Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>ClCCl>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[N:9]=[N:8][C:7]([N:1]2[CH2:2][CH2:3][N:4]([C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:27]([F:26])([F:37])[F:38])=[O:31])[CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: c1ccc(-c2ccc(N3CCNCC3)nn2)nc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3ccccn3)nn2)CC1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a stirred mixture of 3-piperazin-1-yl-6-pyridin-2-ylpyridazine (0.240 g, 1.000 mmol) and triethylamine (0.7 mL) in dichloromethane (15 mL) at room temperature was added 2-trifluoromethylbenzoyl chloride (0.210 g, 1.000 mmol). After 15 minutes, the mixture was washed with citric acid and NaHCO3. The organic layer was separated, dried over anhydrous MgSO4 and evaporated to yield solid residue, which was crystallized from ether to afford the title compound as a white solid in 23% yield (0.097 g). 1H NMR (300 MHz, CDCl3) δ 8.6 (d, J=4.4 Hz, 1H), 8.5 (d, J=8.0 Hz, 1H), 8.3 (d, J=9.5 Hz, 1H), 7.8 (m, 1H), 7.7 (d, J=7.7 Hz, 1H), 7.6 (t, J=7.3 Hz, 1H), 7.5 (t, J=7.5 Hz, 1H), 7.35 (d, J=7.3 Hz, 1H), 7.28 (m, 1H), 7.0 (d, J=9.5 Hz, 1H), 4.1-3.6 (m, 6H), 3.35-3.31 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 159.3, 153.9, 151.4, 148.9, 137.0, 134.4, 132.3, 127.3, 126.8, 123.6, 120.3, 113.1, 46.5, 44.9, 44.6, 41.3. MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.NC1C=CC(OC2C=CN=C3C=C([C:70]([N:72]4[CH2:76][CH2:75][C@@H:74]([N:77]([CH3:79])[CH3:78])[CH2:73]4)=[O:71])SC=23)=C(F)C=1>>[CH3:78][N:77]([CH3:79])[C@@H:74]1[CH2:75][CH2:76][N:72]([C:70]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:22])=[CH:3][C:2]=3[F:1])[CH:15]=2)=[O:71])[CH2:73]1
Reactant: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccccc1
Agent: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)C1
Yield: 38 %

Procedure:
Following the procedure described above for the compound 5a (step 5, example 1) but replacing the amine 9 with the compound 26, title compound 5 g was obtained in 38% yield. MS (m/z): 562.0 (M+H).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[C:11]([O:24][CH3:25])[CH:10]=1)(C)C)(C)(C)C.Br[C:27]1[S:31][C:30]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[N:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=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>[CH3:25][O:24][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:27]1[S:31][C:30]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:39])([CH3:40])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[N:29][N:28]=1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(O)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C

Procedure:
To a stirred suspension of tert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (Intermediate 3) (3.28 g, 9.00 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (1 g, 6.00 mmol) in dioxane (48 mL) under nitrogen was added Pd(PPh3)4 (0.347 g, 0.30 mmol) followed by a solution of Na2CO3 (1.272 g, 12.00 mmol) in water (12 mL). The resulting mixture was refluxed at 120° C. for 18 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc (150 mL) and washed with water (100 mL). The organic phase was separated and the aqueous phase re-extracted with EtOAc (150 mL). The combined organics were dried over MgSO4, filtered, and the filtrate concentrated in vacuo to afford an oily brown residue. The residue was suspended in EtOAc (10 mL) and sonicated, then the resulting suspension was filtered under vacuum to afford the crude product as an off-white solid. The crude mixture was purified by flash chromatography using 3% [7M NH3 in MeOH]/DCM as the eluent to afford the title compound as a pale yellow glass-like solid (0.534 g, 23% yield). LC-MS: Rt 0.75 min; MS m/z 377.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 1H), 7.88 (d, J=8.59 Hz, 1H), 6.54 (d, J=2.53 Hz, 1H), 6.50 (dd, J=8.34, 2.27 Hz, 1H), 4.34-4.25 (m, 1H), 3.86 (s, 3H), 2.94 (s, 3H), 1.59 (dd, J=11.62, 3.03 Hz, 2H), 1.40 (t, J=12.38 Hz, 2H), 1.26 (br. s., 1H), 1.20 (s, 6H), 1.08 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].COCCOC.Br[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1.CC1(C)C(C)(C)OB([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)O1>O.C(OCC)(=O)C>[S:16]1[CH:17]=[CH:18][C:14]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)=[CH:15]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Brc1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(-c2ccsc2)cc1
Temperature: 25 °C

Procedure:
An aqueous sodium carbonate solution and tetrakis triphenylphosphine palladium were added to a DME solution of 3-bromothiophene and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, and the mixture was refluxed under heating for 6 hours with argon atmosphere. After cooling to room temperature, the reaction mixture was added with ethyl acetate and water to separate an organic layer, which was then washed and dried. The solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography, to obtain 4-(3-thienyl)aniline (pale yellow solid). Electron Impact-MS (M)+: 175.
Reaction SMILES: C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C=CC(C[Cl:26])=CC=1.[CH2:27]([P:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[Cl-:26].[CH2:36]([PH+:31]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38][CH3:39]
Reactant: ClCc1ccccc1
Reactant: CCCCP(CCCC)CCCC
Agent: C=Cc1ccc(C=C)cc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CCCC[PH+](CCCC)CCCC
Product: [Cl-]

Procedure:
Merrifield's peptide resin (Aldrich, 1.1 meq/g of Cl), 50.1 g was stirred in 250 mL of CH2Cl2 with 132.3 g of tri-n-butylphosphine under argon for 1 week. The slurry was filtered and the beads washed with 1.5 L of CH2Cl2. The product was dried in the air and then under vacuum to produce 61.9 g of tributylphosphonium chloride substituted polymer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH2:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH:23][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:19]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: Cl
Product: CCOC(=O)CNC(=O)CCCCCNC(=O)OC(C)(C)C
Yield: 127.8 %

Procedure:
By working analogously to what described in example 2, 6-(tert-butoxycarbonylamino)hexanoic acid (163 g) was directly condensed with glycine ethyl ester hydrochloride (118 g; 0.845 moles), obtaining thus N-[6-(tert-butoxycarbonylamino)hexanoyl]glycine ethyl ester (285 g) as a raw product which was used as such in the subsequent reaction.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[C:39](=[O:48])[NH:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:34][CH2:33]1.[O:49]1CCC[CH2:50]1>>[O:24]=[C:3]1[C@H:2]([NH:1][C:50]([N:32]2[CH2:33][CH2:34][CH:35]([C:38]3[C:39](=[O:48])[NH:40][C:41]4[C:46]([CH:47]=3)=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:36][CH2:37]2)=[O:49])[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([F:21])([F:23])[F:22]
Reactant: C1CCOC1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Amino-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (25.6 mg, 0.0766 mmol) and p-nitrophenylchloroformate (15.3 mg, 0.0766 mmol) were dissolved in tetrahydrofuran (0.5 mL) under argon, and cooled to 0° C. Triethylamine (10.7 uL, 0.0766 mmol) was added and the reaction stirred for 1 h. Additional triethylamine was added (26.7 uL, 0.191 mmol) along with 3-(4-piperidinyl)quinolin-2-(1H)-one (17.5 mg, 0.0766 mmol). The reaction was warmed to room temperature and stirred overnight. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution) to give the title compound (30.2 mg). MS 588.2245 (M+1)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[O:10][C@H:9]1[N:39]1[C:48]2[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=2[N:41]=[CH:40]1.[C:49]([CH2:51][CH2:52][O:53][C:54](ON1C(=O)CCC1=O)=[O:55])#[N:50]>CC#N.CCOC(C)=O>[C:49]([CH2:51][CH2:52][O:53][C:54]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[O:10][C@H:9]1[N:39]1[C:48]2[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=2[N:41]=[CH:40]1)=[O:55])#[N:50]
Reactant: N#CCCOC(=O)ON1C(=O)CCC1=O
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCN)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 96.3 %

Procedure:
To a solution of 2′-O-(5-aminopentyl)-5′-O-(4,4′-dimethoxytrityl)-adenosine (1.0 g, 1.52 mmol) in anhydrous CH3CN (8.0 mL) was added with stirring, under argon, N-(2-Cyanoethoxycarbonyl)oxy succinimide (0.43 g, 2.02 mmol) After stirring for 5 h at room temperature the reaction mixture was diluted with EtOAc (50 mL) and washed with aq saturated bicarbonate (3×20 mL) and water (20 mL), dried (Na2SO4) and evaporated to give 53 as a light yellow foam (1.1 g, 98% yield). This compound was used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].B(F)(F)F.[CH3:17][CH2:18]OCC>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:17][CH3:18])=[O:11]
Reactant: CCOCC
Reactant: Nc1ccc(CC(=O)O)c(F)c1
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)cc1F

Procedure:
A solution of 8.2 g. of 2-fluoro-4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate dried and evaporated to yield ethyl 2-fluoro-4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 1-bromohexadecane, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl 2-fluoro-4-(hexadecylamino)phenylacetate.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[N:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH:20]([CH3:23])[CH2:21]Cl.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[N:14][O:15][CH2:19][CH:20]([CH3:23])[CH2:21][N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C1CCCCC1=Cc1ccccc1
Reactant: CN1CCNCC1
Reactant: CC(CCl)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(CON=C1CCCCC1=Cc1ccccc1)CN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The solution of 20.1 g (0.1 moles) of 2-benzalcyclohexanone oxime in 200 ml of anhydrous toluene is dropwise added at 85° C, under continuous stirring, to the suspension of 2.4 g (0.1 moles) of sodium hydride in 50 ml of anhydrous toluene. After boiling the reaction mixture for 2 hours, 18.86 g (0.11 moles) of 1-bromo-3-chloro-2-methylpropane are added, and the reaction mixture is boiled for a few hours. After cooling the mixture to 80° C, a solution of 11 g (0.11 moles) of N-methylpiperazine in 20 ml of anhydrous toluene is dropwise added and the reaction mixture is kept for further 6 hours at this temperature. After cooling and washing with water, a solution of 22 g of fumaric acid in 220 ml of anhydrous ethanol is poured to the toluene solution, the mixture is cooled, and the precipitated crystals are filtered off. Yield in difumarate: 48 g (81.7%); m.p. 190°-191° C. The produce is identical with that described in Example 11.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:14][N:13]3[CH:25]=2)=[CH:6][C:4]=1[NH2:5])#[CH:2].N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C(#N)C>[C:1]([C:3]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:14][N:13]3[CH:25]=2)=[CH:6][C:4]=1[NH:5][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])#[CH:2]
Reactant: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of 2-ethynyl-5-(6-(2-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl)aniline (0.030 g, 0.0913 mmol) in acetonitrile (1 mL) containing pyridine (0.273 mmol) is added trimethylacetylchloride (0.0958 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and residue purified via silica chromatography (hexanes to EtOAc) to afford the title compound (0.029 g, 78%) as a yellow solid: Rf 0.58 (1:1 EtOAc:hexanes); LCMS (m/z)=413.5 [M+H]+, tR=3.19 min. (compound same as Example 321)
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([CH3:13])=[N:4][N:3]=1.[CH3:14][O-].[Na+].CI>CO>[CH3:13][C:5]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([S:1][CH3:14])=[N:3][N:4]=1
Reactant: C[O-]
Reactant: Cc1nnc(S)n1-c1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nnc(C)n1-c1ccccc1
Reaction time: 0.17 h

Procedure:
3-Mercapto-5-methyl-4-phenyl-1,2,4-triazole (19.1 g) was suspended in 200 ml of methanol, and 20 g of 28% sodium methylate was added thereto. After 10 minutes, 15 g of methyl iodide was added dropwise. They were reacted for 2 hours and then the methanol was distilled away. Upon extraction of the residue with ethyl acetate, 5-methyl-3-methylthio-4-phenyl-1,2,4-triazole was obtained.
Reaction SMILES: C(Cl)(Cl)Cl.[NH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]1.[C:19](OC(=O)C)(=[O:21])C.C(O)=O>O>[CH:19]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:9][CH2:10]1)=[O:21]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(C=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A chloroform solution of 2.0 g of tert-butyl piperidin-4-ylcarbamate was added to a mixed solution of 4.7 ml of acetic anhydride and 1.9 ml of formic acid, and the reaction mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and this was extracted with EtOAc. The organic layer was washed with 1 M hydrochloric acid, aqueous saturated sodium hydrogencarbonate and brine. This was dried with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified with silica gel column chromatography (eluent: chloroform/MeOH=50/1) to obtain 1.7 g of tert-butyl (1-formylpiperidin-4-yl)carbamate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:22]1[S:23][C:24]2[C:25]([N:30]=1)=[N:26][CH:27]=[CH:28][CH:29]=2>CN(C=O)C>[S:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:30]=[C:22]1[O:13][C:11]1[CH:10]=[CH:9][C:8]2[C:4]([CH2:3][CH2:2][OH:1])=[CH:5][O:6][C:7]=2[CH:12]=1
Reactant: OCCc1coc2cc(O)ccc12
Reactant: Clc1nc2ncccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
To a solution of 3-(2-hydroxy-ethyl)-benzofuran-6-ol (0.42 g, 2.4 mmol) in DMF (24 mL) was added Cs2CO3 (0.77 g, 2.4 mmol) and 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (0.49 g, 2.4 mmol) and the reaction mixture was stirred (rt, 15 h) and then heated (50° C., 2 h). The reaction mixture was cooled (rt) and partitioned with EtOAc and brine (50 mL each). The aqueous layer was extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-100%) to provide the title compound as an amber oil (0.42 g, 57%). MS (ESI): mass calcd. for C16H12N2O3S, 312.3; m/z not found. 1H NMR (500 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=8.0, 1.6, 1H), 7.61-7.57 (m, 3H), 7.30 (dd, J=8.4, 2.2, 1H), 7.21 (dd, J=8.0, 4.8, 1H), 3.95 (q, J=6.1, 2H), 2.97-2.94 (m, 2H), 1.75 (t, J=5.5, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14])([O-:9])=[O:8].C(OCC)(=O)C.O>ClCCl>[N+:7]([C:10]1[CH:11]=[C:12]([C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:14])[CH:16]=[CH:17][CH:18]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of morpholine (5.0 ml) in dichloromethane (50 ml) was added 3-nitrobenzoyl chloride (5.05 g). The mixture was stirred at room temperature for 15 minutes, then poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with dilute hydrochloric acid, sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give 4-(3-nitrophenylcarbonyl)morpholine (6.46 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].[OH2:20].NN.[CH3:23][OH:24]>[Ni]>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:23](=[O:24])[C:3]2[CH:8]=[CH:7][C:6]([C:9](=[O:20])[CH2:10][CH3:11])=[CH:5][CH:4]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CO
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2[N+](=O)[O-])cc1OC
Reactant: O
Agent: [Ni]
Agent: NN
Product: CCC(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2c2ccc(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.5 g of (+/−)-cis-1,2-dimethoxy-4-(2-nitrocyclohexyl)benzene are dissolved in 400 ml of methanol and treated at RT with 7 ml of hydrazine hydrate and 2.5 g of Raney nickel in portions in the course of 8 h. After stirring overnight at RT, the reaction mixture is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel using a mixture of toluene/ethyl acetate/triethylamine=4/2/0.5. The title compound is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:24](O)=[O:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].S(Cl)(Cl)=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:28])[F:29])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][OH:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: O=C(O)c1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: OCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Yield: 51.4 %

Procedure:
2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoro-methyl)-1,3-thiazole-5-carboxylic acid (2.2 g) was added to 1,2-dichloroethane (50 mL). Thionyl chloride (1.0 g) and one drop of N,N-dimethylformamide were added to the mixture, which was then refluxed under heating for 5 hours. After removing the solvent by evaporation, the residues were dissolved in 1,4-dioxane (20 mL), and then added dropwise to the mixture solution comprising water (30 mL), 1,4-dioxane (30 mL), and sodium borohydride (0.5 g) under ice cooling. After the dropwise addition was completed, the reaction solution was refluxed under heating for one hour. After cooling, the reaction solution was poured over ice water, and then extracted with ethyl acetate. After cooling, the extraction was again carried out by adding water and ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (1.1 g, 65%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[H][H].FC(F)(F)S(O[CH:19]1[CH2:25][CH:24]2[N:26]([CH3:27])[CH:21]([CH2:22][CH2:23]2)[CH2:20]1)(=O)=O>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:19]2[CH2:20][CH:21]3[N:26]([CH3:27])[CH:24]([CH2:23][CH2:22]3)[CH2:25]2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: [H][H]
Reactant: CN1C2CCC1CC(OS(=O)(=O)C(F)(F)F)C2
Agent: [H-]
Agent: [Na+]
Product: CN1C2CCC1CC(Sc1ccc(Cl)cc1)C2
Yield: 65.2 %

Procedure:
In a 3 neck round bottom flask equipped for overhead mechanical stirring sodium hydride (2.03 g, 50.91 mmol, 60% oil dispersion) was rinsed free of oil with hexane (2 washes) and tetrahydrofuran (200 mL) was added followed by 4-chlorothiophenol (6.69 g, 46.28 mmol in 20 mL of tetrahydrofuran). Hydrogen gas freely evolved from the reaction. Upon cessation of hydrogen evolution, 3-trifluoromethanesulfonyloxy-8-methyl-8-azabicyclo-(3.2.1)-octane (9.5 g, 46.28 mmol in 70 mL of tetrahydrofuran) was added. The reaction was refluxed overnight, then cooled and filtered through Diatomaceous earth (with ether rinse). The filtrate was concentrated at reduced pressure and residue was taken up in ether. The organic phase was washed with water and brine, dried over calcium sulfate and concentrated to afford 8.08 g (65%) of 3-(4-chlorophenylsulfanyl)-8-methyl-8-azabicyclo-(3.2.1)-octane as a tan oil which had: NMR δ7.42-7.23 (m, 4 H), 3.22 (sym m, 1 H), 3.20-3.11 (m, 2 H), 2.24 (s, 3 H), 2.03-1.97 (m, 2 H), 1.82-1.66 (m, 4 H), 1.53 (ABq, Δv1-3=14.5 Hz, J=6.5 Hz, 2 H).