Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(SC[C@@H](N)CO)C1C=CC=CC=1.OCCN.[CH:18]([CH:21]1[NH:25][C@H:24]([CH2:26][S:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23]O1)([CH3:20])[CH3:19].O1CCNC1.C(SC[C@@H](NCC(C)C)CO)C1C=CC=CC=1.O=S(Cl)[Cl:59]>>[Cl-:59].[CH2:28]([S:27][CH2:26][C@H:24]([NH2+:25][CH2:21][CH:18]([CH3:20])[CH3:19])[CH2:23][Cl:59])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)C1N[C@H](CSCc2ccccc2)CO1
Reactant: O=S(Cl)Cl
Agent: C1COCN1
Agent: CC(C)CN[C@@H](CO)CSCc1ccccc1
Agent: N[C@@H](CO)CSCc1ccccc1
Solvent: NCCO
Product: CC(C)C[NH2+][C@H](CCl)CSCc1ccccc1
Product: [Cl-]

Procedure:
(1S)-1-(Benzylthiomethyl)-2-hydroxyethylamine was made from (L)-S-benzylcysteine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4-(benzylthiomethyl)-1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((1S)-1-(benzylthiomethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((1S)-1-(benzylthiomethyl)-2-chloroethyl)-N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((1S)-1-(benzylthiomethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method C1b to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(benzylthiomethyl)-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=O)[CH2:9][C:4]=2[NH:3][CH:2]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[O:17][CH2:18][CH2:19][CH2:20][NH:21][CH3:22]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[O:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:22])[C:10]([CH:8]1[CH2:7][CH2:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:9]1)=[O:12]
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Reactant: CNCCCOc1cccc(Cl)c1
Product: CN(CCCOc1cccc(Cl)c1)C(=O)C1CCc2[nH]cnc2C1
Product: Cl

Procedure:
By a similar procedure as described in Example 65, the title compound was prepared from 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid and 3-(3-chlorophenoxy)propylmethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-:14].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:7][C:8](=[O:14])[CH:9]=[CH:2][C:3]2[CH:4]=[CH:5][CH:13]=[C:11]([OH:12])[CH:10]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1cccc(O)c1)C=Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.8 %

Procedure:
3-Hydroxybenzaldehyde (1p, 2.07 g, 17.0) and acetone (19, 0.62 ml, 8.4 mmol) were combined in ethanol (15 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.00 g, 25.0 mmol) and water (4 ml) was added and the solution stirred for 48 hr at room temperature. The resulting mixture was neutralized with hydrochloric acid (1 N), extracted with ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethyl acetate to give 0.42 g (19%) of a brown solid: mp 190-195° C. [expected mp 198-200° C.]; 1H NMR: (DMSO) δ 6.83 (d, 2H, J=7.0 Hz), 7.22 (m, 8H), 7.68 (d, 2H, J=16.1 Hz), 9.63 (s, 2H); 13C NMR: (DMSO) δ 114.7, 117.5, 119.4, 125.4, 129.7, 135.8, 142.7, 157.5, 168.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])=O.Cl.[CH3:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17].C1(C)C=CC=CC=1.O>CCOCC>[CH3:15][N:16]([CH2:18][CH2:19][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:3][C:2]([F:13])([F:12])[F:1])[CH3:17]
Reactant: CN(C)CCCl
Reactant: O=C(c1ccccc1O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN(C)CCOc1ccccc1CC(F)(F)F
Temperature: 25 °C
Yield: 75.8 %

Procedure:
A mixture of 2-trifluoroacetylphenol (380 mg, 2.0 mmol), 2-[N, N-dimethylamino]ethyl chloride, hydrochloride (432 mg, 6.0 mmol) potassium carbonate (1.38 g, 10 mmol) and toluene (5 ml) was refluxed for 3.5 h. After cooling to r.t., the mixture was treated with water and ether. The organic layer was washed twice with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (acetone/ether 1:1 to 1:0) to give the title compound (375 mg, 72%) as a white solid.
Reaction SMILES: [Se](=O)=O.O.[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7].CC[O:19]C(C)=O>O1CCOCC1>[N+:14]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH:5]=[O:19])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1cccc([N+](=O)[O-])c1
Yield: 76 %

Procedure:
To a solution of Selenium dioxide (9.4 g, 85 mmol) in 1,4-Dioxane (50.0 mL) and Water (1.70 mL, 94.4 mmol), was added 3-Nitroacetophenone (12.0 g, 72.9 mmol). The reaction mixture was refluxed for 4 hours with stirring, then taken up with EtOAc (100 mL) and washed with water (2×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and conc. in vacuo. Purification was by ISCO column chromatography (20-70% EtOAc/Hex) to afford (3-Nitro-phenyl)-oxo-acetaldehyde (9.98 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[N+:8]([O-:10])=[O:9].[H-].[Li+].[CH2:13](Br)[CH:14]=[CH2:15]>O1CCCC1>[Cl:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:7])[N:5]([CH2:15][CH:14]=[CH2:13])[N:6]=1.[Cl:1][C:2]1[N:6]([CH2:15][CH:14]=[CH2:13])[N:5]=[C:4]([CH3:7])[C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1n[nH]c(Cl)c1[N+](=O)[O-]
Reactant: C=CCBr
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCn1nc(C)c([N+](=O)[O-])c1Cl
Product: C=CCn1nc(Cl)c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5.0 g (0.031 mole) of 5-chloro-3-methyl-4-nitro-1H-pyrazole in 100 mL of anhydrous tetrahydrofuran under argon, was added 0.37 g (0.0464 mole) of lithium hydride. The mixture was stirred at room temperature for 15 minutes. Then 5.6 g (0.0464 mole) of allyl bromide was added, and the mixture was heated at 80° C. for 10 hours. The mixture was cooled, poured onto ice and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (1:2) to give, as the more polar component, 1.36 g of 3-chloro-5-methyl-4-nitro-1-(2-propenyl)-1H-pyrazole as a colorless oil and, as the less polar component, 0.5 g of 5-chloro-3-methyl-4-nitro-1-(2-propenyl)-1H-pyrazole (XX) as a colorless oil.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26]C)[CH2:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[NH:9]1.C(Cl)Cl.B(Br)(Br)[Br:32]>CO>[BrH:32].[OH:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[OH:26])[CH2:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[NH:9]1
Reactant: COc1ccc(CC[C@H]2CC[C@H](Cc3ccc(OC)c(OC)c3)N2)cc1
Reactant: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Br
Product: Oc1ccc(CC[C@H]2CC[C@H](Cc3ccc(O)c(O)c3)N2)cc1
Temperature: 60 °C

Procedure:
A solution of 1 g. (0.003 mole) of trans-2-(3,4-dimethoxybenzyl)-5-[2-(4-methoxyphenyl)ethyl]pyrrolidine hydrochloride in 35 ml. of methylene chloride was cooled to -65° C. and treated with 2.68 g. (0.012 mole) of boron tribromide dropwise. The reaction mixture was then stirred under N2 and slowly warmed from -65° to room temperature over the course of one hour and 25 minutes. The solution was then cooled again to 31 60° C. and 25 ml. of methanol was cautiously added. Solvent was removed in vacuo, more methanol was added and some insoluble material was filtered off. After removal of methanol in vacuo, the residue was treated with ethyl acetate. Upon standing at room temperature, 0.8 g. of product was obtained as an off-white solid, m.p. 202°-203° C.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=[C:35]([NH:48][CH3:49])[N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:38]4[C:33]([O:32][CH3:31])=[N:34][C:35]([NH:48][CH3:49])=[N:36][CH:37]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: CNc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate AE) and [4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-methyl-amine (Intermediate V) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively to afford the title compound as a white solid. ESI-MS: tR=0.83 min, [M+H]+ 544/546 (LC-MS 1); TLC: Rf=0.38 (9:1 CH2Cl2/MeOH).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].Br[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2>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.CN(C=O)C.CCN(CC)CC>[OH:6][C:2]([CH3:5])([CH3:1])[C:3]#[C:4][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2
Reactant: C#CC(C)(C)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(C)O)c21

Procedure:
Using Method D above, 3-methyl-1-butyn-3-ol (150 mg, 1.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (101 mg, 0.32 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (16 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 43 mg, 38%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[CH2:25][NH:26][S:27]([C:30]3[C:31]([CH3:44])=[C:32]([CH3:43])[C:33]4OC(C)(C)[CH2:36][CH2:35][C:34]=4[C:41]=3C)(=[O:29])=[O:28])[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.NC1C2C(=CC(CC(NC(=O)OC(C)(C)C)[C:59](=[O:66])N3CCCCC3)=CC=2)C=CN=1.OC[C@H](NS(C1C=CC2C(=CC=CC=2)C=1)(=O)=O)C(O)=O.N[C@H](C(O)=O)CO.C1C2C(=CC=CC=2)C=CC=1S([Cl:115])(=O)=O>>[ClH:115].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[C@@H:25]([NH:26][S:27]([C:30]3[CH:31]=[CH:44][C:33]4[C:34](=[CH:35][CH:36]=[CH:43][CH:32]=4)[CH:41]=3)(=[O:29])=[O:28])[CH2:59][OH:66])[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Agent: Cl
Agent: N[C@@H](CO)C(=O)O
Agent: O=C(O)[C@H](CO)NS(=O)(=O)c1ccc2ccccc2c1
Product: Nc1nccc2cc(CC(NC(=O)[C@H](CO)NS(=O)(=O)c3ccc4ccccc4c3)C(=O)N3CCCCC3)ccc12

Procedure:
The procedure described for 5c was used. Deprotection of 5a and coupling with (2S)-3-hydroxy-2-[(2-naphthalenylsulfonyl)amino]propanoic acid (prepared from L-serine and 2-naphthalenylsulfonylchloride using the procedure described for 5b) yielded 7. 1H-NMR 200 MHz (CD3OD) δ: 1.12-1.58 (6H, m), 2.57-2.69 (1H, m) 2.95-3.95 (8H, m), 4.9-5.1 (1H, m), 7.11-7.22 (1H, m), 7.43-8.16 (9H, m), 8.24-8.34 (1H, m), 8.41-8.45 (1H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:13][OH:14])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:3]1=[O:28].CN(C1C=CC=CN=1)C.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1>N1C=CC=CC=1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:4]2[C:5](=[O:15])[C:6]([CH2:13][O:14][CH:40]([CH2:39][CH:38]=[O:44])[C:41]([OH:43])=[O:42])([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:2]([CH3:1])[C:3]2=[O:28])=[CH:17][C:18]=1[C:24]([F:25])([F:27])[F:26])#[N:21]
Reactant: O=C1CCC(=O)O1
Reactant: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COC(CC=O)C(=O)O)c1ccccc1
Reaction time: 12 h

Procedure:
To a solution of 0.20 g of 4-[3-methyl-4-hydroxymethyl-2,5-dioxo-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile in 3 mL of pyridine was added 6 mg of dimethylaminopyridine and 0.052 g of succinic anhydride. The mixture is stirred for 12 hours then evaporated to dryness. The crude product is washed with water and extracted with DCM. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 50/50 cyclohexane/ethyl acetate to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)=[O:4].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 2.9 %

Procedure:
A solution of 1H-[1,2,4]triazole-3-carboxylic acid methyl ester (3.0 g, 0.23 mol) in N,N-dimethylformamide (76 mL) at 25° C. was treated with triphenylmethylchloride (7.2 g, 0.23 mol) and triethylamine (6.41 mL, 0.23 mol). The reaction mixture was stirred at 25° C. for 4 days and then diluted with ethyl acetate. The mixture was then washed with a dilute aqueous hydrochloric acid solution. At this time, methanol was added to the organic layer. A precipitate formed and was removed by filtration. The organics were further washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated with diethyl ether. The solid was collected by filtration and washed again with diethyl ether to afford 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid methyl ester as a white solid (2.45 g, 84%) which was used without further purification: LR-FAB for C23H19N3O2 (M+) at m/z=369.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:11]([O-])=[O:12].[Na+]>C(O)C.O>[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[C:8]=1[N:11]=[O:12]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(O)cc(C)c1N=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
750 ml of concentrated HCl are added to a solution of 3,5-dimethyl phenol (80.6 g) in 750 ml of 95% ethyl alcohol. The mixture is cooled to 0° C. in an ice/methanol bath. While maintaining the temperature of the reaction mixture below 5° C., a solution of NaNO2 (69.0 g) in 150 ml of H2O is added dropwise to the reaction mixture. The mixture is stirred at 0° C. for more than an hour and then poured into 9 liters of water. The aqueous mixture is filtered to give a yellow solid which is recrystallized from hot methanol and filtered to give 71.45 grams of a yellow solid, M.P. 180°-181° C. (dec).
Reaction SMILES: S(Cl)(Cl)=O.CC1SC(C(O)=O)=CC=1.CC1SC(C(Cl)=O)=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.[CH3:45][C:46]1[S:50][C:49]([C:51]([N:53]=[C:54]=[S:55])=[O:52])=[CH:48][CH:47]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:54]([NH:53][C:51]([C:49]2[S:50][C:46]([CH3:45])=[CH:47][CH:48]=2)=[O:52])=[S:55])=[CH:40][CH:39]=1
Reactant: Cc1ccc(C(=O)N=C=S)s1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1ccc(C(=O)Cl)s1
Agent: Cc1ccc(C(=O)O)s1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)s4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 5-methyl-2-thiophenecarboxylic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 5-methyl-2-thiophenecarbonyl isothiocyanate was prepared using the resultant 5-methyl-2-thiophenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 5-methyl-2-thiophenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (42 mg, yield 52%).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:21]([CH3:23])[CH3:22].C(OCC)(=O)C>CC(C)=O.O>[Br:1][C:2]1[C:11]([O:12][CH:21]([CH3:23])[CH3:22])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(Br)c(O)c2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2ccc(Br)c(OC(C)C)c2n1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 7-bromo-2-methylquinolin-8-ol (1.00 g, 4.20 mmol), K2CO3 (1.74 g, 12.6 mmol), and 2-iodopropane (0.84 ml, 8.40 mmol) in acetone (20 mL) was stirred at 88° C. in a seal tube for 24 hours. After cooling to ambient temperature, ethyl acetate (50 mL) and water (30 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 7-bromo-8-isopropoxy-2-methylquinoline (1.13 g, 96.0%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].O[N:22]=[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1)[NH2:24].N1C=CC=CC=1>CC#N>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=3)[N:22]=2)=[CH:10][C:9]=1[C:17]([F:19])([F:20])[F:18]
Reactant: NC(=NO)c1ccc(CO)cc1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 5 (4.32 g, 15.4 mmol) in MeCN (15 mL) was added 1-ethyl-3-dimethyl aminopropylcarbodiimide (4.14 g, 21.6 mmol) followed by Intermediate 72 (2.81 g, 17.0 mmol). The mixture was stirred at RT for 18 hours and then pyridine (5 mL) added. The mixture was heated under microwave irradiation at 150° C. for 30 minutes. The solvent was removed in vacuo and the residue partitioned between DCM and H2O. The layers were separated, the organic layer washed with H2O and the mixture passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was recrystallised from EtOAc and petrol to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.63 (1H, s), 8.40 (1H, d, J=8.0 Hz), 8.20 (2H, d, J=8.0 Hz), 7.54 (2H, d, J=7.9 Hz), 7.47 (1H, d, J=7.9 Hz), 7.38-7.21 (3H, m), 7.16 (1H, d, J=7.5 Hz), 4.81 (2H, d, J=5.7 Hz), 2.14-1.94 (3H, m). LC/MS (Method A): 411 (M+H)+. HPLC (Method G) Rt 4.50 min (Purity: 97.9%).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[Li].C[Si]([NH-])(C)C.[CH2:22](Br)[CH:23]=[CH2:24]>C1COCC1>[CH2:1]([C@H:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:24][CH:23]=[CH2:22])[C:11]([O:13][CH3:14])=[O:12])[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCBr
Reactant: CCCC[C@H]1CCN(CC(=O)OC)C1=O
Agent: C[Si](C)(C)[NH-]
Agent: [Li]
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)OC)N1CC[C@H](CCCC)C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 28.6 %

Procedure:
Step B (4): (S)-Methyl 2-(3-butyl-2-oxopyrrolidin-1-yl)acetate (0.5 g, 2.35 mmol) from step B (3) was dissolved in dry THF (30 mL) and cooled to −78° C. Lithium bis(trimethylsilylamide (1.0M in THF, 2.70 mL, 2.70 mmol, Aldrich) was added while the temperature was maintained below −60° C. The mixture was cooled to −78° C. and stirred for 15 min. A solution of allyl bromide (0.24 mL, 2.72 mmol, Aldrich) in 10 mL of THF was added dropwise and the resulting mixture was stirred for 48 h. The reaction was quenched with acetic acid (0.5 mL) and poured into 75 mL of 0.5 M H2SO4. The aqueous layer was extracted with EtOAc and the organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography (5-35% EtOAc/hexanes linear gradient) to give 170 mg (29% yield) of (s)-methyl 2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate (diastereomer A, first to elute) as a colorless oil and 130 mg of (R)-methyl 2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate (diastereomer B, second to elute) as a colorless oil. Data for diastereomer A: LC-MS (M+H)+=254.3; 1H NMR (500 MHz, CDCl3) δ 5.47-5.95 (m, 1H), 4.98-5.20 (m, 2H), 4.87 (dd, J=10.99, 4.88 Hz, 1H), 3.69 (s, 3H), 3.32-3.51 (m, 1H), 3.15-3.34 (m, 1H), 2.60-2.80 (m, 1H), 2.41-2.53 (m, 1H), 2.26-2.40 (m, 1H), 2.05-2.23 (m, 1H), 1.76-1.94 (m, 1H), 1.61-1.77 (m, 1H), 1.18-1.47 (m, 5H), 0.78-0.97 (m, 3H). Data for diastereomer B: LC-MS (M+H)+=254.36; 1H NMR (500 MHz, CDCl3) δ 5.57-5.78 (m, 1H), 4.99-5.18 (m, 2H), 4.88 (dd, J=10.99, 4.88 Hz, 1H), 3.69 (s, 3H), 3.32-3.48 (m, 1H), 3.21-3.32 (m, 1H), 2.64-2.79 (m, 1H), 2.34-2.53 (m, 2H), 2.10-2.30 (m, 1H), 1.74-1.91 (m, 1H), 1.46-1.74 (m, 1H), 1.20-1.40 (m, 5H), 0.78-1.00 (m, 3H).
Reaction SMILES: [NH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[N:3][C:2]1=[N:14][NH2:15].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=O>C(O)C>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=[N:15][NH:14][C:2]1[N:3]=[N:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[N:1]=1
Reactant: NN=c1nnc2c([nH]1)[nH]c1ccccc12
Reactant: O=Cc1ccccn1
Solvent: CCO
Product: C(=NNc1nnc2c(n1)[nH]c1ccccc12)c1ccccn1
Temperature: 60 °C

Procedure:
To a solution of (1,9-Dihydro-1,3,4,9-tetraaza-fluoren-2-ylidene)-hydrazine 14d (27 mmol, 1 equiv.) in ethanol (50 mL) is added 2-pyridinecarboxaldehyde (27 mmol, 1 equiv.). The mixture is heated at 60° C. for 10 hours. The solution is allowed to cool to room temperature. The product is filtered and dried under vacuum for 15 hours. N-Pyridin-2-ylmethylene-N′-(9H-1,3,4,9-tetraaza-fluoren-2-yl)-hydrazine 14e is obtained as a pale yellow solid.