Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]([CH3:14])[CH2:10][C@H:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]([CH3:22])([CH3:14])[CH2:10][C@H:9]1[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamate (1.2 g, 4.0 mmol) in tetrahydrofuran (20 mL) stirring at −78° C., was added a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (4.4 mL, 4.4 mmol) dropwise over 5 minutes. After 30 minutes, methyliodide (0.33 mL, 5.2 mmol) was added. After an additional 3 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (40 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (2×50 mL). The combined organic layers were washed with water(2×25 mL), saturated sodium bicarbonate (2×25 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated to give Boc-PyroGlu(4,4-dimethyl)-OtBu (0.673 g, 54%). Step 3. Synthesis of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylproline (Boc-Pro(4,4-dimethyl)-OtBu)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]2[C:12]([CH:13]=1)=[C:11]([N+:14]([O-])=O)[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)=[O:4].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]2[C:12]([CH:13]=1)=[C:11]([NH2:14])[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c([N+](=O)[O-])c(OC)ccc2n1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc2c(N)c(OC)ccc2n1C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 9 (1.0 g, 3.78 mmol) in anhydrous methanol (90 mL) was added 10%Pd/C (150 mg) suspended in anhydrous methanol (15 mL) followed by ammonium formate (1.10 g, 17.4 mmol). The reaction mixture was stirred for 1 h, filtered through celite and the methanol removed. The residue was taken up in CH2Cl2/H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and evaporated to afford 10 (595 mg, 67%) as a brown solid which was used without further purification; 1H NMR (CDCl3): δ7.21 (1H, s), 7.06 (1H, d), 6.72 (1H, d), 4.01 (3H, s), 3.90 (3H, s), 3.88 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=O)=[N:14][CH:13]=1)[C:5]([NH2:7])=[O:6].Cl.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1[NH2:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH:34][CH:26]2[CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25]2)=[N:14][CH:13]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)c1ccc(Oc2cnc(C=O)c3ccccc23)c(F)c1
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Product: NC(=O)c1ccc(Oc2cnc(CNC3Cc4ccccc4C3)c3ccccc23)c(F)c1

Procedure:
Using the procedure outlined in Example 100, 3-fluoro-4-(1-formylisoquinolin-4-yloxy)benzamide (Preparation 42) and indan-2-ylamine hydrochloride were converted to the title compound: RT=2.87 min; m/z (ES+)=428.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:12]([I:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:14][CH3:15])[CH:3]=1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].Cl>C(Cl)Cl>[I:13][C:12]1[C:2]([N:1]([S:24]([CH3:23])(=[O:26])=[O:25])[S:24]([CH3:23])(=[O:26])=[O:25])=[CH:3][C:4]([S:14][CH3:15])=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(I)c(N)cc1SC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(I)c(N(S(C)(=O)=O)S(C)(=O)=O)cc1SC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-amino-5-iodo-2-(methylthio)benzoate (13.6 g, 40 mmol) in DCM (100 mL) was added Et3N (13.8 mL, 100 mmol), followed by MsCl (7.7 mL, 100 mmol) at 0° C. After addition the mixture was stirred at rt for 2 h. 1N HCl solution (50 mL) was added to the mixture and the aqueous phase was extracted with DCM (1×100 mL). The organic solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give ethyl 5-iodo-4-(N-(methylsulfonyl)methylsulfonamido)-2-(methylthio)benzoate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:8][CH2:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCc1ccccc1)COCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of 1-benzyloxy-4-phenyl-butan-2-ol, (8.4 g, 32.8 mmol) in dichloromethane (400 mL) is added a mixture of pyridinium chlorochromate (14.1 g, 65.6 mmol) with SiO2 (14 g) and stirred for 3 h at room temperature. The mixture is filtered through a pad of SiO2 and concentrated to provide the title compound 5.7 g (68%) as a colorless liquid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][N:29]=1)[CH3:27].C([Mg]Cl)(C)C>C1COCC1>[CH2:26]([C:28]1[N:29]=[CH:30][C:31]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH:7]=2)=[O:5])=[CH:32][CH:33]=1)[CH3:27]
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Reactant: CCc1ccc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 85 mg (0.25 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2.5 mL THF and 129 mg (0.56 mmol) of 2-ethyl-5-iodo-pyridine in 1 mL THF with 0.29 mL 2M isopropylmagnesium chloride. Yield: 41 mg of a white powder. LC-MSD, m/z for C24H21N3O2 [M+H]+=384.1; HPLC retention time: 0.7 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:61]([O:68][CH2:69][CH2:70][CH2:71][CH2:72]O)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62].N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:72][CH2:71][CH2:70][CH2:69][O:68][Si:61]([C:64]([CH3:65])([CH3:67])[CH3:66])([CH3:62])[CH3:63])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (0.6 g, 1.01 mmol), triphenyl phosphine (0.4 g, 1.52 mmol), and 4-{[tert-butyl(dimethyl)silyl]oxy}-1-butanol (0.31 g, 1.52 mmol, J. Org. Chemn. 1986, 51, 3388-3390) in anhydrous dichloromethane (9 mL) at 0° C. under nitrogen atmosphere was slowly added a solution of diisopropyl azodicarboxylate (0.29 mL, 0.3 g, 1.52 mmol) in anhydrous dichloromethane (2 mL) and the mixture was stirred at ambient temperature for 2 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, hexanes/ethyl acetate, 1:1) to provide the title compound as a solid foam (0.39 g). 1H NMR (DMSO-d6): δ 0.0 (6H, s), 0.78 (3H, d), 0.80 (3H, d), 0.82 (9H, s), 1.22 (1H, dd), 1.4 (1H, quintuplet), 1.55 (2H, quintuplet), 1.7 (2H, quintuplet), 1.8-1.9 (1H, m), 2.35 (1H, t), 2.65-2.80 (3H, m), 2.9 (1H, d), 3.0 (1H, dd), 3.2-3.3 (2H, m), 3.4-3.5 (1H, m), 3.52-3.62 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.9 (2H, t), 4.8 (1H, dt), 5.0 (1H, br s), 5.5 (1H, d), 6.18 (2H, s), 6.77 (2H, d), 7.0-7.1 (3H, m), 7.19 (1H, d), 7.21 (1H, s), 7.3 (1H, d); MS: 801 (M+23); C38H58N2O11SSi.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Cl)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1
Product: COc1cc(-c2cccc(CN(c3ccc(F)c(F)c3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine (625 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Reactant: C#Cc1ccccc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(C#Cc2ccccc2)cc1C(F)(F)F

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and phenylacetylene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (19 mg, 15%); 1H NMR δ (CDCl3): 7.66-7.55 (m, 5H), 6.64 (s, 1H), 3.98 (s, 3H), LCMS m/z: 250.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:23])([F:22])[F:11])=[CH:14][CH:15]=2)[N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1c[nH]nc1C
Product: COC(=O)c1cn(-c2ccc(C(F)(F)F)cc2)nc1C
Yield: 11.1 %

Procedure:
Using a crude product of methyl 3-methyl-1H-pyrazole-4-carboxylate (8.9 g) synthesized in Example 1(3) and 4-trifluoromethylphenylboronic acid (13.3 g) and in the same manner as in Example 17(1), the title object compound (2.0 g, 11%) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13]C(=O)C)([CH3:4])([CH3:3])[CH3:2].O.Cl>C1COCC1>[C:1]([NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Oc1ccccc1C(=O)NC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)c1ccccc1O
Yield: 80.7 %

Procedure:
The product from Step A (2.35 g, 0.010 mol) was dissolved in THF wand 10 mL of water was added to form a clear suspension. Hydrochloric acid (5%) was added until the solution reached a pH˜1. The reaction mixture was then refluxed for 24 hours. TLC indicated that about half of the starting material remained, so an additonal 10 mL of 5% hydrochloric acid was added and the reaction mixture was refluxed for 24 hours. The THF was then removed by rotoevaporation and the remaining aqueous mixture was extracted with hexanes (2×20 mL). The combined hexane layers were washed with water (2×40 mL), dried over MgSO4 and the hexane removed in vacuo to provide 1.56 g (80.8% yield) of the title compound as a white crystalline solid, m.p. 78-79.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(Cl)c(Cl)c1
Yield: 99 %

Procedure:
A mixture of 3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propionic acid (3.03 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propionate (3.15 g, yield 99%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 87–88° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[CH2:29]([Mg]Cl)[CH:30]=[CH2:31].O1CCCC1>C(OCC)C>[CH2:31]([CH:10]1[N:11]2[CH2:20][CH2:19][C:18]3[C:13]([C:12]2=[C:3]([CH2:1][CH3:2])[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]1=2)=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=3)[CH:30]=[CH2:29]
Reactant: C=CC[Mg]Cl
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Agent: [I-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1c2c(ccc(OC)c2OC)C(CC)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a suspension of 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (200 mg, 0.4 mmol) in anhydrous diethyl ether (5 mL) at 0° C. was added a solution of allylmagnesium chloride in tetrahydrofuran (1.7 M, 2.5 mL, 4 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8-allyl-13-ethyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (160 mg, 98%). LC/MS m/e calcd for C25H27NO4 (M+H)+: 406.5, observed: 406.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.20 Hz, 3 H) 2.11-2.20 (m, 1 H) 2.25-2.35 (m, 1 H) 2.55-2.65 (m, 2 H) 2.66-2.76 (m, 2 H) 3.23-3.30 (m, 2 H) 3.80 (d, J=4.55 Hz, 6 H) 4.68-4.81 (m, 3 H) 5.63-5.75 (m, 1 H) 6.04 (d, J=11.87 Hz, 2 H) 6.85 (s, 1 H) 6.90 (s, 1 H) 6.94 (s, 2 H).
Reaction SMILES: C(S[C:4]1[NH:5][C:6](=[O:14])[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1)C.Cl.CC(O)=[O:18]>O>[NH:9]1[C:8]2[CH2:10][CH2:11][CH2:12][S:13][C:7]=2[C:6](=[O:14])[NH:5][C:4]1=[O:18]
Reactant: CCSc1nc2c(c(=O)[nH]1)SCCC2
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2c(c(=O)[nH]1)SCCC2
Reaction time: 8 h
Yield: 72 %

Procedure:
To a suspension of 2-(ethylthio)-7,8-dihydro-3H-thiopyrano[3,2-d]pyrimidin-4(6H)-one (4.5 g, 19.7 mmol) in water (20 mL) was added 3.0 mL of conc. HCl and 6.0 mL of AcOH. The mixture was heated to reflux and stirred overnight. The reaction was cooled and the solid that formed was collected by filtration, washed with water and methanol, evaporated and dried to obtain 7,8-dihydro-1H-thiopyrano[3,2-d]pyrimidine-2,4(3H,6H)-dione as a white solid (2.6 g, 72%). Without further purification, the crude product was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:38])[C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:38])[C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1)=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: O=C(OCCCCCCCCCCCBr)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=C(OCCCCCCCCCCCOC(=O)c1cc(O)ccc1O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 56.6 %

Procedure:
2.78 g (18.0 mmol) 2,5-dihydroxybenzoic acid were dissolved in 36 ml dimethylformamide. 2.96 ml (19.8 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) were added dropwise in the course of 15 minutes. The reaction temperature rise to 30° C., subsequently 8.83 g (19.8 mmol) 3,5-dinitrobenzoic acid 11-bromoundecyl ester were added in one portion. The mixture was then heated at 80° C. for 2 hours. The reaction mixture was cooled and then partitioned between dichloromethane and 1N hydrochloric acid, the organic phase was washed twice with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using Toluene yielded 5.28 g (57%) 3,5-dinitrobenzoic acid 11-[2,5-dihydroxybenzoyloxy]undecyl ester as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:56]([O:58][C:59]([C:61]1[CH:66]=[N:65][C:64]([NH2:67])=[CH:63][N:62]=1)=[O:60])[CH3:57]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:67][C:64]2[N:65]=[CH:66][C:61]([C:59]([O:58][CH2:56][CH3:57])=[O:60])=[N:62][CH:63]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1cnc(N)cn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cn1
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (79.9 mg, 0.171 mmol) in dichloromethane (3 ml) was treated with DIPEA (89.0 mg, 0.685 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (103 mg, 0.428 μmol, Aldrich) and stirred for 30 mins under argon before 5-AMINO-PYRAZINE-2-CARBOXYLIC ACID ETHYL ESTER (30.4 mg, 0.173 mmol, Ark Pharm) was added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane and extracted with H2O. The organic layer was washed with sat NaHCO3, H2O, and sat NaCl and purified by flash chromatography using ethyl acetate and n-hexanes to give ethyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)pyrazine-2-carboxylate (27.6 mg, 26%) which was used in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[CH2:9][SH:10])=[O:6].Cl.[N:22]([O-])=[O:23].[Na+]>O>[NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[CH2:9][S:10][N:22]=[O:23])=[O:6]
Reactant: O=N[O-]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N[C@@H](CCC(=O)N[C@@H](CSN=O)C(=O)NCC(=O)O)C(=O)O
Reaction time: 1 h

Procedure:
N-(N-L-γ-glutamyl-L-cysteinyl)glycine (100 g, 0.325 mol) was dissolved in deoxygenated water (200 ml) and 2N HCl (162 ml) at room temperature and then the reaction mixture was cooled to 0° C. With rapid stirring, a solution of sodium nitrite (24.4 g, 0.35 mol) in water (40 ml) was added and stirring with cooling of the reaction mixture was continued for approximately 1 hour after which time the pink precipitate which formed was collected by vacuum filtration. The filter cake was resuspended in chilled 40% acetone-water (600 ml) and collected by vacumm filtration. The filter cake was washed with acetone (2×200 ml) and ether (100 ml) and then dried under high vacuum at room temperature in the dark to afford the title compound as a pink powder. 1H NMR (D2O) δ: 1.98 (m, 2H), 2.32 (t,2H), 3.67 (t, 1H), 3.82 (s 2H), 3.86 (dd, 1H), 3.98 (dd, 1H), 4.53 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 494 (0.045 g, 0.12 mmol) was dissolved in pyridine (0.3 mL). Ethanesulphonyl chloride (0.017 mL, 0.18 mmol) was added and the solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the oil was dissolved in EtOAc and washed with H2O. The water phase was extracted with EtOAc and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→40:60 as the eluent. This afforded the title compound as yellow solid. 13C NMR (CDCl3) δ 195.5, 159.3 (dd), 155.7 (dd), 148.3, 140.4, 135.3, 134.5, 134.5, 133.8, 132.5, 128.5, 124.6 (dd), 124.2 (dd), 123.2, 121.6, 116.1, 112.8, 111.6 (dd), 105.0 (dd), 45.9, 19.7, 8.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.Cl[CH2:16][CH2:17][N:18]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:20]Cl>>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][N:1]1[CH2:20][CH2:19][N:18]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[O:28][CH2:27][CH2:26][CH2:25]3)[CH2:17][CH2:16]1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: ClCCN(CCCl)c1ccc2c(c1)CCCO2
Product: COc1ccc2[nH]cc(CCN3CCN(c4ccc5c(c4)CCCO5)CC3)c2c1

Procedure:
Analogously to Example 5, reaction of 3.2 g of 3-(2-aminoethyl)-5-methoxyindole with 1.3 equivalents of 6-[N,N-bis(2-chloroethyl)amino]chroman [obtainable by reaction of 2-chloroacetyl chloride with 6-aminochroman and subsequent reduction with diborane] gives 1-[2-(5-methoxyindol-3-yl)ethyl]-4-(chroman-6-yl)piperazine.