Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]([C:22]2([NH:37]C(=O)OC(C)(C)C)[CH2:27][CH2:26][N:25]([C:28]3[C:29]4[CH:36]=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1>ClCCl>[NH2:37][C:22]1([C:20]([NH:19][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17][OH:18])=[O:21])[CH2:23][CH2:24][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(C(=O)NC(CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
TFA (0.7 mL) was added to a suspension of tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 36) (175 mg, 0.33 mmol) in dichloromethane (7 mL) under argon. The resulting solution was stirred at 20° C. for 16 hours. The solvents were removed in vacuo and the reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length) with decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (99 mg, 69.8%) as a white powder.
Reaction SMILES: O1CC[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=2[C:15]=1[CH3:16])=[O:10])[CH3:7].C([N-]C(C)C)(C)C.[Li+].C(I)C>C(OCC)(=O)C>[CH2:6]([O:8][C:9]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[C:26]([CH3:27])([CH3:28])[CH3:29])[C:14]=2[C:15]=1[CH2:16][CH2:2][CH3:3])=[O:10])[CH3:7]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c2c1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: CCOC(C)=O
Product: CCCc1c(C(=O)OCC)oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry tetrahydrofuran (3 ml) solution of 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid ethyl ester (50 mg) was added lithium diisopropylamide (1.2 ml, 0.5N in THF) at −78° C. After 30 minutes ethyl iodide (160 μl) was added at the same temperature. Then reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and dried over anhydrous sodium sulfate then concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-propyl-benzofuran-2-carboxylic acid ethyl ester as a pale yellow oil (5.1 mg). FAB-MS: m/z 462 (MH+); 1H-NMR (CDCl3): δ 1.12-1.54 (21H, m), 2.09 (2H, m), 2.75 (3H, s), 3.52 (2H, dd, J=7.6 Hz, 9.9 Hz), 4.09 (2H, t, J=5.9 Hz), 4.43 (2H, q, J=7.3 Hz), 6.61 (1H, d, J=7.9 Hz), 7.12 (1H, d, J=8.6 Hz), 7.31 (1H, dd, J=8.6 Hz, 7.9 Hz).
Reaction SMILES: F[C:2]1[C:3]([CH3:24])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[C:18]4([CH2:22][CH2:21]4)[CH2:17][NH:16][C:15](=[O:23])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH:25]1([NH:28][C:2]2[C:3]([CH3:24])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[C:18]5([CH2:21][CH2:22]5)[CH2:17][NH:16][C:15](=[O:23])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:27][CH2:26]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C3(CC3)CNC4=O)c2nc1F
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)C3(CC3)CNC4=O)c2nc1NC1CC1
Temperature: 100 °C
Yield: 62.6 %

Procedure:
Prepared according to Example 131 using 2′-(3-fluoro-2-methyl-5-quinoxalinyl)-5′,6′-dihydrospiro[cyclopropane-1,7′-pyrrolo[3,2-c]pyridin]-4′(1′H)-one (Ex. 77a; 39 mg, 0.12 mmol), cyclopropylamine (Alfa Aesar, Ward Hill, Mass.; 14 mg, 0.25 mmol) and DIPEA (47 mg, 0.36 mmol) and heating at 100° C. for 1 h. Purification by chromatography (silica gel, 0-100% EtOAc in hexanes followed by 0-10% MeOH in DCM) provided 2′-(3-(cyclopropylamino)-2-methyl-5-quinoxalinyl)-5′,6′-dihydrospiro[cyclopropane-1,7′-pyrrolo[3,2-c]pyridin]-4′(1′H)-one (27 mg, 62% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br s, D2O exch.), 7.95 (1H, dd, J=7.53, 1.47 Hz), 7.58 (1H, dd, J=8.02, 1.37 Hz), 7.42 (1H, dd, J=2.35, 0.59 Hz), 7.36 (1H, br s, D2O exch.), 7.34 (1H, t, J=7.82 Hz), 7.02 (1H, br s, D2O exch.), 3.29 (2H, d, J=2.35 Hz), 2.91 (1H, tq, J=6.75, 3.52 Hz), 2.51 (3H, s), 1.06-1.12 (2H, m), 0.97-1.02 (2H, m), 0.90-0.97 (2H, m), 0.66-0.74 (2H, m). m/z (ESI, +ve) 360.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].C(N(CC)CC)C.[CH3:33][N:34]=[C:35]=[O:36]>O1CCCC1>[CH3:33][NH:34][C:35](=[O:36])[NH:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)=[O:5]
Reactant: CN=C=O
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,5-Dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride (1.0 g) was suspended in tetrahydrofuran (10 ml). Triethylamine (0.38 ml) was added and the solution was stirred at room temperature for 15 minutes. Methyl isocyanate (0.19 ml) was added and the solution was stirred for 1 hour. The tetrahydrofuran was removed in vacuo and the residue was taken up in ethyl acetate. The organic phase was washed with dilute hydrochloric acid, water and sodium bicarbonate solution. The organic extract was dried (Na2SO4) and evaporated. The residual solid was recrystallised from ethyl acetate/petroleum ether to yield the title compound, (1.17 g), m.p. 66°-68° C. 1H NMR (360 MHz, CDCl3) δ7.99 (1H, s), 7.52 (1H, d, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.16 (1H, t, J=8 Hz), 7.08 (1H, t, J=8 Hz), 6.96 (1H, s), 6.88 (2H, s), 6.76 (1H, s), 5.01 (2H, s), 4.83 (1H, m), 3.26 (2H, d, J=5 Hz), 2.65 (3H, s), 2.30 (6H, s). Found: C, 68.64; H, 6.36; N, 10.86. C22H25O3N3. 0.3(H2O) requires C, 68.57; H, 6.66; N, 10.90.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccc(C(N)=O)c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1cccc(-c2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred, cooled (0° C.) solution of 3′-methoxybiphenyl-3-carboxylic acid amide (0.57 g; 2.5 mmol) in dry CH2Cl2 (28 mL), under N2 atmosphere, a 1M solution of BBr3 in CH2Cl2 (6.4 mL) was added. The mixture was stirred at room temperature for 1 h, quenched with 2N Na2CO3 and extracted with AcOEt. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. Purification of residue by column chromatography (cyclohexane/EtOAc 2:8) gave the desired product as an amorphous solid. Yield 91%. Mp: 148–51° C. (after digestion with i-Pr2O). MS (EI): m/z 213 (M+, 100%). 1H NMR (CDCl3/d6-DMSO): δ 6.06 (br s, 1H); 6.59 (m, 1H); 6.85 (m, 2H); 7.01 (t, 1H); 7.23 (t, 1H); 7.35 (br s, 1H); 7.45 (m, 1H); 7.60 (m, 1H) 7.88 (s, 1H); 8.80 (s, 1H) ppm. IR (Nujol): 3314, 3141, 1669, 1630, 1607, 1577 cm−1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].Br[C:15]1[CH:23]=[CH:22][C:21]2[N:20]([CH3:24])[C:19]3[CH2:25][CH:26]4[NH:30][CH:29]([C:18]=3[C:17]=2[C:16]=1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27]4>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:15]2[CH:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19]4[CH2:25][CH:26]5[NH:30][CH:29]([C:18]=4[C:17]=3[C:16]=2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27]5)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=[N+]([O-])c1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc([N+](=O)[O-])cc4)ccc31)C1CCC(C2)N1
Yield: 54 %

Procedure:
Intermediate 12 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 1:1 hexane/ethyl acetate) to give tert-butyl 2-(4-nitrophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (150 mg, 54%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.27-8.31 (m, 2H), 8.19 (s, 1H), 8.09-8.11 (m, 2H), 7.68 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 5.26 (br s, 1H), 4.70 (br s, 1H), 3.62 (s, 3H), 3.40 (br s, 1H), 2.50 (d, J=16.2 Hz, 1H), 2.17-2.31 (m, 2H), 1.89-1.97 (m, 1H), 1.54-1.65 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17]([NH:19][C@@H:20]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:22]([C:32]([O:34]C)=[O:33])[CH2:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.O.[OH-].[Li+].O1CCOCC1.Cl>O>[C:28]([O:27][C:25]([N:23]1[CH2:24][C@@H:20]([NH:19][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:18]=2)[CH2:21][C@@H:22]1[C:32]([OH:34])=[O:33])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)[C@H]1C[C@H](Nc2nc(-c3ccccc3OC)nc3ccccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1nc(N[C@H]2C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Yield: 96.6 %

Procedure:
(2R,4S)-1-tert-Butyl 2-methyl 4-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-1,2-dicarboxylate (0.415 g, 0.851 mmol) and lithium hydroxide monohydrate (0.089 g, 2.128 mmol) were dissolved in water (8 mL) and dioxane (8 mL) and stirred for 1 hour. Water (30 mL) was added and the mixture was acidified to pH 4 with 1M HCl. The aqueous layer was extracted with ethyl acetate (4×30 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a solid (0.382 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:9]3[C:10]=2[C:5]([CH2:6][CH2:7][N:8]3[CH3:19])=[C:4](F)[C:3]=1[F:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[NH2:1][C:2]1[C:11]2[C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:9]3[C:10]=2[C:5]([CH2:6][CH2:7][N:8]3[CH3:19])=[C:4]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:3]=1[F:21]
Reactant: CN1CCc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: C1CCNC1
Solvent: CC#N
Product: CN1CCc2c(N3CCCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 80 °C

Procedure:
4 mg of the compound (202) obtained in Example 73 and 10 μl of pyrrolidine were added to 1 ml of acetonitrile, and the solution was heated at 80° C. for 3 hours. After air-cooling, the solvent was removed by distillation, and the residue was filtered off and washed with ethanol and ether in this order to obtain 2 mg of the subject compound (203).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[NH:7][CH3:8].[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](Cl)=[O:17].CN(C=O)C.[H-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([N:7]([CH3:8])[C:16](=[O:17])[CH2:15][C:14]([CH3:20])([CH3:19])[CH3:13])[CH:9]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)CC(C)(C)C)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-N-methyl-2-nitroaniline (300 mg), 3,3-dimethylbutanoyl chloride (0.450 ml) and DMF (5 ml) was added NaH (40% oil dispersion, 57.1 mg), and the mixture was heated at 70° C. overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (214 mg) as a solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([C:19]2[N:23]=[C:22]([CH2:24][S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:21][N:20]=2)=[O:18])=[CH:15][CH:14]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOCC>C(Cl)Cl>[Cl:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([C:19]2[N:23]=[C:22]([CH2:24][S:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:6])[O:21][N:20]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)c1noc(CSc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1noc(CS(=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of 5.8 g of m-chloroperoxybenzoic acid (85%) in 150 ml of CH2Cl2 was added dropwise at -70° under N2 to a solution of 9.0 g of 3-(4-chlorobenzoyl)-5-phenylthiomethyl-1,2,4-oxadiazole in 200 ml of CH2Cl2. The reaction temperature was maintained below -65° by controlling the rate of addition. After stirring further for 30 minutes, the reaction mixture was poured directly into a separatory funnel containing 300 ml of 10% Na2S2O3 and 600 ml of Et2O. The organics were washed with saturated NaHCO3 and dried over MgSO4. Concentration gave an oil which solidified on standing. Recrystallization from acetone/hexane gave 6.7 g (67%) of needles, m.p. 93°-95°.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14]([C:17]1[NH:18][CH:19]=[NH+:20][C:21]=1[O-:22])(=[O:16])[NH2:15]>N1C=CC=CC=1>[C:1]12([C:11]([O:22][C:21]3[N:20]=[CH:19][NH:18][C:17]=3[C:14](=[O:16])[NH2:15])=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Solvent: c1ccncc1
Product: NC(=O)c1[nH]cnc1OC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution of 1-adamantanecarbonylchloride (2.980 g) in pyridine (26 ml) was added 4-carbamoylimidazolium-5-olate (1.271 g) and the reaction temperature was kept at 40°-43° C. for 4 hours. Unreacted starting material was recovered by filtration (210 mg). The filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (30 ml) and water (30 ml), and stirred at room temperature for 1 hour. The insoluble solid was filtered and washed with ethyl acetate to give almost pure 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate (1.602 g, α form, m.p. 207°-209° C. (dec.)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([S:64](Cl)(=[O:66])=[O:65])=[C:61]([CH3:63])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:64]([C:60]1[S:59][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[N:62][C:61]=1[CH3:63])(=[O:65])=[O:66])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (510 mg) was reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to yield (S)-2-({(3S,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (526 mg) according to General Procedure E. The title compound (32 mg) was prepared by the hydrolysis of (S)-2-({(3S,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LCMS m/z=968) (40 mg) according to General Procedure B. LCMS (m/z):952.
Reaction SMILES: [CH:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19](I)[CH3:20]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:1]1([C:7]2[N:8]([CH2:19][CH3:20])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc2[nH]c(C3CCCCC3)cc2c1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C2CCCCC2)cc2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-cyclohexyl-5-nitro-1H-indole (5 g; 20.5 mmol) in DMF (100 ml) sodium hydride (50% suspension) (1 g, 20.5 mmol) was added; the mixture was left under stirring for 30 minutes, then ethyl iodide (2.5 ml; 30.8 mmol) in DMF (10 ml) was added dropwise and the resulting mixture was left under stirring at room temperature for 18 hours. The reaction mixture was poured in NaHCO3 (saturated solution, 100 ml) and stirred for 30 minutes. The solid was filtered under vacuum to give 2-cyclohexyl-1-ethyl-5-nitro-1H-indole (4.8 g) which was used without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.CC1C=CC(N=[CH:25][C:26]2[C:27]([NH2:35])=[CH:28][C:29]3[O:33][CH2:32][O:31][C:30]=3[CH:34]=2)=CC=1>>[CH3:15][O:14][C:10]1[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[C:4]2[CH2:5][C:6]3[C:7]([C:8]=2[CH:9]=1)=[N:35][C:27]1[CH:28]=[C:29]2[O:33][CH2:32][O:31][C:30]2=[CH:34][C:26]=1[CH:25]=3
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COc1cc2c(c(OC)c1OC)CCC2=O
Product: COc1cc2c(c(OC)c1OC)Cc1cc3cc4c(cc3nc1-2)OCO4
Yield: 0 %

Procedure:
Using the procedure of Example 1, 4,5,6-trimethoxyindan-1-one (1.10 mg, 4.8 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (1.22 g, 4.8 mmol) to yields 7,8,9-trimethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (0.84 mg, 49.9% of theory).
Reaction SMILES: C([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[CH:13]([S:25][CH3:26])[CH2:14][S:15]CC1C=CC(OC)=CC=1)(C)(C)C.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[SH:15][CH2:14][CH:13]([S:25][CH3:26])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:28])=[O:5])=[O:27]
Reactant: COc1ccc(CSCC(SC)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CSC(CS)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
1-[3-(4-Methoxybenzylmercapto)-2-(methylthio)propanoyl]-L-proline tert-butyl ester (0.5 g.) is dissolved in a mixture of dichloromethane (2 ml.) and anisole (1.1 ml.) under a blanket of argon in an ice bath. Trifluoromethanesulfonic acid (1 g.) is added and the mixture is stirred at room temperature for thirty minutes. The solvent is removed in vacuo and the residue is distributed between water and ethyl acetate. The organic layer is washed six times with water, dried and concentrated to dryness in vacuo to yield 1-[3-mercapto-2-(methylthio)propanoyl]-L-proline.
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(O)(C)C>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:31][C:28]([CH:29]=[C:6]3[CH2:5][CH2:4][CH2:3][N:2]=[C:7]3[C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Cl-]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(-c2ccc(C=C3CCCN=C3c3cccnc3)o2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (95 mg, 0.38 mmol) and 5-(4-nitrophenyl)furfural (99 mg, 0.46 mmol) were combined in a reaction vessel and treated with isopropanol (6 mL). The reaction vessel was sealed and the reaction was heated to 80° C. with stirring overnight. The reaction was then cooled to room temperature, concentrated under reduced pressure and treated with saturated NaHCO3(aq). This mixture was then extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The recovered material was eluted through a 20 gram column of silica gel with 10.5:7:7:1:0.1 hexane:MTBE:CH2Cl2:MeOH:NH4OH (1 liter). One sample was recovered that appeared to be highly crystalline. This material was re-crystallized from hot methanol. The crystals were recovered by vacuum filtration, washed with isopropanol then dried under vacuum giving 50 mg (36%) of an orange crystalline solid. LC-MS: RT=5.16 min, [M+H]+=360.0.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-:25].[Na+]>COCCO>[C:23]([C:20]1[S:21][CH:22]=[C:18]([NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:19]=1)(=[O:25])[NH2:24]
Reactant: [OH-]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C#N)c1
Agent: [Na+]
Solvent: COCCO
Product: CCCCCCCCCCCCCCCCNc1csc(C(N)=O)c1
Reaction time: 8 h

Procedure:
A mixture of 6.9 g. of 4-hexadecylamino-2-cyanothiophene, 80 ml. of methyl cellosolve, and 80 ml. of 1 N sodium hydroxide is refluxed for 21 hours. After cooling in an ice bath, the solid is filtered and thoroughly washed with methylene chloride. The solid is then added to 100 ml. of water and 5 ml. of concentrated hydrochloric acid and stirred for 8 hours. The solid is filtered and recrystallized from isopropanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7])[CH3:2].[Br:10]Br.O=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH2:7][Br:10])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrBr
Agent: O=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)CBr
Temperature: 25 °C
Reaction time: 60 h
Yield: 76.7 %

Procedure:
To a solution of 3-oxo-butyric acid ethyl ester (10.0 g, 78 mmol) in 100 mL of chloroform was added bromine (2.02 mL, 78 mmol) dropwise. The solution was stirred at room temperature for 60 hours without capping the flask (extended stirring at room temperature in an open system with oxygen flow facilitated the bromine migration from C-2 to C-4). The reaction mixture was partitioned between chloroform and water and the organic phase was dried over sodium sulfate. The organic solution was concentrated to provide 4-bromo-3-oxo-butyric acid ethyl ester (12.5 g, 45%). The crude product was taken on to the next step without further purification.