Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:20][C:21]#[N:22])[CH:18]=3)[N:11]3[CH:29]=[CH:30][N:31]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C1C[O:35][CH2:34][CH2:33]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(=O)(O)[O-].[Na+].CCOC(C)=O>[C:34]([N:26]1[CH2:27][CH2:28][CH:23]([CH:19]([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:29]=[CH:30][N:31]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)[CH:15]=[N:16]2)[CH2:20][C:21]#[N:22])[CH2:24][CH2:25]1)(=[O:35])[CH3:33]
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CCNCC4)c3)n2)cn1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(CC#N)n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-(piperidin-4-yl)propanenitrile hydrochloride (10.0 mg, 0.021 mmol) was suspended in THF (211 μL, 0.0211 mmol). To this was added triethylamine (8.81 DIPHOS, 0.0632 mmol) to free-base. Acetic anhydride (2.38 μL, 0.0253 mmol) was added and the reaction mixture stirred at ambient temperature for 30 minutes. The reaction mixture was then diluted in saturated sodium bicarbonate and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated in vacuo. Purification of the resulting crude material by reverse phase HPLC using 0-100% acetonitrile/water gradient afforded the title compound (7.2 mg, 77% yield). MS (apci) m/z=444.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16]([SH:22])=[CH:15][CH:14]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1[nH]cnc1CSCCNC(=N)c1ccc(O)cc1
Solvent: c1ccncc1
Product: Cc1[nH]cnc1CSCCNC(=N)c1ccc(S)cc1

Procedure:
N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]-4-hydroxybenzamidine and a slight excess of phosphorus pentasulphide were refluxed in pyridine for 45 minutes to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].BrN1C(=O)CCC1=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
2-Fluoro-4-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82 g, 10 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved in CCl4 (50 mL). The mixture was heated at reflux, and irradiated with light (100 W bulb) for 4 hours. The reaction mixture was then filtered and concentrated. The residue was dissolved in THF (50 mL). Morpholine (1.91 g, 22 mmol) was added to it. The mixture was stirred at ambient temperature for 1 hour and then filtered. The filtrate was evaporated. The bright orange residue was purified by column chromatography eluted with hexane:ethyl acetate, 10:1 to provide 4-(2-fluoro-4-nitrobenzyl)morpholine (1.32 g, 5.5 mmol, yield 55%).
Reaction SMILES: [I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9](S(C)(=O)=O)[S:8][N:7]=1.[CH3:17][NH:18][CH3:19].O>C(COC)OC>[I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9]([N:18]([CH3:19])[CH3:17])[S:8][N:7]=1
Reactant: CNC
Reactant: CS(=O)(=O)c1snc(OCC#CI)c1C#N
Solvent: COCCOC
Solvent: O
Product: CN(C)c1snc(OCC#CI)c1C#N

Procedure:
3.6 Grams of 3-(3-iodo-2-propynyloxy)-4-cyano-5-methylsulfonylisothiazole was dissolved in 30 ml of dimethoxyethane, 1.5 g of dimethylamine (as 50% aqueous solution) was added at room temperature with stirring, and then the reaction solution was stirred at 50° C. for 2 hours. Water was added to precipitate crystals, which were then collected by filtration, washed with water, dried and recrystallized from ethyl acetate. Thus, 2.2 g of white crystals having a melting point of 171° to 172° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]([CH3:13])[C:8]([C:14]([O:16]C)=O)=[C:7]([OH:18])[C:6]=2[CH:19]=1.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:11])(=[O:12])[N:9]([CH3:13])[C:8]([C:14]([NH:20][C:21]3[S:22][C:23]([CH3:26])=[CH:24][N:25]=3)=[O:16])=[C:7]([OH:18])[C:6]=2[CH:19]=1
Reactant: Cc1cnc(N)s1
Reactant: COC(=O)C1=C(O)c2cc(Cl)ccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1cnc(NC(=O)C2=C(O)c3cc(Cl)ccc3S(=O)(=O)N2C)s1
Yield: 77 %

Procedure:
5.0 gm (16.5 millimols) of methyl 6-chloro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2.1 gm (18.5 millimols) of 2-amino-5-methyl-thiazole were refluxed in 300 ml of anhydrous xylene for 24 hours in a Soxhlet-apparatus equipped with a 4-A-molecular sieve. After cooling, the crude product which had crystallized out was filtered off and recrystallized from dioxane. 4.9 gm (77% of theory) of 6-chloro-4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([NH:21][C:22]([N:11]2[C:12]3[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1000 %

Procedure:
Sodium hydride (802 mg, 20.0 mmol, 60% in oil) was suspended in N,N-dimethylformamide (40 ml); 5-nitroindole (2.50 g, 15.4 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 30 minutes. Phenyl isocyanate (2.01 ml, 1.23 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 1.5 hours. Water (80 ml) was added to the reaction mixture; the reaction mixture was stirred at room temperature for 30 minutes; and the precipitated crystals were filtered off, washed by water and diethyl ether one by one, and dried by means of suction to yield the title compound (3.53 g, 12.3 mmol, 79.8%) as pale yellow crystals.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:21]([C:24]4([C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)[CH2:26][CH2:25]4)=[CH:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1>>[CH3:18][N:19]([CH3:21])[C:1]([C:3]1[CH:11]=[CH:12][C:15]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([C:21]([C:24]5([C:27]6[CH:36]=[C:35]7[C:34](=[CH:29][CH:28]=6)[N:33]=[CH:32][CH:31]=[CH:30]7)[CH2:25][CH2:26]5)=[CH:22][N:23]=4)[N:20]=3)=[CH:13][CH:14]=2)=[CH:16][N:17]=1)=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Product: CN(C)C(=O)c1ccc(-c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4n3)cc2)cn1

Procedure:
This compound was prepared as a TFA salt starting from 6-{1-[2-(4-bromophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline using procedures analogous to those for Example 94. LCMS: (M+H)=512.3
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)(C)(C)C.[C:31]1([OH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[O:37]([CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:22]1[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=1)=[CH:8][C:7]2=[N:6][OH:5])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3ccccc3)cc12

Procedure:
6-(3-Phenoxy-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 24% overall yield using the method described in example 161, starting from 6-(3-chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 101A) and phenol.
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]2[O:12][CH2:13][O:14][C:5]=2[CH:4]=1.[C:17]([O:20][CH2:21][CH3:22])(=O)C>C1COCC1.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>[CH2:13]1[O:14][C:5]2[C:6](=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([C:3]3[CH:4]=[C:5]4[C:6](=[CH:7][CH:8]=3)[CH:22]=[C:21]([O:20][CH3:17])[C:21]([O:20][CH3:17])=[CH:22]4)[CH:4]=2)[O:12]1
Reactant: CCOC(C)=O
Reactant: C[Sn](C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2ccc(-c3cc4c(cc3[N+](=O)[O-])OCO4)cc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (40 mg) and cuprous bromide (8 mg) were added to a solution of 6,7-dimethoxy-2-naphthalenetriflate (160 mg, 0.48 mmol) and trimethyl(3,4-methylenedioxy-6-nitrophenyl)stannane (8, 187 mg, 0.57 mmol) in THF (20 mL). The mixture was stirred at room temperature for 0.5 h., and then refluxed under nitrogen for 18 h. After Cooling, THF was rotaevaporated and ethyl acetate (50 ml) was added to the residue. the solution was washed with water (30 mL). The organic layer was separated and passed through a celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel using 70:30 hexanes:ethyl acetate to give a mixture of two compounds with same Rf value. The mixture can be separated after the hydrogenation step.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[NH2-:9].[Na+]>>[NH2:9][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][N:6]=1
Reactant: [NH2-]
Reactant: CCc1ccncc1
Agent: [Na+]
Product: CCc1ccnc(N)c1

Procedure:
This amine is prepared by the method of Case and Kasper from 4-ethylpyridine (Aldrich Chemical) and sodium amide (Fisher Scientific Co.) in 55% molar yield, mp 66°-70° (lit.1 70°-1°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]2)=[CH:19][CH:18]=1)=O.C(#N)C.O.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][C:10]1[S:11][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[CH:21][CH:22]=2)[N:12]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: NC(=S)Cc1ccc(Cl)c(Cl)c1
Reactant: Cc1cn(-c2ccc(C(=O)CBr)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cn(-c2ccc(-c3csc(Cc4ccc(Cl)c(Cl)c4)n3)cc2)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The thioacetamide 1213 (0.08 mmol) and 2-bromo-1-[4-(4-methyl-imidazole-1-yl)-phenyl]-ethanone (0.08 mmol) 10 were dissolved in 1 ml DMF. The reaction was stirred at 70 C for 6 hours. After cooling to room temperature, the reaction mixture was directly injected into a reversed phase HPLC (Gilson 215) using acetonitrile/water/TFA gradient and C18 stationary phase to isolate and then concentrate to give the title product 1214 as a TFA salt.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=1.[OH-].[Li+]>C1COCC1>[C:12]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[CH:7]=1)[C:3]([OH:14])=[O:2])#[N:13]
Reactant: COC(=O)c1cc(C#N)cc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C#N)cc(C(=O)O)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A solution of 3-cyano-5-methoxy-benzoic acid methyl ester (3.4 g, 18.7 mmol) in THF (45 mL) was treated with 0.5 N lithium hydroxide (45 mL, 22.4 mmol). The reaction was stirred at 75° C. for 2 h and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH 2) by the addition of 1 N HCl. Ethyl acetate was used to extract the precipitate, which was then washed with brine and dried over anhydrous sodium sulfate. After removal of solvent in vacuo, 2.5 g (77%) of 3-cyano-5-methoxybenzoic acid was isolated as a white solid. 1H NMR (DMSO), δ(ppm): 7.86 (s, 1H), 7.71 (m, 2H), 3.87 (s, 3H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:33][CH:32]=1>C1COCC1>[CH3:28][C:27]1[CH:26]=[CH:25][S:24][C:23]=1[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:36]=3)[C:4](=[O:29])[NH:5]2)=[CH:10][CH:9]=1)=[O:13])=[O:22]
Reactant: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCCC(=O)O)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 352, 200 mg, 0.4945 mmol) and THF (5.0 mL). To the resulting solution was added 4-(4-Amino-phenyl)-butyric acid (88.6 mg, 0.494 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by flash silica gel chromatography (CHCl3:MeOH mix eluant with gradient of 1% MeOH to 15% MeOH) to afford the title compound in 43% yield (0.120 g, 0.212 mmol).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:22][N:23]1[C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][N:25]=[CH:24]1>O1CCOCC1.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>[CH3:22][N:23]1[C:27]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:26][N:25]=[CH:24]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cncc1-c1nccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 160 °C

Procedure:
A suspension of N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (350 mg, 1172 μmol), 1-methyl-5-(tributylstannyl)-1H-imidazole (870 mg, 2343 μmol), and tetrakis(triphenylphosphine)palladium (0) (271 mg, 234 μmol) in 1,4-dioxane (4 mL) was sparged with argon for 3 minutes then the vessel was appropriately sealed. The vessel was then heated to 160° C. with microwaves (3 bar; 130 watts) for 20 minutes. The solvents were removed under reduced pressure and the residue was purified on silica (40 g) eluting products with 2-4% of MeOH/DCM to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 345.1 (M+1). IC50 (uM) 0.034.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([CH3:23])[CH2:16][CH2:15][CH:14]([CH:17]([CH3:19])[CH3:18])[CH:13]([O:20][CH2:21]Cl)[CH2:12]1.C(N(CC)CC)C.CC(C)=O>C(OCC)(=O)C.O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][O:20][C@@H:13]2[CH2:12][C@H:11]([CH3:23])[CH2:16][CH2:15][C@H:14]2[CH:17]([CH3:19])[CH3:18])=[O:7])=[CH:4][CH:3]=1
Reactant: CC1CCC(C(C)C)C(OCCl)C1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCOC(=O)c1ccc(O)cc1
Yield: 77.9 %

Procedure:
A mixture comprising 10.86 g (78.6 mmol) of 4-hydroxy-benzoic acid, 16.1 g (78.6 mmol) of (+)-chloromethyl menthyl ether, 12 ml of triethylamine, and 100 ml of acetone was stirred under nitrogen current at room temperature for 7 hours. To the mixture were added 200 ml of water and 200 ml of ethyl acetate, the organic layer was washed with water, a saturated sodium chloride aqueous solution, and water in the order, and the organic layer was dried with sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (SiO2, hexane/ethyl acetate: 10/1) to obtain 18.75 g of ((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-methyl 4-hydroxybenzoate as a white solid. A mixture comprising 9.19 g (0.03 mol) of the solid, 9.48 g (0.03 mol) of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride, 5.0 g of triethylamine, and 130 ml of THF was stirred under nitrogen current at room temperature for 3 hours, and further stirred under reflux for 2 hours. To the solution were added 200 ml of water and 200 ml of ethyl acetate, the organic layer was washed with water, a saturated sodium chloride aqueous solution, and water in the order, and the organic layer was dried with sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (SiO2, hexane/ethyl acetate: 10/1) to obtain 15.26 g of an oily compound having a structure shown below. A mixture comprising 3.9 g (6.47 mmol) of the oily compound, 50 ml of ethanol, 1.06 g of sodium hydrogencarbonate, and 30 ml of water was stirred at room temperature for 10 hours. To the solution were added 200 ml of water and 200 ml of ethyl acetate, the organic layer was washed with water, a saturated sodium chloride aqueous solution, and water in the order, and the organic layer was dried with sodium sulfate. The solvent was concentrated, the residue was dissolved in 100 ml of methanol, and 2.22 g (6.47 mmol) of triphenylsulfonium bromide was added thereto, followed by stirring at room temperature for 3 hours. Chloroform (200 ml) was added to the solution, the organic layer was washed with water, and the residue was purified by column chromatography (SiO2, chloroform/methanol: 10/1) to obtain 5.24 g of an oily compound (A-35).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([O:38][C:39](=[O:64])[N:40]([CH2:51][CH2:52][C:53](=[O:63])[NH:54][O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C@@H:41]([CH2:49]O)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:37])([CH3:36])[CH3:35]>O1CCCC1>[C:34]([O:38][C:39]([N:40]1[CH2:51][CH2:52][C:53](=[O:63])[N:54]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:49][C@H:41]1[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:64])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)NOCc1ccccc1)[C@@H](CO)Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N(OCc2ccccc2)C[C@H]1Cc1ccccc1
Reaction time: 16 h
Yield: 67.7 %

Procedure:
Diisopropyl azodicarboxylate (806 mg, 3.75 mmol) was added at <10° C. to a solution of triphenylphosphine (983 mg, 3.75 mmol) in tetrahydrofuran (60 ml), followed by addition of a solution of (2-benzyloxycarbamoyl-ethyl)-((R)-1-hydroxymethyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (1.24 g, 2.88 mmol) in tetrahydrofuran (12 ml). The reaction mixture was stirred at <10° C. for 16 h, then concentrated. The residue was purified by chromatography (SiO2; heptane/ethyl acetate 7:3) to afford the title compound (800 mg, 68%). Light yellow oil, MS (ISP)=411.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:13])[CH2:21][CH2:22]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-3-fluoro-benzoic acid (37.1 g, 145 mmol), 4-amino-1-benzylpiperidine (35.6 mL, 1.20 equiv.), 1-hydroxybenzotriazole (21.6 g, 1.1 equiv.), and triethylamine (44.1 g, 3.0 equiv.) in ethyl acetate (450 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.7 g, 1.1 equiv.) in one portion. Initially, everything went into solution, but a precipitate formed very rapidly. The reaction was fitted with a reflux condenser and heated at reflux for 5 h. The reaction was diluted with ethyl acetate, washed with water (2×), then 1N sodium hydroxide (2×), then brine, dried over magnesium sulfate, and concentrated to give 67.0 g (quant.) as a white solid which was used without purification. 1H-NMR (CDCl3, 500 MHz) δ 1.48 (s, 9H), 1.55 (m, 2H), 1.99 (bd, J=11.0, 2H), 2.17 (dd, J=11.0, 11.0, 2H), 2.84 (bd, J=11.3, 2H), 3.51 (s, 2H), 3.94 (m, 1H), 6.13 (bd, J=7.6, 1H), 7.10-7.28 (m, 4H), 7.31 (m, 4H), 7.59 (s, 1H). Mass spec.: 428.41 (MH)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C)[O:8][C@@H:7]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=O)C.[Na]>CO>[CH3:22][C:21]1[C:19](=[O:20])[NH:18][C:16](=[O:17])[N:15]([C@@H:7]2[O:8][C@H:9]([CH2:10][OH:11])[C@@H:5]([OH:4])[CH2:6]2)[CH:23]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Agent: [Na]
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 80 %

Procedure:
Crude 3',5'-di-O-acetylthymidine was dissolved in 20 ml methanol, and 0.075 gm sodium was added. After 8 hrs the reaction was quenched with Amberlite IR 120 resin, filtered and concentrated to yield beta-thymidine (2.4 gm, 80%). m.p. 181°-183° C.