Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]=[C:23]=[S:24])=[O:21])=[CH:16][CH:15]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([CH3:47])[CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]=[C:23]=[S:24])=[O:21])=[CH:18][CH:19]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:23]([NH:22][C:20](=[O:21])[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[S:24])=[C:42]([CH3:47])[CH:41]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Methoxy-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (37 mg, yield 45%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16].O>CN(C=O)C.C(OCCCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@H:14]([CH3:18])[C:15]([OH:17])=[O:16]
Reactant: Fc1cccc2[nH]ccc12
Reactant: C[C@H](Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](C(=O)O)n1ccc2c(F)cccc21
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 27.6 %

Procedure:
To a cooled (0-5° C.) solution of 4-fluoro-indole (44.2 g, 327 mmol) in dry DMF (400 mL) was added sodium hydride (55-65% dispersion in mineral oil, 36 g, 817 mmol) in portions. The resulting suspension was stirred at 0-5° C. for 20 minutes. (2S)-(−)-2-Bromopropionic acid (31.8 mL, 343 mmol) was added dropwise. During the addition, the temperature was kept below 10° C. by cooling in an ice-bath. Upon completion of addition, the mixture was stirred at RT for 2 hours. The mixture was poured into water (1300 mL), and the aqueous solution was washed with heptanes (400 mL) and EtOAc (2×400 mL). The aqueous layer was acidified with concentrated aqueous HCl solution (85 mL, pH<1), and extracted with EtOAc (2×400 mL). The combined organic layers were washed with 1 N aq. HCl solution (2×300 mL) and with a saturated aqueous NaCl solution (300 mL). The solution was dried over sodium sulfate, filtered, and evaporated to dryness to afford a yellow oil (67.6 g, 99%, 82% ee). This oil (67.6 g, 323 mmol) was dissolved in 200 mL n-butyl acetate and (5)-L-(−)-α-methylbenzylamine (41.1 mL, 323 mmol) was added to the warm (50° C.) solution. The mixture was left crystallizing over the weekend. The formed solid was collected by filtration and washed with butyl acetate and heptanes (2×) (68.7 g, 91% ee). This material was recrystallized twice from 500 mL water/15% ethanol (1st recr.: 95% ee, 2nd recr.: 97.5% ee). This material was dissolved in EtOAc (300 mL) and washed with 1 N aqueous HCl (2×200 mL) and saturated aqueous NaCl solution (200 mL), dried over sodium sulfate, filtered, and evaporated to dryness giving (2R)-2-(4-fluoro-indol-1-yl)-propionic acid (18.7 g, 28%) as a greenish oil (purity: 97.5%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH2:6])[CH3:3].[CH3:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13](=O)[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=O)=[CH:11][CH:10]=1.O>C(O)(=O)C>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][N:6]1[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=2[CH:14]=[C:13]1[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:24][CH:23]=1
Reactant: CN(C)CCN
Reactant: COc1ccc(C(=O)CC2CCCCC2=O)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3c(n2CCN(C)C)CCCC3)cc1

Procedure:
4.41 g (0.05 mole) of dimethylaminoethylamine are added dropwise to a stirred suspension of 12.32 g (0.05 mole) of 2-(p-methoxyphenacyl)cyclohexanone in glacial acetic acid. After refluxing overnight, ice and water are added, and the cloudy mixture is washed with ether. The aqueous solution is basified with 10% sodium carbonate and extracted with ether. Removal of the ether after drying over sodium sulfate gives a light brown oil which solidifies on cooling. The resulting solid is recrystallized from methanol to give 1-(2-dimethylaminoethyl)-2(p-methoxyphenyl)-4,5,6,7-tetrahydroindole as white needles, m.p. 81°-82° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][C:22]=1[C:23]#[N:24])[CH2:9][N:10]1[C:14]([CH2:15][O:16]C(=O)C)=[CH:13][N:12]=[CH:11]1.[OH-].[Na+]>C1COCC1>[ClH:2].[Cl:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:9][N:10]2[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[CH:11]2)[CH:20]=[CH:21][C:22]=1[C:23]#[N:24]
Reactant: CC(=O)OCc1cncn1Cc1ccc(C#N)c(Oc2ccccc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CO)cc1Oc1ccccc1Cl
Reaction time: 3.5 h

Procedure:
To a solution of acetic acid 3-[3-(2-chloro-phenoxy)-4-cyano-benzyl]-3H-imidazol-4-ylmethyl ester hydrochloride (as described in Example 14)(0.112 g, 0.268 mmol) in THF (2.0 mL) was added 1M NaOH (0.536 mL). After 3.5 hr. the reaction was partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc layer was washed with H2O, brine, and dried (MgSO4). Filtration and concentration in vacuo gave the title compound after conversion to the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:23]#[CH:24])([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO.Cl>O.[Fe]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[NH2:20])([C:23]#[CH:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)OCC)CC1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: C#CC1(Oc2ccc(F)cc2N)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a stirred solution of 22.3 g of 1-ethoxycarbonyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine in 535 methanol was added 37 ml of concentrated hydrochloric acid in 150 ml of water. To the stirred mixture was added 78.6 g of iron (reduced, electrolytic) in aliquots. The reaction temperature rose to 45°. The reaction mixture cooled to ambient temperature over 1.5 hr. The mixture was poured into water/ice/sodium carbonate solution, extracted with dichloromethane, washed with water and saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of solvent provided 20.2 g of an oil. An aliquot of 10.0 g of the oil was dissolved in ether and filtered through 200 g of alumina and the filtrate was evaporated. The residue was dissolved in 10% methanol/dichloromethane, filtered through 200 g of silica gel, and the filtrate was evaporated to provide 8.6 g (84.7%) of product, as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH:4]=[CH:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][CH:5]1[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: NCc1ccccc1
Product: CC1(C)C=CC(NCc2ccccc2)CC1

Procedure:
Using the procedure outlined in Example 1, 4,4-dimethyl-2-cyclohexen-1-one and benzylamine were converted to the title compound: RT=2.39 min; m/z (ES+)=216.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:15]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]1>[Pd].CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:15]1[CH2:19][CH2:18][C:17]([F:20])([F:21])[CH2:16]1
Reactant: CNc1cc(N2CCC(F)(F)C2)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1cc(N2CCC(F)(F)C2)c(C(=O)OC)cc1N
Reaction time: 5 h

Procedure:
A mixture of methyl-2-[3,3-difluoro-pyrrolidinyl]-4-methylamino-5-nitro-benzoate (1.32 g, 4.19 mmol), Pd/C (100 mg) and MeOH (25 mL) is stirred for 5 h under 3 bar H2-atmosphere. The mixture is filtered, and the filtrate is concentrated.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=2)=[CH:13][C:12]=1[F:31]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH:18]=2)=[CH:13][C:12]=1[F:31]
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(Cl)c(F)c2)CC1
Product: Fc1cc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)ccc1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:26])[N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C:11]=2[CH:12]=1)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:26]=[C:4]1[C:3]([C:1]#[N:2])=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(C#N)c(=O)n2-c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc2c(n(-c3ccccc3)c1=O)CCNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-cyano-2-oxo-1-phenyl-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate (150 mg, 0.427 mmol) was dissolved in CH2Cl2 (3 mL) and TFA (0.3 mL). The mixture was stirred at room temperature overnight. All solvents were removed under vacuum to give crude 2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carbonitrile. LCMS: m/z 252.15 (M+H)+, 0.78 min (method 7).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][O:5][C:6]=1[CH3:7].[Cl:8][C:9]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:10]=1[NH2:11]>COCCOC.O.CCOC(C)=O>[Cl:8][C:9]1[CH:15]=[C:14]([C:2]2[CH:3]=[N:4][O:5][C:6]=2[CH3:7])[CH:13]=[CH:12][C:10]=1[NH2:11]
Reactant: Cc1oncc1I
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1oncc1-c1ccc(N)c(Cl)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 44 %

Procedure:
Prepared according to Method B (Preparation 83) using 4-iodo-5-methylisoxazole and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in DME/H2O 1/1 (1.4 mL). The reaction mixture was stirred at 80° C. for 7 hours before being diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified using Biotage silica gel column chromatography eluting with Cyclohexane/EtOAc 99/1 to 80/20 to give the title product as a colourless oil (36 mg, 44%). 1H NMR (500 MHz, CDCl3): δ 2.54 (s, 3H), 4.16 (br s, 2H), 6.83 (d, J=8.2 Hz, 1H), 7.09 (dd, J=8.2, 2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 8.28 (s, 1H).
Reaction SMILES: CC1OC(C2NC3C(=CC=CC=3)N3[C:8]2=[C:9]2[N:31]([CH3:32])[C:29](=[O:30])[N:28]([CH3:33])[C:26](=[O:27])[C:10]2=C3C2C=CC=CC=2)=CC=1.CC1NC(=O)NC(=O)C=1.COS(OC)(=O)=O>>[CH3:32][N:31]1[C:9]([CH3:8])=[CH:10][C:26](=[O:27])[N:28]([CH3:33])[C:29]1=[O:30]
Reactant: Cc1ccc(C2Nc3ccccc3-n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Agent: Cc1cc(=O)[nH]c(=O)[nH]1
Solvent: COS(=O)(=O)OC
Product: Cc1cc(=O)n(C)c(=O)n1C

Procedure:
Synthesis of PPQ-102—Synthesis of PPQ-102 was achieved in six steps as illustrated in FIG. 2B. Commercially available 6-methyluracil 1 was methylated using dimethylsulfate to produce 1,3,6-trimethyluracil 2, which upon Friedel-Crafts acylation using zinc chloride as a catalyst yielded 5-benzoyl-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione 3 as a white powder. Bromination of 3 followed by reaction with N-(2-aminophenyl)acetamide generated amino-protected intermediate 5. The acetamido function of 5 was hydrolyzed and resultant intermediate 6 was cyclocondensed with 5-methylfurfural to yield yellowish-white racemic PPQ-102 7. Aromatic compound 8, which lacks a stereocenter, was prepared from 7 by oxidation with potassium permanganate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.[Cl-].[NH4+:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:18])=[N:13]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)COCC(=O)N1
Reactant: [NH4+]
Agent: [Cl-]
Product: C[C@@]1(c2cc(Br)ccc2F)COCC(N)=N1

Procedure:
In analogy to step a) in the synthesis of Building block I, the treatment of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one followed by the nucleophilic substitution with ammonium chloride yielded the title compound; its hydrochloride was obtained as a white solid (74% of theory). Mass (calculated) C11H12BrFN2O [287.13]; (found) [M+H]+=287, [M+2-H]+=289.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[C:14]([CH2:16]CSSCCC#N)#[N:15].IC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:4]2[C:3]([S:2][CH2:1][CH2:16][C:14]#[N:15])=[CH:7][NH:6][N:5]=2)[CH:9]=1
Reactant: N#CCCSSCCC#N
Reactant: CSc1c[nH]nc1-c1cccnc1
Agent: Ic1c[nH]nc1-c1cccnc1
Solvent: CCOC(C)=O
Product: N#CCCSc1c[nH]nc1-c1cccnc1
Yield: 62 %

Procedure:
Compound 21R was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 3-(2-cyano-ethyldisulfanyl)-propionitrile as the disulfide and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flash chromatography (ethyl acetate)) Yield: 62%. (oil). 1H-NMR (200 MHz, CDCl3): δ 9.20 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.33 (dt, J=8 Hz, 2 Hz, 1H), 7.82 (s, 1H), 7.43-7.37 (m, 1H), 2.76 (t, J=7 Hz, 2H), 2.45 (t, J=7 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:15])=[N:4][C:5](=[O:14])[N:6]([C@H:8]2[CH2:11][C@@H:10]([CH2:12][OH:13])[CH2:9]2)[CH:7]=1.P(Cl)(Cl)(Cl)=O.O.C([O:24][P:25]([O:30]CC)([O:27]CC)=[O:26])C>>[P:25]([OH:30])([OH:27])([OH:26])=[O:24].[F:1][C:2]1[C:3]([NH2:15])=[N:4][C:5](=[O:14])[N:6]([C@H:8]2[CH2:9][C@@H:10]([CH2:12][OH:13])[CH2:11]2)[CH:7]=1
Reactant: CCOP(=O)(OCC)OCC
Agent: Nc1nc(=O)n([C@H]2C[C@@H](CO)C2)cc1F
Agent: Nc1nc(=O)n([C@H]2C[C@@H](CO)C2)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=P(O)(O)O
Reaction time: 20 h

Procedure:
A solution of 5-fluoro-1-[cis-3-(hydroxymethyl)cyclobutyl]cytosine (23 mg, 0.11 mmol) in triethylphosphate was cooled to 0° C. and treated dropwise with phosphorus oxychloride. The mixture was aged for 20 h at 0° C. and then treated with water (0.1 mL). The mixture was aged for 6 h and then concentrated under high vacuum. The crude gum was purified by chromatography on SP207 resin with a gradient from 0-20% methanol in water. Fractions were analyzed by HPLC (reverse phase) and appropriate fractions were lyophilized to give 5-fluoro-1-[cis-3-(hydroxymethyl)cyclobutyl]cytosine mono-phosphate (30 mg) as a gum and was used in next step without further purification. A suspension of 5-fluoro-1-[cis-3-(hydroxymethyl)cyclobutyl]cytosine monophosphate (30 mg) in tert-butanol (1 mL) and water (1 mL) was heated under a gentle reflux while a solution of DCC (91 mg, 0.44 mmol) in tert-butanol was added dropwise over a 1 h period. After 8 h under reflux, the mixture was cooled to rt and the resulting precipitate was filtered and washed with water (3×20 mL). The filtrate was extracted with ether (3×40 mL) and then frozen and lyophilized to give the phosphomorpholidate intermediate (65 mg) as pale yellow solid. A solution of the phosphomorpholidate intermediate (65 mg), anhydrous tributylammonium pyrophosphate (176 mg, 0.386 mmol) in dry DMSO (2 mL) was aged for 4 d at ambient temperature. The yellow mixture was applied directly to a column of DEAE Sephadex (11 mm×220 mm) and eluted with water (50 mL) and then a gradient from 0.35M to 0.45M triethylammonium bicarbonate. Fractions were analyzed by HPLC (reverse phase) and appropriate fractions were pooled and lyophilized. The resulting gum was co-evaporated with ethanol (3×20 mL) under high vacuum to give the triethylammonium-tributylammonium salt of 5-fluoro-1-[cis-3-(hydroxymethyl)-cyclobutyl]-cytosine triphosphate (50 mg) as a sticky white solid. 1H NMR (D2O, 400 MHz): δ 1.22 (t, 20H, Et3N), 2.14 (m, 2H), 2.49 (m, 3H), 3.08 (d, 2H), 3.19 (q, 12H, Et3N), 4.64 (m, 1H),), 8.12 (d, J=7.2 Hz, 1H). 31PNMR (D20, referenced to H3PO4) δ −22.9 (1P), −10.5 (2P).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][CH2:7][C:8]1([C:13]([O:15]CC)=O)[S:12][CH2:11][CH2:10][S:9]1)#[N:4]>O1CCOCC1.O>[O:15]=[C:13]1[CH:5]([C:3]#[N:4])[CH2:6][CH2:7][C:8]21[S:9][CH2:10][CH2:11][S:12]2
Reactant: CCOC(=O)C1(CCCC#N)SCCS1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CC1CCC2(SCCS2)C1=O
Temperature: 100 °C

Procedure:
A mixture of NaH (60%, 31.8 mg, 0.79 mmol) and ethyl 2-(3-cyanopropyl)-1,3-dithiolane-2-carboxylate (171.5 mg, 0.66 mmol) in dioxane (5 mL) was heated at 100° C. overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried with Na2SO4, and evaporated to afford crude 6-oxo-1,4-dithiaspiro[4.4]nonane-7-carbonitrile: LCMS tR=1.67 Min (5 min run, UV254nm), Mass calculated for, M+213.0, observed LC/MS m/z 214.1 (M+H).
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)=[N:8][CH:9]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:33](C)=O.[Na+].C([O-])(O)=O.[Na+].Cl>C(Cl)CCl>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH3:33])[CH2:18][CH2:17]3)[N:15]=2)=[N:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Brc1cnc(Nc2nc(C3CCNCC3)cs2)c(Oc2ccccc2)c1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CN1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 123.5 %

Procedure:
To a mixture of 5-bromo-3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine dihydrochloride (80 mg, 0.16 mmol), paraformaldehyde (7.15 mg, 0.24 mmol), and ClCH2CH2Cl (2 mL) was added NaBH(OAc)3 (134 mg, 0.64 mmol) and the reaction was stirred at ambient temperature for 2 days. Poured into saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (10% methanol in EtOAc with 0.2% NH3) to afford the title compound (51.2 mg, 62.3% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.00 (bs, 1H), 10.22 (bs, 1H), 8.23 (s, 1H), 7.48-7.38 (m, 3H), 7.22 (t, 1H), 7.12 (m, 2H), 6.77 (s, 1H), 3.46 (m, 2H), 3.05 (m, 2H), 2.82 (m, 1H), 2.74 (d, 3H), 2.14 (m, 2H), 1.88 (m, 2H). Mass spectrum (apci) m/z=445.3 (M+H-2HCl).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])[CH:2]=1.S(Cl)([Cl:18])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:18])=[O:11])[CH:2]=1
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(-c2cccnc2)c1

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-3-yl)benzoic acid (1.5 g, 7.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 1.5 g crude 3-(pyridin-3-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (950 mg, 5.8 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added 3-(pyridin-3-yl)benzoyl chloride (1.5 g, 7 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(3-(pyridin-3-yl)benzamido)benzoate as a yellow solid (1.8 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([CH2:14][NH:16][CH:17]2[CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H]1CN(Cc2ccccc2)C[C@@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
(3R,4R)-1-Benzyl-N-cyclopropyl-4-methyl-3-pyrrolidinecarboxamide (70.0 g) was dissolved in toluene (700 mL). While this solution was chilled in an ice water bath, a borane/dimethyl sulfate complex (90%, 34.3 mL) was added dropwise. The mixture was then stirred for 15 min, was refluxed and was allowed to cool to room temperature. A 10% aqueous Na2CO3 solution (400 mL) was added, and the mixture was stirred at 100° C. for 2 hours and was then allowed to cool to room temperature. The toluene layer was separated, washed with water (2×250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by distillation under reduced pressure to give (3S,4R)-1-benzyl-3-cyclopropylaminomethyl-4-methylpyrrolidine as a colorless oil (62.1 g).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)[CH3:14]>>[CH2:13]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH3:14]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 18 and using ethyl 4-iodobenzoate (1.4 mL) and (R)-4-ethyloxazolidin-2-one (979 mg) described in Preparation Example 26, the title compound (2.6 g) was obtained.