Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[S:11])[NH2:10])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:24])[CH2:18][C:19](=O)[CH:20](Br)[CH3:21])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17](=[O:24])[CH2:18][C:19]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=2)[S:11][C:20]=1[CH3:21])[CH3:15]
Reactant: CCOC(=O)CC(=O)C(C)Br
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 47.2 %

Procedure:
To a solution of 4-trifluoromethyl-benzene-thioamide (1.845 g, 9 mmol) in ethanol (15 mL, 200 proof) add ethyl-4-bromo-3-oxo-pentanoate (2.07 g, 9 mmol). Seal this solution warm the solution to 170° C. in a Personal Chemistry™ microwave oven and stir at this temperature for 20 min. Cool the resulting solution to room temperature, concentrate under reduced pressure and purify the residue by flash chromatography (elute with 30% ethyl acetate/10% dichloromethane in heptane) and obtain the title compound as a white solid (1.4 g). MS (ESI) m/z 330 (M+H); H1 NMR (CDCl3) δ1.87 (bs, 1H), 2.49 (s, 3H), 4.86 (s, 2H), 7.67 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=[O:31])[CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:18])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].[BH4-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([OH:31])[CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[OH:18])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)CCC(=O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(O)CCC(O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.1 %

Procedure:
1-(3,4Dimethoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione (4.65 g, 10.74 mmole) was dissolved in 40 mL THF and the solution was diluted with 75 mL of methanol. To this solution sodium borohydride (0.73 g, 19.33 mmole) in 20 mL of water was added dropwise. The solution was stirred at room temperature for 2.5 hours, and the reaction mixture cooled, quenched with water, and the aqueous layer extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to provide 4.61 g of product (98.3%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].C(N(C(C)C)C(C)C)C>>[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][N:14]([C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH2:15][CH2:16][C:10]=2[CH:9]=1
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 98 %

Procedure:
The title compound was prepared in analogy to Example 1 d) from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and methoxy-acetic acid chloride with N-ethyl-diisopropylamine as the base. Yield: 98% of theory as a colourless oil; MS: m/e=344 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1.II>CN(C=O)C.C(OCC)(=O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14]([NH:3][NH:2][C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])([CH3:21])[CH3:20])[CH3:19]
Reactant: NNC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: II
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)NNC(=O)OCc1ccccc1
Temperature: 97.5 °C
Reaction time: 1.25 h

Procedure:
Benzyl carbazate (25 g, 0.15 mol) was dissolved in 50 mL of DMF in a round bottom flask. The solution was heated to 95-100° C. From two separate addition funnels, ethyl 2-bromoisobutyrate (58.5 g, 0.3 mol) and pyridine (29.7 g, 0.375 mol, 30 mL) were added drop-wise separately and simultaneously over 30-120 minutes. Heating was continued if necessary to propel the reaction to completion. The reaction was monitored by TLC (30% ethyl acetate in hexanes, I2 visualization). The mixture was allowed to cool, and then poured onto ice water. The aqueous mixture was extracted with ethyl ether, and the solvent was removed in vacuo. 2-(N′-benzyloxycarbonyl-hydrazino)-2-methyl-propionic acid ethyl ester was isolated, optionally after silica gel chromatography. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.36 (br s, SH), 6.6 (br s, 1H), 5.15 (br s, 2H), 4.2 (q, 2H), 1.3 (s, 6H), 1.25 (t, 3H). 1H NMR analysis alone is insufficient to ascertain the extent of the reaction.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][CH2:11][CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH2:15]([N:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20](=[O:22])[CH3:21])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([NH:19][C:20](=[O:22])/[CH:21]=[CH:12]/[CH2:11][O:10][CH2:9][C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(=O)N(CC(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCOCC#Cc1ccccc1
Agent: [Cl-]
Product: CC(C)CNC(=O)/C=C/COCC#Cc1ccccc1

Procedure:
N-isobutyl-4-(3phenyl-2-propynoxy)-(2E)-butenamide was prepared from 2-(3-phenyl-2-propynoxy) ethanal and N-isobutyl acetamidotriphenylphosphonium chloride as in Example 9.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C@@H:8]1[CH2:13][N:12]2[CH2:14][CH2:15][CH2:16][C@H:11]2[C:10](=[O:17])[NH:9]1)([CH3:4])[CH3:3].[H-].[Na+].I[CH3:23]>CN(C)C=O>[CH3:4][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C@@H:8]1[CH2:13][N:12]2[CH2:14][CH2:15][CH2:16][C@H:11]2[C:10](=[O:17])[N:9]1[CH3:23])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCC[C@H]2C(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)[C@@H]2CCCN2C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
(3S,8aS)-3-({[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (1.51 g, 5.32 mmol) in dimethylformamide (8 mL) was added to an ice-cooled suspension of sodium hydride (60 wt. % dispersion in oil; 213 mg, 5.32 mmol) in dimethylformamide (8 mL). The mixture was stirred at 0° C. for 0.25 h and then iodomethane (0.332 mL, 5.32 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 h and then was stirred at 70° C. for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as a yellow oil (1.552 g, 5.21 mmol) which was dissolved in tetrahydrofuran (20 mL) and treated with tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran; 10.4 mL, 10.4 mmol) for 2 h at room temperature. The mixture was concentrated in vacuo and purified by column chromatography (10% methanol in dichloromethane) to afford (3S,8aS)-3-(hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as a yellow oil (496 mg, 2.70 mmol, 51% yield from (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one). 1H NMR (400 MHz, CDCl3): 3.98-3.93 (m, 1H), 3.86 (dd, 1H), 3.61-3.55 (m, 1H), 3.29-3.25 (m, 1H), 3.09-3.03 (m, 1H), 3.03-2.97 (m, 1H), 3.02 (s, 3H), 2.93 (dd, 1H), 2.87-2.79 (m, 1H), 2.32-2.21 (m, 1H), 2.00-1.86 (m, 2H), 1.83-1.64 (m, 1H); MS (EI) for C9H16N2O2: 185 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:26]3[CH2:30][C:29]4([CH2:34][CH2:33][CH2:32][CH2:31]4)[O:28][N:27]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].FC(F)(F)C(O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]([C:26]3[CH2:30][C:29]4([CH2:34][CH2:33][CH2:32][CH2:31]4)[O:28][N:27]=3)=[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)c(C3=NOC4(CCCC4)C3)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1ncc2c(NC3CCNCC3)c(C3=NOC4(CCCC4)C3)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-{[1-ethyl-5-(1-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}piperidine-1-carboxylate (950 mg, 0.00196 mole) (example 9) was taken in dichloromethane. At 0° C., trifluoroacetic acid (10 ml) was added and the reaction mixture was stirred at room temperature for about 2 hours. It was diluted with dichloromethane and basified with saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C:11]1[N:12]=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][N:17]=[C:16]([Cl:21])[CH:15]=2)(C(C)(C)C)(C)C>O.CO.C(Cl)Cl.CCCCCCC>[Cl:21][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:11]([CH2:10][OH:9])[N:12]=[CH:13]2)=[CH:18][N:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2cnc(Cl)cc2cn1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: OCc1cc2cnc(Cl)cc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
A solution of 5.0M hydrogen chloride in water (0.73 mL) was added to a solution of 3-((tert-butyldimethylsilyloxy)methyl)-7-chloro-2,6-naphthyridine (1.13 g, 3.7 mmol) in methanol (15 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride (150 mL), and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was suspended in heptane (10 mL) and filtered to provide the title compound as a white powder (645 mg, 90%). 1H NMR (400 MHz, DMSO) δ 9.37 (s, 2H), 8.23 (s, 1H), 8.06 (s, 1H), 5.65 (t, J=5.6 Hz, 1H), 4.78 (d, J=5.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][CH2:6][CH:7]([CH3:9])[N:8]=1.[Mn]([O-])(=O)(=O)=O.[K+]>C(#N)C>[CH3:1][O:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COCC1=NC(C)CN1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: COCc1nc(C)c[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 2-(methoxymethyl)-4-methyl-4,5-dihydro-1H-imidazole (compound 222.1, 19 g, 148.4 mmol) in acetonitrile (200 mL). Al2O3 (19 g, 182.7 mmol) was added to the reaction. This was followed by the addition of potassium permanganate (58 g, 367.1 mmol) in several batches at 0° C. The reaction mixture was stirred for 2 h at 0° C., then warmed to room temperature overnight. The reaction was quenched with 20 mL of sodium sulfite (sat.). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. This resulted in 19 g (crude) of the title compound as yellow oil.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C>C(OCC)(=O)C>[CH2:14]([NH:26][C:11](=[O:13])[CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCN
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)CNC(=O)c1ccccc1
Temperature: 160 °C

Procedure:
A mixture consisting of 10 gm (0.056 mol) of N-benzoyl-glycine and 10.5 gm (0.056 mol) of n-dodecyl-amine was heated for 90 minutes at 160°C., while stirring. Thereafter, ethyl acetate and activated charcoal were added to the reaction mixture, and the mixture was vacuum-filtered while still hot. Upon cooling of the filtrate, a crystalline substance separated out which was collected and again recrystallized from ethyl acetate, yielding 11.9 gm (58% of theory) of the compound of the formula ##EQU4## having a melting point of 124°C.
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:4][N:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[Cu][C:29]#[N:30].[OH-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:5]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:2]([C:29]#[N:30])[C:3]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:4]1
Reactant: N#C[Cu]
Reactant: Cc1ccc(-c2c(Br)c(-c3ncccn3)nn2Cc2ccccc2F)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C#N)c(-c3ncccn3)nn2Cc2ccccc2F)cc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
To a suspension of 2-(4-bromo-1-(2-fluorobenzyl)-5-p-tolyl-1H-pyrazol-3-yl)pyrimidine (145 mg, 0.343 mmol) in N,N-dimethylformamide was added copper(I) cyanide (178 mg, 1.884 mmol). The solution was cooled to 23° C. and 5 mL of water, 5 mL of ammonium hydroxide, and 5 mL of ethyl acetate were added. The blue heterogeneous mixture was stirred rapidly for 45 min, and then further diluted with ethyl acetate (75 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were combined and washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give the crude product as an oil. Purification by silica gel chromatography (hexanes/ethyl acetate) gave 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-5-p-tolyl-1H-pyrazole-4-carbonitrile (114 mg, 0.309 mmol, 90% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.92 (d, 2H), 7.34-7.23 (m, 6H), 7.09-6.98 (m, 3H), 5.52 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[C:5]([CH3:28])[CH:6]=[C:7]([C:19]([C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:20])[CH:8]=2)[N:3]=1.Br[C:30]1[S:31][CH:32]=[CH:33][C:34]=1[CH3:35].[Li]CCCC>C1COCC1>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[C:5]([CH3:28])[CH:6]=[C:7]([C:19]([C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)([C:30]3[S:31][CH:32]=[CH:33][C:34]=3[CH3:35])[OH:20])[CH:8]=2)[N:3]=1
Reactant: Cc1ccsc1Br
Reactant: Cc1ccc(C(=O)c2cc(C)c3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2cc(C)c3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)c2sccc2C)cn1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A yellow mixture of (2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(6-methylpyridin-3-yl)methanone (35 mg, 0.0859 mmol, Intermediate 47, step c) and 2-bromo-3-methylthiophene (25.2 mg, 0.142 mmol) in THF (0.52 mL) was stirred at ˜−70° C. under argon while n-BuLi (0.0811 mL, 1.59 M in hexane, 0.129 mmol) was added dropwise over 1.5 min. The reddish-amber reaction was stirred for an additional 15 min at ˜−70° C. before transferring it to an ice bath. The resulting solution was stirred at 0° C. for 5 min, and was then quenched with 5 M NH4Cl (1 mL) and extracted with EtOAc (2×3 mL). The combined yellow organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout) and then, after neutralization, further purified with flash chromatography with a 2% EtOAc/heptane to 100% EtOAc gradient to yield the title compound as a white powder. 1H NMR (400 MHz, MeOH-d4) δ 8.38-8.46 (m, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.73 (dd, J=2.08, 8.19 Hz, 1H), 7.43-7.57 (m, 3H), 7.26-7.38 (m, 3H), 7.22 (d, J=5.13 Hz, 1H), 6.93 (d, J=5.13 Hz, 1H), 2.73 (s, 3H), 2.54 (s, 3H), 1.97 (s, 3H); MS m/e 505.0 [M+H]+.
Reaction SMILES: S(O[C@H:6]1[C@@H:10]([CH2:11][O:12][C:13]([O:15][CH3:16])=[O:14])[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(C)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C)C=O>[N:26]([C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13]([O:15][CH3:16])=[O:14])[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A mixture of 1-[2-deoxy-3-O-mesyl-5-O-methoxycarbonyl-β-D-threopentofuranosyl]-thymine (5.0 g, 13.2 mmoles) from Example A13 and sodium azide (1.07 g, 16.5 mmoles) in dimethylformamide (40 mL) was heated at 85°-90° C. for 4 h. The suspension was cooled to ambient temperature poured into 300 mL of water and the aqueous solution extracted with 3×100 mL portions of ethyl acetate. The combined organic extracts were washed with 2×100 mL portions of water and concentrated by rotary evaporation affording 3.88 g (90.2%) of 3'-azido-3'-deoxy-5'-O-(methoxycarbonyl)thymidine as a colorless oil: 1H NMR (CDCl3) δ1.91 (d, J=1.15 Hz, 3H, C-5-CH3), 2.30-2.49 (m, 2H, C-2'H), 3.83 (s, 3H, CO2CH3), 3.97-4.44 (m, 4H, C-3'H, C-4'H and C-5'H), 6.21 (t, J=6.26 Hz, 1H, C-1'H), 7.29 (q, J=1.15 Hz, 1H, C-6H) and 8.75 (broad, 1H, NH); 13C NMR (CDCl3) δ12.42, 37.57, 55.28, 60.04, 66.39, 81.56, 84.94, 111.38, 135.28, 150.45, 155.18 and 164.03; TLC, Rf =0.78, silica gel, CHCl3 :CH3OH/90:10.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]2[CH:26]=1>CN(C=O)C>[N:19]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:26][N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=12
Reactant: BrCc1cn2ccccc2n1
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cn3ccccc3n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (638 mg, 4.5 mmol) was dissolved in anhydrous DMF (20 mL), then potassium carbonate (1.86 g, 13.5 mmol) and 2-(bromomethyl)imidazo[1,2-a]pyridine (1.42 g, 6.7 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, where the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 12% DCM/MeOH to afford 2-({imidazo[1,2-a]pyridin-2-ylmethyl}sulfanyl)-6-methylpyrimidin-4-ol as a white solid (631 mg, 52% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.46 (s, 2H), 5.99 (bs, 1H), 6.84 (dt, J=1.7 Hz, J=6.7 Hz, 1H), 7.17-7.22 (m, 1H), 7.45 (dd, J=9.0 Hz, J=0.8 Hz, 1H), 7.86 (s, 1H), 8.46-8.49 (m, 1H); LRMS (ES+) m/z 273 (60%, M+1).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=2)[C:5](=[O:21])[O:4]1.[OH-].[Na+].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([CH2:34][CH2:35][N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[C:5](=[O:21])[O:4][CH:3]([CH3:2])[CH2:12]4)[CH2:20][CH2:19]2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: COc1cc(CC=O)ccc1C#N
Reactant: CC1Cc2cc(CCN3CCNCC3)ccc2C(=O)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3)CC(C)OC4=O)CC2)ccc1C#N
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a flask containing 3-methyl-6-[2-(piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one hydrochloride (123 mg, 0.40 mmol) was added in 2 mL of EtOH and NaOH (79 μl, 0.40 mmol). The solvent was removed and the free amine redissolved in DCM and filtered directly into a flask containing 2-methoxy-4-(2-oxoethyl)benzonitrile (58 mg, 0.33 mmol). The mixture was allowed to stir for 20 minutes before sodium triacetoxyborohydride (210 mg, 0.99 mmol) was added. The reaction stirred for 1 hour before being quenched with MeOH. The crude reaction was stirred an additional 30 minutes and the excess solvent was removed. The crude material was redissolved in DCM, filtered, concentrated and purified via MPLC [10-50% (10% MeOH in DCM)/DCM)] to afford 90 mg (63% yield) of 2-methoxy-4-(2-{4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H NMR (500 MHz; DMSO): 7.80 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.65 (m, 1H), 3.88 (bs, 4H), 2.94 (m, 4H), 2.78 (m, 4H), 2.43 (m, 4H), 1.38 (d, J=6.8 Hz, 3H). LC-MS (IE, m/z): 375 [M+1]+. (0.098 μM)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][CH:36]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CC(=O)N1CCC(=O)CC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C2CCN(C(C)=O)CC2)C3)cc1

Procedure:
Compound ef was synthesized according to the procedure described in Example 8 reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1-acetylpiperidin-4-one. LC-MS: m/z=+522 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[C:31]=2[F:32])[C:10]=1[CH3:11])[C:5](O)=[O:6].Cl.[NH2:34][C:35]1([C:46]2[N:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[C:31]=2[F:32])[C:10]=1[CH3:11])[C:5]([NH:34][C:35]1([C:46]2[N:47]=[CH:48][CH:49]=[CH:50][N:51]=2)[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CC(N)(c2ncccn2)C1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(F)c3C)c(F)c12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CN(C(=O)OC(C)(C)C)C4)cc(F)c3C)c(F)c12
Reaction time: 8 h

Procedure:
To a mixture of 3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (50 mg, 0.114 mmol) and tert-butyl 3-amino-3-(pyrimidin-2-yl)azetidine-1-carboxylate hydrochloride (35.9 mg, 0.125 mmol) in DMF (1 ml) in a 25 ml round-bottomed flask was added PyBop (77 mg, 0.148 mmol) and then triethylamine (0.032 ml, 0.228 mmol). The reaction mixture was stirred overnight, and then diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The crude product was then purified by column chromatography (2% methanol in chloroform) to afford tert-butyl 3-(3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate. Yield: 40 mg (52.4%). LCMS: (ES+) m/z observed=572.2 (M+H)+ of 4-fluoro-5-(3-fluoro-2-methyl-5-(3-(pyrimidin-2-yl)azetidin-3-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide