Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>ClCCl>[C:28]([O:20][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: C=C(C)C(=O)Cl
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC(COCc1ccccc1)COCc1ccccc1
Temperature: 0 °C
Yield: 81 %

Procedure:
1,3-bis(benzyloxy)propan-2-ol (0.45 mL, 0.50 g, 1.8 mmol) and triethylamine (0.52 mL, 0.37 g, 3.7 mmol) were dissolved in dichloromethane and chilled to 0° C. Methacryloyl chloride (0.27 mL, 0.29 g, 2.8 mmol) was then added drop wise to the mixture. After mixing for 16 h, the mixture was then washed 100 mM pH 8.0 phosphate buffer (50 mL×3) and dried over anhydrous sodium sulfate. The solvent was subsequently removed using rotary evaporation under reduced pressure, and the product was isolated using silica gel chromatography at 81.0% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([OH:20])[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].[Cl-]>ClCCl.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:20][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
1,3-di(tert-butyloxycarbonylamino)propan-2-ol (example 10a) (2.89 g, 10 mmol) and triethylamine (2.22 ml, 16 mmol) were dissolved in anhydrous dichloromethane (100 ml). The reaction mixture was cooled in an ice bath followed by dropwise addition of tosyl chloride (2.272 g, 12 mmol) dissolved in dichloromethane (30 ml). The reaction mixture was then stirred at room temperature for 72 hours. One equivalent of chloride and 1.6 of triethylamine were added after 48 hours. Water was added to stop the reaction and the medium was allowed to settle. The organic phase was washed several times with water. The aqueous phases were combined and extracted again with dichloromethane. The organic phase was dried on magnesium sulfate, filtered and the solvent was evaporated. The residue obtained (6.44 g) was purified by chromatography on silica gel (eluent:dichloromethane followed by dichloromethane/methanol 99:1) to yield the desired compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9]1)(C)(C)C.CO.[ClH:20]>>[ClH:20].[CH3:16][S:13]([N:10]1[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]1)(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)C1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)N1CCC(N)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a 10 mL round-bottomed flask, (1-methanesulfonyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (0.18 g, 0.68 mmol) was dissolved in 1.0 M hydrogen chloride solution in MeOH (3.2 mL, 3.2 mmol). The reaction mixture was stirred at 50° C. for 3 h then cooled to room temperature and concentrated to afford 137 mg of 1-methanesulfonyl-pyrrolidin-3-ylamine hydrochloride as a light yellow solid which was used without further purification.
Reaction SMILES: Br[C:2](=[CH:5]OC(C)C)[CH:3]=[O:4].[NH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[N:10]1[C:2]([CH:3]=[O:4])=[CH:5][N:12]2[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=12
Reactant: CC(C)OC=C(Br)C=O
Reactant: NC1=NCc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cn2c(n1)-c1ccccc1C2
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 21.9 %

Procedure:
The solution of 2-bromo-3-isopropoxy-propenal (4.97 g) in dry acetonitrile (3 mL) was added to the mixture of 3-amino-1H-isoindole (3.4 g) in dry acetonitrile (100 mL). The reaction mixture was stirred for 3.25 h at room temperature. Then triethylamine (3.6 mL) was added to the mixture and heated to reflux for 2 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 20% potassium hydrogen carbonate. After filtration through a pad of Celite, the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then eluted with ethyl acetate—hexane (3/1˜4/1). The crude compound was crystallized from ethyl acetate and n-hexane to give the title compound (1.04 g, 22%). 1H NMR (400 MHz, CDCl3) δ 5.01 (s, 2H), 7.28–7.52 (m, 3H), 7.90 (s, 1H), 7.91–7.93 (m, 1H), 9.92 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O.Cl[CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:21][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1c2ccccc2C(=O)N1CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(SCN2C(=O)c3ccccc3C2=O)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
A vessel was charged with 12.19 grams of 3,5-di-tert-butyl-4-hydroxybenzene thiol and 3.30 grams of potassium hydroxide dissolved in 50 ml of acetone and 2 ml of water at 0° C. which was mixed with 10.0 grams of N-(chloromethyl)phthalimide. After stirring for one hour, the precipitated product was removed by filtration and then recrystallized from ethyl acetate-hexane to give 14.9 grams of produt, m.p. 151°-53° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:38][CH2:37][N:12]2[C:13]3[C:18]([C:19]([C:20]4[C:21](=[O:36])O[C:23](=[O:35])[C:24]=4[C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[CH:26]=4)=[C:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40](C)C=O>N>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:38][CH2:37][N:12]2[C:13]3[C:18]([C:19]([C:20]4[C:21](=[O:36])[NH:40][C:23](=[O:35])[C:24]=4[C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[CH:26]=4)=[C:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(NC(=O)OC(C)(C)C)C4)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(NC(=O)OC(C)(C)C)C4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 80 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 2 ml of dimethylformamide and 2 ml of 33% aqueous ammonia was heated to 100° C. for 1 hour. The solution was cooled and gave 60 mg of 3-[8-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 153°-155° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH:14]=[CH:13][C:12]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](N1CCOCC1)=[O:19].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][C:14]([CH:18]=[O:19])=[CH:13][C:12]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN1CCOCC1
Reactant: C1=Cc2cc(Oc3ccccc3)ccc2OC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=CC1=Cc2cc(Oc3ccccc3)ccc2OC1
Temperature: 60 °C

Procedure:
6-Phenoxy-2H-1-benzopyran (3.36 g, 15 mmol) and N-formylmorpholine (10.4 g, 90 mmol) are dissolved in 10.5 ml of methylene chloride and treated with phosphorus oxychloride (13.8 g, 90 mmol) at 0° C. over 15 minutes. The mixture is then heated at 60° C. for 27 hours, cooled and poured slowly into an ice-water mixture. The mixture is then neutralized with aqueous ammonium hydroxide, and extracted twice with methylene chloride. The combined organic extracts are washed with water, dried (MgSO4), and evaporated to give crude 6-phenoxy-2H-1-benzopyran-3-carboxaldehyde, which is used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][C:12](=[O:28])[NH:13][C:14]1[CH:15]=[CH:16][C:17]([N+:25]([O-:27])=[O:26])=[C:18]([CH:24]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)C.CC[O-].[Na+]>C(O)C>[N+:25]([C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:4](=[O:3])[C:6]3[CH2:10][CH2:9][CH2:8][C:7]=3[NH:11][C:12]2=[O:28])=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])([O-:27])=[O:26]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2ccc([N+](=O)[O-])c(C(=O)OCC)c2)CCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1[N+](=O)[O-]

Procedure:
using ethyl 5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-2-nitrobenzoate with sodium ethylate in ethanol there is obtained ethyl 2-nitro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 205°-208° C.,
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[C:18]1[S:22][N:21]=[CH:20][C:19]=1[N+:23]([O-:25])=[O:24]>O1CCOCC1.C(OCC)(=O)C>[N+:23]([C:19]1[CH:20]=[N:21][S:22][C:18]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cnsc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2sncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1B2) (464 mg, 2.3 mmol) in dioxane (10 mL) at room temperature was added NaH (114 mg, 2.8 mmol). The mixture was stirred for 20 min and 5-bromo-4-nitroisothiazole (P) (400 mg, 1.9 mmol) was added. The mixture was stirred at 65° C. for 5 hours, cooled to room temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo at room temperature (25° C.). The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to afford the product tert-butyl 4-(4-nitroisothiazol-5-yloxy)piperidine-1-carboxylate (1C3) (280 mg, 0.85 mmol).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](O)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][O:21][CH3:22]>CN(C=O)C>[CH3:20][O:21][CH2:22][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCCl
Reactant: COC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1cc(F)ccc1C(=O)OC
Reaction time: 48 h
Yield: 57.5 %

Procedure:
Into a DMF (200 mL) solution of methyl 4-fluoro-2-hydroxybenzoate (17.0 g, 100 mL), cooled in an ice bath, was added K2CO3 (27.6 g, 200 mmol) and chloromethymethyl ether (9.11 mL, 120 mmol) dropwise. The reaction mixture was allowed to come to room temperature slowly and was stirred 48 h. To the reaction mixture at room temperature was added additional K2CO3 (6.9 g, 50 mmol) and chloromethylmethyl ether (4.5 mL, 60 mmol), and stirring was continued for 24 h. Most of the solvent was evporated in a bath at 60° C., and the residue was partitioned between ether (250 mL) and water (250 mL). The organic layer was washed with 1 N HCl (200 mL), dried (MgSO4), and evaporated. The crude product was chromatographed over silica (eluting with 0 to 20% EtOAc in hexane gradient), giving 11.38 g (57% yield) of the named product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:27]=[CH:26][C:25]([N:22]5[CH2:23][CH2:24][O:19][CH2:20][CH2:21]5)=[CH:33][CH:32]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: N#Cc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: N#Cc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc32)cc1

Procedure:
Compound 405 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-cyanophenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C25H21N5O2: 424.17; found: 424.09.
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])[C:9]([Cl:24])=[CH:8][C:7]=1[Cl:25])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].CI>>[CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:26])[C:13]2=[O:23])[C:9]([Cl:24])=[CH:8][C:7]=1[Cl:25])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCON=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl
Agent: [K+]
Solvent: CI
Product: CCON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl

Procedure:
69.3 g (0.175 mol) of 2,4-dichloro-5-(6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)benzaldehyde (O-ethyl)oxime, 26.6 g (0.19 mol) of potassium carbonate and 27.3 g (0.19 mol) of methyl iodide were reacted in the manner described for precursor 3.3. Yield: 69.0 g; m.p.: 140-143° C.
Reaction SMILES: C[CH:2]([CH3:9])[CH2:3][CH2:4][C:5](NN)=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:21][C@@H:22]([C:24]([N:26]([CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)[NH:27][C:28](=[O:48])[C@@H:29]([C@@H:34]([C:44](=[O:47])[NH:45][OH:46])[CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:25])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.N[C@@H](C(N(C1CCCC1)NC(=O)[C@](C)([C@H](C(O)=O)C/C=C/C1C=CC=CC=1)CCC)=O)C>>[NH2:21][C@@H:22]([C:24]([N:26]([CH:49]1[CH2:50][CH2:51][CH2:52][CH2:53]1)[NH:27][C:28](=[O:48])[C@H:29]([C@H:34]([C:44](=[O:47])[NH:45][O:46][CH:5]1[CH2:4][CH2:3][CH2:2][CH2:9][O:6]1)[CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:25])[CH3:23]
Reactant: CC(C)CCC(=O)NN
Reactant: CC(C)C[C@@H](C(=O)NN(C(=O)[C@@H](C)N)C1CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Agent: CCC[C@](C)(C(=O)NN(C(=O)[C@@H](C)N)C1CCCC1)[C@@H](C/C=C/c1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C[C@H](C(=O)NN(C(=O)[C@@H](C)N)C1CCCC1)[C@@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1

Procedure:
In a manner analogous to that described in the first paragraph of Example 5, starting from 0.058 g of a mixture of (E)-2′-(D-alanyl)-2′-cyclopentyl-2(R)-[1(S)-[tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methylvalero-hydrazide and (E)-2′-(D-alanyl)-2′-cyclopentyl-2(S)-[1(R)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methylvalerohydrazide there was obtained 0.048 mg of a mixture of (E)-2′-(D-alanyl)-2′-cyclopentyl-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide p-toluene-sulphonate and (E)-2′-(D-alanyl)-2′-cyclopentyl-2(S)-[1(R)-(hydroxycarbonyl)-4-phenyl-3-butenyl]-methylvalerohydrazide p-toluenesulphonate in the form of a pale pink solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:22])=[C:16]3[C:21]=2[CH2:20][NH:19][CH2:18][CH2:17]3)=[C:8]([O:23][CH2:24][CH3:25])[CH:7]=1)[CH3:2].C(N(C(C)C)C(C)C)C.[F:36][C:37]1[CH:54]=[CH:53][C:40]([CH2:41][O:42][C:43](=O)[O:44]N2C(=O)CCC2=O)=[CH:39][CH:38]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][O:42][C:43]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:26])=[CH:7][C:8]=4[O:23][CH2:24][CH3:25])[CH:13]=[CH:14][C:15]=3[F:22])[CH2:20]2)=[O:44])=[CH:53][CH:54]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(F)c3c2CNCC3)c(OCC)c1
Reactant: O=C(OCc1ccc(F)cc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(-c2ccc(F)c3c2CN(C(=O)OCc2ccc(F)cc2)CC3)c(OCC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3-ethoxy-4-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (1.49 g, 4.2 mmol, 1.00 eq.) and N-ethyldiisopropylamine (3.56 mL, 20.8 mmol, 5.00 eq.) in DCM (50 mL), carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-fluoro-benzyl ester (1.17 g, 4.4 mmol, 1.05 eq.) was added. The mixture was stirred at r.t. for 18 hours. The solution was diluted with sat. aq. NaHCO3 soln. (100 mL). The layers were separated. The aq. phase was extracted with DCM (2×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 100 fractions of 45 mL, Heptane 100% to Heptane+40% AcOEt) to yield the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH3:17][C:18]1[N:22]=[C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=O)[O:31]C3C=CC([N+]([O-])=O)=CC=3)[CH:26]=[CH:27][CH:28]=2)[O:20][N:19]=1.CN(C)C=O>C(#N)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:30]([NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]4[O:20][N:19]=[C:18]([CH3:17])[N:22]=4)[CH:24]=3)=[O:31])[C:7]=2[CH:8]=1)#[N:13]
Reactant: Cc1noc(-c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)n1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1noc(-c2cccc(NC(=O)N[C@@H]3c4cc(C#N)ccc4OC(C)(C)[C@H]3O)c2)n1

Procedure:
A mixture of (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.65 g, 3.0 mmol, from Example 1, part B) and [3-[3-methyl(1,2,4-oxadiazol-5-yl)]phenyl]carbamic acid, 4-nitrophenyl ester (1.12 g, 3.3 mmol, title A compound) in acetonitrile (20 mL) and dimethyl-formamide (40 mL) was stirred at 80° C. for two hours. The reaction mixture was concentrated in vacuo and the residue, diluted with ethyl acetate, was washed with 10% citric acid and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (Sorbisol C 60 flash silica gel, 400 mL) and eluted with Hexane/EtOAc (1:1). The solvent was removed in vacuo, to give a solid that was triturated in hexane and dried in vacuo to yield 1.10 g of the title compound, m.p. 157°-161 ° C. TLC, silica gel, EtOAc/Hexane(2:1), Rf =0.41. 1H-NMR (DMSO-d6) δ9.1 (s, 1H), 8.4 (s, 1H), 7.5 (m, 5H), 6.9 (d, J=9.4 Hz, 1H), 6.8 (d, J=8.2 Hz, 1H), 5.7 (d, J=5.9 Hz, 1H), 4.7 (t, J=8.8 Hz, 1H), 3.7 (dd, J =5.9 & 4.1Hz, 1H), 2.4 (s, 3H), 1.4 (s, 3H), 1.2 (s, 3H); 13C-NMR (DMSO-d6) δ174.9, 167.6, 156.3, 155.6, 141.4, 132.6, 132.5, 130.0, 125.9, 123.8, 122.1, 120.4, 119.1, 117.9. 116.6, 102.76, 80.4, 71.2, 49.5, 26.5, 18.9, 11.3; IR (KBr) 2980, 2228, 1670, 1574, 1553, 1489 cm-1. M.S. (M+H)+ at 420, M.W. 419; [α]D =-43.6° (c=0.77 DMSO).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]3[C:11]4[C:16]([CH2:17][C:7]3([CH3:18])[C:6]=2[C:5]([CH3:19])=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22])=[CH:15][CH:14]=[CH:13][CH:12]=4.[CH3:23][Li].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH3:23][C@@:8]12[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][C@:7]1([CH3:18])[C:6]1[C:5]([CH3:19])=[C:4]([O:20][CH3:21])[C:3]([CH3:22])=[C:2]([CH3:1])[C:10]=1[NH:9]2
Reactant: COc1c(C)c(C)c2c(c1C)C1(C)Cc3ccccc3C1=N2
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(C)c(C)c2c(c1C)[C@@]1(C)Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (-80° C.) solution of 1.1 g (0.0038 mol) of 9b,10-dihydro-6,7,9,9b-tetramethyl-8-methoxyindeno[1,2-b]indole in 20 ml of dry THF was added 4 ml of 1.6M methyl lithium in ether under argon. The mixture was stirred at -78° C. for 1 hour and then at -20° C. for 1 hour. After attaining 0° C. aqueous NH4Cl and ether was added. The phases were separated, and the organic phase was washed once with water, dried (MgSO4) and evaporated. The resulting crude product was purified by chromatography on silica using ethyl acetate/isooctane (2/10) as eluant. This gave 0.3 g (25%) of the expected product. 1H NMR (CDCl3): 1.41 (3H,s), 1.43 (3H,s), 1.96 (3H,s), 2.07 (3H,s), 2.35 (3H,s), 3.0 (1H,d), 3.55 (3H,s), 3.65 (1H,d), 7.1 (3H,m), 7.25 (1H,m).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=3[Cl:36])[CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:17]=2)=[CH:12][CH:11]=1>CN(C=O)C>[Cl:36][C:35]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=1[N:18]1[C:19](=[O:21])[NH:20][C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)=[N:17]1
Reactant: C1CCNC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(CBr)cc3)[nH]c2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(CN4CCCC4)cc3)[nH]c2=O)c1
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a cold solution of pyrolidine (0.060 g, 0.830 mmol) in DMF was added NaH (0.034 g, 0.830 mmol) at 0° C. and stirred the reaction mass for 1 h. Then solution of N-(3-(3-(4-(bromomethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide (Intermediate-103, 0.200 g, 0.419) in DMF was added at 0° C. and continued stirring at 5-10° C. for 2-3 h. The reaction mass was quenched in ice and pH adjusted to 6-7 and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified by column chromatography on basic alumina, eluting with 5% MeOH:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 9H), 1.79 (br s, 4H), 2.53 (br s, 4H), 3.66 (s, 2H), 4.48 (d, J=5.7 Hz, 2H), 6.08 (m, 1H), 7.26-7.54 (m, 5H), 7.79 (d, J=7.8 Hz, 2H); MS (m/z): 468.51 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:16][O: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][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][O:11][S:12]([CH3:15])(=[O:14])=[O:13])(=[O:7])=[O:6].[CH3:36][N:37]([CH3:39])[CH3:38]>C1(C)C=CC=CC=1>[S:12]([O-:14])(=[O:13])(=[O:11])[CH3:15].[CH3:1][O:2][CH:3]([CH2:16][O: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][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][N+:37]([CH3:39])([CH3:38])[CH3:36])(=[O:7])=[O:6]
Reactant: CN(C)C
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCCOS(C)(=O)=O)OC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCC[N+](C)(C)C)OC
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 10 ml of toluene containing 2.0 g of trimethylamine are dissolved 1.45 g of 3-mesyloxypropyl 2-methoxy-3-octadecyloxypropyl sulfone and the solution is stirred at room temperature for 3 days. The reaction solution is then concentrated to dryness and the residue is purified by silica gel column chromatography to give 1.04 g of the captioned compound.