Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:15](=[O:28])[NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([F:27])[CH:18]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:15](=[O:28])[NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:27])[CH:18]=3)=[CH:11][C:10]([C:29]([F:32])([F:30])[F:31])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C(=O)O)c(F)c1
Temperature: 45 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
To a stirred solution of methyl 4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)-2-fluorobenzoate (120 mg, 0.25 mmol, 1.0 eq) in THF (10 mL) was added LiOH (21.4 mg, 0.51 mmol, 2.0 eq) dissolved in H2O (2 mL) at RT and stirred for 6 h at 45° C. The reaction mixture was concentrated, diluted with water (20 mL), brine (20 mL), the pH was adjusted to 4 with HCl (1N), and extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) brine (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified by CC using EtOAc/PE (7:3) to obtain 4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)-2-fluorobenzoic acid (100 mg; 85%) as a yellow solid (TLC: EtOAc/PE (7:3); Rf: 0.2).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([O:18]CC)=[O:17])=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:12]=2[C:29]#[N:30])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([OH:18])=[O:17])=[C:13]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[C:12]=2[C:29]#[N:30])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)c(C#N)c1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(-c2sc(C(=O)O)c(Cc3ccc(Cl)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
To a solution of ethyl 5-[2-(acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxylate (0.080 g, 0.18 mmol) in tetrahydrofuran (1.28 mL) and water (0.85 mL) was added lithium hydroxide (1.0M solution in water, 0.236 mL, 0.236 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was acidified to pH 6 using aqueous 1N HCl (0.300 mL). The mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, and then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.058 g, 78%). LCMS: (FA) ES+, 412. 1H NMR (400 MHz, d6-DMSO) δ: 10.72 (s, 1H), 8.46-8.41 (m, 2H), 7.42-7.39 (m, 1H), 7.36-7.32 (m, 4H) 4.53 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:13])[CH2:6][CH2:5]1)=O.C(Cl)Cl>C(N(CC)CC)C>[O:13]=[C:7]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH:4]([N+:3]#[C-:1])[CH2:5][CH2:6]1
Reactant: O=CNC1CCC(=O)c2sccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]C1CCC(=O)c2sccc21
Reaction time: 0.75 h

Procedure:
A sample of N-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine (5.0 g) is dissolved methylene chloride (250 ml) under a nitrogen atmosphere and triethylamine (5.95 g) is added. Phosgene is then bubbled into the solution at 15° C and an exothermic reaction occurs. The temperature of the reaction mixture rises from 20° to 35° C and after 45 minutes, drops to 30° C. The flow of phosgene is terminated and nitrogen is then bubbled into the solution for about 20 minutes followed by ammonia gas. A brown precipitate is formed during the ammonia addition. The flow of ammonia gas is stopped when the reaction mixture becomes alkaline. The mixture is then flushed with nitrogen and is filtered to remove the precipitate. The filtrate is evaporated to dryness in vacuo, the residue is dissolved in ethanol (50 ml), the solution is filtered and evaporated to dryness in vacuo. The residue is scratched to afford a light brown solid, which is washed with water, dried and recrystallized from hexane-acetone to afford 2.1 g of the title isocyanide, m.p. 74° to 77° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[C:10]([CH2:12][C:13]3[C:14](=[O:25])[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17](=[O:20])[C:18]=3[CH3:19])[CH:9]=[CH:8][C:7]=2[O:26]C(=O)C)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>CO.O>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[C:10]([CH2:12][C:13]3[C:14](=[O:25])[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17](=[O:20])[C:18]=3[CH3:19])[CH:9]=[CH:8][C:7]=2[OH:26])[CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)NC3CC3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)NC3CC3)c2)=C(C)C1=O
Yield: 55.6 %

Procedure:
N-Cyclopropyl-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.050 g, 0.121 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.023 g, 0.0673 mmol, 56%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([NH:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH3:15])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](OC=O)(=[O:26])C>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([N:16]([CH:24]=[O:26])[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH3:15])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC=O
Reactant: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Product: C[C@@H]([C@@H](CCCc1ccccc1)C(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of (2R,3S)-2-(3-phenyl-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid (21.4 g, 66.7 mmol) in pyridine (100 mL) at 0° C. is added formic acetic anhydride (30 mL). The resulting solution is allowed to warm to 25° C., stirred for 6 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in EtOAc (300 mL) and washed sequentially with 1 N hydrochloric acid (200 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure providing (2R,3S)-2-(3-phenyl-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)butanoic acid as an oil (18.9 g, 81% yield). ESI-MS m/z 372 (M+Na)+348 (M−1)31 .
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Cl)(Cl)([Cl:23])=O.N>C(Cl)(Cl)Cl>[Cl:23][CH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2oc(-c3ccccc3)c(C)[n+]2[O-])cc1
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(CCl)c(-c3ccccc3)o2)cc1
Temperature: 0 °C

Procedure:
6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide are dissolved in 50 ml of chloroform, 2.4 ml of phosphorus oxychloride are added and the mixture is, under reflux, heated at the boil for 30 minutes. The reaction mixture is cooled to 0° C., the pH is made slightly alkaline using ammonia and the mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4, and the solvent then removed under reduced pressure. This gives 5.4 g of 4-chloromethyl-5-phenyl-2-p-tolyloxazole as a yellow solid. C17H14CINO (283.76), MS(ESI)=284 (M+H+), Rf(n-heptane:ethyl acetate)=7:1)=0.41.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=1[CH3:14])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[CH2:24]([CH2:26][NH2:27])[OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:25][CH2:24][CH2:26][NH:27][C:11]([C:9]1[NH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[CH:8]=1)=[O:13]
Reactant: CCOC(=O)c1[nH]c(C(=O)O)cc1C
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1[nH]c(C(=O)NCCO)cc1C
Yield: 20.8 %

Procedure:
To a solution of 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.160 g, 0.812 mmol) in DMF (4 ml) was added DIPEA (0.140 mL, 0.790 mmol). The reaction mixture was stirred and the solution was divided into four equal portions, one of which was added to a glass vial with a stir bar. To the vial was added ethanolamine (0.012 mL, 0.2 mmol) and HATU (0.075 g, 0.197 mmol) and the reaction mixture stirred overnight. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were collected and lypholized to afford ethyl 5-{[(2-hydroxyethyl)amino]carbonyl}-3-methyl-1H-pyrrole-2-carboxylate (0.010 g, 48%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.63 (br. s., 1H) 8.25-8.42 (m, 1H) 6.61 (s, 1H) 4.25 (q, 2H) 3.48 (t, 2H) 3.28 (q, 2H) 2.25 (s, 3H) 1.30 (t, 3H). MS: m/z 241.4 (M+1).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[O:13])C)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[O-].[Na+].S(=O)(O)[O-:18].[Na+].Cl>>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:18])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc2c(c1)CCCO2
Reactant: O=S([O-])O
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A mixture of 1-(3,4-dihydro-2H-chromen-6-yl)ethanone (3.80 g, 22.0 mmol) and sodium hypochlorite [150 mL of a 6.0% aqueous solution, (Clorox brand of bleach)] in a 55° C. oil bath is stirred for 2 h. The mixture (now homogeneous) is cooled to rt and solid sodium bisulfite is added until a clear color persisted. HCl (ca 15 mL of a 6.0 M aqueous solution) is added, followed by extraction with EtOAc. The organic layer is washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 3.10 g (82%) of chromane-6-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.55, 7.67, 7.6, 6.79, 4.20, 2.77, 1.96-1.90.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[SH:12][CH:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[S:12][CH:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C(S)C(C)C
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Sc1c(Cl)cccc1[N+](=O)[O-])C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2,3-dichloronitrobenzene (3.84 g), methyl 2-mercapto-3-methybutyrate (2.96 g), potassium carbonate (2.37 g), and N,N-dimethylformamide (40 ml) was stirred at room temperature for 5 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), from which the solvent was evaporated off, to give quantitatively methyl 2-(2-chloro-6-nitrophenylthio)-3-methylbutyrate as an oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:33][C:34]1[NH:35][C:36]2[NH:37][CH2:38][CH:39]([CH:45]([OH:49])[CH:46]([OH:48])[CH3:47])[NH:40][C:41]=2[C:42](=[O:44])[N:43]=1>C(Cl)Cl.N1C=CC=CC=1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:13]([N:40]1[CH:39]([CH:45]([OH:49])[CH:46]([OH:48])[CH3:47])[CH2:38][NH:37][C:36]2[NH:35][C:34]([NH2:33])=[N:43][C:42](=[O:44])[C:41]1=2)=[O:15])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1c2c([nH]c(N)nc2=O)NCC1C(O)C(C)O
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred solution of N-Boc-L-Valine (4.56 g, 21 mmol) in DCM (15 ml) at 0° C. was added a solution of DCC (2.17 g, 10.5 mmol) in DCM (10 ml). The resulting solution was stirred for 1 h after which a white precipitate formed. The white solid was filtered and filtrate added to a stirred solution of 2-amino-6-(1,2-dihydroxy-propyl)-5,6,7,8-tetrahydro-1H-pteridin-4-one dihydrochloride (3.0 g, 9.55 mmol) dissolved in pyridine (80 mL). The mixture was stirred at room temperature under an atmosphere of nitrogen for 1.5 h. The reaction mixture was quenched by addition of methanol (20 ml). The solvent was evaporated in vacuo and the residue purified by preparative RP-HPLC to give the sub-title product as a tan solid (3.2 g, 76%). MS: ESI (positive): 441 (M+H).
Reaction SMILES: [NH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[NH2:2].C(O)(=O)C.CN(C)/[CH:20]=[CH:21]/[C:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])=O>C(O)C>[OH:34][C:25]1[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:29][C:24]=1[C:22]1[N:1]([CH:3]2[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]2)[N:2]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Reactant: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)ccc1O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of crude tert-butyl 3-hydrazinoazetidine-1-carboxylate, (Preparation 858, 5.7 g, 0.030 mol) in ethanol (66 mL) at 0° C. was added acetic acid (6.6 mL) dropwise. Then (2E)-3-(dimethylamino)-1-[2-hydroxy-5-(trifluoromethyl)phenyl]prop-2-en-1-one, (Preparation 859, 6.4 g, 24.68 m mol) was added portionwise and allowed to stir at room temperature for 20 hours. The reaction mixture was concentrated in vacuo and neutralised with aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate (150 mL). The combined organic layer was washed with water (100 mL), saturated aqueous sodium chloride solution (50 mL) and dried over anhydrous sodium sulphate. After concentration of organic layer in vacuo, the crude product was washed with 20% v/v ethyl acetate in hexane to get the title compound as a white solid (7.4 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16].[CH3:48][C:49]1([CH3:56])[CH2:54][C:53](=[O:55])[O:52][C:50]1=[O:51]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:37])([CH3:38])[C@@H:26]([O:39][C:53](=[O:55])[CH2:54][C:49]([CH3:56])([CH3:48])[C:50]([OH:52])=[O:51])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 46.8 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1S,3R)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 8, 0.250 g, 0.385 mmol) 2,2-Dimethylsuccinic anhydride (0.26 ml, 2.31 mmol) and DMAP (0.094 g, 0.77 mmol) in pyridine (10 ml) were added at room temperature then the reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with EtOAc, the organic layer was washed with water, 1N HCl, water, brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200, elution 35% EtOAc in hexane) to afford the title compound as a off white solid. Wt: 0.140 g: Yield: 46.8%; 1H NMR. (300 MHz, CDCl3): δ 5.95 (d, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.52-4.43 (m, 1H), 4.19-4.09 (m, 1H), 3.82-3.40 (m, 8H), 3.17-3.04 (m, 1H), 2.92-1.82 (m, 1H), 2.71-2.29 (m, 6H), 2.00-1.91 (m, 3H), 1.80-1.09 (m, 28H), 1.00-0.77 (m, 21H); Mass: [M+1]+ 779 (100%), [M+Na]+ 801 (15%); IR (KBr, cm−1): 3419, 2952, 2867, 1757, 1733, 1729, 1638, 1631, 1460, 1452, 1376, 1243, 1180, 1117, 1067, 978, 879, 775; M.R: 248.7° C.-252.6° C.; HPLC: 87.7%
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[NH:12][C:13]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17].N.CO>O1CCCC1>[NH2:5][C:3]([NH:10][C:11]1[NH:12][C:13]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:4]
Reactant: NC(=O)c1cc(-c2ccc3ccccc3c2)[nH]c1N
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)cc1C(N)=O
Reaction time: 1.5 h
Yield: 58 %

Procedure:
Trichloroacetyl isocyanate (470 μL, 4.0 mmol) was added dropwise to a solution of 2-amino-5-(2-naphthyl)pyrrole-3-carboxamide (Reference compound No. 1-1, 1.0 g, 4.0 mmol) in anhydrous tetrahydrofuran (20 mL) at −30° C. over 5 minutes, and the whole was stirred for 1.5 hours. Furthermore, 2.0 M ammonia solution in methanol (20 mL, 40 mmol) was added thereto, and the whole was stirred at room temperature for 3 days. The precipitated solid was filtered off and washed with a mixed solvent of diethylether-ethanol (3:1) (20 mL). The obtained solid was dried at 40° C. under reduced pressure to give the target compound (0.67 g) as a pale gray solid (Yield 58%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[C@@:18]1([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([OH:24])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[C@@]1(O)CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O[C@@H]1CCCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and (R)-3-methyl-piperidin-3-ol (1.11 g, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated. The material was purified by flash chromatography (silica, Biotage 50 g column, 50-100% ethyl acetate in cyclohexane) to afford the title compound (0.75 g, 69%). 1H NMR (CDCl3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.14 (m, 2,H), 3.85-3.76 (m, 1H), 3.45 (s, 2H), 2.45 (s, 3H), 2.29-2.16 (m, 1H), 1.86-1.70 (m, 1H) 1.67-1.45 (m, 3H) plus 1 exchangeable not observed. LCMS (Method G): RT=2.00 min, M+H+=270.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[C:3]=1[C:4]1[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=1[C:6](=[O:17])[O:7]2.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].CCOCC>CN(C=O)C>[Si:31]([O:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[C:3]=1[C:4]1[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=1[C:6](=[O:17])[O:7]2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)CCCC3
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCc1cc(O[Si](C)(C)C(C)(C)C)c2c3c(c(=O)oc2c1)CCCC3
Reaction time: 20 h
Yield: 99.2 %

Procedure:
32 g (112 mmol) of 1-hydroxy-3-pentyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one were initially introduced in 200 ml of DMF, 10 g of imidazole (145 mmol) were added, a solution of 21 g (135 mmol) of tert-butyldimethyl-silyl chloride in 100 ml of DMF was added dropwise at 0° C., and the mixture was stirred at room temp. for 20 h. MTB ether was subsequently added to the batch, which was then washed with water and dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography with heptane/ethyl acetate (6:1), giving 44.5 g (94%) of 1-tert-butyl-dimethylsilyloxy-3-pentyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]([O:10]C)=O)[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1.C1(C)C(C)=CC=CC=1>CO>[F:26][C:22]1[N:21]=[C:20]([NH:19][C:8]([CH:7]2[C:6](=[O:12])[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[S:3](=[O:18])(=[O:17])[N:2]2[CH3:1])=[O:10])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C1C(=O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1cccc(F)n1
Solvent: CO
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cccc(F)n2)C(=O)c2ccccc2S1(=O)=O
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A mixture consisting of 7.68 g (0.0285 mole) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide, 4.8 g (0.0428 mole) of 2-amino-6-fluoropyridine, and 29 ml of xylene was refluxed for 17 hours, during which the methanol formed by this reaction was continuously distilled off. After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration. The filtrate was concentrated and then cooled to obtain an additional precipitate, which was combined with the previously obtained precipitate and washed with hot chloroform. Thus, 7.2 g of crystals having a melting point of 246°-248° C. (decomp.) were obtained in a 72.3% yield.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([NH:19][C:20]1[CH:30]=[C:29]2[C:23]([C:24]([Cl:35])=[C:25]([O:31][CH2:32][CH2:33][CH3:34])[O:26][C:27]2=[O:28])=[CH:22][CH:21]=1)=[O:18])CC1C=CC=CC=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:36](N[C@H](C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCCC)OC2=O)=CC=1)=O)C)=O)C)(=O)[C:37]1C=CC=C[CH:38]=1.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCC)OC2=O)=CC=1)=O)C(C)C)(OC(C)(C)C)=O.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCC)OC2=O)=CC=1)=O)C)(OC(C)(C)C)=O.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCCC3C=CC=CC=3)OC2=O)=CC=1)=O)C)(OC(C)(C)C)=O>>[C:1]([NH:8][C@H:9]([C:17]([NH:19][C:20]1[CH:30]=[C:29]2[C:23]([C:24]([Cl:35])=[C:25]([O:31][CH2:32][CH2:33][CH3:34])[O:26][C:27]2=[O:28])=[CH:22][CH:21]=1)=[O:18])[CH:37]([CH3:38])[CH3:36])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCCOc1oc(=O)c2cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)ccc2c1Cl
Reactant: CCCOc1oc(=O)c2cc(NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)c3ccccc3)ccc2c1Cl
Agent: CCOc1oc(=O)c2cc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc2c1Cl
Agent: CCOc1oc(=O)c2cc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)ccc2c1Cl
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2c(Cl)c(OCCc3ccccc3)oc(=O)c2c1
Product: CCCOc1oc(=O)c2cc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc2c1Cl

Procedure:
7-(Boc-phenylalanyl)amino-4-chloro-3-propyloxyisocoumarin, 7-(benzoylalanylalanyl)amino-4-chloro-3-propyloxyisocoumarin, 7-(Boc-valyl)amino-4-chloro-3-ethoxyisocoumarin, 7-(Boc-alanyl)amino-4-chloro-3-ethoxyisocoumarin and 7-(Boc-alanyl)amino-4-chloro-3-(2-phenylethoxy)isocoumarin can be prepared by the same procedure.