Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=O)[CH2:17][CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1.Cl.[NH2:21][OH:22].CC([O-])=O.[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=[N:21][OH:22])[CH2:17][CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: NO
Reactant: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(=NO)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 89.1 %

Procedure:
To a solution of 170 (100 mg, 0.39 mmol) in MeOH (5 mL) was added hydroxylamine hydrochloride (54 mg, 0.78 mmol) and NaOAc (100 mg, 1 mmol). The mixture was refluxed overnight. The mixture was extracted with EtOAc, washed sequentially with H2O and brine and dried (Na2SO4), filtered and concentrated in vacuo to afford 95 mg (90%) of 1-[1-(tetrahydro-pyran-2-yl)-1H-benzoimidazol-5-yl]-propan-1-one oxime (172) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]([S:23]([CH3:26])(=[O:25])=[O:24])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+].O>O1CCCC1.CO.Cl>[CH3:1][C:2]([S:23]([CH3:26])(=[O:24])=[O:25])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCc1ccc(Oc2ccccc2)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoate (312 mg, 0.829 mmol) in tetrahyrofuran/methanol (4:1, 10 mL) was added a solution of lithium hydroxide monohydrate in water (1.66 M, 3.32 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCl (1 N in water) and extracted with ether 2×. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoic acid as an oil. 285 mg. LCMS: (M−1) 347.3
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Br:7][C:8]1[CH:9]=[N:10][C:11](I)=[N:12][CH:13]=1.[OH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>O.C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:7][C:8]1[CH:9]=[N:10][C:11]([C:21]2[CH:22]=[C:17]([CH2:16][OH:15])[CH:18]=[CH:19][CH:20]=2)=[N:12][CH:13]=1
Reactant: Brc1cnc(I)nc1
Reactant: OCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCc1cccc(-c2ncc(Br)cn2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 70.0 g (660 mmol) of sodium carbonate in 325 ml of water is added to a solution, kept under nitrogen, of 95.0 g (332 mmol) of 5-bromo-2-iodopyrimidine in 325 ml of toluene, and the mixture is heated to 80° C. 2.3 g (3.3 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, and a solution of 50.0 g (329 mmol) of 3-(hydroxymethyl)benzeneboronic acid in 650 ml of ethanol is subsequently added dropwise. The reaction mixture is stirred at 80° C. for 18 hours. The reaction mixture is cooled to room temperature and filtered. 1 l of ethyl acetate and 1 l of water are added to the filtrate. The organic phase is separated off, dried over sodium sulfate and evaporated. The residue is recrystallised from 2-propanol: [3-(5-bromopyrimidin-2-yl)-phenyl]methanol as pale-yellow crystals; m.p. 115-116° C.; LCMS 265, 267.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1Br
Temperature: 85 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
Into a round-bottom flask, was placed a solution of 2-bromo-4-fluorobenzoic acid (21.8 g, 99.5 mmol, 1.00 equiv) in a solvent mixture of sulfuric acid (20 mL) and methanol (20 mL). The resulting solution was stirred for 5 h at 85° C., then cooled and cooled and concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL) and washed with brine (200 mL) then aqueous NaHCO3 (100 mL. Note: gas evolution), dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a light yellow oil (22.0 g, 95%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[CH:6]=1.[Br-].[CH3:9][C:10]1[N:15]=[C:14]([Zn+])[CH:13]=[CH:12][CH:11]=1.C1COCC1>CCOCC.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>[Cl:7][C:5]1[CH:6]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:9])[N:15]=2)[S:3][CH:4]=1
Reactant: Cc1cccc([Zn+])n1
Reactant: Clc1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(-c2cc(Cl)cs2)n1
Temperature: 40 °C
Yield: 28 %

Procedure:
To a solution of 2-bromo-4-chloro-thiophene (Gronowitz, Rosén Chemica Scripta, 1971, 1, 33) (1.50 g, 7.60 mmol) and 0.5 M solution of 6-methyl-2-pyridylzinc bromide in THF (23.00 mL, 11.39 mmol) is added Pd(PPh3)4 (0.18 g, 0.15 mmol). The solution is heated at 40° C. overnight, diluted with Et2O (50 mL), washed with sat. NH4Cl (40 mL), dried over MgSO4, filtered on concentrated. The residue is purified by ISCO column chromatography (5%-20% EtOAc/hexane gradient) furnish the title compound (0.45 g, 2.15 mmol, 28%). 1H NMR (CDCl3), δ 2.56 (s, 3H), 7.02 (d, 7.7 Hz, 1H), 7.13 (d, J=0.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.39 (d, J=0.9 Hz, 1H), 7.54 (dd, J=7.9, 7.7, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:26])[CH2:25][O:24]3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.O1CCCC1.C([BH-](CC)CC)C.[Li+].OO>O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:24])([CH3:25])[CH3:26])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Agent: CC[BH-](CC)CC
Agent: OO
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 2.5 °C

Procedure:
To a 2.0 L 3-neck oven-dried RBF was charged the crude (S)-3-[(S)-1-(4-bromo-phenyl)-ethyl]-6-(2-methyl-oxiranylmethyl)-6-phenyl-perhydro-1,3-oxazin-2-one (7) and 750 mL of anhydrous tetrahydrofuran. The resulting solution was agitated and cooled to Tint=2-3° C. To the agitated clear solution was charged 1.0 M lithium triethylborohydride in tetrahydrofuran (Super Hydride, 348 mL, 348 mmol, 1.8 equiv). The addition is exothermic and addition controlled to maintain Tint=<8° C. The resulting solution was agitated at Tint=2-3° C. for 1.5 h and then allowed to warm to Tint=10-13° C. over a 2.5 h, which HPLC analysis indicates ˜94 A % (220 nm) conversion. To the agitated solution was charged a solution of hydrogen peroxide (95.7 mL of a 35 wt % aqueous solution diluted with 400 mL of water, 1.08 mol, 5.60 equiv). The addition is highly exothermic and addition controlled to maintain Tint=<25° C. The resulting solution was diluted with 1.00 L of methyl tert-butyl ether (MTBE) and washed with 1.00 L of water followed by 500 mL of a ˜30 wt % solution of sodium thiosulfate. The organic solution was dried with anhydrous sodium sulfate, filtered, and then concentrated via reduced pressure. The resulting material was subjected to flash silica chromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 g of material consisting of both diastereomers (1.98:1 dr) and 41 g of the desired diastereomer (>99:1 dr). The material consisting of the mixed fractions was recrystallized from 250 mL of isopropyl acetate (IPAC) and 200 mL of heptane (anti-solvent) to produce upon filtration 31.3 g of product (95.7 A % at 220 nm, 74:1 dr). The two samples were combined to produce 72.3 g of product (83.6% yield for the two step operation). Analytical data for 8: 1H-NMR spectroscopy (400 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 7.25-7.21 (m, 2H), 6.82-6.79 (m, 2H), 5.61 (q, J=6.9 Hz, 1H), 2.83 (ddd, J=2.5, 5.4 and 11.6 Hz, 1H), 2.39 (ddd, J=5.7, 12.0 and 14.1 Hz, 1H), 2.27 (ddd, J=2.6, 4.8 and 14.0 Hz, 1H), 2.21-2.14 (m, 3H), 2.08 (s, 1H), 1.49 (d, J=7.0 Hz, 3H), 1.18 (s, 3H), 1.13 (s, 3H). 13C-NMR spectroscopy (100 MHz, CDCl3) δ 153.2, 142.6, 138.5, 131.6, 129.13, 129.10, 128.0, 125.3, 121.6, 84.2, 71.4, 54.1, 53.3, 36.4, 33.6, 32.1, 30.8, 15.6.
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.C(C1CC=CCCC=CCC(C(C)C)N=N1)(C)C.[CH:37]1([CH:42]2[CH2:53][CH:52]=[CH:51][CH2:50][CH2:49][CH:48]=[CH:47][CH2:46][CH:45]([CH:54]3[CH2:58][CH2:57][CH2:56][CH2:55]3)[N:44]=[N:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[NH2:43][CH:42]([CH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH:45]([NH2:44])[CH:54]1[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: C1=CCC(C2CCCC2)N=NC(C2CCCC2)CC=CCC1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Agent: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Product: NC(CCCCCCCCC(N)C1CCCC1)C1CCCC1

Procedure:
If there are used in the manner described under (a), instead of 250 g (1 mol) of 3,12-diisopropyl-1,2-diaza-1,5,9-cyclododecatriene, 200 g (0.666 mol) of crude 3,12-dicyclopentyl-1,2-diaza-1,5,9-cyclododecatriene (diasterioisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, the procedure otherwise being the same, there is obtained, after chromatographical purification and distillation, 39.2 g (19% of theory) of 1,10-diamino-1,10-dicyclopentyldecane in the form of colourless oil [b.p. 174°-178° C./0.002 Torr; nD20 =1.4885; IR (liquid) inter alia bands at 3355, 3278 and 1613 cm-1 ].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=O)=[CH:17][C:16]=4[CH3:24])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]=[O:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)(Cl)=O>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:23]=[CH:22][C:18]([C:19]#[N:21])=[CH:17][C:16]=4[CH3:24])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(N)=O)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a mixture of 4-(9-chloro-6-formyl-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl)-3-methylbenzamide (100 mg, 0.271 mmol) and triethylamine (0.189 mL, 1.36 mmol) in N,N-dimethylformamide (2.7 mL) was added thionyl chloride (0.0293 mL, 0.406 mmol) at room temperature, and the mixture was stirred at 40° C. for 30 min. After triethylamine (0.189 mL, 1.36 mmol) and thionyl chloride (0.0293 mL, 0.406 mmol) were added to the reaction mixture, the mixture was stirred at 40° C. for 10 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow solid (66.2 mg, 0.189 mmol, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[F:9][C:10]([F:29])([F:28])[C:11]1[CH:12]=[C:13]([C:17]2[N:18]=[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[NH:20][CH:21]=2)[CH:14]=[CH:15][CH:16]=1.C(N(CC)C(C)C)(C)C.O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[NH:20][CH:21]=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:29])([F:28])[F:9])[CH:12]=3)[N:18]=2)[CH2:23][CH2:24]1
Reactant: FC(F)(F)c1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Reactant: Clc1ccncc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1cccc(-c2c[nH]c(C3CCN(c4ccncc4Br)CC3)n2)c1
Temperature: 160 °C
Yield: 64 %

Procedure:
A mixture of 3-bromo-4-chloropyridine (100.0 mg; 0.52 mmol; 1.0 eq.), 4-[4-(3-trifluoromethyl-phenyl)-1h-imidazol-2-yl]-piperidine (153.4 mg; 0.52 mmol; 1.0 eq.), N,N-diisopropylethylamine (0.26 ml; 1.56 mmol; 3.0 eq.) in NMP (2.0 ml) in a microwave vial was heated at 160° C. for 4 h. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound in 64% yield. LC-MS: (M+1=451, obsd.=451).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH:10](Br)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CN(C)C=O>C(N(CC)CC)C>[CH2:1]([O:8][C:9](=[O:16])[CH:10]([O:25][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(Br)C(=O)OCc1ccccc1
Reactant: O=C(O)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(OC(=O)c1ccncc1)C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
A total of 29.5 g of benzyl-(RS)-α-bromo-isocaproate was added dropwise at 60° with stirring over a period of 15 minutes to a solution of 12.8 g of isonicotinic acid in a mixture of 60 ml. of dimethyl-formamide and 14.8 ml of triethylamine. The reaction mixture was stirred for 5 hours at 90°. The triethylamine hydrobromide was then filtered off by suction and the filtrate evaporated under reduced pressure at 60°. The residue was dissolved in 100 ml of ethyl acetate and filtered and the filtrate washed three times with 15 ml portions of 1-N potassium bicarbonate solution and twice with 20 ml portions of water. The ethyl acetate solution was dried with magnesium sulphate and evaporated under reduced pressure at 45°. Benzyl-(RS)-2-(isonicotinoyloxy)-isocaproate was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][C:10]1[C:5]2[C:4]([Cl:11])=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: ClCCl
Product: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (105 mg, 0.560 mmol) in CH2Cl2 (7 mL) at room temperature, NBS (109 mg, 0.610 mmol) was added. The mixture was stirred at room temperature for 18 h. CH2Cl2 was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (142 mg).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([NH:17][C:16](=[O:18])[C:15]4[CH:19]=[C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C5CCCCO5)=[O:26])[CH:21]=[CH:22][C:14]=4[O:13]3)[CH2:8]2)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([NH:17][C:16](=[O:18])[C:15]4[CH:19]=[C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:21]=[CH:22][C:14]=4[O:13]3)[CH2:8]2)=[CH:35][CH:36]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2)NO
Yield: 66.8 %

Procedure:
A solution of (±)-(E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (45 mg, 0.091 mmol) in DCM (5 ml) was treated with 4 M HCl in dioxane (0.5 ml) as described in Example 30, STEP C to give (±)-(E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide (25 mg, hydrochloride salt) as a white solid.
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1>C(Cl)Cl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:37]3[CH2:36][CH2:35][NH:34][C@@H:33]([CH3:32])[CH2:38]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: C[C@H]1CNCCN1
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1
Temperature: 85 °C
Reaction time: 18.5 h
Yield: 93.1 %

Procedure:
A dimethyl sulfoxide suspension (5 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (476.1 mg, 1.23 mmol) and (2S)-2-methylpiperazine (616.4 mg, 6.15 mmol) was heated at 100° C. to dissolve and the resulting mixture was stirred at 85° C. for 18.5 hours. (2S)-2-Methylpiperazine (123.3 mg, 1.23 mmol) was added and the resulting mixture was further stirred at 85° C. for 5.5 hours, left standing to cool, poured into methylene chloride-methanol (10:1), and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 9:1) to give the title compound (516.0 mg, 93%) as a pale yellow solid.
Reaction SMILES: [CH3:1]N(C)C1C=CC=CC=1.[C:10]([O:13][CH2:14][C:15]1[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=[C:22]([OH:23])[N:17]2[N:16]=1)(=[O:12])[CH3:11].C(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[C:10]([O:13][CH2:14][C:15]1([CH3:1])[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=[C:22]([OH:23])[N:17]2[NH:16]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OCc1cc(O)n2nc(COC(C)=O)nc2n1
Reactant: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC1=NC2=NC(C)(COC(C)=O)NN2C(O)=C1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In 300 ml of phosphorus oxychloride was added dropwise 28 ml of N,N-dimethylaniline, and 30.5 g of 2,5-bis(acetoxymethyl)-7-hydroxy-s-triazolo[1,5-a]pyrimidine was added to the mixture and the mixture was stirred at 50 ° C. for 1.5 hours. An oily residue obtained by removing phosphorus oxychloride was dissolved in 500 ml of chloroform and ice-cooled. After addition of crushed ice and water to the mixture and stirring thereof, a chloroform layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, the mixture was condensed. This was applied to a silica gel column chromatography (eluent chloroform) and fractions containing the title compound were condensed to obtain 14 g of the title compound as an oily product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:22]4[CH:21]=[CH:20][N:19]=[C:18]([C:17]([F:32])([F:16])[F:31])[CH:23]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: FC(F)(F)c1cc(Nc2ccccn2)ccn1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Product: O=C(N(c1ccnc(C(F)(F)F)c1)c1ccccn1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added N-(2-(trifluoromethyl)pyridin-4-yl)pyridin-2-amine (48 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 427.4, found 428.1 (M+1)+. Retention time 2.91 minutes.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27]OS(C)(=O)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:33]([O-:36])(=[S:35])[CH3:34].[K+]>CN(C)C=O>[C:33]([S:35][CH2:27][C@@H:11]1[CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:36])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-methanesulfonyloxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5.21 g) in N,N-dimethylformamide (52 ml) was added potassium thioacetate (1.83 g) and the mixture was stirred at 50°-60° C. for 1 hour. The reaction mixture was poured into ice-water (150 ml) and extracted 3 times with ethyl acetate (50 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was subjected to a column chromatography on silica gel (150 g) and eluted with a mixture of n-hexane and ethyl acetate (3:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-acetylthiomethyl-4-t-butyldimethylsilyloxy-1-(4nitrobenzyloxycarbonyl)pyrrolidine (4.70 g).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20].C[O-].[Na+]>CO>[NH2:20][C:19]1[N:21]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:3][N:18]=1
Reactant: N=C(N)N
Reactant: CN(C)C=CC(=O)c1ccccc1
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Product: Nc1nccc(-c2ccccc2)n1
Yield: 82 %

Procedure:
To a stirred solution of 3.0 g (17.1 mmol) 3-(dimethylamino)acrylophenone and 10.2 g (56.5 mmol) guanidine carbonate in 50 ml methanol was added 21.2 ml (114 mmol) sodium methylate (5.4M in methanol) and the mixture heated at reflux for 3 hours. The reaction mixture was then concentrated in vacuo. On addition of 50 ml water, a precipitate appeared which was collected by filtration and washed sequentially with water and ether to afford 2.4 g (82%) 2-amino-4-phenylpyrimidine as a crystalline solid. EI-MS m/e (%): 171 (M+, 100), 170 ([M—H]+, 94).