Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].C[N:17]1[CH2:22][CH2:21][C:20]2=[C:23]([CH:26]=O)[NH:24][CH:25]=[C:19]2[C:18]1=[O:28].N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:23]1[NH:24][CH:25]=[C:19]2[C:20]=1[CH2:21][CH2:22][NH:17][C:18]2=[O:28])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (45.2 mg, 0.2 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (35.6 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.Cl.[NH2:24][CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:24][CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2ncc(C(F)(F)F)cc2Cl)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester, 2-aminomethyl-3-chloro-5-(trifluoromethyl)pyridine hydrochloride and DBU in DME. ES-MS m/e (%): 396 (M{37Cl}+H+, 40), 394 (M{35C}+H+, 100).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][CH2:41][C:42]#[N:43]>CC#N>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:39][CH2:40][CH2:41][CH2:42][NH2:43]
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: N#CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.169 g, 0.451 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.25 mL, 1.44 mmol) followed by 4-bromobutyronitrile (0.10 mL, 1.01 mmol). The resultant mixture was heated to 80° C. for 5 d then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (20 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (30:1:1 CH2Cl2—CH3OH—NH4OH) provided 108 mg (54%) of a yellow foam.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:6]([O:8][CH2:9][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[O:12])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(C(=O)OCCCCCCCCCCCCCCCCCC)cc1
Temperature: 130 °C
Yield: 96.2 %

Procedure:
To a 2 L Buchi reactor equipped with a double turbine agitator and distillation apparatus was charged Dimethyl terephthalate (315.8 grams), Stearyl Alcohol (879.7 grams) and heated to 130° C. under Nitrogen purge for 1 hour, after which stirring was commenced followed by the addition of Tyzor catalyst (3.0 grams, available from Dupont). The reaction mixture was then heated to 145° C., followed by slowly ramping the temperature to 190° C. over a 3-4 hour period such that the evolution of methanol is distilled in a controlled manner. The reaction temperature was maintained at 190° C. for an additional 16 hours until >96% conversion to the product was achieved as determined by 1H NMR spectroscopy. The product was discharged as a low viscosity liquid which solidified on cooling to give a 1050 gram of a white solid (96.2% yield). The product was shown to be pure by 1H NMR spectroscopy with trace amounts of the mono-ester. Physical properties of this compound are shown in Table 2.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][NH:18][O:19][CH3:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH3:17][N:18]([O:19][CH3:20])[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of 30 g Boc-proline and 13.6 g N,O-dimethylhydroxylamine hydrochloride in 250 ml of dichloromethane was added 26.73 g 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 18.83 g N-hydroxy-benzotriazol and 49.34 g N-methyl-morpholine at 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was washed sequentially with saturated sodium bicarbonate, a 5% aqueous solution of citric acid and brine. The organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo to give 22.9 g N-methyl-N-methoxy-(Boc-proline)-amide.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Br[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:12][C:11]1[C:6]([CH:4]2[CH2:5][N:2]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:3]2)=[N:7][CH:8]=[CH:9][N:10]=1
Reactant: Clc1nccnc1C1CNC1
Reactant: Brc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Temperature: 110 °C
Reaction time: 19 h
Yield: 42.7 %

Procedure:
A mixture of 2-(azetidin-3-yl)-3-chloropyrazine hydrochloride (8) (163 g, 0.79 mol), 2-bromoquinoline (164 g, 0.79 mol, 1 eq., Combi-Blocks) and cesium carbonate (772 g, 2.37 mol, 3 eq., Aldrich) in anhydrous DMF (6.5 L) was heated to 110° C. and stirred for 19 h. After cooling to RT, the mixture was transferred to 50 L separatory funnel and diluted with water (13 L). Then it was extracted with ethyl acetate (20 L×2) and the organic extracts were combined, washed with water (8 L), brine (8 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 3:1). All fractions containing desired compound were combined and concentrated. The obtained solid was triturated with MTBE (250 mL), washed with MTBE (100 mL×2) and dried to obtain 100 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. The mother liquor was concentrated and purified by column chromatography and trituration with MTBE again to give 4.5 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. Yield: 45% for two steps.
Reaction SMILES: [F:1][CH:2]([O:7][C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[O:10][C:11]([F:19])([F:18])[CH2:12][O:13][CH2:14][CH2:15][CH2:16]Br)[C:3]([F:6])([F:5])[F:4].[CH2:24]([O:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[N:36][CH:37]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:24]([O:31][C:32]1[CH:37]=[N:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([O:44][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([O:10][C:9]([F:21])([F:20])[C:8]([F:23])([F:22])[O:7][CH:2]([F:1])[C:3]([F:6])([F:5])[F:4])([F:19])[F:18])=[CH:42][CH:43]=2)=[N:34][CH:33]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: FC(OC(F)(F)C(F)(F)OC(F)(F)COCCCBr)C(F)(F)F
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)C(F)(F)F)cc2)nc1

Procedure:
Using essentially the procedure of Comparative Example A, the title compound was prepared by combining 3-(2-(2-(tetrafluoroethoxy)tetrafluoroethoxy)-2,2 -difluoroethoxy)-l-bromopropane (5.1 g, 38.5 mmol), 5 -heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 11.0 mmol), potassium carbonate (1.6 g, 12.7 mmol), and acetonitrile (58 mL). The resulting crude product was isolated and purified essentially as in Comparative Example A to yield 5.1 g.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](=[NH:16])OCC)([O-:4])=[O:3].CO[CH:19](OC)[CH2:20][NH2:21].Cl.[OH-].[Na+]>C(O)C>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[NH:16][CH:19]=[CH:20][N:21]=1)([O-:4])=[O:3]
Reactant: COC(CN)OC
Reactant: CCOC(=N)Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1Cc1ncc[nH]1
Temperature: 25 °C

Procedure:
Ethanol (2,200 ml) and 5,156 g (8.81 moles) of ethyl 2-(2-nitrophenyl)acetimidate hydrochloride were charged into a 22 liter flask. The suspension was stirred under nitrogen at room temperature and 1022.9 g (9.73 moles) of aminoacetaldehyde dimethylacetal were added all at once. The mixture was stirred for 1 hour and 1,693 ml of 12N hydrochloric acid were added all at once to cause a gentle exotherm (to 40°). Heat was then applied and the temperature was maintained at 70°-80° for 30 minutes. The solution was cooled to 20° (ice-water bath) and diluted with 2,700 ml fo 10N sodium hydroxide solution to precipitate the product. The suspension was stirred at 10° for 1 hour under nitrogen atmosphere, the solid collected by filtration and washed with 3×2,000 ml of water to give 2-(2-nitrobenzyl)-imidazole, m.p. 155°-7°.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[CH2:8])[C:6]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[O:5][C:4]1=[O:14])[CH3:2].C(N(CC)CC)C.[I-].[K+].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:32][CH2:33][CH2:34]Cl)=[CH:27][CH:26]=1>C(C(C)=O)C>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[CH:32][CH2:33][CH2:34][N:11]2[CH2:12][CH2:13][C:6]3([O:5][C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:7]3=[CH2:8])[CH2:9][CH2:10]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(C(=CCCCl)c2ccc(F)cc2)cc1
Reactant: C=C1N(CC)C(=O)OC12CCNCC2
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: C=C1N(CC)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reaction time: 15 h
Yield: 68.7 %

Procedure:
A mixture containing 7.8 g of 3-ethyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 8.5 ml of anhydrous triethylamine, 80 ml of anhydrous methyl ethyl ketone, 3.0 g of potassium iodide and 16.7 g of 4,4-bis(4-fluorophenyl)-3-butenyl chloride is refluxed under nitrogen while stirring for 15 hours, then the solvent is distilled off under reduced pressure. After adding benzene and water to the residue, the benzene layer is washed with water to neutral, dried over anhydrous magnesium sulfate, filtered through an aluminum oxide bed and evaporated under reduced pressure. After recrystallizing the residue from ethanol, the title product is obtained in 68.7% yield, m.p.: 138°-139° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4](Cl)([O:6][CH2:7][CH:8]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5]>C(Cl)Cl.O>[OH:3][NH:2][C:4](=[O:5])[O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NO)OCC1c2ccccc2-c2ccccc21
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
hydroxylamine hydrochloride (6.0 g, 86 mmol) in CH2Cl2 (250 mL) and water (100 mL) at 0° C. After 10 mins, solid FmocCl (21 g, 81 mmol) is added portionwise with vigorous stirring. After 1 h a white precipitate forms and more CH2Cl2 (100 mL) is added. The solution is allowed to warm to 20° C. and left to stir for 3 d. The white solid that remains is filtered away, re-dissolved in ethyl acetate (300 mL), washed with brine and dried over MgSO4 to yield (9H-fluoren-9-yl)methyl hydroxycarbamate (Mellor, S. L.; McGuire, C.; Chan, W. C.; Tet. Lett., 1997, 38, 3311-3314) as a white solid (15 g, 68%). Furthermore, the mother-liquor is concentrated and purified by column chromatography (silica gel, ethyl acetate/CH2Cl2 1:1 to 1:0) to yield the title compound (by-product) as a white solid (0.55 g, 1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
A solution of (3,4-dichloro-phenyl)-acetic acid (14.0 g, 0.068 mol) in methanol (71 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 12 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3,4-dichloro-phenyl)-acetic acid methyl ester (15.0 g, quant.) as a white solid: mp 30-32 ° C.; EI-HRMS m/e calcd for C9H8Cl2O2 (M+) 217.9901, found 217.9907.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][O:17][S:58]([CH3:57])(=[O:60])=[O:59])[CH:14]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCO)cn2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCOS(C)(=O)=O)cn2)n1
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 119e (65 mg, 0.10 mmol) in DCM (1.5 mL) was added DIPEA (71 μL, 0.41 mmol) followed by methanesulfonyl chloride (16 μL, 0.20 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.23 min, m/z 717 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH3:21]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]#[N:10]
Reactant: CCCCBr
Reactant: COc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C#N)cc1OC
Temperature: 37 °C
Yield: 105.3 %

Procedure:
2-methoxy-4-cyano-phenol (0.25 g, 1.67 mmol) and anhydrous DMF (2.00 mL) were added into a flask, then cooled in a water bath while stirring. Several batches of K2CO3 (0.347 g, 2.50 mmol) were added to the mixture and stirred at 20° C. to react for 1 h. n-butyl bromine (0.23 ml, 2.14 mmol) was added into the mixture, which was stirred at room temperature overnight, then heated at 37° C. to react for 6 h. Poured the solution into a mixture of ice/H2O (25 mL), then stirred for 10 min, a precipitate was formed. Filtered, washed with H2O, and air-dried to yield 0.361 g of white solid product with a recovery rate of 92%.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[OH-].[Na+].[CH2:20](Br)[CH3:21]>CO.O>[CH2:20]([O:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)[CH3:21]
Reactant: CCBr
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 16 h
Yield: 52 %

Procedure:
The 2'-deoxy-5-hydroxyuridine (244 mg.,1mmol) was suspended in a mixture of methanol (10ml) and water (5ml) at room temperature, and 1 ml of 1.0N sodium hydroxide solution (1mmol) was added to generate the monoanion. Ethyl bromide (0.312ml, 4mmol) was added, and the reaction mixture was stirred for 16 hours. The solvent was removed in vacuo, and ethanol was added to and evaporated from the residue. The desired 5-ethoxy product was separated from small amounts of the 3 ethyl-5-ethoxy dialkyl byproduct by chromatography on a silica gel column using chloroform-methanol (9:1, v/v) as the solvent. Following crystallization from absolute ethanol, 5-ethoxy-2'-deoxyuridine was obtained in 52% yield (140 mg); mp 179°-181° C.; 1H NMR (methyl sulfoxide-d6),δ11.38 (1H, br s, NH), 7.58 (1H, s, H-6), 6.18 (1H, t, H-1'), 5.19 (1H, d, 3'-OH), 5.09 (1H, t, 5'-OH), 4.25 (1H, m, H-3'), 3.79 (3H, m. H4'and OCH2CH3 ), 3.59 (2H, br s,H-5'and H-5"), 2.10 (2H, m, H-2'and H-2") and 1.23ppm (3H, t, OCH2CH3). Anal. Calcd. for C11H16N2O6C, 48.53; H, 5.92; N, 10.29. Found: C, 48.69; H, 6.0-1; N, 10.36.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of aniline (9.31 g, 100 mmol) and triethylamine (15.2 g, 150 mmol) in THE (150 mL) is cooled to −40° C. before chloroacetic acid chloride (11.3 g, 100 mmol) is slowly added in portions such that the temperature does not rise above 0° C. After completion of the addition, the brown suspension is stirred at rt for 1 h. The dark purple mixture is poured onto water (300 mL) and extracted twice with EA (300 mL). The organic extracts are washed with sat. aq. NaHCO3, 0.5 N aq. HCl, followed by water, and evaporated. The brown residue is suspended in diethyl ether, filtered off, washed with additional diethyl ether and dried under high vacuum to give 2-chloro-N-phenyl-acetamide. LC-MS: tR=0.75 min, [M+1]+=170, 1H NMR (CDCl3): δ 8.22 (s br, 1H), 7.56-7.51 (m, 2H), 7.40-7.24 (m, 2H), 7.20-7.14 (m, 1H), 4.20 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:1]([CH2:7][C:6]1[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc2c1C(=O)NCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NCCc2cccc(N(Cc3ccccc3)Cc3ccccc3)c21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1.466 g (9.039 mmol) 8-amino-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 15 ml DMF and combined with 3.226 g (23.340 mmol) potassium carbonate and with 3.808 ml (31.420 mmol) benzylbromide. This reaction mixture is stirred for 16 h at 50° C. The reaction mixture is diluted with ethyl acetate and extracted with sodium hydrogen carbonate solution. The organic phases are dried and the solvent is eliminated in vacuo.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.C1CCCCC1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>C1COCC1>[CH2:1]([NH:3][C:4](=[O:17])[C:5]1[C:10]([Si:38]([CH3:40])([CH3:39])[CH3:37])=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)c1ccccc1-c1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)c1c(-c2ccccc2)cccc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
This amide (2.25 g, 10 mmol) and TMEDA (1.2 eq) in THF were mixed and cooled to -78° C. and a 1.3 M s-BuLi solution in cyclohexane (2.2 eq) was added dropwise. The resulting reaction mixture was stirred at -78° C. for 30 min and TMSCl (1.2 eq) was added dropwise. The reaction was stirred at -78° C. for 30 min and allowed to warm to -30° C. The reaction was worked up in the usual manner. The crude product was purified by flash chromatography and recrystallization from hexanes to afford the title compound as a white solid (1.15 g, 39%). m.p. 159-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Cc1cccc(CCl)n1
Agent: Cl
Product: Cc1cccc(Cn2cc(C#Cc3cccc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=322.4 (M+H30), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 471 [M+1]+.