Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[CH:14]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[N:43]([O-:45])=[O:44].[Na+]>>[N+:43]([C:14]1[N:13]([C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=2[C:15]=1[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:28]=1)([O-:45])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)c([N+](=O)[O-])n2[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 143.7 %

Procedure:
(R)-tert-Butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (2) (400 mg, 0.85 mmol) was treated with TFA (6 mL). The resulting mixture was stirred at rt for 30 min, then NaNO2 (41 mg, 0.59 mmol) was added. After the stifling was continued for 1 hr, the reaction was concentrated under vacuum. DCM (10 mL×2) was added and concentrated to remove the residue TFA to afford (R)-6-nitro-5-(4-phenoxyphenyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (160) (353 mg, quant. yield) as a yellow oil, which was used directly in next step without purification. LC-MS (ESI): m/z (M+1) 417.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>C1COCC1>[F:16][C:17]([F:24])([F:23])[C:18](=[O:19])[CH2:12][C:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(C)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a THF suspension of 1-(3-methyl-4-nitro-phenyl)-ethanone (2.0 g), sodium hydride (0.6 g) was slowly added and the mixture was stirred for 1 hour. After adding ethyl trifluoroacetate (1.6 g), the reaction mixture was refluxed for 5 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was suspended in ethyl acetate and washed with 1N aqueous solution of hydrochloric acid. After drying the organic layer with sodium sulfate, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 4,4,4-trifluoro-1-(3-methyl-4-nitro-phenyl)-butane-1,3-dione (2.5 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCCCc1ccccc1
Yield: 87 %

Procedure:
The title compound was prepared by the procedure of Preparation 2 in 87% yield from 5-phenylvaleric acid (Aldrich Chem. Co.) and lithium aluminum hydride.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]#[N:27])[CH:20]=3)[O:16][N:15]=2)=[N:12][CH:13]=1)=[O:7])(C)(C)C>C(O)=O>[OH:7][C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]#[N:27])[CH:20]=3)[O:16][N:15]=2)=[N:12][CH:13]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2noc(-c3cc(F)cc(C#N)c3)n2)nc1
Solvent: O=CO
Product: N#Cc1cc(F)cc(-c2nc(-c3ccc(C(=O)O)cn3)no2)c1
Temperature: 40 °C

Procedure:
A mixture of 3-(5-tert-butoxycarbonylpyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (69 mg, 0.19 mmol) in formic acid (98%, 3.5 mL) was heated at 40° C. for 17 hours. Evaporation of the solvent in vacuo afforded crude 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-cyano-5-flourophenyl)-1,2,4-oxadiazole as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-fluoro-1-methylbenzene (5 g, 26.4 mmol) dissolved in conc. sulfuric acid (20 mL) was added potassium nitrate (2.67 g, 26.4 mmol) in sulfuric acid (5 mL) at 0° C. After stirring at 0° C. for 1 hr, the reaction was diluted with water, extracted with ethyl acetate (3×40 mL). The combined organic phases were washed with saturated sodium bicarbonate solution and brine sequentially, and then dried over Na2SO4. The crude product obtained after concentration was purified by silica gel column chromatography with mixed solvent hexanes/EtOAc (95/5) to afford 1-bromo-5-fluoro-2-methyl-4-nitrobenzene as an orange solid. 1H NMR (400 MHz, chloroform-d) δ 7.93 (d, 1H, J=7.6 Hz), 7.50 (d, 1H, J=10 Hz), 2.43 (s, 3H).
Reaction SMILES: N1CCCC1.C([O:9][C:10]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[C:19]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC=C)=[O:43])=[CH:37][CH:36]=3)=[C:31]([Cl:48])[CH:30]=2)[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C=C>O1CCOCC1.O.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>[C:15]([O:14][C:12]([C:11]1[C:10]([OH:9])=[C:22]([C:23]([F:26])([F:24])[F:25])[CH:21]=[CH:20][C:19]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=2)=[C:31]([Cl:48])[CH:30]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3)c(Cl)c2)ccc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
Pyrrolidine (0.525 ml, 6.29 mmol) and tetrakis(triphenylphosphine)palladium (0) (41 mg, 0.035 mmol) were added to a solution of tert-butyl 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-2-chloro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (960 mg, 1.56 mmol) obtained in Example (13-4) in a mixture of 1,4-dioxane (9.5 ml) and water (0.5 ml), and the mixture was stirred at room temperature for 3 hours. After water was poured into the reaction mixture and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=75/25-40/60) to give the title compound as a white powder (446 mg, yield: 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][Si:10]([CH3:17])([CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.[C@H:32]1([NH2:42])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:16][Si:10]1([CH3:17])[CH2:11][C@@H:12]([C:13](=[O:15])[NH:42][C@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][CH2:34][CH2:33]2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[Si](C)(C)C[C@H]1C(=O)O
Reactant: N[C@@H]1CCCc2ccccc21
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[Si](C)(C)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid (1.0 g, 3.9 mmol) in DMF (9 mL) at 0° C. was added EDC (1.3 g, 6.6 mmol) and 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol (0.53 g, 3.9 mmol). The resulting mixture was stirred for 5 minutes and treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 0.60 g, 4.1 mmol) in DMF (4 mL) and then DIEA (0.94 mL, 5.4 mmol). The reaction mixture was stirred at rt for 1.5 h and diluted with ethyl acetate and brine. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 (eluting with 20% EtOAc/hexane) to afford the title compound (1.25 g, 83%). 1H NMR (400 MHz, CDCl3) δ 7.22-7.02 (m, 4H), 5.22-4.61 (m, 2H), 3.16-2.65 (m, 3H), 2.52 (d, J=14.5 Hz, 1H), 2.12-1.95 (m, 1H), 1.88-1.76 (m, 3H), 1.52-1.28 (m, 11H), 0.43-0.16 (m, 6H); MS(ESI+) m/z 389.4 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.O>[OH:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1
Reactant: CCOC(=O)[C@@H](Cc1ccsc1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@@H](CO)Cc1ccsc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
A solution of 2.15 g of ethyl (2R)-2-(acetylamino)-3-(3-thienyl)propanoate in 24 cm3 of ethanol, stirred under an inert atmosphere, is brought to a temperature of 20° C. 0.5 g of sodium borohydride is added and the reaction medium, which is slightly brown, is stirred for 24 hours at room temperature. A further 0.2 g of sodium borohydride is added and stirring is continued for 24 hours. After evaporation of the reaction mixture under reduced pressure (2 kPa) at a temperature in the region of 40° C., a solid residue is obtained, which is taken up in 30 cm3 of water. This mixture is extracted with twice 100 cm3 of ethyl acetate and the organic phase is then dried over magnesium sulfate and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. to give an off-white solid which is dried in an oven under vacuum (10 Pa) at a temperature in the region of 48° C. 1.4 g of N-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]acetamide are obtained in the form of an off-white solid melting at about 105° C. to become pasty. 1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.78 (s: 3H); 2.64 (dd, J=14 and 8 Hz: 1H); 2.87 (dd, J=14 and 5.5 Hz: 1H); from 3.20 to 3.40 (mt: 2H); 3.90 (mt: 1H); 4.76 (t, J=5.5 Hz: 1H); 6.99 (dd, J=5 and 1 Hz: 1H); 7.16 (dd, J=3 and 1 Hz: 1H); 7.43 (dd, J=5 and 3 Hz: 1H); 7.70 (d, J=8.5 Hz: 1H).
Reaction SMILES: Br[CH:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[CH:8]([CH3:10])[CH3:9])[CH3:7]
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)C(C)C
Product: CCOC(=O)C(Sc1ccc(OC)cc1)C(C)C
Yield: 99 %

Procedure:
2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product was isolated. Yield 99%; Light yellow oil; MS: 271 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:7]2=[N:8][C:9]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][C:11](=[O:12])[N:6]2[CH2:5][CH2:4][CH2:3]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[O:12]=[C:11]1[N:6]2[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[C:7]2=[N:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:10]1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCCn2c1nc(-c1ccncc1)cc2=O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC1CCCn2c1nc(-c1ccncc1)cc2=O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.07 g (0.29 mmol) of (+/−) 9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one dissolved in 1 mL of dichloromethane at 10° C. was added 0.034 g (0.29 mmol) of phenylisocyanate dissolved in 1 mL at 10° C. The resulting mixture was stirred at 10° C. for 30 min. The mixture was stirred at room temperature for 1 h.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=2)=[CH:13][C:12]=1[F:18]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Cc1cc(Br)cc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Br)c(F)c2)cc(C)n1
Temperature: 150 °C
Yield: 73.8 %

Procedure:
A mixture of 4-bromo-2,6-dimethyl-pyridine (1 g, 5.4 mmol), 4-bromo-3-fluoro-phenol (0.59 g, 5.4 mmol), and potassium carbonate (0.89 g, 6.4 mmol) in xylenes (2 ml) was heated at 150° C. (oil bath temperature) in a sealed tube for 48 hours. After cooling to room temperature the mixture was diluted with EtOAc and filtered through a diatomaceous earth pad. The filtrate was evaporated till dryness and the crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 10% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 17 (1.18 g, 72%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].CC(C)([O-])C.[K+].[CH3:14][O:15][C:16]1[CH:39]=[CH:38][C:19]([CH2:20][C@H:21]([CH:35]([CH3:37])[CH3:36])[CH2:22][C@H:23]([NH:27][C:28](=[O:34])[O:29]C(C)(C)C)[C@@H:24]2[CH2:26]O2)=[CH:18][C:17]=1[O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45]>CS(C)=O>[CH3:14][O:15][C:16]1[CH:39]=[CH:38][C:19]([CH2:20][C@H:21]([CH:35]([CH3:37])[CH3:36])[CH2:22][C@H:23]2[C@H:24]([CH2:26][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]3=[O:7])[O:29][C:28](=[O:34])[NH:27]2)=[CH:18][C:17]=1[O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Reactant: O=C1CCCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCCOc1cc(C[C@@H](C[C@@H]2NC(=O)O[C@H]2CN2CCCCC2=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.115 g of piperidin-2-one and 0.136 g of potassium tert-butoxide in 3 ml of dimethyl sulphoxide is stirred at room temperature over 30 minutes, admixed with 0.25 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1(S)-(R)-oxiranylpentyl}carbamate (font size changed from Arial 10 to 11) (Example 1b) and subsequently stirred further at room temperature overnight. The reaction mixture is poured onto ice-water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellow oil. Rf=0.33 (95:5 dichloromethane-methanol); Rt=3.94 (gradient I).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[C:1]([NH:9][C:10]([NH:16][CH2:15][CH:12]1[CH2:14][CH2:13]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCC1CC1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCC1CC1)c1ccccc1
Yield: 100.4 %

Procedure:
Add benzoyl isothiocyanate (500 g, 3.06 mol) to chloroform (5 L) and cool to <5° C. Add a solution of cyclopropylmethylamine (230 g, 3.22 mol) in chloroform (500 mL) with vigorous stirring maintaining a temperature below 20° C. Remove the ice-water bath, and stir the mixture at room temperature overnight. Concentrate the mixture in vacuo to obtain the desired intermediate as a white solid (720 g, 100%). MS (APCI) m/z: 235 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10](O)=[O:11])[CH:7]=1.C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:8]2[CH2:13][C:14](=[O:16])[O:15][C:10](=[O:11])[CH2:9]2)[CH:7]=1
Reactant: O=C(O)CC(CC(=O)O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2cc(Cl)ccc2[N+](=O)[O-])CC(=O)O1
Temperature: 130 °C

Procedure:
Asymmetry, 2001, 12, 419-426), 4-(5-chloro-2-nitro-phenyl)tetrahydropyran-2,6-dione (18c) is prepared by heating 3-(5-chloro-2-nitro-phenyl)pentanedioic acid (18b) (2.88 g, 10.0 mmol) in acetic anhydride (Ac2O) (2.83 mL, 3.06 g, 30 mmol) at reflux (about 130° C. oil bath temperature). After cooling to room temperature, the title compound (18c) is precipitated with diethyl ether (Et2O) the solid collected by filtration, washed with cold Et2Oand dried under reduced pressure to remove residual solvents.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C:3]([O:5][C@H:6]([C@H:9]1[O:18][C@@H:12]2[O:13][C:14]([CH3:17])(C)[O:15][C@@H:11]2[CH2:10]1)[CH2:7][CH3:8])=[O:4].[C:20]([O:23]C(=O)C)(=[O:22])[CH3:21].C(O)(=O)C.S(=O)(=O)(O)O>C(Cl)Cl>[CH3:19][CH:2]([CH3:1])[C:3]([O:5][C@H:6]([C@@H:9]1[CH2:10][C@@H:11]([O:15][C:14](=[O:13])[CH3:17])[C@@H:12]([O:23][C:20](=[O:22])[CH3:21])[O:18]1)[CH2:7][CH3:8])=[O:4]
Reactant: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@@H](OC(C)=O)[C@@H](OC(C)=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a stirred solution of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl] 2-methylpropanoate (compound 42a, 470 mg, 1.73 mmol), acetic anhydride (0.81 mL, 8.64 mmol) and acetic acid (0.51 mL, 8.64 mmol) in DCM (10 mL) was added concentrated sulfuric acid (18.4 μL, 0.17 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-20% EtOAc in petroleum ether) to afford 105 mg of [(1S)-1-[(2S,4R,5R)-4,5-diacetoxytetrahydrofuran-2-yl]propyl] 2-methylpropanoate (compound 42b).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([CH:11]=O)=[C:6]2[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:3]=1.C(O)C.[NH:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26].N1CCCCC1>O>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([CH:11]=[C:30]3[NH:24][C:25](=[O:26])[NH:27][C:28]3=[O:29])=[C:6]2[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:3]=1
Reactant: O=C1CNC(=O)N1
Reactant: Nc1cc(Nc2cccc(Cl)c2)nc2c(C=O)cnn12
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: Nc1cc(Nc2cccc(Cl)c2)nc2c(C=C3NC(=O)NC3=O)cnn12
Temperature: 80 °C
Yield: 54 %

Procedure:
To the reaction vial, 7-amino-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (411 mg, 1.4 mmol) was added to ethanol (5.2 mL) along with hydantoin (143 mg, 1.4 mmol) and piperidine (141 μL, 1.4 mmol). The reaction was heated at 80° C. for 60 minutes in the microwave. The reaction was then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water and cold ethanol. The material was dried under vacuum overnight. The product, 5-((7-amino-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was recovered as a red solid in 54% yield. LCMS (M+1=370)
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25](=O)[C:26]#[CH:27])[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.Cl.[OH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[NH:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][N:36]=[C:34]([C:33]([OH:32])([CH3:38])[CH3:37])[N:35]=3)[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)c(Cl)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)cc1
Temperature: 75 °C
Yield: 42.5 %

Procedure:
To a solution of 5-chloro-6-(4-methoxy-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one from Step H (660 mg, 1.56 mmol) in acetonitrile (3 mL) was added 2-hydroxy-2-methylpropionamidine HCl (324 mg, 2.34 mmol) and potassium carbonate (645 mg, 4.68 mmol) and heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated to provide a dark red oil. Normal phase chromatography (ethyl acetate/heptanes) provided the pyrimidine as a yellow oil (336 mg, 42%). MS (M+H): 507
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].Cl.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20]Cl)[CH3:17]>CO>[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)[CH3:17]
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCOc1ccc(-n2ccnc2)cc1

Procedure:
Dissolve 4-(1H-imidazol-1-yl)phenol (4.02 g, 25.1 mmol) in methanol (100 mL) containing potassium hydroxide (3.52 g, 62.74 mmol). Add 2-diethylaminoethyl chloride hydrochloride to this mixture and heat to reflux under nitrogen overnight. Cool the mixture and concentrate in vacuo. Dissolve the residue in water (50mL) and adjust the pH to 13 with 1N NaOH solution. Wash with 2×100 mL of methylene chloride, combine, dry (Na2SO4) and concentrate in vacuo. This residue is dissolved in ethanol and 37% hydrochloric acid is added until pH=1.0. Concentration affords crystals which are recrystallized from isopropanol/ethanol (ca. 4+1). Drying at 80° C. for 5 hr at 1.0 mm give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10]OS(C)(=O)=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]2([CH3:30])[CH3:29])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH2:25][C:24]2([CH3:30])[CH3:29])=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cn1
Reactant: COc1ccc(CN2CCNCC2(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(Cc3ccc([N+](=O)[O-])cn3)CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
A mixture of methanesulfonic acid 5-nitro-pyridin-2-ylmethyl ester (Step 112.3) (0.5 g, 2.16 mmol), 1-(4-methoxy-benzyl)-2,2-dimethyl-piperazine (Step 108.2) (0.655 g, 2.8 mmol, 1.3 equiv), cesium carbonate (0.845 g, 2.6 mmol, 1.2 equiv), and DMF (4 ml) was stirred for 5 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by by silica gel column chromatography (DCM DCM/MeOH, 99:1) to provide 0.642 g of the title compound as a red solid: ESI-MS: 371.2 [M+H]+; tR=3.18 min (System 1); TLC: Rf=0.44 (DCM/MeOH, 9:1).