to 3:2 hexanes-ethyl acetate) provided 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (1.77 g, 83%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.44 (d, 1 H), 8.05 (d, 1 H), 7.60 (d, 2 H), 7.28 (m, 1 H), 7.06–6.96 (m, 3 H), 6.38 (d, 1 H), 5.31 (broad, 1 H), 4.38 (m, 1 H), 3.88 (s, 3 H), 2.12 (m, 2 H), 1.84–1.53 (m, 6 H); MS m/z 420 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspenson of 2,6-dichloro-3-nitropyridine (1.0 g, 0.00518 mole) and glycine ethyl ester hydrochloride (0.725 g, 0.00518 mole) in absolute ethanol (10 ml) was added triethylamine (1.05 g, 0.0104 mole). The resulting solution was stirred overnight at room temperature under nitrogen. An additional portion of absolute ethanol (10 ml) was added and the suspension was filtered and the solid was washed with 3-10 ml portions of absolute ethanol. The combined filtrate and washings were evaporated under reduced pressure at room temperature to give a yellow solid which was triturated in water (30 ml) collected by filtration, and rinsed with additional water. The solid was recrystallized from isopropyl ether/light petroleum ether, and the resulting solid was purified by column chromatography (10 g of silica gel) with 1:1 isopropyl ether/light petroleum ether as the eluting solvent. The appropriate fraction was recrystallized from isopropyl ether and dried under high vacuum to give the title compound, mp 77.5°-80° C.