Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:37]=1.[C:55]1([C:61]2[CH:62]=[C:63]([OH:67])[CH:64]=[CH:65][CH:66]=2)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1COCC1.CN(C=O)C>[C:61]1([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:66]=[CH:65][CH:64]=[C:63]([O:67][CH2:36][CH2:37][N:28]2[CH:29]=[CH:30][N:31]=[C:26]([N:23]3[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]3)[C:27]2=[O:32])[CH:62]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1c(N2CCNCC2)nccn1CCOc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
TMAD (0.060 g, 0.35 mmol) was dissolved in THF (1 mL) and DMF (0.5 mL) and the resulting solution was added dropwise to a mixture of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (0.100 g, 0.31 mmol), triphenylphosphine (0.092 g, 0.35 mmol) and 3-phenylphenol (0.170 g, 1.00 mmol) in THF (0.5 mL). The reaction mixture was stirred overnight at room temperature, concentrated, and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H2O (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) as eluent to give 16 mg (16%) of the title compound. HRMS m/z calcd for C22H24N4O2 (M)+ 376.1899, found 376.1888.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH2:10]1[O:13][CH:11]1[CH3:12]>CO>[CH3:1][N:2]([CH2:10][CH:11]([OH:13])[CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1
Reactant: CNc1ccc(C)cc1
Reactant: CC1CO1
Solvent: CO
Product: Cc1ccc(N(C)CC(C)O)cc1

Procedure:
N-methyl-p-toluidine, 29.3 g, and methanol, 50 g, were placed in a reactor. Propylene oxide, 25.4 g, was slowly added to the reactor over two hours. Afterwards, the reactor was heated under reflux for 6 hours. The low boilers were removed by distillation. Then, the mixture was vacuum distilled to give 2HPMT. The boiling point is 92° C. at 5 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N:10]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:11]=1[CH3:12].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:12][C:11]2[CH:13]=[CH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: Cc1ccc2ccccc2n1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C=Cc2ccc3ccccc3n2)cc1
Temperature: 130 °C

Procedure:
A solution of 25 g of p-hydroxybenzaldehyde and 28 ml of quinaldine is 100 ml of acetic anhydride are heated at 130° C. overnight. The reaction mixture is concentrated in vacuo and then passed through a flash silica gel column slurry packed with hexanes and eluted with 15% acetone in hexanes. Concentration of the desired fractions gives a yellow solid which is recrystalized from Et2O/hexanes to give 2-(2-(4-acetoxyphenyl)ethenyl)quinoline (M.P. 127°-128° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2cccc(F)c2)c1
Yield: 63.6 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.044 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([CH2:15]O)[CH2:14][CH2:13]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[O:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: OCC1CC1
Reactant: Cc1cc(F)ncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(F)ncc1C(=O)OCC1CC1
Reaction time: 72 h
Yield: 58 %

Procedure:
To a solution of 6-fluoro-4-methylpyridine-3-carboxylic acid (4.94 g, 31.8 mmol), cyclopropylmethanol (3.78 mL, 47.8 mmol) and N,N-dimethylpyridin-4-amine (778 mg, 6.37 mmol) in DMF (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (6.71 g, 35.0 mmol), and the mixture was stirred for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 3:1) to give the title compound (3.86 g, yield 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(Cl)Cl.[CH3:38][O:39][C:40]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH:43][CH2:42][C:41]5[CH:44]=[CH:45][C:46]([O:48][CH3:49])=[CH:47][C:40]=5[O:39][CH3:38])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1nn2ccc(C=O)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNCc2ccn3nc(C)c(-c4nc(Cc5ccc(Cl)cc5)c(-c5nnc[nH]5)s4)c3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a suspension of 3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde (0.300 g, 0.690 mmol) in acetic acid (0.20 mL, 3.5 mmol) and dry methylene chloride (10 mL, 200 mmol) was added 2,4-dimethoxybenzylamine (0.207 mL, 1.38 mmol), followed by additional of sodium triacetoxyborohydride (0.363 g, 1.71 mmol). The mixture was stirred at rt. for 16 hours. The mixture was basified with NaHCO3 solution to =pH 8 then extracted with DCM. The DCM solution was washed with water. The crude product was purified by column chromatography (SiO2, elution with 0-100% MeOH in DCM) to afford a solid product (0.252 g, yield 62%). LCMS: (FA) ES+ 586, 588; ES− 584, 586. 1H NMR (400 MHz, CDCl3 and d4-methanol) δ: 8.23-8.25 (d, J=7.03 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.28-7.30 (d, J=8.53 Hz, 2H), 7.09-7.11 (d, J=8.53 Hz, 2H), 7.01-7.03 (d, J=8.28 Hz, 1H), 6.78-6.80 (d, J=7.03 Hz, 1H), 6.33-6.37 (m, 2H), 4.53 (s, 2H), 3.65 (s, 2H), 3.64 (s, 6H), 3.61 (s, 2H), 2.61 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[C:13]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)O)cc1O
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC(C)=O
Temperature: 140 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
17.0 g of 3-hydroxy-4-methoxy-benzoic acid and 51.6 g of acetic anhydride were combined and stirred at 140° C. for 3 h. Then 50 ml of water were added at 100° C., the mixture was heated under reflux for 30 min, another 200 ml of water were added and the mixture heated under reflux for 30 min. The mixture was cooled to 0° C., and the product was filtered off, washed with water and dried in vacuo to yield 18.8 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[O:7][CH:6]=1.[OH-].[Na+].C1COCC1>CO>[CH3:23][C:17]1[C:16]([CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C:5]([CH2:4][C:3]([OH:24])=[O:2])=[CH:6][O:7][C:8]=3[CH:13]=2)=[CH:21][CH:20]=[C:19]([CH3:22])[N:18]=1
Reactant: COC(=O)Cc1coc2cc(OCc3ccc(C)nc3C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(COc2ccc3c(CC(=O)O)coc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzofuran-3-yl)acetate (430 mg), 1N NaOH (5 mL), THF (5 mL) and MeOH (5 mL) was stirred at room temperature for 1 h. The mixture was washed with Et2O. Water and 1N HCl (5 mL) were added to the water layer to be pH=4. The precipitate was collected by filtration and washed with water and Et2O respectively to give crystals. The crystals were recrystallized from acetone-hexane to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:10]([CH:12]1[CH2:14][CH2:13]1)=O)=[CH:6][N:7](C)C)[CH3:2].Cl.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:10]([CH:12]3[CH2:14][CH2:13]3)=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:6]=[N:7]2)=[CH:20][CH:19]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C1CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C1CC1

Procedure:
Ethyl-2-(cyclopropanecarbonyl)-3-dimethylamino-prop-2-enoate (Intermediate#32) (316 mg, 1.5 mmol) was dissolved in ethanol (5 mL). 4-bromophenylhydrazine hydrochloride (335 mg, 1.5 mmol) and DIPEA (264 μL, 1.5 mmol) were added and the mixture was heated to reflux for 2 h. The reaction mixture was cooled to ambient and evaporated under reduced pressure. The residue was dissolved in DCM (10 mL) washed with water and poured through a phase separating tube. The product was recovered from the filtrate by flash column chromatography (SiO2, elution gradient 0-25% EtOAc in isohexane). Pure fractions were combined and evaporated to give ethyl 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylate as an oil that crystallised on standing. (343 mg, 87%)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:9](=[O:10])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.CC([O-])(C)C.[K+].[H][H]>CC(O)C>[CH3:1][CH:2]1[CH2:11][CH:9]([OH:10])[C:5](=[C:6]([CH3:7])[CH3:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)=C1CCC(C)CC1O
Temperature: 30 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
A 200 ml capacity autoclave was charged with 30.4 g (200 mmol) of pulegone, 19.1 mg (0.02 mmol) of RuCl2(PPh3)3(propanediamine), 44.9 mg (0.4 mmol) of t-BuOK and 2-propanol (15 ml), and the mixture was stirred at 30° C. for 18 hours while forcing 3 Mpa of hydrogen. After completion of the reaction, hydrogen was purged and the reaction solution was concentrated and distilled under a reduced pressure to obtain 30.2 g of pulegol. The yield was 98%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([F:31])[C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[C:15]([F:31])=[CH:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:30][CH:29]=1)(=[O:4])=[O:3]
Reactant: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 63 μL (0.816 mmol) of methanesulfonyl chloride was added dropwise to a solution of 0.20 g (0.544 mmol) of 2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethanol and 0.11 mL (0.816 mmol) of triethylamine in 10 mL of DCM and the mixture was stirred for 16 hours at RT. A further 0.11 mL (0.816 mmol) of triethylamine and 63 μL (0.816 mmol) of methanesulfonyl chloride were added and the mixture was stirred for 8 hours. The reaction mixture was diluted with DCM, and the organic phase was washed with water and dilute aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.24 g (99% of theoretical); C22H17ClFNO4S (M=445.892); calc.: molpeak (M+H)+: 446/448 (Cl); found: molpeak (M+H)+: 446/448 (Cl); HPLC-MS: 6.19 minutes (method B).
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>CN(C=O)C.O>[CH2:22]([S:1][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1)[CH2:23][CH3:24]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: S
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydrogen sulfide (220 m, 3 mmol) was added over 30 min. to a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) in DMF (20 ml) at room temperature. Potassium carbonate (1.24 g, 9 mmol) and iodopropan (0.76 g, 4.5 mmol) were added. The reaction mixture was stirred at room temperature for 30 min. Water was added and the mixture extracted with ether. The combined ether phases were dried and evaporated to give the title compound in 89% (0.63 g) yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16]C)=[O:15])#[N:2].O[Li].O>C1COCC1.CCOCC.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([OH:16])=[O:15])#[N:2]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1cc2c(cc1F)OCCC2C(=O)O
Yield: 81.7 %

Procedure:
Methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (3.3 g, 14.0 mmol) and LiOH—H2O (5.89 g, 140 mmol) were stirred together in THF (25 mL) and water (25 mL) at ambient temperature for 1 hour. The reaction was diluted with ether and water, and filtered to remove undissolved solids. The filtrate was collected and the aqueous layer was washed with additional ether. The aqueous layer was acidified to pH 1-2 and the resulting solid was collected. The solid was then dissolved in ethyl acetate, dried, filtered and concentrated to provide the desired product (2.53 g, 81%) as a light yellow solid.
Reaction SMILES: CC(O)(C)C.Br[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)#[CH:15].[N-:23]=[N+:24]=[N-:25].[Na+]>O.[O-]S([O-])(=O)=O.[Cu+2]>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([C:14]2[N:23]=[N:24][N:25]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:15]=2)=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccccn1
Reactant: C#Cc1ccc(C)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc(-c2cn(Cc3ccccn3)nn2)cc1
Yield: 35.2 %

Procedure:
A mixture of tBuOH (1.5 mL), water (1.5 mL), 2-(bromomethyl)pyridine (253 mg, 1 mmol), 1-ethynyl-4-methylbenzene (122 mg, 1.05 mmol) and NaN3 (68 mg, 1.05 mmol) was added to a microwaveable vial. A cooper wire (50 mg) and CuSO4 (200 μl of 1M aq. solution) was added to the stirred suspension. The vial was sealed and the mixture was irradiated (Microwave, Personal Chemistry, Biotage from Upsala Sweden) at 125° C. for 5 min. The mixture was then diluted with water and the product was extracted to EtOAc, washed with 1M ammonium citrate, 0.25 M aq. HCl and brine, dried over MgSO4, filtered and evaporated. The crude product was purified on silica gel (Eluent: 10% MeOH in DCM) to give 2-((4-p-Tolyl-1H-1,2,3-triazol-1-yl)methyl)pyridine (88 mg, 35%). 1H NMR (300 MHz, dMSO): δ 2.30 (s, 3H), 5.72 (s, 2H), 7.30-7.45 (m, 4H), 7.77-7.89 (m, 3H), 8.60 (s, 1H); MS (M+H, 251).
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[C:12]([C:16]1[C:17](=[O:23])[CH:18]=[CH:19][C:20](=[O:22])[CH:21]=1)([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[C:12]([C:16]1[C:17](=[O:23])[CH:18]2[CH:19]([C:20](=[O:22])[CH:21]=1)[C:3]1([Cl:10])[C:2]([Cl:11])([Cl:1])[C:6]2([Cl:7])[C:5]([Cl:8])=[C:4]1[Cl:9])([CH3:15])([CH3:13])[CH3:14]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: CC(C)(C)C1=CC(=O)C=CC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Hexachlorocyclopentadiene, 40 g., and 15.4 g. of tert-butyl-p-benzoquinone were dissolved in 300 ml. of toluene and refluxed for four hours. The solution solidified upon cooling to room temperature. The solid was washed with methanol and recrystallized from benzene. Yellow crystals were obtained melting at 124°-125° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)[CH2:14][CH2:13]1)(=[O:11])[CH3:10]
Reactant: Fc1cccc(F)n1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCN(c2cccc(F)n2)CC1
Yield: 99.9 %

Procedure:
A solution of 2,6-difluoropyridine (9.0 g), 1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) in acetonitrile (100 ml) was refluxed under heating for 18 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid (8.7 g). The obtained pale-brown solid was crystallized from ethyl acetate-hexane to give the title compound (5.5 g) as pale-brown crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([OH:13])=O)[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=2[N:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:37]([CH3:39])[CH3:38])C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CNC>CN(C=O)C.C1COCC1>[CH3:38][N:37]([CH3:39])[C:11]([C:9]1[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCC(CC)n1c(C(=O)O)cc2cnc(Cl)nc21
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(CC)n1c(C(=O)N(C)C)cc2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To a solution of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (80 mg, 0.30 mmol), BOP (159 mg, 0.36 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) in DMF (3 mL) is added 0.164 mL of 2 N dimethylamine in THF solution at room temperature. The mixture is stirred at room temperature for 3 h, quenched with 1N NaOH aqueous solution, and extracted with EtOAc. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, 5% MeOH in CH2Cl2) to give 64 mg of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:42][CH:43]([CH3:52])[C@H:44]([NH2:51])[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:51][C@@H:44]([CH:43]([CH3:52])[CH3:42])[CH2:45][N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CC(C)[C@H](N)CN1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](CN1CCCC1)NC(=O)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
4-Chlorobenzoic acid (1.061 g, 6.78 mmol), TBTU (2.25 g, 7.01 mmol) and DIPEA (20.3 mmol) was mixed in DMF (25 mL). After 10 min was (S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.962 g, 6.16 mmol), which is commercially available, added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (1.48 g, 82%). 1H NMR (400 MHz, CDCl3) δ 0.97, 1.80, 1.94-2.32, 2.47-2.76, 2.80-3.01, 4.13, 6.66, 7.41, 7.80. Total no of protons: 23. LCMS (M+H)+: 295.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[CH3:14]>CO>[CH3:14][N:13]([CH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:7]2[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=2)[N:20]=1)[CH3:12]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
To a cooled (6° ) suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (0.74 g; 4.17 mmoles) in 80 ml of methanol was added dropwise over a period of 45 minutes a solution of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine (0.96 g; 4.17 mmoles) [prepared in Step E] to give 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide, Rf=0.64 [Silica/CH2Cl2 : CH3OH (9:1)]. The temperature was maintained at 6° and anhydrous methylamine was bubbled into the solution for 8 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 80 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined and the residue was rechromatographed on 25 g of aluminum oxide using a gradient elution of methylene chloride-methanol to give 0.52 g of product. Recrystallization from isopropyl alcohol/ether yielded the title compound, mp 144°-148° (foaming).