Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(C2SC(C(N)=O)=C(OCC3C=CC=CC=3C(F)(F)F)N=2)C2C=CC=CC=2N=C1.Cl[C:31]1[S:32][C:33]([C:48]([NH2:50])=[O:49])=[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]([F:47])([F:46])[F:45])[N:35]=1.[CH3:51][C:52]1[C:60]([CH3:61])=[CH:59][C:55]2[N:56]=[CH:57][NH:58][C:54]=2[CH:53]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:51][C:52]1[C:60]([CH3:61])=[CH:59][C:55]2[N:56]([C:31]3[S:32][C:33]([C:48]([NH2:50])=[O:49])=[C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]([F:47])([F:46])[F:45])[N:35]=3)[CH:57]=[N:58][C:54]=2[CH:53]=1
Reactant: NC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: NC(=O)c1sc(-n2cnc3ccccc32)nc1OCc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2ncn(-c3nc(OCc4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cc1C

Procedure:
Following the procedure described above for the preparation of 2-(1H-benzimidazol-1-yl)-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide using the following materials: 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide (0.050 g, 0.14 mmol), 5,6-dimethylbenzimidazole (0.012 g, 0.08 mmol), K2CO3(0.011 g, 0.08 mmol) and DMF (4 mL). The title compound was afforded by preparative HPLC. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.70-7.58 (m, 4H), 7.54-7.49 (m, 1H), 6.81 (bs, 1H), 5.82 (s, 2H), 5.60 (bs, 1H), 2.42 (s, 1H), 2.40 (s, 1H). MS m/z 447 (m+1).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][N:13]([CH3:21])[C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH2:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:20][C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]2[N:13]([CH3:21])[CH3:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1ccc(C#N)cc1
Yield: 63 %

Procedure:
The titled amide was prepared according to general procedure B using p-cyanobenzoyl chloride (1.65 g.; 0.01 mole), the trans-2-(dimethylamino)cyclohexylamine (1.42 g.; 0.01 mole) and triethylamine (1.01 g.; 0.01 mole) but using CH2Cl2 for extraction. The crude solid was crystallized from ether to give colorless needles, 1.71 g. (63% yield), m.p. 160°-161°. uv λmax 236 nm (ε 17,900); sh 285 (2,550). ir NH 3320; N-alkyl 2780; C≡N 2220; C=O 1635; C=C 1610, 1500; amide II 1550; aromatic 860. NMR in CDCl3 (60 MHz) was in accord. Mass spectrum M+ 271.
Reaction SMILES: [C:1]([CH:4]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:5][CH:6]=[CH2:7])(=O)[CH3:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:5]([C:4]1[N:8]=[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[O:18][C:1]=1[CH3:2])[CH:6]=[CH2:7]
Reactant: C=CCC(NC(=O)c1ccc(OC)cc1)C(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCc1nc(-c2ccc(OC)cc2)oc1C
Yield: 75.4 %

Procedure:
The above prepared N-(1-acetyl-but-3-enyl)-4-methoxy-benzamide (6.45 g, 26.1 mmol) was stirred in a mixture of 43.9 ml of trifluoro-acetic acid (22 eq.) and 21.75 ml of trifluoro-acetic anhydride (6 eq.) for 7 h at 40° and for 16 h at ambient temperature. Pouring onto crashed ice, twofold extraction with EtOEt, three times washing with Na2CO3-solution, drying over natrium sulfate and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1) produced finally 4.51 g of the title compound as colorless oil.
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[NH:15][CH:14]=[C:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:34])=[C:23]([CH:33]=3)[C:24]([N:26]3CCC[NH2+]CC3)=O)[N:12]2[CH:35]=1.[Cl:36]C1C=C2C(=O)NC=C(CC3C=CC(F)=C(C=3)C#N)N2C=1.ClN1C(=O)CCC1=O>C1COCC1>[Cl:36][C:35]1[N:12]2[C:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:34])=[C:23]([CH:33]=3)[C:24]#[N:26])=[CH:14][NH:15][C:16](=[O:17])[C:11]2=[CH:10][C:9]=1[Cl:8]
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cc(Cl)cn23)ccc1F)N1CCC[NH2+]CC1
Reactant: N#Cc1cc(Cc2c[nH]c(=O)c3cc(Cl)cn23)ccc1F
Agent: O=C([O-])C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: N#Cc1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F

Procedure:
A mixture of Example 6, F5 (1 eq) and N-chlorosuccinimide (2 eq) in THF was stirred at RT. The solvent was removed under reduced pressure and the resulting crude was used as such in the next step without purification. MS (ES) C15H8Cl2FN3O requires: 335, found: 336 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1)[CH3:2].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>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)I.C(N(CC)CC)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.6 mL of 1-ethyl-4-iodobenzene, 75 mL of triethylamine, 6 mL of trimethylsilylacetylene, 0.49 g of dichlorotriphenylphosphine palladium II and 0.314 g copper iodide was magnetically stirred at ambient temperature for 18 hrs. The thick dark brown mixture was filtered, washing the gray precipitate with hexanes. The filtrate and washings were evaporated in vacuo and the residue dissolved in hexanes. This solution was 96.7% pure by GC analysis. The solution was passed down a column of silica gel which had been equilibrated in the same solvent and the eluates evaporated in vacuo to yield 9.3 g of 4-ethyl-1-trimethylsilyl ethynylbenzene as a dark amber liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]#[CH:11])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][SH:19])=[CH:16][CH:15]=1.[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:9])/[CH:10]=[CH:11]\[CH:18]([S:19][CH:18](/[CH:11]=[CH:10]\[C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CS)cc1
Reactant: C#Cc1ccc(O)c(OC)c1
Agent: [Na]
Product: COc1ccc(C(/C=C\c2ccc(O)c(OC)c2)SC(/C=C\c2ccc(O)c(OC)c2)c2ccc(OC)cc2)cc1

Procedure:
A solution of 3-methoxy-4-hydroxyphenylacetylene (0.02 mol), 4-methoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-hydroxystyryl-4-methoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]([CH2:23][OH:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]([CH:23]=[O:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
Next, to a solution of [(R)-2-(3′-chloro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (2.0 g, 5.53 mmol) in DCM (30 mL) is added Dess-Martin periodinane (2.81 g, 6.63 mmol). After being stirred at room temperature for 2 h, the reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 aqueous solution and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluent; heptane/EtOAc=100:0 to 0:100) to give [(R)-2-(3′-chloro-biphenyl-4-yl)-1-formyl-ethyl]-carbamic acid tert-butyl ester (1.05 g). HPLC retention time=1.27 minutes (condition A): MS (m+1)=360.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N+:23]([O-])=O)=[C:11]([CH:26]=[CH:27]N(C)C)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.C(Cl)Cl.[Zn]>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[NH:23][CH:27]=[CH:26][C:11]=2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=Cc1nc(OCc2ccccc2)nc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(COc2nc(OCc3ccccc3)c3[nH]ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a suspension of 2,4-Bis-O-Benzyl-5-nitro-6-β-dimethylaminovinyl pyrimidine 14 (2 g, 4.9 mmol) in AcOH (40 ml), Zn (4 g) was added in lot of 2 g with an interval of 4 hrs. The reaction mixture was stirred overnight at room temperature during which a dark yellow suspension became pale yellow suspension. The reaction mixture was filtered and the filtrate concentrated in vacuo to obtain syrup which was dissolved in CH2Cl2 then washed with saturated aq. NaHCO3 followed by brine. The organic phase was dried over MgSO4 and loaded on silica. The product 15 was purified using column chromatography eluting with 4:1 and 1:1 hexanes/EtOAc to obtain product as pale-yellow solid (1.45 g, 90%). Rf 0.3 in 1:3 hexanes/EtOAc. 1H NMR (400 MHz, CDCl3): δ 5.47 (s, 2H), 5.54 (s, 1H), 6.50-6.51 (dd, 1H, J=1.84, 2.28), 7.29-7.38 (m, 7H), 7.43-7.45 (m, 2H), 7.52-7.53 (m, 2H), 8.41 (br s, 1H, NH). 13C NMR (400 MHz, CDCl3): δ 68.3, 69.0, 102.6, 111.9, 127.8, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8, 136.1, 137.3, 151.8, 156.79, 159.7. FAB-MS for C20H17N3O2 calculated [M+H]+ 332.1394. found 332.1398.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[Cl:12][C:13]1[C:14]([C:30]([F:33])([F:32])[F:31])=[N:15][N:16]([CH2:19][C:20]([N:22]2[CH2:29][CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[CH2:23]2)=[O:21])[C:17]=1[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:26]2[CH2:25][CH:24]3[CH2:23][N:22]([C:20](=[O:21])[CH2:19][N:16]4[C:17]([CH3:18])=[C:13]([Cl:12])[C:14]([C:30]([F:33])([F:31])[F:32])=[N:15]4)[CH2:29][CH:28]3[CH2:27]2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CC2CNCC2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CN2CC3CN(C(=O)Cn4nc(C(F)(F)F)c(Cl)c4C)CC3C2)ccc1Cl
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of 4-chloro-3-methoxybenzaldehyde (34 mg) and compound 7 (35 mg) in THF (1 mL) was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (85 mg) was added in one portion. The mixture was stirred at room temperature for another hour and EtOAc (1 mL) was added followed by the addition of saturated aqueous ammonium chloride (1 mL). The aqueous phase was extracted by EtOAc (3×1 mL) and the combined organic extractants was dried, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound 8 as a white solid (36 mg, 95%). LCMS: Rf: 3.460 min, M+H+: 491.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccccc1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of 1.84 g (5 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole, 0.56 g (6 mmol) of phenol, 0.83 g (6 mmol) of powdered potassium carbonate and 20 ml of dry dimethylformamide is stirred at room temperature for 26 hours, then poured into 100 ml of water and extracted three times with chloroform. The chloroform solution is washed twice with water and three times with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is purified by chromatography on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate. There is obtained phenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 211°-212°.
Reaction SMILES: I[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>COCCOC.O.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>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Reactant: OB(O)c1ccccc1F
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1ccccc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
5-Iodo-1-{3-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-propyl}-1H-pyrimidine-2,4-dione (Prep40, 80 mg, 0.16 mmol) was dissolved in degassed DME-water solution (5-1, 10 mL). 0.2-Fluorophenyl-boronic acid (33 mg, 0.23 mmol), Na2CO3 (34 mg, 0.32 mmol), 2-(dicyclohexylphosphino)biphenyl (14 mg, 0.04 mmol) and Pd(PPh3)4 (46 mg, 0.04 mmol) were added and the mixture stirred for 3 hours at 90° C. The solvents were evaporated under vacuum and the crude was redissolved in ethyl acetate, and washed with water. The organic phase was dried (Na2SO4) and evaporated; the crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2) followed by SCX cartridge washing with MeOH and eluting with MeOH/NH3 95:5 to give the title compound (58 mg, 76% yield) as free base.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]C)(=O)[CH2:5][C:6](OC)=[O:7].[NH2:13][C:14]1[N:18]=[C:17]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:16][N:15]=1>CO.C(O)C>[CH2:20]([S:19][C:17]1[N:18]=[C:14]2[N:13]=[C:4]([OH:11])[CH:5]=[C:6]([OH:7])[N:15]2[N:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Oc1cc(O)n2nc(SCc3ccccc3)nc2n1
Temperature: 25 °C
Yield: 127.8 %

Procedure:
A solution of 125 g (0.58 mol) of a 25% solution of sodium methoxide in methanol dissolved in 100 ml of absolute ethanol was treated with 66.3 ml (0.29 mol) of dimethyl malonate followed by 60.0 g (0.20 mol) of 3-amino-5-benzylthio-1,2,4-triazole. The resulting solution was heated at reflux for 5 days. On cooling to room temperature the solid which had separated was collected by filtration, washed with cold ethanol and dissolved in 1000 ml of water. The resulting yellow solution was acidified with concentrated HCl to precipitate a solid. The solid was collected by filtration and dried to yield 70.1 g (82%) of the desired product as a white solid, m.p. 199°-210° C. (decomposition). IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
A mixture of 1-(4-trifluoromethylphenyl)piperazine (5.2 g, 22.59 mmol), N-(2-bromoethyl)phthalimide (5.22 g, 20.53 mmol) and potassium carbonate (3.36 g, 24.28 mmol) in DMF (30 ml) was stirred at 100° C. for 2 hours. The reaction mixture was allowed to return to room temperature, to which water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=50/1), and the resulting solid was washed with methanol, and then dried in vacuo to afford N-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}phthalimide (4.85 g, yield 53%) as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:14]([O:13][C:11](=[O:12])[NH:10][C:6]1([CH2:4][OH:3])[CH2:9][CH2:8][CH2:7]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C1(NC(=O)OC(C)(C)C)CCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 15 ml round-bottomed flask, 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid ethyl ester (180 mg, 0.74 mmol) was dissolved in THF (4 ml). The colorless solution was cooled to 0° C. and lithium aluminum hydride (1.0 M in THF, 0.78 ml, 0.78 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h then sodium sulfate decahydrate was carefully added. When gas evolution has ceased, the ice bath was removed, sodium sulfate was added and the mixture was stirred for 30 min at room temperature. The suspension was filtered over Celite and rinsed with ethyl acetate/methanol. The filtrate was concentrated to give (1-hydroxymethyl-cyclobutyl)-carbamic acid tert-butyl ester as an off-white waxy solid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>C(#N)C>[Br:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCBr
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K2CO3 (12.5 g), and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100 mI) was heated at reflux for 3 hours and left standing at room temperature overnight. The solvent of the reaction was removed on a rotary evaporator, and the crude solid was extracted into methylene chloride (500 ml). The insolubles were filtered off. The dichloromethane solution was concentrated and the material was purified on a flash chromatography column (SiO2, 105 g; eluted with 2:3 dichloromethane:hexane, and then with dichloromethane). The desired product thus purified weighed 7.74 g (52%). Recrystallization twice from ethanol gave analytically pure 4-(3-bromopropoxy)-3-methoxybenzonitrile, m.p.=99°-101° C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].C(C(C#N)=C(C#N)C#N)#N>CC(N(C)C)=O>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[NH:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:19]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1N
Agent: N#CC(C#N)=C(C#N)C#N
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Resin-bound 4-carboxybenzaldehyde (subn. 0.65 mmol/g, 400 mg, 0.26 mmol) was suspended in DMA (3 mL) and treated with 1,2-phenylenediamine (2.6 mmol) and TCNE (2.6 mmol). The suspension was sonicated for 1 h and shaken at 25° C. for an additional 22 h. The resin was filtered, washed with DMA, DCM, and dried under high vacuum. The benzimidazole was cleaved from the solid support with 20% (v/v) TFA in DCM (2×5 mL, 15 min) and the combined filtrates were evaporated to give the title compound. 1H NMR (d6-DMSO) δ 7.35-7.43 (m, 2H), 7.69-7.78 (m, 2H), 8.19 (d, 2H, J=8.3 Hz), 8.26-8.34 (m, 2H), 12.50-14.20 (br s, CO2H). MS (API-ES+) m/z 239 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[O:9]1[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: OC1CCOCC1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1cncc(OC2CCOCC2)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromopyridin-3-ol (146 g, 834 mmol), tetrahydro-2H-pyran-4-ol (128 g, 1250 mmol), and triphenylphosphine (329 g, 1250 mmol) in toluene (2.0 L) was heated to reflux, and 750 mL of distillate was removed via a Dean-Stark trap. The reaction mixture was cooled to 60° C., and 547 g (1.25 mol) of a 40% (w/w) solution of DEAD in toluene was added drop-wise over a 1 hour period. The addition was exothermic with the reactor temperature at the end of addition near 95° C. The reaction mixture was stirred at 115° C. for 18 h, and a portion of the reaction solution was sampled and analyzed by HPLC to establish that the reaction was complete. Upon completion of reaction, 500 mL of solvent was removed by distillation, and the pot residue was cooled to ambient temperature. This organic layer was washed with 10% aqueous sodium hydroxide (2×0.50 L) and concentrated under vacuum to produce a viscous oil, which was dissolved in 2N hydrochloric acid (1.0 L). Diatomaceous earth (100 g) was added with stirring and the resulting suspension was filtered. The pad was rinsed with 2N hydrochloric acid (1.0 L), and the filtrates were combined and extracted with diisopropyl ether (500 mL). The diisopropyl ether layer was discarded, and the aqueous layer was treated with carbon black (10 g) and stirred at 45-50° C. for 1 h. The suspension was filtered through a pad of diatomaceous earth (25 g). The filtrate was collected, cooled to 5° C., and the pH adjusted with 50% aqueous sodium hydroxide (250 mL) to pH=13. The solution was extracted twice with chloroform (1.0 L, 600 mL), and the chloroform extracts were combined and concentrated under vacuum to give 12 as a dark red viscous oil/low melting solid (187 g, 87%), which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.29 (s, 1H), 8.24 (s, 1H), 7.38 (s, 1H), 4.52 (m, 1H), 3.98 (m, 2H), 3.60 (m, 2H), 2.05 (m, 2H), 1.81 (m, 2H).