Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9].[CH:13]1[CH:18]=[C:17]2[C:19]([CH:22]=O)=[CH:20][S:21][C:16]2=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[C:22]([C:19]1[C:17]3[CH:18]=[CH:13][CH:14]=[CH:15][C:16]=3[S:21][CH:20]=1)[NH:10][C:8]2=[O:9]
Reactant: O=Cc1csc2ccccc12
Reactant: COc1ccc(N)c(C(N)=O)c1
Product: COc1ccc2nc(-c3csc4ccccc34)[nH]c(=O)c2c1

Procedure:
Compound 19 was synthesized from 5-methoxy-2-aminobenzamide (9) (1.2 g, 7.3 mmol) and thianaphthene-3-carboxaldehyde (16) (1.2 g, 7.3 mmol): yield 1.3 g (60%); brown crystals; mp 289 to 290° C.; 1H NMR (DMSO-d6) δ 3.89 (3H, s, OCH3), 7.43-7.57 (4H, m, 4×ArH), 7.76-7.80 (1H, m, 1×ArH), 8.07-8.11 (1H, m, 1×ArH), 8.73 (1H, s, 1×ArH), 8.98-9.01 (1H, m, 1×ArH), 12.49 (1H, br s, NH) ppm; MS (ESI) m/z 308; Anal. (C14H12N2O2S): C, H, N.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1>CN(C)C=O>[OH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([NH:16][CH:3]=[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[NH:6][C:5]2=[O:15])=[CH:18][CH:19]=1
Reactant: Nc1ccc(CO)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2C1=CNc1ccc(CO)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (203 mg, 1.0 mmol) in N,N-dimethylformamide (2.5 mL) is added 4-aminobenzyl alcohol (123.2 mg, 1.0 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to ambient temperature, product precipitated out of solution. The product is recovered by filtration, rinsing with diethyl ether, and drying to yield 263.3 mg 4-[(4-Hydroxymethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[C:6]([CH2:8][NH2:9])[CH:7]=1.C([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])(OC(C)(C)C)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[C:6]([CH:7]=1)[CH2:8][NH:9][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][NH:22]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1cc(F)ccc1-n1cnnn1
Product: O=C(NCc1cc(F)ccc1-n1cnnn1)[C@@H]1CCCN1

Procedure:
The title compound was prepared essentially according to the procedures described in Example 26, Step B, starting from 1-[5-fluoro-2-(1H-tetraazol-1-yl)phenyl]methanamine and Boc-L-proline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18](OCC)=[O:19]>CC(C)=O>[Br:9][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:18](=[O:19])[C:17]([CH3:24])([CH3:23])[O:8][C:7]=2[CH:6]=1
Reactant: Nc1ncc(Br)cc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)Oc2cc(Br)cnc2NC1=O
Reaction time: 18 h
Yield: 84 %

Procedure:
To a mixture of 2-amino-5-bromopyridin-3-ol (0.500 g, 2.64 mmol) and K2CO3 (1.09 g, 7.93 mmol) in acetone (11.0 mL) was added ethyl bromoisobutyrate (0.50 mL, 3.4 mmol). The solution was stirred under N2 for 18 h and then heated to reflux. After 18 h, the solution was cooled and concentrated. The light-pink, sweet-smelling solid was dissolved in CH2Cl2 (50 mL) and MeOH (5 mL). The solution was diluted with H2O (150 mL) and then washed with CH2Cl2 (3×75 mL). The combined organic layers were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.57 g, 84%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.03 (d, J=1.2 Hz, 1H), 7.66 (d, 0.9 Hz, 1H), 1.43 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[C:16]([Cu])#[N:17]>CN1CCCC1=O.ClCCl>[C:16]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6])#[N:17]
Reactant: N#C[Cu]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C(=O)O)ccc1OC(F)(F)F
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
3-Bromo-4-(trifluoromethoxy)benzoic acid (1.4 g, 4.91 mmol) and cyanocopper (0.572 g, 6.39 mmol) were mixed in N-methyl-2-pyrrolidinone (NMP) (14 mL). The mixture was heated in a microwave at 200° C. for 2 h. The reaction was diluted with dichloromethane (150 mL). Celite® was added and the mixture was stirred vigorously for 10 min. The solids were removed by filtration. The organic layer was washed with water (125 mL) and concentrated. The residue was purified by HPLC to give the title compound as an off-white solid (0.979 g). LCMS m/z=232.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([NH:25][CH3:26])=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([N:25]([CH3:26])[C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:20]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (76 mg, 0.28 mmol, CAS RN 1271-19-8) was added to a solution of 6-chloro-N-methyl-4-o-tolylpyridin-3-amine (30 mg, 0.13 mmol, prepared as described in WO2005/002577) and DIPEA (50 μL, 0.29 mmol) in THF (1.5 mL). The reaction mixture was stirred overnight, filtered and all volatiles removed in vacuo. The desired product was isolated by flash chromatography on silica gel (25% EtOAc in n-hexane) as a waxy solid (48 mg, 79%). MS (ESI): m/z=472.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[CH:7][S:8][CH:9]=2)[NH:5][C:4](=[O:11])[C:3]=1[C:12]#[N:13].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:10]3[C:6](=[CH:7][S:8][CH:9]=3)[NH:5][C:4](=[O:11])[C:3]=2[C:12]#[N:13])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: N#Cc1c(Cl)c2cscc2[nH]c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C#N)c(=O)[nH]c3cscc23)CC1

Procedure:
Compounds of structure (II) with R2 as carbonitrile, and R1 and R3 as defined above were also prepared from intermediate 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (33). Intermediate 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (33), was reacted with tert-butyl-1-piperazine carboxylate to yield 7-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (36). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield intermediate of structure (37), which was deprotected and reacted with an appropriate acid chloride (R3—COCl) or acid (R3—COOH) to yield target compounds of structure (II) with R2 as carbonitrile, and R1 and R3 as defined above, as shown in Scheme 18.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:17]#[C:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[C:6]2[CH:17]=[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][C:7]=2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[Br:15])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Br)c(NC(C)=O)c(C#CC(C)(C)C)c1O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)c(NC(C)=O)c2cc(C(C)(C)C)oc12
Temperature: 25 °C
Yield: 81.5 %

Procedure:
Methyl 4-acetylamino-5-bromo-3-(3,3-dimethyl-1-butynyl)salicylate (I-250) (202 mg, 0.55 mmol) was dissolved in a mixed liquid of triethylamine (4 ml) and toluene (10 ml), and stirred with heating under reflux for 2 hours. After cooling to room temperature, the reaction liquid was concentrated under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane/ethyl acetate (2:1) gave the entitled compound (165 mg, 82%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C@@H:8]([CH3:12])[C:9]([OH:11])=O.[C:13]([O:17][C:18](=[O:26])[CH2:19][CH:20]([NH2:25])[CH:21]([OH:24])[CH2:22][F:23])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:13]([O:17][C:18](=[O:26])[CH2:19][CH:20]([NH:25][C:9](=[O:11])[C@@H:8]([N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])[CH3:12])[CH:21]([OH:24])[CH2:22][F:23])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: C[C@@H](C(=O)O)n1ccccc1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C[C@@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF)n1ccccc1=O
Temperature: 0 °C
Yield: 91.5 %

Procedure:
A stirred mixture of (S)-2-(2-Oxo-2H-pyridin-1-yl)-propionic acid (70 mg, 0.42 mmol), 3-Amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (91 mg, 0.44 mmol), HOAt (63 mg, 0.46 mmol) and DMAP (59 mg, 0.48 mmol) and anhydrous THF (5 ml) was cooled to 0° C. then EDC (88 mg, 0.46 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (3% methanol in ethyl acetate) to afford the title compound as a white foam (137 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 1.3-1.5 (9H, 2×s), 2.5-2.7 (2H, m), 3.4-3.7 (1H, m), 3.9-4.6 (4H, m), 5.4-5.6 (1H, m), 6.2-6.3 (1H, m), 6.5-6.6 (1H, m), 7.1-7.6 (3H, m); 19F NMR (376 MHz, CDCl3) δ −230.14, −230.14, −230.17, −230.95, −231.07.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]1[CH2:24][CH2:23][C@@H:22](O)[CH2:21]1.C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:22]1[CH2:23][CH2:24][N:20]([CH3:19])[CH2:21]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CC[C@@H](O)C1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1CC[C@@H](OC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (I3) (400 mg, 1.59 mmol) in THF (20 ml), were added (R)-1-methylpyrrolidin-3-ol (193 mg, 1.91 mmol), N,N′-methanediylidenedicyclohexanamine (394 mg, 1.91 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol (258 mg, 1.91 mmol). The reaction was stirred at RT for 15, hours, and then the solvent was evaporated. The residue was taken up with DCM, the insoluble was filtered off, and the clear solution was washed twice with aq. Na2CO3 and brine, dried over Na2SO4 and evaporated to obtain (R)-1-methylpyrrolidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (340 mg; 64% yield).
Reaction SMILES: C([O-])(=O)C.[Na+].Br[C:7]1[C:15]2[O:16][CH2:17][CH2:18][C:14]=2[C:13]2[C:12](=[O:19])[CH2:11][CH2:10][C:9]=2[C:8]=1Br.[H][H]>C(O)(=O)C.[C].[Pd]>[CH2:18]1[CH2:17][O:16][C:15]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][C:12](=[O:19])[C:13]=3[C:14]1=2
Reactant: [H][H]
Reactant: O=C1CCc2c(Br)c(Br)c3c(c21)CCO3
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCc2ccc3c(c21)CCO3

Procedure:
5% Palladium carbon (50% hydrous, 2.9 g) and sodium acetate (17.9 g, 0.22 mol) were added to a solution of 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (29.0 g, 87.4 mmol) in acetic acid (550 ml), and the mixture was catalytically reduced in a hydrogen atmosphere at ordinary temperature and ordinary pressure. After absorption of the calculated amount of hydrogen, the palladium carbon was filtered off and the solvent was distilled off under reduced pressure. Water was added to the residue and the organic matter was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous sodium chloride solution and water and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatogarphy (ethyl acetate:hexane=15:85) to give the target compound. The yield was 13.5 g (89%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:17]([O-])=O)[C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:17][C:7]1[C:8]([O:15][CH3:16])=[C:9]([CH:14]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: [H][H]
Reactant: COC(=O)c1cc(C(C)(C)C)cc([N+](=O)[O-])c1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C(C)(C)C)cc(N)c1OC
Reaction time: 12 h

Procedure:
2.7 g methyl 5-tert-butyl-2-methoxy-3-nitro-benzoate are dissolved in 120 ml of methanol, combined with 270 mg of 10% palladium on charcoal and hydrogenated for 12 hours at ambient temperature and 4 bar hydrogen pressure. Then the catalyst is filtered off, the solvents are eliminated in vacuo and the residue thus obtained is further reacted directly.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C:10]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC>C(O)(=O)C.[Zn]>[CH2:16]([O:15][C:13](=[O:14])[C:12]1[CH:23]=[C:24]([NH2:26])[CH:25]=[C:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:29])[CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1cc(C(=O)OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
In acetic acid (15 mL) was stirred 5-nitroisophthalic acid dibenzyl ester (1.3 g, 3.3 mmol). To this was added in parts zinc dust (1.75 g, 26.6 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was filtered free of insoluble material and the acetic acid solution evaporated at reduced pressure. This residue was dissolved in ethyl acetate (120 mL) and washed successively with saturated sodium bicarbonate solution (50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over magnesium sulfate and evaporated in vacuo to give a solid. The solid was stirred into ether (75 mL) and brought to reflux. The solution allowed to recrystallize to give 260 mg (22%) of a white solid. MS: M+1=362.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([NH2:27])=[CH:21][CH:22]=3)[C:17](=[O:28])[C:16]=2[CH:15]=1>C1COCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:13][C:14]2[CH:26]=[CH:25][C:24]3[C:23]4[C:18](=[CH:19][C:20]([NH:27][S:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=5)(=[O:11])=[O:10])=[CH:21][CH:22]=4)[C:17](=[O:28])[C:16]=3[CH:15]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc2c(c1)C(=O)c1cc(N)ccc1-2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2ccc3c(c2)C(=O)c2cc(NS(=O)(=O)c4cccc(OC)c4)ccc2-3)c1
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
3-Methoxybenzenesulfonyl chloride (4.75 g, 23.0 mmol) in THF (40 mL) was treated with the product from Example 16A (5.05 g, 24 mmol) in THF (60 mL) and pyridine (60 mL) over 10 minutes. After an additional 30 minutes, the mixture was quenched with a mixture of 1.0M (pH 6) aqueous potassium phosphate buffer (30 mL) and brine (20 mL). The aqueous phase was separated and extracted with diethyl ether. The organic phases were combined, washed 1.0M (pH 6) aqueous potassium phosphate buffer (10 mL) and brine (10 mL), and the aqueous phase was extracted with diethyl ether. All the organic phases were combined, dried (Na2SO4), concentrated, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/CH2Cl2). The appropriate fractions were concentrated, dissolved in a small quantity of hot methanol and triturated with diethyl ether. The resulting precipitate was collected by filtration and washed with (10% methanol/diethyl ether) to provide the title compound as an orange powder (3.51 g). 1H HNMR (DMSO-d6) δ 10.55 (bs, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.47 (t, J=8.0 Hz, 2H), 7.33 (d, J=7.6 Hz, 2H), 7.28-7.24 (m, 6H), 7.18 (dd, J=8.5, 2.1, 2H), 3.77 (s, 6H); MS calculated for (M+H): 550.0868; observed: 550.0848; IR 3232, 2971, 1719, 1599, 1466, 1256, 1155.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[C:16]2[C:15]3[C:14]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:1][CH2:2][CH2:3][C@H:4]1[C:16]2[C:15]3[C:14]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:20][CH2:19]4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:42])=[O:41]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CCC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCOS(C)(=O)=O)CCC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(13S)-13-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (490 mg, 1.09 mmol, 1.00 equiv) in DCM (20 mL) was added triethylamine (201 mg, 1.99 mmol, 1.80 equiv) and methanesulfonyl chloride (189 mg, 1.65 mmol, 1.50 equiv) at 0° C. The resulting solution was stirred for 2 h at room temperature and then washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to provide 530 mg of tert-butyl N-(4-[[(13S)-13-[2-(methanesulfonyloxy)ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid.
Reaction SMILES: [CH:1](OCC)=[O:2].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C@@H:13]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:15]([CH2:16][CH2:17][C@@H:18]3[C@@H:29]2[C:28](=[O:34])[CH2:27][C@@:26]2([CH3:35])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C:23](=[O:25])[CH3:24])[CH2:14]1.[H-].[Na+].CO>CS(C)=O>[CH:1]([CH2:24][C:23](=[O:25])[C@@H:22]1[C@:26]2([CH3:35])[C@H:19]([C@H:18]3[C@H:29]([C:28](=[O:34])[CH2:27]2)[C@:30]2([CH3:33])[C@H:15]([CH2:14][C@H:13]([O:12][CH:7]4[CH2:8][CH2:9][CH2:10][CH2:11][O:6]4)[CH2:32][CH2:31]2)[CH2:16][CH2:17]3)[CH2:20][CH2:21]1)=[O:2]
Reactant: CCOC=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: C[C@]12CC[C@@H](OC3CCCCO3)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CC=O)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 4 h

Procedure:
Ethyl formate (0.7 ml) was added to a mixture of 3α-(tetrahydropyran-2ξ-yloxy)-5α-pregnane-11,20-dione (840 mg) and sodium hydride (130 mg) in dry dimethyl sulphoxide (15 ml). The mixture was stirred, under nitrogen for 11/4 hrs., then treated with methyl alcohol to destroy excess sodium hydride, and poured into dilute hydrochloric acid. The precipitate was collected, washed and dried to give title compound (943 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:18][CH:15]([CH:16]=[CH2:17])[CH:4]([CH:5]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:6][CH:7]=O)[O:3]1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:19])[O:18][CH:15]([CH:16]=[CH2:17])[CH:4]([CH:5]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:6][CH:7]=[N:21][OH:22])[O:3]1
Reactant: C=CC1OC(C)(C)OC1C(CC=O)OC(C)OCC
Reactant: NO
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=CC1OC(C)(C)OC1C(CC=NO)OC(C)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The obtained 4,5-(dimethylmethylenedioxy)-3-(1-ethoxyethoxy)-6-heptenal was dissolved in 2 ml of pyridine under a nitrogen atmosphere, and 442 mg of hydroxylamine hydrochloride was added at 0° C. The mixture was stirred at room temperature for 4 hours, and the obtained reaction mixture was diluted with ether. The diluted reaction mixture was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford 1.00 g of 4,5-(dimethylmethylenedioxy)-3-(1-ethoxyethoxy)-6-heptenal oxime.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([Br:15])[CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH:30]([C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([Br:15])[CH:3]=1)=[O:31]
Reactant: Brc1cc(Br)c2c(c1)oc1ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc(Br)cc2oc3ccccc3c12
Temperature: -50 °C

Procedure:
To a stirred solution of the 1,3-dibromobenzofuran 11 (10 g, 30.9 mmol) in anhydrous THF (250 mL) at -78° C. under nitrogen was added a 2.5M butyllithium in hexane solution (13.6 mL, 33.9 mmol). The resulting red solution was warmed to -50° C. and held there for 10 min. before anhydrous DMF (2.6 mL, 33.9 mmol) was added dropwise. The resulting rust colored solution was stirred an additional 20 min. at -50° to -40° C. before being quenched with saturated ammonium chloride solution (25 mL). The THF was removed under vacuum and the residue was dissolved in ethyl acetate (EtOAc) and washed sequentially with water, saturated aqueous ammonium chloride solution, water and brine. The organic solution was then dried with magnesium sulfate and decolorized with Norite. The mixture was then filtered and concentrated under vacuum. The residue was triturated with ether/hexane to provide 4.0 g of pale yellow flakes of dibenzofuran 35. The mother liquor was then chromatographed (silica gel, 30% EtOAc in hexanes) to provide an additional 2.1 g of dibenzofuran 35 (total yield: 73%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([CH:9]=[CH:10][C:11]([NH:13][CH2:14][C:15]([N:17]([C:19]2[C:20]([Cl:28])=[C:21]([C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:22]Br)[CH3:18])=[O:16])=[O:12])=[CH:7][CH:6]=1)=[O:4].[CH2:31]([O:33][C:34]1[C:43]2[C:38](=[C:39]([OH:44])[CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([CH3:45])[CH:35]=1)[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:28][C:20]1[C:19]([N:17]([CH3:18])[C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[CH:10]=[CH:9][C:8]2[CH:29]=[CH:30][C:5]([C:3](=[O:4])[NH:2][CH3:1])=[CH:6][CH:7]=2)=[CH:26][CH:25]=[C:24]([Cl:27])[C:21]=1[CH2:22][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:38]=1[N:37]=[C:36]([CH3:45])[CH:35]=[C:34]2[O:33][CH2:31][CH3:32]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Reactant: CCOc1cc(C)nc2c(O)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C)nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)NC)cc4)c3Cl)cccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
To a solution of 3-[N-[4-(methylcarbamoyl)-cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyl bromide (60 mg) and 4-ethoxy-8-hydroxy-2-methylquinoline (24.9 mg) in dimethylformamide (0.6 ml) was added potassium carbonate (48.5 mg), and the mixture was stirred for 5 hours at ambient temperature. Water was added thereto, and the mixture was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]-amino]benzyloxy]-4-ethoxy-2-methylquinoline (67 mg) as an amorphous powder.