Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc(F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
3-Fluorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42](=[O:52])[N:43]([CH2:48][CH2:49][CH2:50][CH3:51])[CH2:44][CH2:45][CH2:46][CH3:47])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:41])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[N:53]([CH2:56][C@@H:57]1[CH2:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH2:59][NH:58]1)=[N+:54]=[N-:55]>>[N:53]([CH2:56][C@@H:57]1[CH2:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH2:59][N:58]1[C:10]([C:9]1[CH:13]=[C:14]([C:17](=[O:41])[NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[C:25]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH:15]=[CH:16][C:8]=1[N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:42]([N:43]([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:48][CH2:49][CH2:50][CH3:51])=[O:52])=[N:4]1)=[O:11])=[N+:54]=[N-:55]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C)c1Cl
Yield: 73.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy) naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 183B, 50 mg, 0.066 mmol) and (S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate 92A, 37 mg, 0.20 mmol) were converted to the title compound (45 mg, 73%). 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 9.23-9.11 (m, 1H), 8.21 (d, J=1.9 Hz, 0.5H), 8.13-7.93 (m, 3.5H), 7.76-7.58 (m, 3H), 7.32-7.06 (m, 4.5H), 6.93 (d, J=7.2 Hz, 0.5H), 5.28 (d, J=18.3 Hz, 0.5H), 4.98 (br s, 0.5H), 4.73-4.62 (m, 2H), 4.59-3.21 (m, 15.5H), 3.18-2.69 (m, 3.5H), 2.58 (d, J=16.1 Hz, 0.5H), 2.48-2.40 (m, 0.5H), 2.34-2.21 (m, 3H), 1.55-0.82 (m, 1H), 0.78-0.70 (m, 2H), 0.69-0.55 (m, 1H); MS(ESI+) m/z 924.3 (M+H)+.
Reaction SMILES: [C:1](=[O:27])(ON1C(=O)CCC1=O)[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:18])[NH:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>ClCCl>[CH3:28][N:29]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=1)[C:1](=[O:27])[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:18])[NH:16][CH3:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CNCc1cccc(-c2ccccc2)c1
Reactant: CNC(=O)c1ccc(-c2ccc(OC(=O)ON3C(=O)CCC3=O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2ccc(OC(=O)N(C)Cc3cccc(-c4ccccc4)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask was placed a solution of 4-[4-(methylcarbamoyl)phenyl]phenyl 2,5-dioxopyrrolidin-1-yl carbonate from Example 1 Step 4 (560 mg, 1.5 mmol, 1 equiv) in dichloromethane (40 mL), N-methyl (3-biphenyl)methylamine (301 mg, 1.5 mmol, 1 equiv) and triethylamine (153 mg, 1.5 mmol, 1 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was washed with 2×20 mL of water and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product (650 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-002(Agilent)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 2 min); Detector, uv 220 & 254 nm. The title compound was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:8][C:9]=2[CH2:10][CH2:11][CH:12]=1)#[N:2].CCO.[H][H]>[Pd].C(O)(=O)C>[C:1]([CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:15])=[O:16])[CH:6]=[CH:5][C:4]1=2)#[N:2]
Reactant: N#CC1=CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Yield: 90.1 %

Procedure:
N-(5-Cyano-7,8-dihydro-naphthalen-2-yl)-bezenesulfonamide (5.27 g, 17.2 mmol), 70 mL EtOH, and 50 mL acetic acid were placed in a Parr vessel, and 1.0 g of 10% Palladium on carbon (Fluka Chemica Co.) was added. The reaction mixture was shaken for 15 hours under 55 psi hydrogen. The Parr vessel was purged with nitrogen and the reaction mixture was filtered. The filtrate was added to 500 mL, water, and the aqueous mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4) and evaporated to yield 4.85 g (15.5 mmol, 90%) of N-(5-Cyano-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide as an oil. MS: 314 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6](C)[CH2:5][CH2:4]1)#[N:2].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(C#N)(c2ccccc2Oc2ccccc2)CC1
Solvent: ClCCl
Product: N#CC1(c2ccccc2Oc2ccccc2)CCN(C(=O)Oc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2.5 g of 4-cyano-1-methyl-4-(2-phenoxyphenyl)piperidine, free base of Example 1, and 1.7 g of phenyl chloroformate in 50 ml of methylene chloride is permitted to stand for 24 hours before being poured onto 100 g of ice. Thereafter, the mixture is extracted with 50 ml of methylene chloride and the organic solution is successively washed twice with 50 ml portions of water, washed once with 40 ml saturated sodium bicarbonate solution, washed once with 40 ml saturated sodium chloride solution, dried and evaporated to provide an oil. The oil is chromatographed (silica gel 60 column, ether eluant) and then chromatographed (silica gel 60 column, ether-hexane (1:1) mixture eluant) until there is no indication of contamination by the layer chromatography. Thereafter, the product is chromatographed through the same absorbent, ether eluant to provide a glassy solid of 4-cyano-1-phenoxycarbonyl-4-(2-phenoxyphenyl)piperidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[CH2:32][CH3:33]>C(#N)C>[CH2:32]([C:31]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:6][N:7]2[CH:30]=1)[CH3:33]
Reactant: CCC(=O)CBr
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Solvent: CC#N
Product: CCc1cn2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)ccc2n1
Yield: 100.1 %

Procedure:
Compound 5 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.08 g (0.53 mmol) of 1-bromobutan-2-one in 4 mL of acetonitrile. 0.112 g of the expected product is thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:15][O:16][C:17]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26](OC2C=CC([N+]([O-])=O)=CC=2)=[O:27])[CH2:22][CH2:21]1)=[O:18]>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:26]([N:23]3[CH2:24][CH2:25][CH:20]([CH2:19][C:17]([O:16][CH3:15])=[O:18])[CH2:21][CH2:22]3)=[O:27])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COC(=O)CC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCN(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)CC1

Procedure:
1.3 g of 4-(4-cyanophenyl)-piperidine and 2.9 g of 4-(methoxycarbonylmethyl)-1-[(4-nitrophenyl)-oxycarbonyl]-piperidine are stirred at 140° C. for 2.5 hours. The mixture is left to cool and the residue is dissolved in ethyl acetate. The organic phase is washed twice with 0.5N sodium hydroxide solution and once with water. The ethyl acetate phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue remaining is chromatographed over silica gel. Yield: 1.5 g (58% of theory), Melting point: 115°-118° C. Rf value: 0.32 (silica gel; ethyl acetate/cyclohexane=1:1)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[S:22][C:15]=12)=[O:8].Br[CH2:30][CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([O:25][CH2:30][CH2:31][CH2:32][OH:33])=[O:24])[S:22][C:15]=12)=[O:8]
Reactant: OCCCBr
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc3cc(C(=O)O)sc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc3cc(C(=O)OCCCO)sc23)c1
Temperature: 50 °C

Procedure:
To a stirred solution of 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.30 mmol) in anhydrous DMF (10 ml) were added 3-bromo-1-propanol (63 mg, 0.45 mmol) and potassium carbonate (83 mg, 0.60 mmol). The mixture was heated at 50° C. for 5 hours and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to give 3-hydroxypropyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate as white solid. Yield: 25 mg, 18%.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][S:10]([NH:13][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:11])=[O:12])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 76 %

Procedure:
A mixture of 4-nitrostyrylsulfonamide (18.2 g., 0.08 mole), benzoyl chloride (12.6 g., 0.09 mole) and phosphorus oxychloride (13.8 g., 0.09 mole) is heated at steam bath temperature for 1.5 hr. The reaction mixture diluted with 20 ml. of ethyl acetate, cooled and filtered affords 19.0 g. (76% yield) of N-(4-nitrostyrylsulfonyl)benzamide, m.p. 192°-195° C., from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][C@@H:2]([C@:6]1([CH3:51])[C@@H:45]([C:46]([OH:48])=[O:47])[C@@:44]2([CH3:49])[C@@:9]([CH3:50])([C@@H:10]3[C:41](=[CH:42][CH2:43]2)[C@@:14]24[CH2:21][C@@H:20]([N:22]5[C:26]([C:27]6[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=6)=[N:25][CH:24]=[N:23]5)[C@H:19]([O:33][CH2:34][C@@H:35]5[CH2:39][CH2:38][CH2:37][NH:36]5)[C@@:18]([CH3:40])([C@@H:13]2[CH2:12][CH2:11]3)[CH2:17][O:16][CH2:15]4)[CH2:8][CH2:7]1)[CH:3]([CH3:5])[CH3:4].C=O.[CH3:54]C(O)=O.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH3:1][C@@H:2]([C@:6]1([CH3:51])[C@@H:45]([C:46]([OH:48])=[O:47])[C@@:44]2([CH3:49])[C@@:9]([CH3:50])([C@@H:10]3[C:41](=[CH:42][CH2:43]2)[C@@:14]24[CH2:21][C@@H:20]([N:22]5[C:26]([C:27]6[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=6)=[N:25][CH:24]=[N:23]5)[C@H:19]([O:33][CH2:34][C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5[CH3:54])[C@@:18]([CH3:40])([C@@H:13]2[CH2:12][CH2:11]3)[CH2:17][O:16][CH2:15]4)[CH2:8][CH2:7]1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@@H]4CCCN4)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@@H]4CCCN4C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
To a solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-15-[(2S)-2-pyrrolidinylmethoxy]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 304; 98 mg, 0.14 mmol) in MeOH (6.0 mL) were added sequentially 30% (wt/wt) aqueous formaldehyde (126 mg, 4.21 mmol), HOAc (200 μL) and sodium cyanoborohydride in (448 μL of a 1.0 M solution in THF, 0.45 mmol). The reaction mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and water and this mixture was extracted with 10% i-PrOH in CH2Cl2. The combined organic extracts were then dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by RP HPLC (0.1% TFA water/methanol gradient) to provide the title compound (38 mg, 38%) as a white powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.I.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:33][C:34]([CH3:54])([CH3:53])[C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]3[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]3)=[CH:43][CH:44]=2)[CH:39]=[N:38]1)=[O:36].Cl>CN(C=O)C>[CH3:33][C:34]([CH3:54])([CH3:53])[C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]3[CH2:52][CH2:51][CH2:50][N:49]([C:6](=[O:8])[C:5]4[CH:9]=[CH:10][CH:11]=[C:3]([S:2][CH3:1])[CH:4]=4)[CH2:48]3)=[CH:43][CH:44]=2)[CH:39]=[N:38]1)=[O:36]
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3CCCNC3)ccc21
Reactant: CSc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cccc(C(=O)N2CCCC(Nc3ccc4c(cnn4C(=O)C(C)(C)C)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
To a solution of 3-(methylthio)benzoic acid (200 mg, 1.2 mmol) in DMF (4.5 mL) was added in succession N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydroiodide (345 mg, 1.75 mmol) 1-hydroxybenzotriazole hydrate (186 mg, 1.2 mmol) and diisopropylethylamine (0.630 mL, 3.6 mmol). After stirring at room temperature for 10 min, 2,2-dimethyl-1-(5-(piperidin-3-ylamino)-1H-indazol-1-yl)propan-1-one (300 mg, 1.0 mmol) was added in one portion. The solution was stirred under a nitrogen atmosphere overnight. The solution was poured into 1.0 M HCl (20 mL), extracted twice with EtOAc, and the organic phases were washed with 10% NaOH, dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel, eluting with EtOAc/heptane, gave the title compound as a pale yellow foam (240 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[NH:9]2)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=[C:20]=[O:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[N:9]2[C:20]([NH:19][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Cl)cc2)N1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Cl)cc2)N1C(=O)Nc1ccc(C#N)cc1
Reaction time: 5 h

Procedure:
To a solution of (1R,3S)-1-(4-chlorophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline (50 mg, 194 μmol, example 80, step 2) in CH2Cl2 (1.0 mL) at RT was added 4-isocyanatobenzonitrile (42 mg, 291 μmol). The reaction was stirred 5 h and directly purified by reverse phase HPLC to give (1R,3S)-1-(4-chlorophenyl)-N-(4-cyanophenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 402 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:32]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)(=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1

Procedure:
A mixture of 2.0 g of product from Example 4, 8.9 ml acetic anhydride, 0.0863 g 4-dimethylaminopyridine and 30 ml pyridine is heated at reflux temperature for 23 hours, cooled, poured into 150 ml of water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatogaphy (silica ge1:15-20% ethyl acetate/hexane) to give 1.4 g of the desired product as light yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:15]([C:18]1[CH:19]=[C:20]2[C:25](=O)[O:24][C:22](=[O:23])[C:21]2=[CH:27][CH:28]=1)([O-:17])=[O:16]>C(Cl)(Cl)Cl>[N+:15]([C:18]1[CH:19]=[C:20]2[C:21](=[CH:27][CH:28]=1)[C:22](=[O:23])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:25]2=[O:24])([O-:17])=[O:16]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)C1(C)OCCO1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
Ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (800 mg, 3.94 mmol) was dissolved in 15 mL of chloroform, and 4-nitrophthalic anhydride (988 mg, 4.33 mmol) was added to the obtained solution. The resulting mixture was then refluxed at 80° C. for 5 days. After the reaction was completed, the solvent was evaporated by distilling under a reduced pressure. The residue was purified by performing column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain the desired product as a yellow solid (1.24 g, 83%). Rf=0.32 (n-hexane/ethyl acetate=1/1)
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][C:8]([CH3:12])([CH3:11])[C:9]#[CH:10])=[CH:5][CH:4]=1)#[N:2]>CCN(C1C=CC=CC=1)CC>[CH3:12][C:8]1([CH3:11])[O:7][C:6]2[CH:13]=[CH:14][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH:10]=[CH:9]1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Solvent: CCN(CC)c1ccccc1
Product: CC1(C)C=Cc2cc(C#N)ccc2O1
Yield: 70 %

Procedure:
Cyclisation of the 3-(p-cyanophenoxy)-3-methybut-1-yne (9.77 g) was accomplished by heating in diethylaniline at 210°-220° C. under nitrogen. Purification by distillation, and extraction with dilute hydrochloric acid gave 2,2-dimethyl-6-cyano-2H-benzo[b]pyran as a colourless oil (6.84 g), which slowly crystallised on standing, having a nmr spectrum showing signals at δ1.46, 6.25 (d, J=10), 5.67 (d, J=10), 6.74 (d, J=8), 7.18 (d, J=2), 7.34 (q, J=8,2)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:5].[CH2:16]([C@@H:23]1[CH2:29][C@@H:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27](=[O:37])[O:26][C:24]1=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:5][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:29][C@@H:23]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:24]([OH:26])=[O:25]
Reactant: COC(=O)[C@@H](N)CSCc1ccccc1
Reactant: O=C1OC(=O)[C@H](Cc2ccccc2)C[C@H]1Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A solution of 4.5 g of S-benzyl-(L)-cysteine methyl ester and 2.8 g of (S,S)-2,4-dibenzylglutaric anhydride in 25 ml of pyridine and 25 ml of methylene chloride is stirred at room temperature overnight. The mixture is concentrated, the residue is dissolved in ether and the solution is washed with 1N hydrochloric acid, saturated sodium chloride, dried over magnesium sulfate, concentrated, to yield N-[(S,S)-2,4-dibenzyl-4-carboxy-butyryl]-S-benzyl-(L)-cysteine methyl ester (oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[C:9](=[O:11])[CH3:10].C(O)(=O)C.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][CH2:10][C:9](=[O:11])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:12]
Reactant: CC(=O)C(=O)c1ccccc1Cl
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)C(=O)c1ccccc1Cl
Temperature: 60 °C

Procedure:
A mixture of 1-(2-chlorophenyl)propane-1,2-dione (1.2592 g, 6.9 mmol), glacial acetic acid (0.20 mL, 3.4 mmol, 0.5 eq), and bromine (0.35 mL, 6.8 mmol, 1 eq) in CHCl3 (17 mL) was heated at 60° C. for 12 h. The mixture was concentrated under reduced pressure to provide 3-bromo-1-(2-chlorophenyl)propane-1,2-dione as yellow liquid. The yellow liquid was carried on crude without purification for the next step. 1H NMR (CDCl3) δ ppm 7.71 (1 H, dd, J=7.8, 1.6 Hz), 7.53-7.59 (1 H, m), 7.40-7.49 (2 H, m), 4.52 (2H, s). Mass Spectrum (ESI) m/e=261.0 [M+1 (79Br)] and 262.9 [M+1 (81Br)].
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[S:37])=[CH:31][CH:30]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=4)=[S:37])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc(OC(F)(F)F)cc5)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 97 μl (2 molar equivalents) of 4-(trifluoromethoxy)phenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 151 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=91%) which was characterized as follows: