Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C([O-])(O)=O.[Na+].[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17].Cl>CC(C)=O.O>[NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Yield: 81 %

Procedure:
In an ice-water bath, a solution of D-glutamic acid (H-D-Glu-OH, 29.4 g, 1.0 eq) in a mixture of acetone and H2O (V/V=1:1) was stirred. After the solid was fully dissolved, NaHCO3 (23.3 g, 1.1 eq) was added in portions, then Fmoc-OSu (67.4 g, 1.0 eq) were added slowly and the reaction was stirred for additional 3 days at r.t. The mixture was then cooled in ice-water bath again, and pH was adjusted to 2-3 with 2.0N HCl. After removal of acetone under reduced pressure, the remaining solution was extracted with AcOEt (400 mL×4). The organic layer was separated and combined, dried with MgSO4 overnight, and concentrated to a small volume under reduced pressure. Then residue was recrystallized with ethylacetate-cyclohexane system. After filtration, 59.8 g of target product was obtained as a white solid with a yield of 81%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[Cl:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]([C:23]1[CH:22]=[CH:21][C:20]([Cl:19])=[C:25]([Cl:26])[CH:24]=1)[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1Cl
Solvent: C1CCOC1
Product: CCCCC1(C(O)c2ccc(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a stirred solution of 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.753 g, 2.95 mmol) in THF (12 mL) at 0° C. and under nitrogen was added 3,4-dichlorophenylmagnesium bromide (11.8 mL of a 0.5 M solution in pentanes, 5.9 mmol) dropwise over 10 minutes. After 20 minutes, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl (30 mL) then extracted with EtOAc. The combined extracts were washed with brine then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (1.9 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) gave 2-butyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.548 g, 1.36 mmol, 46%) as a colourless gum and as an inseparable mixture of diastereomers
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)[CH2:26]1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@@H:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:26]2)=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: CS(=O)(=O)N(CC#N)[C@@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@@H](N(CC#N)S(C)(=O)=O)C4)n3)cc2CC1

Procedure:
rel-N-((1R,3R)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and rel-N-cyanomethyl-N-[(1R,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (113 mg, 58%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.42 (d, 1H, J=8.5 Hz), 7.16 (s, 1H), 7.09 (d, 1H, J=8.5 Hz), 6.81 (s, 1H), 5.10 (d, 1H, J=6.6 Hz), 4.30-4.05 (m, 3H), 3.99-3.84 (m, 1H), 3.56 (t, 2H, J=5.8 Hz), 3.52-3.47 (m, 1H), 3.38 (s, 3H), 3.02-2.85 (m, 4H), 2.93 (s, 3H), 2.81-2.66 (m, 6H), 2.48-2.38 (m, 1H), 2.21-2.11 (m, 1H), 2.07-1.96 (m, 2H), 1.60-1.45 (m, 2H), 1.30-1.19 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19]=[C:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CN(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1nc2ccccc2s1

Procedure:
5-(4-[2-(N-Methyl-N-(2-benzothiazolyl)amino)ethoxy]benzylidene)-2,4-thiazolidinedione (2 g) in dry 1,4-dioxan (70 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (3 g) at ambient temperature and atmospheric pressure until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (m.p. 167°-8° C.) was obtained after crystallisation from methanol.
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1.CN(C)C=O.S(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:20][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccsc2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1cc(-c2ccsc2)cs1

Procedure:
100 mg of 2-hydroxymethyl-4-(3-thienyl)thiophene was suspended in 5 ml of chloroform, and with stirring under ice cooling, 2 microliters of dimethylformamide and 80 microliters of thionyl chloride were added. The mixture was stirred for 30 minutes, and neutralized with a saturated aqueous solution of sodium hydrogen carbonate under ice cooling. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the chloroform was evaporated to give 2-chloromethyl-4-(3-thienyl)thiophene as a yellow powder.
Reaction SMILES: [Cl:1]C1C=CC=CC=1N[C:9](=[O:29])[CH2:10][N:11]1[CH2:16][C@H:15]([CH3:17])[N:14]([C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH3:27])[C@H:13]([CH3:28])[CH2:12]1.Cl.C([O:33]CC)C>ClCCl>[ClH:1].[CH3:17][C@H:15]1[N:14]([C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH3:27])[C@@H:13]([CH3:28])[CH2:12][N:11]([CH2:10][C:9]([OH:29])=[O:33])[CH2:16]1
Reactant: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1c1ncnc2c1ncn2C
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2c1ncn2C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from step (iii) (0.12 g) in dichloromethane was treated with 1M hydrogen chloride in diethyl ether (12 ml). The mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure to give the subtitle product as a pale yellow solid. Yield 0.15 g.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)(=[O:15])=[O:14].[CH3:25][S-:26].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20]([S:26][CH3:25])=[CH:21][CH:22]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nn3)cccc12
Reactant: C[S-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)nn1
Temperature: 100 °C
Yield: 37.7 %

Procedure:
5-Dimethylamino-N-(6-chloro-3-pyridazinyl)-1-naphthalenesulphonamide (0.72 g) was dissolved in N,N-dimethylformamide and sodium thiomethoxide (0.42 g) added. The mixture was heated to 100° C. for 6 hours, then cooled and 7% aqueous citric acid solution (15 ml) was added with stirring. The solid formed was collected by filtration and washed with water (10 ml). The solid was then purified by chromatography on silica gel (20 g) under reduced pressure, eluting with an ethyl acetate/toluene gradient, to give 5-dimethylamino-N-(6-methylthio-3-pyridazinyl)-1-naphthalenesulphonamide (0.28 g), m.p. 188°-190° C.; mass spectrum (+ve CI): 375 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:33][C:32]([F:35])([F:34])[CH2:31][CH2:30][C:29]=5[C:36]5[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=5)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[C:50](Cl)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>ClCCl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:29]2[CH2:30][CH2:31][C:32]([F:34])([F:35])[CH2:33][C:28]=2[CH2:27][N:24]2[CH2:23][CH2:22][N:21]([C:19]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:10][C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[N:2][N:1]5[C:50]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)[C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH:20]=3)[CH2:26][CH2:25]2)=[CH:37][CH:38]=1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2[nH]ncc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 521F (1.81 g) and triethylamine (0.85 mL) in dichloromethane (10 mL) was added trityl-chloride (1.06 g) and the reaction stirred at room temperature. After stirring for 16 hours the reaction was loaded onto silica gel (Reveleris 80 g) and eluted using a gradient of 0.1% to 1.5% methanol/dichloromethane over 40 minutes (flow=40 ml/min) to give the title compound.
Reaction SMILES: CC([S@]([NH:7][CH:8]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:9])=O)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[O:13]1[CH2:14][CH2:15][CH:10]([C@@H:8]([NH2:7])[CH3:9])[CH2:11][CH2:12]1
Reactant: CC(N[S@](=O)C(C)(C)C)C1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)C1CCOCC1
Reaction time: 2 h
Yield: 150.5 %

Procedure:
To a solution of (R)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)Propane-2-sulfinamide (1.2 g) in CH2Cl2 (4 mL) was added HCl-dioxane (4 mL) at 25° C. The reaction was stirred for 2 hrs. Then the mixture was concentrated in vacuo, diluted with water and washed with ethyl acetate to give crude (S)-1-(tetrahydro-2H-pyran-4-yl)ethanamine (1.0 g) as a yellow oil.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9](=[O:15])[NH:8][C:7](=[O:16])[CH:6]=1>C(O)C>[NH:2]([C:5]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9](=[O:15])[NH:8][C:7](=[O:16])[CH:6]=1)[NH2:3]
Reactant: CC(C)Cn1c(Cl)cc(=O)[nH]c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(NN)cc(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
Hydrazine hydrate (5.9 ml) was added to a solution of 6-chloro-1-isobutylpyrimidine-2,4(1H,3H)-dione synthesized according to procedure described in Heterocycles, 1990, 31(9), 1641-1646, (5.9 g) in ethanol (100 ml). The mixture was heated at reflux for 16 hours, cooled to room temperature and then evaporated under reduced pressure. The residue was crystallized from ethanol to give the subtitle compound (5.8 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[N+:18]([C:17]1[C:12]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 69 %

Procedure:
5-Aminoindole and 2-chloro-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was stirred at room temperature for 4 days. The resulting reaction mixture was filtered to afford the title compound (69%) as an orange solid: mp, 162.0°-163.5° C.; 13C NMR (CDCl3) δ 155.6, 150.5, 135.5, 133.5, 129.7, 127.9, 127.6, 125.9, 118.5, 115.0, 113.4, 111.2, 101.2; Anal. calcd for C13H10N4O2 : C, 61.41; H, 3.96; N, 22.04. Found: C, 61.22; H, 3.80; N, 22.08.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.Cl.[C:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:8]([NH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)Nc2ccncc2)CC1
Reaction time: 24 h
Yield: 34.6 %

Procedure:
To a solution of O-phenyl N-(4-pyridyl)carbamate (0.81 g) in chloroform (10 ml) were added 1-acetyl-4-aminopiperidine hydrochloride (0.68 g) and triethylamine (1.06 ml) at ambient temperature. After stirring for 1 day, the mixture changed to a solution. The solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 100 ml, dichloromethane:methanol=10:1 to 5:1, and silica gel 50 ml, dichloromethane:methanol:aqueous ammonia=10:1:0.1). The solvents of desired fractions were removed under reduced pressure. A residue was dissolved with methanol (5 ml) and dichloromethane (5 ml), and 4N hydrogen chloride in dioxane (1.5 ml) was added to the solution. The solvents were removed under reduced pressure, and the residue was evaporated azeotropically with methanol. After crystallization from diisopropyl ether and n-hexane, N-(1-acetylpiperidin-4-yl)-N′-(4-pyridyl)urea (343 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:20])[CH3:23]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) suspension of 4-nitroaniline (10 g, 0.072 mol) and Et3N (10 mL) in CHCl3 (120 mL), was added dropwise ethyl chloroformate (6.9 mL) and the mixture was stirred under an argon atmosphere at room temperature overnight. CHCl3 was added and the resulting solution was washed with 1N HCl. The layers were separated, the aqueous phase was washed with CHCl3 and the combined organic extracts were dried and concentrated. The residue was chromatographed on silica gel (hexane:EtOAc, 30%) to afford N-(ethoxycarbonyl)-4-nitroaniline (1.7 g).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-formylbenzoic acid (24) (300 mg, 1.99 mmol) in DCM (4 mL) were added N,N-dimethylethane-1,2-diamine (193.8 mg, 2.19 mmol), HATU (911.8 mg, 2.4 mmol), NMM (505 mg, 5.0 mmol), and DMAP (24 mg, 0.199 mg) at RT. The reaction mixture was stirred at RT for 16 h. The reaction was monitored by LCMS. After 16 h, RM was washed with water and organic layer was concentrated after drying over Na2SO4. Column purification of crude material afforded pure product as oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:29])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1.C(N(CC)C(C)C)(C)C.[CH2:39]([O:41][C:42](Cl)=[O:43])[CH3:40]>ClCCl>[C:42](=[O:43])([O:41][CH2:39][CH3:40])[O:29][C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:18]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:1])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=2
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CN4CCCC4)c3)c2n1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Oc1nc2c(N)nc(OCCOC)nc2n1Cc1cccc(CN2CCCC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
6-Amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H-purin-8-ol (Example A) (60 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (0.1 mL) was added and the mixture was cooled to 0° C. Ethylchloroformate (0.04 mL, 0.42 mmol) was added. After stirring for 30 minutes, the reaction was quenched with water and concentrated under vacuum. Purification by preparative reverse phase HPLC (5-45% acetonitrile/40 mM aqueous HCl) gave 9-(3-(pyrrolidin-1-ylmethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-purin-8-yl ethyl carbonate (Example Q) (24 mg) as a white glassy solid, HCl salt.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][N:18]([CH3:33])[C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:18]([CH3:33])[CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1coc(Cn2ncc(N)n2)n1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CN(C)c1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)co3)n2)c1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-difluoro-ethyl)-oxazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-(dimethylamino)phenyl)oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC1(O)c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC=C1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
The product of above-mentioned (10-a) (0.23 g, 0.69 mmol) was added into a mixed solvent of methylene chloride (3.5 ml) and trifluoroacetic acid (1.4 ml), and triethylsilane (0.15 ml, 0.96 mmol) was added dropwise thereto, followed by stirring at 25° C. for 2 hrs. The reaction solution was added into 1N aqueous K2CO3 solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=5:1) to give 91 mg of 5,6-dimethyl-3-hexylidene-2-(3-pyridyl)isoindolin-1-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([OH:16])[C@@H:10]([NH:12][C:13](=[O:15])[O-])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.CO.[OH-].[K+]>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@@H:9]2[O:16][C:13](=[O:15])[NH:12][C@H:10]2[CH3:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)[O-])[C@@H](O)c1cc(F)cc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1NC(=O)O[C@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate (900 mg, 2.80 mmol) in THF (28.6 mL) was added MeOH (14.3 mL) and 7.5 N KOH (7.2 mL). The reaction was stirred at room temperature for 4 hours and then extracted with EtOAc (2×75 mL). The organic extracts were washed with water and brine (50 mL each), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 75% EtOAc/hexanes) afforded (4S,5S)-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one. Rf=0.07 (25% EtOAc/hexanes). LCMS=214.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 6.89-6.93 (m, 2H), 6.82 (m, 1H), 6.24 (bs, 1H), 5.01 (d, J=6.8 Hz, 1H), 3.79 (m, 1H), 1.42 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17](O)=[O:18])[CH2:15][N:16]=1)=[CH:8]2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:18])[CH2:15][N:16]=1)=[CH:8]2)[S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22]
Reactant: CN(c1cccc2cc(C3=NCC(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C3=NCC(C(=O)N4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a mixture of 2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-5-carboxylic acid (0.25 g), morpholine (0.10 g), 1H-1,2,3-benzotriazol-1-ol (0.10 g) and N,N-dimethylformamide (4 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.14 g) at room temperature, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried. The obtained solid was subjected to basic silica gel column chromatography to give the title compound (0.25 g, yield 86%) as pale-yellow crystals from a fraction eluted with tetrahydrofuran. melting point 238-239° C.