Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][Si:8]([CH3:23])([CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[CH2:16][O:15]1>C(O)C>[CH3:23][Si:8]([CH3:7])([CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]([OH:15])[CH2:16][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: C1COCCN1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN1CCOCC1
Temperature: 70 °C

Procedure:
Morpholine (0.634 g; 7.28 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:14][C:11]1[O:10][C:9]([C:4]2[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=2)=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cc(-c2ccco2)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(-c2ccc(Br)o2)nc(Cl)n1
Yield: 65.4 %

Procedure:
To a stirred solution of 2,4-Dichloro-6-furan-2-yl-pyrimidine (1.44 g, 6.71 mmol) in DMF (20 ml) was added N-bromosuccinimide (1.31 g, 7.38 mmol) in a portionwise fashion. The resultant mixture was stirred at room temperature for a 2.5 hours before being diluted in EtOAc (50 ml) and washed with water (2×50 ml). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to give an orange, semi-crystalline slurry. The crude residue was washed with ether and filtered to leave the desired product (1.29 g, 99%) as a whited crystalline solid in suitably clean form to be used without any further purification. m/z (LC-MSW, ESP):294 [M+H]+, R/T=5.09 mins.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)([O-])=O.[Sn](Cl)Cl>C(Cl)(Cl)Cl.Cl>[NH2:15][C:18]1[CH:19]=[C:20]([S:24]([O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(OS(=O)(=O)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To 50 g (0.463 mole) of p-cresol (4-methylphenol) and 37 mL (0.458 mole) of pyridine dissolved in 250 mL of chloroform was added 50 g (0.226 mole) of 3-nitrobenzenesulfonyl chloride. The reaction was allowed to stir at ambient temperature. After 2 hours, the reaction was judged complete by TLC and the volatiles were removed by rotary evaporation. The resulting residue was treated with 400 mL of 0.5 M sodium bicarbonate. The insoluble product was collected and washed with sodium bicarbonate (2 times, 200 mL each) and water (2 times, 300 mL each). The solid was then treated with methanol (200 mL) followed by water (200 mL). The solid was collected by vacuum filtration and washed with water. This solid was treated with 170 g (0.897 mole) of tin (II) chloride dissolved in 250 mL of concentrated HCl. The reaction was allowed to stir at ambient temperature for 40 hours. TLC indicated that the reaction was incomplete, so the reaction was heated at 50 C. for 27 hours. The solid precipitate was collected by vacuum filtration and was washed with 6N HCl. The solid was extracted with ethyl acetate and, water. The ethyl acetate layer was washed with brine, dried with magnesium sulfate, filtered, and the volatiles removed by rotary evaporation to yield 42.5 g of compound as an oil that solidified on standing.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.I[CH2:43][CH:44]([CH3:46])[CH3:45]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: CC(C)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 66.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), 1-iodo-2-methylpropane (0.115 mL; 1 mmol) in DMF (4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.140 g (66%) of the title compound as a yellow solid.
Reaction SMILES: C([O:3]C1C=CC(F)=C(F)C=1CCN)C.[CH2:15]([O:17][C:18]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[C:19]=1[CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1)=S)[CH3:16].C1C(=O)N(Br)C(=O)C1>>[CH2:15]([O:17][C:18]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[C:19]=1[CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1)=[O:3])[CH3:16]
Reactant: CCOc1ccc(F)c(F)c1CCN
Reactant: CCOc1ccc(F)c(F)c1CCNC(=S)Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Product: CCOc1ccc(F)c(F)c1CCNC(=O)Nc1ccc(Br)cn1

Procedure:
The methods described in Example 151 of WO 93/03022 was then used to transform this compound to 2-ethoxy-5,6-difluoro-phenethylamine. The method described in Example 411 of WO 93/03022 was then used to prepare N-(2-ethoxy-5,6-difluorophenethyl)-N′-(5-bromopyrid-2-yl)-thiourea. This product was then oxidised with NBS as Example 4 to provide N-(2-ethoxy-5,6-difluorophenethyl)-N′-(5-bromopyrid-2-yl)-urea. 1H-NMR (250 MHz, CDCl3): 1.4 (t, 3H), 3.0 (q, 2H), 3.95 (q, 2H), 6.5 (m, 1H), 6.8 (d, 1H), 6.95 (dd, 1H), 7.68 (dd, 1H), 8.90 (d, 1H) 8.9 (s, 1H), 9.0 (s, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26](=O)[NH2:27])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CC(C)=O.N1C=CC=CC=1>[C:19]([O:18][C:16]([NH:23][C@@H:24]([CH2:25][C:26]#[N:27])[C:29]([OH:31])=[O:30])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](CC#N)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
A solution of dicyclohexylcarbodiimide (DCC, 8.3 g, 40 mmol) in acetone (100 ml) was added dropwise a suspension of Boc-asparagine (9.3 g, 40 mmol) in pyridine (50 mL) at 0° C. under nitrogen. The reaction mixture was stirred at ambient temperature for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (400 mL) and the solution was washed with 2 N aqueous HCl (20 mL×3) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to afford (S)-2-(tert-butoxycarbonylamino)-3-cyanopropanoic acid (5.5 g, 56% yield), which was used directly without further purification.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O.C(Cl)Cl>C1COCC1>[CH:1]1([C:4]2[N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Ic1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To the solution of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-iodo-2-phenylpyrimidin-4-amine (0.4 g, 0.99 mmol, 1.0 eq) in dry THF (50 mL), NaH (0.4 g, 60% dispersion in oil, 10.0 mmol, 10.0 eq) was added by portions. The reaction mixture was stirred at rt for 1 h. Then, BOC2O (0.26 mL, 1.19 mmol, 1.2 eq) was added to the reaction mixture and the resulting reaction was stirred at rt for 2 h. CH2Cl2 was added and organic layer was washed (water), dried and concentrated. The residue was purified by silica gel chromatography (hexane as eluant) to afford tert-butyl 5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (0.32 g, 60.3%). LC-MS (m/z): 504.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 0.81-0.85 (m, H), 1.09-1.15 (m, 2H), 1.67 (s, 1H), 2.49 (m, 1H), 6.86 (s, 2H), 7.50-7.60 (m, 3H), 8.41-8.44 (m, 2H), 9.40 (s, 1H), 10.46 (s, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH2:24][CH2:25][OH:26])[CH2:22][O:21][C:20]1([CH3:28])[CH3:27])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:12]([O:16][C:17]([N:19]1[CH:23]([CH2:24][CH2:25][O:26][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:22][O:21][C:20]1([CH3:28])[CH3:27])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Yield: 90.6 %

Procedure:
Dry, freshly crystallised p-toluenesulphonyl chloride (1.86 g, 9.8 mmol) and 4-dimethylaminopyridine (10 mg, 0.082 mmol) were added to a solution of alcohol 5 (2.00 g, 8.15 mmol) and triethylamine (2.6 ml, 18.75 mmol) in dichloromethane (20 ml) at 5° C. with stirring. The resulting solution was protected from moisture and kept at 5° C. until all the starting material 5 had reacted (33 h, TLC). A colourless solid, presumably triethylamine hydrochloride, crystallised out of the reaction, and was filtered away. The filtrate was diluted with dichloromethane to a volume of 90 ml, and washed with water (2×20 ml), brine (20 ml), dried over Na2SO4, and concentrated to give the crude tosylate 7 as white solid. This material was purified by dissolving in ether (ca. 330 ml), filtering through celite 545 on a wad of cotton wool to give 2.95 g (90%) of 7. 1H NMR (200 MHz, CDCl3) 7.78 (m, 2H), 7.35 (d, 2H), 4.09 (m, 2H), 4.09 (m, 2H), 3.90 (m, 2H), 3.73 (m, 1H), 2.95 (m, 2H), 1.51 (s, 6H), 1.44 (s, 9H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][O:8][N:9]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:11]#[N:12].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC>[Br:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10](=[N:9][O:8][CH3:7])[C:11]#[N:12]
Reactant: CON=C(C#N)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CON=C(C#N)c1ccccc1CBr
Reaction time: 8 h
Yield: 76 %

Procedure:
Benzene (80 ml) was added to α-methoxyimino-2-methylphenylacetonitrile (isomer A)(4.0 g, 23 mmol) and N-bromosuccinimide (4.9 g, 28 mmol), and the mixture was heated under reflux for 1 hour in the presence of 2,2′-azobisisobutyronitrile (190 mg, 1.2 mmol) as a radical initiator. After allowing the mixture to stand for cooling, n-hexane (100 ml) was added, and the mixture was allowed to stand overnight, and the resulting insoluble materials were filtered off. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-bromomethyl-α-methoxyiminophenyl-acetonitrile (4.4 g, 76%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cncc(F)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@@]2(CS1)c1cc(-c3cncc(F)c3)ccc1Oc1ncc(Br)cc12
Temperature: 100 °C
Yield: 46 %

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (300 mg, 0.63 mmol, prepared as described in Method BB26), potassium carbonate (437 mg, 3.16 mmol), 5-fluoropyridin-3-ylboronic acid (178 mg, 1.27 mmol), tetrakis(triphenylphosphine)palladium(0) (73.1 mg, 0.063 mmol), dioxane (4.22 mL) and water (2.12 mL). The reaction was stirred and heated at 100° C. for 1 h. After cooling for rt, the organic layer was separated with a separatory funnel, dried over sodium sulfate, filtered, and concentrated to afford a yellow oil which was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (24 g), 0-50% EtOAc in hexanes to provide a white solid, (S)-3-bromo-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (130 mg, 0.29 mmol, 46%). MS m/z=443.0 [M+H]+. Calc'd for C19H12BrFN4OS: 441.99.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1>[C:25]1(=[O:35])[N:29]([CH2:2][CH2:3][C:4]2[N:8]3[C:9]4[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=4[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:20])=[N:12][CH2:13][C:7]3=[N:6][N:5]=2)[C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, 1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with diethyl azodicarboxylate to give 1-(2-phthalimidoethyl)-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2>>[CH3:28][C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[CH:20][C:19]([NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=1)=[CH:27][CH:26]=2
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)ccc2[nH]1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 5-amino-2-methylindole (41 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.66 (s, 1H), 8.75-8.72 (m, 2H), 8.08 (s, 1H), 7.46-7.34 (m, 4 H), 7.10 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 6.45 (s, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=C(C)[N+:13]([O-])=[CH:14][C:15]=1[CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[CH:11]=[C:10]([O:9][CH3:8])[C:15]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:14][N:13]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1c[n+]([O-])c(C)cc1OC
Solvent: Cc1ccccc1
Product: CCCCc1cnc(COC(C)=O)cc1OC

Procedure:
20.4 g (0.2 mol) of acetic anhydride are added dropwise to a solution of 19.5 g (0.1 mol) of 4-methoxy-5-n-butyl-2-picoline-N-oxide in 100 ml of toluene over the course of 15 minutes, whilst stirring. Thereafter the mixture is heated for 8 hours under reflux. After evaporation to dryness in vacuo, the mixture is rendered alkaline with 2 N aqueous sodium carbonate solution and is extracted with ether. The ether phases are combined, dried with sodium sulphate, filtered and evaporated. Distillation of the residue in a bulb tube in a high vacuum at 120° yields 2-acetoxymethyl-4-methoxy-5-n-butyl-pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[CH2:10][C:11]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([N+:23]([O-])=O)=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:23][C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[CH2:14]2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1)Cc1ccccc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2ccc(N)cc2C1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product (0.43 g) from Step A above in 4 mL of methanol was added 20% palladium hydroxide on carbon (Pearlman's catalyst, 0.04 g). The reaction was placed under a balloon of hydrogen and allowed to stir at room temperature overnight. The reaction flask was purged, the mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; 55% ethyl acetate/hexanes) to afford the title compound. LC/MS: 328 (M−100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][N:18](C)[CH2:19]CCN=C=NCC.Cl.CNC.C(Cl)Cl>CN(C)C1C=CN=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:18]([CH3:19])[CH3:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-L-proline (10.75 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.6 g), dimethylamine hydrochloride (5.33 g), 4-dimethylaminopyridine (6.1 g) and methylene chloride (200 ml) was stirred at ambient temperature for 4 hours. The mixture was poured into water. The organic layer was separated, washed in turn with a 1N aqueous potassium hydrogen sulphate solution, with a 5% aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give 1-(tert-butoxycarbonyl)-N,N-dimethyl-L-prolinamide (11.2 g); NMR Spectrum: (CDCl3) 1.4 and 1.5 (2 s, 9H), 1.8–1.9 (m, 2H), 1.95–2.2 (m, 2H), 3.0 and 3.1 (2 d, 6H), 3.35–3.6 (m, 2H), 4.55 and 4.7 (2 m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Clc1ccc(I)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccc(Cl)cc4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-4-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[C:10]([F:17])[CH:9]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:26])[CH3:25])[N:3]=1.C1(C)C=CC=CC=1.[CH3:34][O-:35].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]([O:35][CH3:34])[C:11]([C:12]#[N:13])=[C:10]([F:17])[CH:9]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:25])[CH3:26])[N:3]=1
Reactant: C[O-]
Reactant: CC(C)[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(N)n1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(N3CCOC[C@H]3C(C)C)nc(N)n2)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile (380 mg, 1.06 mmol) was azeotroped with toluene (2×12 mL). The residue was dissolved in 5 mL of DMF as a clear yellow solution, to which was added NaOMe (2.30 mL of a stock solution with concentration of 0.52 mmol/mL, 1.19 mmol, 1.12 equiv) at room temperature in one portion. The resulting mixture was stirred at room temperature for 18 hours. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc, providing the title compound (276 mg) as a light yellow oily residue. LC-MS (ES) m/z=372 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[N+](C1C=C(S(O[CH2:32][CH:33]2[CH2:35][O:34]2)(=O)=O)C=CC=1)([O-])=O>CC#N>[N+:10]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[O:9][CH2:32][CH:33]1[CH2:35][O:34]1)[C:1]#[N:2])([O-:12])=[O:11]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCC2CO2)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
4-Cyano-2-nitrophenol (0.80 g; 4.9 mmol) and K2CO3 (0.68 g; 4.9 mmol) were refluxed in MeCN (40 mL) for 1 h. The solvent was removed on a rotary evaporator and the residue dissolved in DMF (10 mL). 2-{[(3-Nitrophenyl)sulfonyloxy]methyl}oxirane (1.2 g, 4.9 mmol; see Example B above) was added to the resultant solution. The solution was stirred at 40° C. for 12 h and filtered. The precipitate was washed with H2O to give the sub-title compound in a 65% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17]2)[CH2:6]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH:27][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:18][CH2:17]2)[CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
A solution of 0.030 g (0.06 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-aminopropyloxymethyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine, 0.02 mL (0.24 mmol) of methanesulfonyl chloride, and 0.03 mL (0.15 mmol) of diisopropylethyl amine in 0.5 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, CH2Cl2:methanol, 95:5) to give the title compound. Mass Spectrum (ESI) m/e=574 (M+1 35Cl, 35Cl), 576 (M+1 35Cl, 37Cl), and 578 (M+1 37Cl, 37Cl). [a]D=+11.0 (c=0.815, CHCl3).