Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH:3]([NH:6][C:7]1[N:8]=[CH:9][C:10]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:11]=2[N:12]=1)[CH2:4][OH:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[CH:3]([NH:6][C:7]1[N:8]=[CH:9][C:10]2[CH2:16][CH2:15][NH:14][CH2:13][C:11]=2[N:12]=1)[CH2:4][OH:5]
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(NC(CO)C(F)(F)F)nc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCC(Nc1ncc2c(n1)CNCC2)C(F)(F)F
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a stirred solution of 352 (53 mg, 0.15 mmol) in DCM (750 μL) at RT under nitrogen was added TFA (750 μL). The solution was stirred for 2 h and was then concentrated in a rotovap under high vacuum. The residue was redissolved in DCM (10 mL) and stirred rapidly with 1M Na2CO3 (10 mL) for 5 min. The layers were separated and the aqueous phase was extracted with DCM (2×10 mL). The combined extracts were dried (MgSO4), filtered and concentrated to afford 29 mg (76%) of 3,3,3-trifluoro-2-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ylamino)propan-1-ol (354) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:37][SiH:38]([CH3:40])[CH3:39])([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25]([CH:27]=[O:28])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-:41].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:37][SiH:38]([CH3:40])[CH3:39])([C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25]([C:27]([OH:41])=[O:28])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: C[SiH](C)O[C@](CCc1ccccc1C(=O)C=O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[SiH](C)O[C@](CCc1ccccc1C(=O)C(=O)O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a solution of the aldehyde from Step 2 (14 g, 24.6 mmol) in EtOH (118 mL) was added a solution of AgNO3 (10 g, 59 mmol) predissolved in H2O (23 mL) followed by a solution of KOH (118 mL, 118 mmol of 1M) dropwise. The mixture was stirred at room temperature overnight. The bulk of the EtOH was removed by evaporation, the aqueous was acidified with 1N HCl (118 mL) and extracted with EtOAc twice (100 mL). The organic extracts were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography first with pure EtOAc then using 95:5 EtOAc: AcOH, to yield 5.0 g of the title compound. 1H NMR (CD3COCD3) d 0.15 (s, 6H), 0.95 (s, 9H), 2.0 (m, 2H), 2.95-3.18 (m, 2H), 4.95 (t, 1H), 7.35-7.65 (m, 8H), 7.75-7.97 (m, 5H), 8.0 (s, 1H), 8.32 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[S:7])=[O:4].[F:8][C:9]([F:32])([F:31])[C:10]1[CH:11]=[C:12]([S:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH:27][C:28]([NH2:30])=[O:29])=[C:24]([CH:26]=2)[NH2:25])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.C(OC(C)C)(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:25][C:24]1[CH:26]=[C:20]([O:19][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:8])([F:31])[F:32])[CH:11]=2)(=[O:18])=[O:17])[CH:21]=[CH:22][C:23]=1[NH:27][C:28]([NH2:30])=[O:29])=[S:7])=[O:4]
Reactant: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: COC(=O)N=C=S
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: COC(=O)NC(=S)Nc1cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1NC(N)=O
Reaction time: 4 h

Procedure:
12 ml of methoxycarbonyl isothiocyanate are added dropwise, with stirring, to 18.7 g of 5-(3-trifluoromethylphenylsulfonyloxy)-2-ureidoaniline in 300 ml of dioxane, the temperature rising to about 40° C. The mixture is stirred for a further four hours without cooling, 60 ml of diisopropyl ether are added and the precipitate is filtered off with suction. After washing with diisopropyl ether, recrystallization is carried out from methanol/diisopropyl ether with the addition of active charcoal, melting point 190° C., decomposition.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCc1ccccc1
Reactant: O=Cc1ccccc1OCCN1CCOCC1
Solvent: Cc1ccccc1
Product: C(=NCCc1ccccc1)c1ccccc1OCCN1CCOCC1
Yield: 85.6 %

Procedure:
2-[2-(4-Morpholinyl)ethoxy]benzaldehyde (55.9 g) is reacted with 29 g of phenethylamine in 240 ml of toluene following the procedure described in Example 1A to yield 68.8 g of product as an oil, boiling point 204°-210° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([OH:21])=[CH:17][CH:18]=2)[C:13]1=[O:22])([O:3][CH3:4])=[O:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][C:29]([Cl:35])=[CH:30][CH:31]=2)[N:26]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:35][C:29]1[CH:28]=[C:27]2[C:32]([CH:33]=[CH:34][C:25]([CH2:24][O:21][C:16]3[CH:15]=[C:14]4[C:19]([CH2:20][CH:12]([CH2:11][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[C:1]([O:3][CH3:4])=[O:2])[C:13]4=[O:22])=[CH:18][CH:17]=3)=[N:26]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Reactant: COC(=O)c1ccccc1CC1Cc2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1CC1Cc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc2C1=O
Yield: 76 %

Procedure:
A mixture of the product of Step 3 (17.5 g, 59 mmol), 2-bromomethyl-7-chloroquinoline (16.65 g, 65 mmol) and K2CO3 (8.97 g, 65 mmol) in acetone (200 ml) was refluxed for 14 hrs. The mixture was filtered and the filtrate was concentrated in vacuo. Chromatography of the resulting crude product on silica gel (eluted with 30% EtOAc/hexane) gave 21.15 g(80%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:9])=[N:7][CH:8]=1)=O.[NH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[C:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[CH2:11][O:10][C:5]1[CH:4]=[C:3]([CH2:1][NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH:8]=[N:7][C:6]=1[CH3:9])#[N:16]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ncc(C=O)cc1OCc1cccc(C#N)c1
Product: Cc1ncc(CNc2ccc(C#N)cc2)cc1OCc1cccc(C#N)c1
Yield: 22.4 %

Procedure:
The reductive amination of 3-((5-formyl-2-methylpyridin-3-yloxy)methyl)benzonitrile (134) (300 mg, 1.2 mmol) and 4-aminobenzonitrile (422 mg, 3.6 mmol), as described in Example 21, gave 4-((5-(3-cyanobenzyloxy)-6-methylpyridin-3-yl)methylamino)benzonitrile (135) (95.24 mg, 22.58% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH2:7].[NH2:9][C:10]1[C:11]([C:18](N2C=CN=C2)=[O:19])=[N:12][C:13]([Br:17])=[C:14]([NH2:16])[N:15]=1>O1CCCC1>[NH2:9][C:10]1[C:11]([C:18]([NH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH2:7])[CH3:8])=[O:19])=[N:12][C:13]([Br:17])=[C:14]([NH2:16])[N:15]=1
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Br
Reactant: CN(CCN)CCN
Solvent: C1CCOC1
Product: CN(CCN)CCNC(=O)c1nc(Br)c(N)nc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
A mixture of 8.20 g (72.0 mmol) of N-(2-aminoethyl)-N-methyl-1,2-ethanediamine and 6.80 g (24.0 mmol) of 1-(3,5-diamino-6-bromopyrazinoyl)imidazole in 48 ml of tetrahydrofuran was stirred at ambient temperature for 30 minutes. The solution was evaporated and the residue triturated with ether. There was obtained 5.85 g (17.6 mmol, 73%) of 3,5-diamino-N-[2-[(2-aminoethyl)methylamino]ethyl]-6-bromopyrazinecarboxamide; mp 148°-150° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36]>>[CH3:33][O:34][C:35](=[O:36])[C:37]1[CH:42]=[CH:41][C:40]([C:15]2[N:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)[N:17]([CH3:18])[C:16]=2[C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:25][CH2:26]2)=[O:20])=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3ccc(C(=O)OC)cc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with (4-methoxycarbonylphenyl)boronic acid to give the title compound as light brown oil. MS: 557.3 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[NH:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8]1[NH:9][C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)[nH]c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2Cl)nc1C(=O)O
Temperature: 95 °C
Reaction time: 17 h
Yield: 89.9 %

Procedure:
To 11.2 g of 2-(2-chloro-phenyl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester in 150 ml of ethanol was added 80 ml of a 2N-NaOH solution and the reaction mixture was stirred at 95° C. for 17 hours. After such time ethanol was removed in vacuo and the remaining aqueous solution was treated with a 2N HCl solution until obtaining pH=3. The precipitate was filtered and dried under high vacuum to yield 9.0 g of a pale yellow powder.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:10]([O:11][CH2:12][CH:13]=[CH2:14])[C@H:9]([O:15][CH2:16][CH:17]=[CH2:18])[C@@H:8]([CH2:19][O:20][CH2:21][CH:22]=[CH2:23])[O:7][C:6]1([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=2)[CH:26]=1)[OH:24])[CH:2]=[CH2:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:4][C@H:5]([C@@H:10]([O:11][CH2:12][CH:13]=[CH2:14])[C@H:9]([O:15][CH2:16][CH:17]=[CH2:18])[C:8](=[O:7])[CH2:19][O:20][CH2:21][CH:22]=[CH2:23])[C:6]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=2)[CH:26]=1)=[O:24])[CH:2]=[CH2:3]
Reactant: C=CCOC[C@H]1OC(O)(c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCC=C)[C@@H](OCC=C)[C@@H]1OCC=C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C=CCOCC(=O)[C@@H](OCC=C)[C@H](OCC=C)[C@@H](OCC=C)C(=O)c1ccc(Cl)c(Cc2ccc(OCC)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of compound from Step D (0.93 g, 1.59 mmol) in CH2Cl2 (25 ml) was added Dess-Martin periodinane (0.68 g, 1.59 mmol). The mixture was stirred at room temperature for 1 hour and then a second portion of Dess-Martin periodinane (1 eqiv.) was added. Stirring was continued for another hour and then the reaction was quenched with 1NNaOH (˜4 ml). H2O was added and the organic layer separated. The aqueous layer was back extracted with CH2Cl2, dried and concentrated to give a yellow waxy solid. Purification by silica gel chromatography (15%-20% EtOAc/hexanes) afforded (2R,3R,4S)-2,3,4,6-tetrakis-allyloxy-1-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-hexane-1,5-dione (0.60 g, 1.03 mmol, 65%) as a white solid. MS (ES+) [M+NH4]+=600.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:23])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([S:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(CSc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.7 %

Procedure:
To a solution of benzyl phenyl sulfide (Aldrich; 1.068 g, 5.33 mmol) in 25 mL of CH2Cl2 at −78° C. was slowly added a solution of m-chloroperbenzoic acid (Aldrich, 50-60%; 760 mg, 2.64 mmol if 60%) in 10 mL of CH2CL2. After warming to room temperature and stirring overnight, the solution was added to 20 mL of a saturated NaHCO3 solution. The aqueous layer was separated and extracted with CH2Cl2 (2×10 mL). The pooled organic layers were then dried (MgSO4) and concentrated. The residue was subjected to flash column chromatography (silica gel, 10% acetone/hexane and 15% acetone/hexane) affording the sulfoxide (632 mg, 55%) as a white solid, mp 123-126° C.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([CH2:10]O)[C:5]=1[CH3:12].S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:10][C:6]1[C:5]([CH3:12])=[C:4]([O:3][CH:2]([F:13])[F:1])[N:9]=[CH:8][N:7]=1
Reactant: Cc1c(CO)ncnc1OC(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(CCl)ncnc1OC(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6-(difluoromethoxy)-5-methylpyrimidin-4-yl)methanol 49 (15 g, 78.94 mmol) dissolved in DCM (150 ml) added thionyl chloride (8.59 ml, 118.42 mmol). The reaction mixture was stirred for 4 h at RT. The solvent was removed under vacuum pump to afford 4-(chloromethyl)-6-(difluoromethoxy)-5-methylpyrimidine 50 as a brown solid. Yield: 14 g (85%); 1H NMR (400 MHz, DMSO-d6) δ=8.74 (s, 1H), 7.77 (t, 1H, J=95.4 Hz), 4.81 (s, 2H), 2.24 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:12]3[CH2:13][N:8]([C:9]4[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:10]=4[CH2:11]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[CH:12]3[CH2:13][N:8]([C:9]4[CH:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:10]=4[CH2:11]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: Nc1ccc2c(c1)N1CCN(CC3CC3)C(C2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)N1CCN(CC3CC3)C(C2)C1
Reaction time: 2 h

Procedure:
A mixture of 4-cyclopropylmethyl-9-amino-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (3 g.), acetic anhydride (10 ml.) and pyridine (25 ml.) was let stand for two hours at room temperature, then concentrated to dryness. The residue was partitioned between aqueous ammonia and chloroform. The chloroform layer was dried and concentrated to dryness. Recrystallization of the residue from ether afforded 4-cyclopropylmethyl-9-acetamido-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (2.5 g., m.r. 131°-132° C.), the compound of Formula V wherein Q is cyclopropylmethyl and R"CONH is acetamido.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[O:22])[CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[O:22])[CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)CC1CCCNC1
Product: COC(=O)c1cccc(N2CCCC(CC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 45.2 %

Procedure:
Using 3-[2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]-2-oxoethyl]piperidine (140 mg, 0.418 mmol) and 3-(methoxycarbonyl)phenylboric acid (150 mg, 0.836 mmol), the same procedure was followed as in Example 2 to give 88.7 mg (45%) of the desired compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OB(O)c1ccco1
Reactant: Clc1cc(Cl)nc(Cl)n1
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: Cc1ccccc1
Product: Clc1cc(-c2ccco2)nc(Cl)n1
Temperature: 130 °C
Yield: 116.9 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (0.5 g, 2.73 mmol), 2-furanboronic acid (0.152 g, 1.36 mmol), potassium carbonate (0.377 g, 1.36 mmol)) in toluene (2.5 ml) was added tetrakis(triphenylphosphine)palladium (0.08 g, 0.068 mmol). The reaction vessel was sealed and heated under the influence of microwave radiation (130° C., 600 seconds, low absorption setting). The crude reaction was concentrated in vauo to give an orange oil which was purified by flash chromatography (SiO2) (19:1—Hexanes:EtOAc) to give the title compound (342 mg, 58%) in suitably clean form to be used without further purification. m/z (LC-MSW, ESP):215.1 [M+H]+, R/T=4.68 mins
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4]([NH:12][CH2:13][C:14]([OH:16])=O)[N:3]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][CH3:31])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([N:30]([CH3:31])[C:14](=[O:16])[CH2:13][NH:12][C:4]2[N:5]=[C:6]([CH3:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[N:3]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: Cc1nc(NCC(=O)O)nc(C)c1[N+](=O)[O-]
Product: Cc1nc(NCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1[N+](=O)[O-]

Procedure:
The title compound was synthesized from Compound 11 and 1-benzyl-N-methylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[S:13])[S:8][C:4]=2[CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(Cl)cc2s1
Solvent: CC#N
Product: S=C(Nc1nc2ccc(Cl)cc2s1)n1ccnc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To 6-chlorobenzo[d]thiazol-2-amine (1.14 g, 6.17 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (1.43 g, 8 mmol). The reaction was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 1 hour to yield N-(6-chlorobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (1.16 g, 3.9 mmol, 64% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:9]1[C@@H:12]([C@H:13]([C:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:16])[CH3:14])[NH:11][C:10]1=[O:24])[CH3:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:34](=[O:41])[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36]>ClCCl>[CH2:38]([O:37][C:35](=[O:36])[C:34]([N:11]1[C@H:12]([C@H:13]([C:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:16])[CH3:14])[C@@H:9]([C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:26])[CH3:25])[CH3:8])[C:10]1=[O:24])=[O:41])[CH:39]=[CH2:40]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)Sc1ccccc1
Reactant: C=CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=S)Sc1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of (3S,4S)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl] -4-[(1R)-1-{(phenylthio)thiocarbonyl}ethyl]-2-oxoazetidine (5.12 g) in dichloromethane (50 ml) were added pyridine (1.8 ml) and allyl chloroglyoxylate (2.3 ml) successively at 0° C. After stirring for 2 hours at the same temperature, to the solution were added pyridine (0.9 ml) and allyl chloroglyoxylate (0.75 ml). After stirring for 1 hour at 0° C., the solution was washed with water, 1N hydrochloric acid and brine, and dried. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane=1:9) to afford (3S,4S)-1-(allyloxyoxalyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(phenylthio)thiocarbonyl}ethyl]-2-oxoazetidine (4.77 g).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH2:25].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:10]([O:26][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCC=CCC=CCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: C=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 110 °C

Procedure:
A mixture of 57.0 g (0.300 mole) of 5-bromo-2-furoic acid, 119.0 g (0.450 mole) of 9,12,15-hexadecatrienol, and 84 g (0.750 mole) of potassium tert-butoxide in dry toluene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off, and the mixture is refluxed at 110° C. with stirring for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with ice water. The toluene organic layer is separated, washed with water, then extracted three times with 5% sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5-(9,12,15-hexadecatrienyloxy)-2-furoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[I:15])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:18][CH2:19][C@@H:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][NH:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:10]=[N:11][C:12]([N:21]2[CH2:22][C@H:23]([OH:25])[CH2:24][C@H:20]2[CH2:19][OH:18])=[CH:13][C:14]=1[I:15])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC[C@@H]1C[C@@H](O)CN1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1I
Temperature: 130 °C
Reaction time: 32 h
Yield: 48 %

Procedure:
A mixture of 26.5 g (71.8 mmol) (6-chloro-4-iodo-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester and 25.4 g (144 mmol) (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine in 260 ml dimethyl sulfoxide was stirred at 130° C. for 32 h. The reaction mixture was concentrated in vacuo, treated with 200 ml 2 N sodium carbonate solution and extracted with three 200-ml portions of ethyl acetate. The organic layers were washed with 200 ml 2 N sodium carbonate solution and 200 ml brine and dried over sodium sulfate. Flash chromatography gave 15.5 g (48%) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[I:37]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([I:37])=[C:9]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCNC(=O)c1cc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) and N-iodosuccinimide (2.0 eq), were dissolved in acetonitrile, ceric ammonium nitrate (0.1 eq) added and the solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the resulting gum was partitioned between ethyl acetate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with 4:1 hexane:ethyl acetate, to give 5-(2,4-bis-benzyloxy-5-isobutyl-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide as an oil.