Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1>[OH:16][CH:15]([CH:12]1[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1)[CH:17]=[CH2:18]
Reactant: O=CC1CCN(C(=O)c2ccccc2)CC1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 500 mg of 1-benzoylpiperidine-4-carboxaldehyde (Step C) in 10 mL THF at −78° C., was added 2.99 mmol of vinyl magnesium bromide. The solution was warmed to 0° C. and stirred for 1 h. The reaction was quenched with 15 mL of aq. ammonium chloride and extracted with 3×20 mL ether and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography with 2:1 hexane:ethyl acetate followed by 1:1 hexane:ethyl acetate followed by hexane:ethyl acetate:methanol, 50:50:5 to give 411 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([OH:12])[CH:10]=[CH:9][CH2:8][O:7]1)=[O:5])[CH3:2].[CH3:13][C:14](OC(C)=O)=[O:15]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCN(CC)CC>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([O:12][C:14](=[O:15])[CH3:13])[CH:10]=[CH:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1OCC=C[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1OCC=C[C@H]1OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (70 mg, 0.41 mmol) and DMAP (24 mg, 0.2 mmol) in CH2Cl2-Et3N (9:1, 5 mL) was added Ac2O (54 mg, 0.53 mmol). The resulting solution was stirred at ambient temperature for 2 H. The solution was diluted with CH2C12 (40 mL), washed with H2O (20 mL×2), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C=O)C.[CH2:12]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=C2)[CH:13]=[CH2:14]>C(Cl)Cl>[CH2:12]([O:15][C:16]1[CH:24]=[C:23]2[C:22](=[CH:18][CH:17]=1)[NH:21][CH:20]=[C:2]2[CH:1]=[O:5])[CH:13]=[CH2:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOc1ccc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOc1ccc2[nH]cc(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.22 mL, 14.1 mmol) in dry CH2Cl2 (20 mL) was added at 0° C. under nitrogen a solution of dry DMF (1.3 mL) in dry CH2Cl2 (20 mL). The mixture was stirred at 0° C. for 30 min and a solution of 5-allyloxy-1H-indole (1.25 g, 7.22 mmol) in CH2Cl2 (10 mL) was added. The resulting solution was allowed to reach RT and stirred for 4 h. The solvent was concentrated and the residue dissolved in THF (35 mL) and 20% aqueous ammonium acetate (48 mL) and heated at reflux for 30 min, cooled, treated with an aqueous saturated solution of NaHCO3, and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude solid was taken up in CH2Cl2 and filtered-off to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:2)=0.56; MS (LC/MS): 202.0 [M+H]+, 224.1 [M+Na]+, 200.1 [M−H]−, 159.1 [M−H-allyl]−; tR (HPLC conditions a): 2.89 min.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:34]=[C:33](O)[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][O:27][C:33]3[CH:32]=[CH:31][C:30]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:29]([F:28])[CH:34]=3)=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: Cc1cccc(COc2cc(C(C)(C)C)nn2Cc2ccc(CO)cc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3OCc3cccc(C)n3)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a mixture of [4-({3-tert-butyl-5-[(6-methylpyridin-2-yl)methoxy]-1H-pyrazol-1-yl}methyl)phenyl]methanol (0.80 g, 2.2 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.49 g, 2.3 mmol), tributylphosphine (1.10 mL, 4.41 mmol) and tetrahydrofuran (40 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.11 g, 4.40 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and diisopropyl ether was added to the residue. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:3) to give the title compound (1.11 g, yield 90%) as a yellow oil. MS: m/z 560 (MH+).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([Li])CCC.[Sn:29](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1>[C:1]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Sn:29]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=C(N[C@@H](Cc1ccc(Cl)cc1)C(=O)O)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-CBZ p-chloro phenylalanine 1 (one equivalent) in anhydrous THF at 100° C. is added n-butyllithium (3.3 equiv.). After one hour, a solution of Bu3SnCl (excess) is added. Other tri-alkyl-Sn compounds may be used in place of Bu3SnCl. The solution is warmed to 0° C. and quenched by the addition of saturated NH4Cl. Extractive work-up into diethyl ether affords the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]([C:17]2[CH:34]=[C:33]3[C:20]([S:21](=[O:37])(=[O:36])[NH:22][C:23]4[C:32]3=[CH:31][C:30]([Cl:35])=[C:29]3[C:24]=4[N:25]=[CH:26][CH:27]=[CH:28]3)=[CH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]([C:17]2[CH:34]=[C:33]3[C:20]([S:21](=[O:37])(=[O:36])[NH:22][C:23]4[C:32]3=[CH:31][C:30]([Cl:35])=[C:29]3[C:24]=4[N:25]=[CH:26][CH:27]=[CH:28]3)=[CH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)c2ccc3c(c2)-c2cc(Cl)c4cccnc4c2NS3(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OC1CCNCC1)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 50.7 %

Procedure:
A solution of 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 1-tert-butoxycarbonyl-piperidin-4-yl ester 534 (70 mg, 0.12 mmol) in 4M HCl in dioxane (3 ml) was stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue was washed with MeOH to give the title compound (27 mg, 47%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C([Li])CCC.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]2[O:15][C:14](=[O:16])[C:5]3[S:6][C:7]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[C:3]([C:1]#[N:2])[C:4]2=3)=[CH:25][CH:24]=1
Reactant: N#Cc1cc(C(=O)O)sc1N1CCOCC1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc2c1C(c1ccc(Cl)cc1)OC2=O
Temperature: -70 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
A solution of 4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (0.1 g, 0.42 mmol) in anhydrous THF (1.5 mL) was cooled down to −70° C. To this cooled solution was added a 2.5 M solution of n-butyl lithium in hexanes (0.672 mL, 1.68 mmol) dropwise under nitrogen. The resulting solution was stirred at −70° C. for 2 h and 4-chlorobenzaldehyde (0.142 mL, 1.26 mmol) was added. The reaction mixture was stirred at −70° C. for a further 2 h and was quenched with water. The mixture was concentrated to a small volume and the aqueous residue was washed with EtOAc. The aqueous solution was separated, acidified with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography to give the title compound (0.020 g, 13%), LCMS: (FA) ES+ 361, 363. 1H NMR (400 MHz, d6-DMSO) δ: 7.54 (d, J=8.48 Hz, 2H), 7.38 (d, J=8.48 Hz, 2H), 6.72 (s, 1H), 3.77-3.73 (m, 4H), 3.65-3.60 (m, 4H)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2N3C(CNCC#C)=NN=C3CN=[C:7]([C:20]3[C:25](F)=[CH:24][CH:23]=[CH:22][C:21]=3F)[C:6]=2[CH:28]=1.C=[O:30]>C(O)=O>[C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:30])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:28]=1
Reactant: C=O
Reactant: C#CCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Solvent: O=CO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 1, 8-chloro-1-[[(2propynyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated in formic acid with aqueous formaldehyde to give 5-chloro-2',6'-difluoro-2-[3-[[(2propynyl)methylamino]methyl]-5-(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]2[NH:10][C:11](=[O:12])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:2]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2c(F)cc(Cl)cc2Br)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c(F)cc(Cl)cc32)CC1
Temperature: 80 °C

Procedure:
Under an argon atmosphere, 1,1-dimethylethyl 4-({[(2-bromo-4-chloro-6fluorophenyl)amino]carbonyl}amino)-1-piperidinecarboxylate (D7) (1.09 mmol, 0.493 g), 1,4-dioxane (4.4 ml), Pd2 dba3 (0.05 eq., 0.054 mmol, 50 mg), BINAP (0.055 eq., 0.059 mmol, 37 mg), NatBuO (1.5 eq., 1.63 mmol, 157 mg) were mixed together and heated to 80° C. under argon for 4 days. The reaction mixture was cooled to room temperature, quenched with water and the aqueous solution obtained was extracted with ethyl acetate. The solvent was evaporated and the crude was purified by MDAP. Fractions were collected and the solvent evaporated to yield the title compound, 15 mg, 3%, M+−H=368.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@@H:17](Br)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[N-:29]=[N+:30]=[N-:31].[Na+].C(O)(=O)C.O>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([N:29]=[N+:30]=[N-:31])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](Br)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 87.5 %

Procedure:
A solution of 36 (0.10 g, 0.22 mmol), sodium azide (0.05 g, 0.77 mmol) and glacial acetic acid in DMF (3 mL) was stirred at room temperature for 4 h. H2O (30 mL) was added and the mixture was extracted with EtOAc (20 mL). The EtOAc solution was washed with H2O (2×20 mL) and saturated NaCl (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude solid. The crude solid was purified by column chromatography (eluent: 30% EtOAc/n-hexanes) to afford 0.08 g (86%) of 38 as a white solid, mp 200-203° C. (EtOAc/n-hexanes); 1H NMR (CDCl3): δ 1.13 (3H, s); 1.48 (3H, s); 1.68 (5H, m); 2.14 (31H, m); 2.34 (1H, ddd, J=3.6, 7.2, 27); 2.60 (1H, dd, J=5.1, 13.2); 2.72 (1H, dd, J=3.3, 13.2); 3.74 (3H, s); 3.92 (1H, dd, J=7.5, 12.6), 5.56 (1H, dd, J=5.1, 11.7); 6.39 (1H, dd, J=0.9, 1.8); 7.41 (1H, dd, J=1.2, 2.1); 7.43 (1H, dd, J=0.9, 1.5).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)[CH3:3].Cl>C(OCC)(=O)C.CO.O1CCOCC1>[CH3:1][CH:2]([C@H:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)[CH3:3]
Reactant: CC(C)[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@H]1CNCCN1
Yield: 93.7 %

Procedure:
A solution of tert-butyl (2S)-2-propan-2-ylpiperazine-1-carboxylate (2 g, 8.76 mmol) in a mixture of ethyl acetate (20 mL) and methanol (20.00 mL) was stirred at room temperature with 4M HCl in dioxane (30 mL) for 40 h under nitrogen. The reaction mixture was evaporated to dryness. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness to afford (2S)-2-propan-2-ylpiperazine (1.052 g, 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:15]3[C:14](=[O:26])[N:13]([CH3:27])[C:12](=[O:28])[N:11]([CH3:29])[C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[CH2:17][N:16]1[C:15]2[C:14](=[O:26])[N:13]([CH3:27])[C:12](=[O:28])[N:11]([CH3:29])[C:10]=2[N:9]=[C:8]1[C:4]1[CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c2c(nc(-c3cccc(N)c3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2nc3c(c(=O)n(C)c(=O)n3C)n2Cc2c(F)cccc2Cl)c1
Reaction time: 1.5 h
Yield: 14.6 %

Procedure:
A solution of 8-(3-aminophenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (25 mg, 0.06 mmol) in 255 μL CH2Cl2 was treated with acetic anhydride (6.6 μL, 0.07 mmol). The reaction was stirred for 1.5 hr and then blown dry under nitrogen. The crude product was purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with EtOAc:hexane (3:1) to give 4 mg (15% yield) of the title compound as a clear oil: 1H NMR (CDCl3, 400 MHz) 7.67-7.61 (m, 2H), 7.36-7.26 (m, 2H), 7.21-7.15 (m, 1H), 7.13-7.01 (m, 2H), 6.84-6.75 (m, 1H), 5.86 (s, 2H), 3.62 (s, 3H), 3.38 (s, 3H), 2.97 (s, 3H); MS (ESP+) m/e 456 (MH+); TLC (EtOAc:hexanes/3:1) Rf=0.11.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:15][S:16][C:17]1[C:22]2[CH:23]=[C:24]3[N:29]([C:21]=2[N:20]=[CH:19][CH:18]=1)[CH2:28][CH2:27][CH2:26][CH:25]3[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>ClCCCl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH:25]1[C:24]2[N:29]([C:21]3[N:20]=[CH:19][CH:18]=[C:17]([S:16][CH3:15])[C:22]=3[C:23]=2[C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:28][CH2:27][CH2:26]1)[CH3:35]
Reactant: CCOC(=O)CC1CCCn2c1cc1c(SC)ccnc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)CC1CCCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(SC)ccnc12
Reaction time: 4 h

Procedure:
To a solution of 4-chlorobenzoyl chloride (0.30 g, 1.7 mmol) in 1,2-dichloethane (6.0 mL) was added AlCl3 (0.24 g, 1.8 mmole). After a period of 5 min. a solution of ethyl [4-(methylthio)-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-6-yl]acetate from Example 1 Step 8 (0.15 g, 0.47 mmole) in 1,2-dichloroethane (6.0 mL) was added to the previous mixture. After a period of 4 h, at 80° C., the reaction mixture was partitioned between EtOAc and NaHCO3. The organic phase was separated, dried over Na2SO4 and evaporated. The title compound was purified by flash chromatography.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[O:1]([CH2:8][C:9]([Cl:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenoxyacetic acid (d5) was treated with 25 ml of thionyl chloride and stirred for 18 hours at room temperature. After the end of the reaction, the reaction mixture was concentrated under vacuum at 30° C. to provide phenoxyacetyl chloride (4.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:8]([NH2:10])=S.[CH2:18](N)[CH2:19][NH2:20]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:8]1[NH:20][CH2:19][CH2:18][N:10]=1)([CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCN
Reactant: CC(C(N)=S)(c1ccccc1)c1ccccn1
Product: CC(C1=NCCN1)(c1ccccc1)c1ccccn1
Temperature: 140 °C

Procedure:
Under a nitrogen atmosphere, heat (bath at 140° C) under reflux conditions 2 g. of α-(2-pyridyl)-α-phenylthiopropionamide and 20 ml. of ethylene diamine. Evaporate off the excess diamine, dissolve the residue in benzene, filter, wash, dry and evaporate the benzene solution. Crystallize the residual pale green oil from isopropyl ether to yield 2-[α-(2-pyridyl)-α-methylbenzyl]-imidazoline, m.p. 102°-103° C. The maleate salt, crystallized from acetonitrile, melts at 156.5°-158° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:18][CH:17]=3)[CH2:11][CH2:12][C:13](=[N:14]O)[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].CO>[CH2:1]([C:5]1[N:9]2[CH:10]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:20][CH:21]=3)[CH2:11][CH2:12][CH:13]([NH2:14])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=NO
Agent: [Pd]
Solvent: CO
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2N

Procedure:
Alternatively, the title compound of Example 1451 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 1449) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under 50 psi of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1451.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11]OS(C(F)(F)F)(=O)=O)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:20]#[N:21].Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: BrCCc1ccccc1
Reactant: N#Cc1ccc2c(c1Cl)CC(COS(=O)(=O)C(F)(F)F)O2
Product: N#Cc1ccc2c(c1Cl)CC(CCCc1ccccc1)O2
Yield: 68 %

Procedure:
Following the process described in example 3 (point B), starting from 4-chloro-2-trifluoromethanesulfonyloxymethyl-2,3-dihydrobenzofuran-5-carbonitrile and 2-bromoethylbenzene, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl ether, 95:5 (68% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][CH:9]=[CH:8][C:7]=1I)[CH3:2].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>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.[Cu]I.C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[C:7]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:8][CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2]
Reactant: CCOC(=O)Nc1c(I)cccc1OC(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1c(C#C[Si](C)(C)C)cccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108.6 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (1.1 g, 1.6 mmol) and copper(I) iodide (0.3 g, 1.6 mmol) were added to triethylamine (600 mL) and heated with stirring for 20 min. The mixture was cooled to room temperature and (2-iodo-6-trifluoromethoxy-phenyl)-carbamic acid ethyl ester (60.2 g, 160 mmol) was added. After stirring for 30 min at room temperature trimethylsilylacetylene (21.1 g, 152 mmol) was added and the mixture was stirred for another 2 h at room temperature. Triethylamine was removed in vacuo and the residue was partitioned between water and diethyl ether. The organic phases were washed with 1N HCl, brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 57 g of brownish solid, which was purified by chromatography on silica gel with hexane/ethyl acetate (9:1). This yielded the title compound, (52.8 g, 95%) as a beige amorphous solid. (EI-MS: m/e 345.0 (M+)).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:17])[C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C@H:27](Cl)[CH3:28])=[CH:23][N:22]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:17])[C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:27]([C:24]3[CH:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH3:28])=[N:6][C:5]=2[N:19]=1
Reactant: CCC[C@H](CO)N(C)c1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1ccc(Cl)nc1
Product: CCC[C@H](CO)N(C)c1nc(S[C@@H](C)c2ccc(Cl)nc2)nc2nc(N)sc12
Yield: 15.7 %

Procedure:
The title compound was prepared using General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)(methyl)amino]pentan-1-ol (96 mg, 0.32 mmol) and 2-chloro-5-[(1R)-1-chloroethyl]pyridine (85 mg, 0.48 mmol). Purification by flash column chromatography (eluent DCM:ethyl acetate) yielded 22 mg (16% yield) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[O:3]1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[N:23]=[C:11]([C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[O:3][C:4]=4[CH:10]=3)[O:13][N:15]=2)[CH:18]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2[nH]c(=O)oc2c1
Agent: N
Product: O=c1[nH]c2ccc(-c3nc(-c4cccnc4)no3)cc2o1

Procedure:
The title compound was prepared according to Method C using 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (Eur. J. Med. Chem. 1974, 9, 491-6.) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.35 (d, J=8.7 Hz, 1H), 7.65 (dd, J=7.5, 4.4 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H), 8.07 (s, 1H), 8.44 (dt, J=7.9, 2.0 Hz, 1H), 8.82 (dd, J=4.8, 1.6 Hz, 1H), 9.25 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 281 (M+H)+.