Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:12][CH3:13])=[C:5]([C:8]([F:11])=[CH:9][CH:10]=1)[C:6]#[N:7])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[F:11][C:8]1[C:5]([C:6]#[N:7])=[C:4]([O:12][CH3:13])[C:3]([CH:1]2[CH2:2][O:22]2)=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(F)c(C#N)c1OC
Solvent: ClCCl
Product: COc1c(C2CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Ethenyl-6-fluoro-2-methoxybenzonitrile (1.67 g, 9.43 mmol) was added to DCM (50 mL) at 0° C. then mCPBA (4.88 g, 28.3 mmol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was washed with saturated aqueous Na2S2O3, then with 1N NaOH followed by brine. The organic layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by chromatography through a 120 g Redi-sep column and eluting with a 0-100% EtOAc/hexane solvent system. Isolated 6-fluoro-2-methoxy-3-(oxiran-2-yl)benzonitrile.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([N:34]([CH2:40][CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH3:33]>O1CCOCC1>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH2:40][CH3:41])[CH2:32][CH3:33])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1F
Reactant: CCN(CC)CCCCN
Solvent: C1COCCO1
Product: CCN(CC)CCCCNc1ncc2c(n1)N(C1CCCC1)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2
Yield: 86 %

Procedure:
In a 1-L round bottom flask, 8.00 g (17.78 mmol) of 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one in 260 mL of dioxane was treated with 5.10 g (35.36 mmol) of 4-diethylamino-butylamine and heated at reflux for 10 hours under nitrogen atmosphere. The dioxane was evaporated in vacuo. The crude product was purified using medium-pressure chromatography eluting with a gradient of 9:0.5:0.25 to 9:1:0.5 ethyl acetate/methanol/triethylamine to give 8.14 g (86%) of the title compound as a pure partially crystalline solid. A 50 mg portion of the solid was recrystallized with 25% ethanol in hexanes to give 35 mg of title compound as pure crystalline solid: mp 132° C.–133° C. MS (APCI) (m+1)/z 533.3.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:25]=[CH:24][C:17]([CH2:18][C@@H:19]([C:21](O)=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].[OH-].[K+]>O>[CH2:1]([N:8]1[C:21](=[O:22])[CH:19]([CH2:18][C:17]2[CH:24]=[CH:25][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[NH:20][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C=NCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1NC(Cc2ccc([N+](=O)[O-])cc2)C(=O)N1Cc1ccccc1
Reaction time: 2 h
Yield: 87.7 %

Procedure:
Benzyl isocyanate (3.2 g, Aldrich) was added dropwise at 0° C. over 20 minutes to a stirred mixture of p-nitrophenylalanine (4.2 g, Fluka) and KOH (1.3 g) in water (40 ml). When addition was complete, the mixture was stirred at 60°-70° C. for 2 hours, then cooled, filtered, and the filtrate treated with c.HCl. The resulting white solid was filtered off, washed with ice-water, dried in vacuo, then suspended in 50% aqu. HCl (20 ml) and refluxed for 2 hours. The suspension was cooled, diluted with water, filtered, and the residue dried in vacuo to give the desired product (5.7 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([N+:19]([O-])=O)[CH:11]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=3)=[O:36])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:41]([C:40]3[CH:39]=[CH:38][C:37]([C:35]([NH:34][C:31]4[CH:30]=[CH:29][C:28]([N:25]5[CH2:24][CH2:23][O:22][CH2:27][CH2:26]5)=[CH:33][CH:32]=4)=[O:36])=[CH:44][CH:43]=3)=[N:19][C:12]=2[CH:11]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(-c4nc5ccccc5s4)ccc3[nH]2)cc1

Procedure:
Compound 638 was prepared according to the procedure similar to that described in Scheme III from 1-(benzothiazol-2-yl)-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C31H25N5O2S: 532.18; found: 532.07.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:7]=1.[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)=O>[CH3:16][C:14]1[N:15]=[C:3]2[C:2]([NH:1][CH2:22][C:21]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=3[CH2:18][CH3:19])=[CH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][N:4]2[C:13]=1[CH3:17]
Reactant: CCOC(=O)c1cc(N)c2nc(C)c(C)n2c1
Reactant: CCc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(NCc2c(C)cccc2CC)c2nc(C)c(C)n2c1
Yield: 10.9 %

Procedure:
Ethyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (0.7 g, 3.0 mmol), 2-ethyl-6-methylbenzylchloride (0.5 g, 3.0 mmol), sodium carbonate (0.64 g, 6.0 mmol) and a cat. amount of potassium iodide were added to acetone (50 ml) and were refluxed for 20 h. Following filtration, the acetone was evaporated under reduced pressure to give an oil. The oily product was purified by column chromatography on silica gel using diethyl ether:petroleum ether (1:1) as eluent to give 0.12 g (9%) of the title product.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:14]2[CH2:15][CH2:16][CH:11]([CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]#[N:10])[CH2:12][CH2:13]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: N#CC(c1ccccc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of α-phenyl-4-piperidineacetonitrile hydrochloride (0.05 mole), 1-fluoro-4-nitrobenzene (0.06 mole) and potassium carbonate (0.15 mole) in DMF (200 ml) was stirred at 50° C. for four hours. Water and DIPE were added. The mixture was cooled. The precipitate was filtered off, washed with water and DIPE and dried, yielding 11.6 g of (±)-1-(4-nitrophenyl)-α-phenyl-4-piperidine-acetonitrile (intermediate 12, melting point 118° C.).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[CH3:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1

Procedure:
1-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine is prepared by heating a solution of 1 g of 2-chloro-3-methyl-5-nitro-pyridine (Maybridge Chemical Company Ltd.) and piperazine (5 g) in DMA at 110° C. for 16 h. Partition between EtOAc and water and wash the organic layer with water (2×). Dry the organic layer with Na2SO4 and concentrate to give crude product. Purify via flash chromatography eluting with MeOH:DCM:NH4OH (9:90:1) to give the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[C:44]([C:46]([F:48])([F:47])[F:49])[CH:43]=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: FC(F)(F)c1ccnc(CCl)c1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cc(C(F)(F)F)ccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 81.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-chloromethyl-4-trifluoromethylpyridine (0.67 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.79 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[CH3:13][CH2:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)=[O:17].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]([O:15][CH2:14][CH3:13])=[O:17])=[CH:23][CH:22]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(CCC(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)CCc2ccc(C)cc2)cc1

Procedure:
A solution of 15 g. of 3-(4-methylphenyl)propionyl chloride in 100 ml. of dichloromethane is created with stirring with a solution of 15 g. of benzocaine and 9.13 g. of triethylamine in 100 ml. of dichloromethane. The mixture is stirred overnight, then washed with 100 ml. each of 10% hydrochloric acid, water, and brine, then dried with magnesium sulfate, and evaporated to yield a solid. This solid is crystallized from 200 ml. of acetonitrile and dried in vacuo, giving 22.08 g. of the desired product, m.p. 154°-155° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C@@H:9]1[OH:25])([CH3:4])([CH3:3])[CH3:2].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[C@@H:9]1[O:25][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(CS[C@@H]2CCC[C@@H](NC(=O)OC(C)(C)C)[C@H]2O)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CS[C@@H]2CCC[C@@H](NC(=O)OC(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)c(C)c1
Temperature: 80 °C
Reaction time: 120 h
Yield: 94 %

Procedure:
A solution of [(1R,2R,3R)-2-hydroxy-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-carbamic acid tert-butyl ester+(1S,2S,3S) diastereomer (2.46 g, 6.49 mmol) in 50 ml of dimethylformamide was treated with tert-butyldimethylsilyl chloride (978 mg, 6.49 mmol) and imidazole (552 mg, 8.11 mmol) and stirred at 80° C. for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 0.1 N HCl and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. After chromatography (silica, cyclohexane/ethyl acetate=10/1) [(1R,2R,3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclo-hexyl]-carbamic acid tert-butyl ester+(1S,2S,3S) diastereomer (Rf=0.25, 3.0 g, 94% yield) was obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[NH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:29][C:30]1[N:34]=[C:33]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)[O:32][N:31]=1>C(#N)C>[F:41][C:39]1[CH:40]=[C:35]([C:33]2[O:32][N:31]=[C:30]([CH2:29][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:1])([F:20])[F:21])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[C:6]3[CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:34]=2)[CH:36]=[C:37]([F:42])[CH:38]=1
Reactant: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1C(F)(F)F
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CCC(F)(F)F)n2Cc2noc(-c3cc(F)cc(F)c3)n2)c1C(F)(F)F
Yield: 23.9 %

Procedure:
To a solution of 4-(trifluoromethyl)-2-(3,3,3-trifluoropropyl)-1H-indole-5-carbonitrile (Example 302A) (0.200 g, 0.653 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (0.851 g, 0.2.612 mmol) and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole (0.226 g, 0.979 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.078 g, 24% yield): MS (ES) m/z 500 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.[CH3:12][CH2:13][O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:18]([NH:17][C:15](=[O:16])[O:14][CH2:13][CH3:12])=[S:19])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)N=C=S
Reactant: COc1ncc(OC)c(N)n1
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(=S)Nc1nc(OC)ncc1OC
Temperature: 78 °C
Reaction time: 11 h
Yield: 87 %

Procedure:
2,5-Dimethoxypyrimidin-4-amine (6) (3 g, 0.0193 moles) was dissolved in 18 g of ethyl acetate. Ethyl isothiocyanatidocarbonate (2.77 g, 0.0208 moles) was added in one portion. The solution was heated to 78° C. and held at that temperature for 11 h. An additional 1.4 g of the ethyl isothiocyanatidocarbonate was added and the mixture heated for 2.5 h. The mixture was allowed to cool to 22° C. and filtered. The resulting solid was washed with ethyl acetate (20 mL) and dried to a constant weight in a fume hood to afford the title compound as a yellow solid (4.81 g, 89%): 13C NMR (DMSO-d6, 100 MHz) δ 177.5, 158.4, 153.3, 149.5, 142.3, 139.5, 62.6, 57.6, 55.2, 14.4; HRMS (ESI), calcd for C10H14N4O4S, 286.0736; found, 286.0727.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:13]([C:3]2[C:2]([CH3:1])=[N:6][N:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:4]=2)=[O:15])=[CH:25][CH:26]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Product: COCCN(C)c1ccc(NC(=O)c2nn(-c3ccccc3)nc2C)cn1

Procedure:
With a procedure similar to example 16 above, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H22N6O2 (m/e) 366, obsd 367 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][N:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[N:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cn4)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cn4)cnc32)cc1
Yield: 91.6 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(5-(piperazin-1-yl)pyridin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg. 0.164 mmol) was alkylated using (S)-2-methyloxirane (18 mg, 0.329 mmol), DIPEA (58 μL, 0.329 mmol) and ethanol (10 mL) to get 100 mg (91.7%) of the titled compound.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]2[CH2:15][CH:14]([CH2:16][S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:13][C:12]2=[O:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(S(NC(CC2OC2)C(OC)=O)(=O)=[O:38])=CC=1.CCN(CC)CC.C1(S)C=CC=CC=1>C1C=CC=CC=1.O>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:15][CH:14]([OH:38])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]([OH:13])=[O:24])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(CSc2ccccc2)CC1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)C(CC(O)CSc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
3-[[(1,1′-Biphenyl)-4-yl]sulfonyl]amino-2-oxo-5-[(phenylthio)methyl]-tetrahydrofuran: To a solution of methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4,5-epoxypentanoate 16b (0.36 g, 1.47 mmol) in benzene (5 mL) and Et3N (0.27 g, 1.91 mmol) at room temperature is added slowly benzenethiol (0.38 mL, 3.67 mmol). The reaction mixture is stirred for 3 hrs. The resulting mixture is diluted with water, and then the mixture is extracted three times with EtOAc. The combined EtOAc layer is washed with water, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with EtOAc/hexane (1:4 to 3:7) to give the desired product as a mixture of two isomers (ratio: ˜2:1).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[CH3:23][N:24]([CH3:44])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[N:26]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][N:24]([CH3:44])[C:25]1[N:26]=[C:27]([C:2]2[C:10]3[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=3[CH:5]=[C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:3]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N(C)C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccc(N(C)C)n3)c2s1
Temperature: 100 °C
Yield: 4.3 %

Procedure:
To a solution of 1-(7-bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.125 g, 0.33 mmol) in DMF (5 mL) was added dimethyl-(6-tributylstannanyl-pyridin-2-yl)-amine (0.14 g, 0.33 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.023 g, 0.033 mmol). The reaction mixture was then again degassed for half an hour and heated at 100° C. for 15 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified by prep HPLC to get the title compound (0.006 g, 5.0%) as off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Na]>ClCCl.C([O-])(O)=O.[Na+]>[CH:2]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:1]
Reactant: COC(=O)c1ccnc(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccnc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
Methyl 2-(hydroxymethyl)isonicotinate (8.36 g, 50 mmol) (from reference compound 38, step 1) was dissolved in dichloromethane (150 mL). Dess-Martin periodinane (25 g, 58.94 mmol) was added and the mixture stirred at room temperature for 2 h 30 min. Sodium sulfothioate (59.3 g, 375.00 mmol) was dissolved in satd NaHCO3 and added to the reaction mixture. The suspension was vigorously stirred at room temperature for 15 min, DCM was added and the phases were separated. The aqueous phase was extracted with DCM twice and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. Gradient heptanes/EtOAc 80:20 to 65:35 over 5 CV was used as mobile phase. Methyl 2-formylisonicotinate (7 g, 85%) was isolated as an off-white solid. 1H NMR (400 MHz, cdcl3) δ 4.00 (s, 3H), 8.09 (dd, 1H), 8.49 (s, 1H), 8.95 (d, 1H), 10.15 (s, 1H). MS m/z 165 (M)+
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH:25]=[CH2:26]>C1COCC1>[OH:8][C@:1]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)c2ccccc2)C1
Reactant: C=CCCC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCC[C@](O)(c1ccccc1)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Yield: 88 %

Procedure:
A stirred solution of tert-butyl 3-benzoylpiperidine-1-carboxylate (160 mg, 0.55 mmol) in dry THF (2 mL) was cooled to −70° C. and 4-pentenylmagnesium bromide in THF (1.8 mL of ˜2.5 M, 2.8 mmol) was added dropwise. The mixture was stirred at −78° C. and allowed to warm to rt overnight. The reaction was quenched with satd aq ammonium chloride. The aqueous layer was extracted with Et2O (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography on a prepacked silica cartridge eluted with an EtOAc/hexanes gradient. tert-Butyl 3-((R)-1-hydroxy-1-phenylhex-5-enyl)piperidine-1-carboxylate (174 mg, 88%) was isolated as an oil. MS ESI+ve m/z 382 (M+Na)+.