Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6](=[O:21])[N:7]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH3:2].[C:23](=[S:25])=[S:24].[OH-].[K+].Cl/[CH:29]=[CH:30]\Cl>CS(C)=O.O>[S:24]1[CH:30]=[CH:29][S:25][C:23]1=[C:5]([C:6](=[O:21])[N:7]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1cccnc1
Reactant: Cl/C=C\Cl
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)N(CCC(=O)OC)Cc1cccnc1)=C1SC=CS1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl[N-(3-pyridylmethyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (1.0 g) and carbon disulfide (0.2 ml) are dissolved in dimethylsulfoxide (12 ml), and thereto is added a solution of potassium hydroxide (378 mg) in water (1 ml). The mixture is stirred at room temperature for 20 minutes. A solution of cis-1,2-dichloroethylene (0.245 ml) in dimethylsulfoxide (2 ml) is added dropwise to the mixture, and the mixture is stirred at 50°-55° C. for 6 hours. After cooling, the mixture is poured into water, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, ethyl acetate) to give ethyl 2-(1,3-dithiol-2-ylidene)-2-[N-(3-pyridylmethyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (429 mg) as oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C@:8]1([CH3:22])[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)(=O)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:32]2)=CC=1>C1(C)C=CC=CC=1>[CH3:13][C:10]1([CH3:14])[N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@:8]([CH3:22])([C:6]2[S:32][C:1]([CH3:2])=[N:4][N:5]=2)[CH2:12][O:11]1
Reactant: CC(=O)NNC(=O)[C@]1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1nnc([C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)s1
Temperature: 110 °C
Reaction time: 4 h
Yield: 110.2 %

Procedure:
To a solution of 3.36 g of tert-butyl (4S)-4-[(2-acetylhydrazino)carbonyl]-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate in 100 ml of toluene was added 2.8 g of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide, followed by stirring at 110° C. for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 2.39 g of tert-butyl (4S)-2,2,4-trimethyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].[Br:19]Br.[C:21]([O:24]C(=O)C)(=O)[CH3:22]>C(O)(=O)C>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][C:21](=[O:24])[CH3:22])[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([Br:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: BrBr
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Temperature: 25 °C

Procedure:
A suspension of 3'-azido-2',3'-dideoxyuridine (1.0 g, 3.95 mmol) in 25 ml of acetic anhydride was heated until dissolution occurred (oil bath temperature of approximately 100° C. used). A solution of bromine (0.7 g, 4.35 mmol) in 3 ml of glacial acetic acid was added to the above solution with cooling, to maintain a temperature of 25° C. After being maintained overnight in the cold (4 C.), the solution was evaporated to dryness under reduced pressure (vacuum pump utilized) to yield 3'-azido-5'-O-acetyl-2',3'-dideoxy-5-bromouridine as a thick yellow syrup, which was disclosed immediately in 50 mL of absolute methanol containing 7 g of anhydrous ammonia. This solution was then kept at 4° C. for 48 hours. The solvent was removed in vacuo at 30° C. and then residue chromatographed on silica gel column (CH2Cl2 :EtOAc, 1:1). The fractions containing the desired product (Rf = 0.51) were pooled together and the solvent evaporated in vacuo to afford 0.55 g (42%) of white plate-like crystals mp 150-151° C.; IR (KBr) 4.70 (azido) μm; UV (EtOH)λmax 278 nm (ε14,300), UV (EtOH) λmin 240 nm, UV (0.1 N HCl)λmax 278 nm (ε9,400), UV (0.1 N HCl)λmin 240 nm, UV (0.1 N NaOH)λmax 274 nm (ε6,800), UV (0.1 N NaOH)λmin 248 nm; NMR (DMSO-d6) ε2.28-2.33 (m, 1H, 2'-Ha) 2.42-2.46 (m, 1H, 2'-Hb), 3.59 (d, 1H, 5'-Ha), 3.68 (d, 1H, 5'-Hb), 3,83 (m, 1H, 4'-H), 4.37 (q, 1H, 3'-H), 5.35 (br s, 1H, 5'-OH, D2O exchangeable), 6.01 (t, 1H, 1'-H), 8.37 (s, 1H, 6-H), 11.81 (br s, 1H, 3-NH, D2O exchangeable).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: Brc1ccc2c(c1)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCc3ccc(Br)cc3C2)cn1
Temperature: 160 °C
Yield: 34.1 %

Procedure:
A mixture of 7-bromo-1,2,3,4-tetrahydroisoquinoline (0.30 g, 1.4 mmol), 5-bromopyridine-2-carbonitrile (0.28 g, 1.5 mmol) and potassium carbonate (0.39 g, 2.8 mmol) in dimethyl sulfoxide (2.0 mL) was heated at 160° C. for 2 h. After cooled to r.t., the mixture was quenched with water (10 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with 30% ethyl acetate in hexanes to afford the desired product (0.15 g, yield: 34%). Analytic LCMS (M+H)+: m/z=314.2/316.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17][O:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C[C@@H](CO)C[C@@H](C)CCCCC)(C)(C)C>>[C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17][O:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][C@@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Agent: CCCCC[C@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Product: CCCCC[C@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Yield: 64 %

Procedure:
A procedure similar to that used to prepare compound 159 was used except that (3S,5S)-3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167 (4.164 g, 15.29 mmol) was used as a reactant to give 168 as an oil (4.17 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=8.30 Hz, 2H), 7.31 (d, J=8.30 Hz, 2H), 3.97 (dd, J=9.52, 4.15 Hz, 1H), 3.90 (dd, J=9.52, 5.13 Hz, 1H), 2.42 (s, 3H), 2.28, 2.19–2.13 (m, 2H), 1.37 (s, 9H), 1.27–1.01 (m, 11H), 0.85 (t, J=7.08 Hz, 3H), 0.76 (d, J=6.35 Hz, 3H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[NH:6]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19]>CN(C)C(=O)C>[C:18]([O:3][C:1](=[O:4])[CH2:2][N:6]1[CH2:17][CH2:16][N:15]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:14][CH2:13][N:12]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: C1CNCCNCCNCCN1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Sodium acetate (1.23 g, 15 mmol) was added to a stirred suspension of 1,4,7,10 tetraazacyclododecane (0.864 g, 5 mmol) (prepared in accordance with J. Am. Chem. Soc. 96 2268 (1974) and Liebigs Ann. Chem. 1340 (1977)) in N, N-dimethylacetamide (DMA) (15 ml) at ambient temperature. A solution of bromoacetic acid t-butyl ester (2.93 g, 15 mmol) in DMA (8 ml) was added dropwise to the stirred mixture, and the mixture was stirred at ambient temperature for 6 days. The solvent was evaporated and 1,4,7,10 -tetraazacyclododecane-4,7,10-triacetic acid trit-butyl ester was purified by flash chromatography on a silica column with chloroform:methanol 8:2 as eluent. Yield 1.8 g (70%). White solid, m.p. 165°-175° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br>O.C(O)C>[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:1]#[N:2]
Reactant: [C-]#N
Reactant: BrCc1ccccc1Br
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccccc1Br
Yield: 102.2 %

Procedure:
To a suspension of 220.0 g of sodium cyanide in 265 ml of water and 380 ml of absolute ethanol, is added, while stirring, a solution of 911.0 g of o-bromobenzyl bromide in 911 ml of ethanol. The reaction proceeds exothermally, but is eventually heated under reflux for about 0.5 hour, then cooled in an ice-bath, and filtered. The solid is washed with ether, the filtrate is concentrated, the residue is suspended in 300 ml of water and extracted with three 500 ml portions of ether. The ether extracts are washed, dried, and the solvent is removed. The residue is distilled to give 730 g of the named product, bp 141°-142° (12mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[S:9][CH3:10])N.[OH:11]S(O)(=O)=O.N([O-])=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[S:9][CH3:10]
Reactant: CSc1ccc(N)cc1Cl
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(O)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
The product from stage (ii) (11.5 g, 66.2 mmol) was dissolved in the minimum THF (˜15 mL) and water (500 mL) was added with vigorous stirring, followed by conc H2SO4 (25 mL). The mixture was cooled in an ice-water bath and a solution of NaNO2 (5.0 g, 72.5 mmol) in iced water (10 mL), was added via pipette under the surface of the reaction mixture. The reaction was stirred at 0° C. for 1.5 h and the resulting yellow/brown solution was decanted from the remaining solid into a dropping funnel containing ice (˜200 g). This solution was added at a steady rate over 7 min to a vigorously stirred mixture of Cu(NO3)2 (230 g, 0.99 mol) and Cu2O (8.52 g, 67.4 mmol) in water (1 L) at room temperature. After the addition was complete the mixture was stirred for a further 15 min before being extracted with ether (500 mL). The residual red/brown solid in the reaction flask was taken up in MeOH (100 mL) and diluted with ether (300 mL) before being poured into the aqueous layer from above. The ether layer was separated and the combined organic layers were extracted with 1M NaOH (3×100 mL). The aqueous extracts were acidified with conc. HCl and then extracted with ether (2×150 mL). The ether layers were then washed with brine, dried (MgSO4) and the solvent was removed in vacuo to give the phenol (5.465 g, 47%) as a brown crystalline solid; δH (400 MHz, CDCl3) 2.44 (3H, s), 5.08 (1H, br), 6.77 (1H, d), 6.93 (1H, d), 7.18 (1H, d); MS m/z (ES−) 173 (M−H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.O>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([C:14]2[CH:13]=[N:12][C:11]([F:10])=[CH:19][CH:18]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Cl)cc1
Reactant: O=C(Cl)c1ccc(F)nc1
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1ccc(F)nc1

Procedure:
A 2 M solution of 4-fluorophenyl magnesium chloride (7 ml, 14 mmol) was slowly added at −30° C. to a solution of 6-fluoronicotinoyl chloride (3.35 g, 21 mmol,) in ether (30 ml). After complete addition, the cooling bath was removed and the reaction was allowed to reach 10° C. Hydrolysis was performed by addition of water, and the mixture is then diluted with ether. After separation of the layers, the ether solution was washed with brine, dried over Na2SO4 and evaporated in vacuum to yield a yellow solid. After purification by chromatography on silica gel (CH2Cl2/Hexane 85/15), the (4-fluorophenyl)(6-fluoro-3-pyridinyl)methanone 38 was obtained as a white solid (1.52 g, 50%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.[CH2:21](I)[CH3:22].CC[N:26](C(C)C)C(C)C>CN(C)C=O.O>[F:20][C:17]([F:18])([F:19])[C:10]1[CH:11]=[C:12]([C:13]([F:14])([F:15])[F:16])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:21][CH2:22][NH2:26])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: CCI
Solvent: CN(C)C=O
Solvent: O
Product: NCCc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 50 °C
Yield: 24 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.15 g, 0.58 mmol), ethyl iodide (0.10 mL, 1.26 mmol), and Hunig's base (0.20 mL, 1.14 mmol) in N,N-dimethylformamide (10 mL) was heated to 50° C. under argon with stirring. After 24 hours the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was washed with water (4×25 mL), brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography (ethyl acetate/hexanes) followed by recrystallization from ethanol/water to give the above-named compound (0.045 g) as yellow crystals. mp 54° C. NMR (CDCl3, 400 MHz): δ 7.26 (d, 2H), 7.02 (s, 1H), 6.64 (d, 2H), 3.93 (br s, 1H), 3.22 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:29]1[C:33](=[O:34])[NH:32][CH2:31][CH:30]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:32]4[CH2:31][CH:30]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:29][C:33]4=[O:34])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CC(c2ccccc2)CN1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4CC(c5ccccc5)CC4=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-phenyl-2-pyrollidinone.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:16]2[CH2:19][CH:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[CH2:17]2)=[CH:11][CH:10]=1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]2[CH2:17][CH:18]([N:20]([CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[C:37](=[O:39])[CH3:38])[CH2:19]2)=[CH:31][CH:32]=1
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
1.6 cm3 of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 2 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)amine in 75 cm3 of dichloro-methane. The mixture is cooled to around 0° C. before adding dropwise thereto 0.66 cm3 of acetyl chloride, and then it is stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 cm3 of dichloromethane and is then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent:dichloromethane/methanol (98/2 by volume)]. 1.2 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)acetamide are obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ in ppm). A mixture of rotamers is observed. *2.06 and 2.14 (2s:3H in total); 2.97 (mt:2H); 3.43 (mt:2H); 4.20 and 4.25 (2s:1H in total); 4.54 and from 4.75 to 4.80 (mt:1H in total); 4.68 and 4.78 (broad 2s:2H in total); 6.70 (mt:3H); 7.24 (broad s :8H)].
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2>C(O)C>[N:29]1[C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:8][C:4]=3[CH:3]=2)=[C:22]2[C:26]([N:25]=[CH:24][NH:23]2)=[N:27][CH:28]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Solvent: CCO
Product: O=C(Nc1nc2ccc(Nc3ncnc4nc[nH]c34)cc2s1)c1ccccc1

Procedure:
N-[6-(Purin-6-ylamino)benzothiazol-2-yl]benzamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 50 mg, 0.186 mmol) and 6-chloropurine (29 mg, 0.186 mmol) in ethanol (3 ml) to 80° C. for 4 h. The resulting precipitate was separated by filtration and washed with ethanol (69 mg, 0.178 mmol, 96%). LC/ESI-MS: m/z 388 [M+H]+; m/z=386 [M−H]−; Rt=3.07 min.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[CH:37][N:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[O:17]=[C:16]1[C:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]2[N:36]=[CH:37][N:38]=[C:12]2[N:11]1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (20 g), 6N hydrochloric acid (150 mL) and tetrahydrofuran (200 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (14 g, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7](OC)=[O:8])([O-:3])=[O:2].[NH3:14]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([NH2:14])=[O:8])([O-:3])=[O:2]
Reactant: N
Reactant: COC(=O)c1ccnc([N+](=O)[O-])c1
Product: NC(=O)c1ccnc([N+](=O)[O-])c1

Procedure:
A mixture of 400 mg. of methyl 2-nitroisonicotinate and 2 ml. of 28% aqueous ammonia were stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was recrystallized from ethanol-ether to give 348 mg. of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][CH2:19]CS([O-])(=O)=O)=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][CH2:19][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCCS(=O)(=O)[O-]
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Temperature: 70 °C
Yield: 53.2 %

Procedure:
3-(4-[(3-Chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propylmethanesulfonate (19 mg, 0.051 mmol) was dissolved in anhydrous ACN (100 μL,) followed by addition of DIPEA (44 μL, 0.26 mmol) and morpholine (6.7 μL, 76.8 μmol). The reaction was stirred and heated at 70° C. for 3 h. The reaction was concentrated and purified with silica gel chromatography (60-100% ethyl acetate/hex) to give the desired product (10 mg, 54%). LCMS for C16H19ClFN4O3(M+H)+: m/z=369.1.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:5][CH2:4]1.[CH2:26](Br)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C.C(=O)([O-])O.[Na+]>[CH2:26]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:5][CH2:4]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(C=CC1=Cc2cnc3cccc(n23)S1)NC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(C=CC1=Cc2cnc3cccc(n23)S1)NC1CCN(CCc2ccccc2)CC1

Procedure:
In 10 ml of ethanol was suspended 0.998 g (2.5 mM) of N-(piperidin-4-yl)-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylamide dihydrochloride as well as 0.703 g (3.8 mM) of phenethyl bromide, followed by addition of 1.74 ml (12.5 mM) of triethylamine, and the mixture was refluxed for 5 hours. To this reaction mixture was further added 0.070 g (0.38 mM) of phenethyl bromide, and the mixture was refluxed overnight. This reaction mixture was diluted with 5% aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over Na2SO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol=4/1) and concentrated and the residue was crystallized from ether to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:8].[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35]O)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35][O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:18]=[C:19]([CH3:21])[CH:20]=[C:2]([CH3:1])[CH:3]=2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 94.8 %

Procedure:
A mixture of 6-[2-(3,5-dimethyl-phenoxy)acetylamino]hexanoic acid (Intermediate 15, 3.0 g, 10.2 mmol), 2-(m-nitrobenzenesulfonyl)ethanol (available from Aldrich 2.3 g, 10.0 mmol), and p-toluenesulfonic acid hydrate (0.5 g) in 100 mL of toluene was refluxed overnight with Dean-Stark trap. Then water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution two times, dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting residual oil was purified by column chromatography (1% MeOH in CH2Cl2) to give Intermediate 16 (4.8 g, 89%) as a yellowish thick oil.