Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=1)[C:30](O)=[O:31])[CH3:25]>>[CH2:37]([O:36][C:34]1[CH:33]=[C:29]([CH:28]=[C:27]([O:26][CH2:24][CH3:25])[CH:35]=1)[C:30]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:31])[CH3:38]
Reactant: CCOc1cc(OCC)cc(C(=O)O)c1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCOc1cc(OCC)cc(C(=O)Nc2c[nH]nc2-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4CC)c1

Procedure:
3,5-Diethoxy-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3,5-diethoxybenzoic acid (186 mg, 0.89 mmol). The title compound was obtained as brown powder (99 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([OH:17])=O)[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[N+:27]([C:30]1[CH:65]=[CH:64][C:33]([CH2:34][O:35][C:36]([N:38]=[C:39]([NH:50][C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=2)=[O:52])[NH:40][CH2:41][C:42]([NH:44][C@H:45]2[CH2:49][CH2:48][NH:47][CH2:46]2)=[O:43])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(#N)C.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[N+:27]([C:30]1[CH:65]=[CH:64][C:33]([CH2:34][O:35][C:36]([N:38]=[C:39]([NH:50][C:51]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=2)=[O:52])[NH:40][CH2:41][C:42]([NH:44][C@H:45]2[CH2:49][CH2:48][N:47]([C:15]([C@@H:11]3[CH2:10][C@H:9]([S:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=4)[CH2:13][N:12]3[CH3:14])=[O:17])[CH2:46]2)=[O:43])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Reactant: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)CNC(=NC(=O)OCc4ccc([N+](=O)[O-])cc4)NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
1.09 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methylpyrrolidine-2-carboxylic acid were suspended in 30 ml of dry acetonitrile, and 691 mg of N,N'-carbonyldiimidazole were added to this suspension, after which the mixture was stirred at 40° C. for 1 hour. At the end of the time, the reaction mixture was cooled with ice, and 2.98 g of (3S)-3-[2-[2,3-bis(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidine trifluoroacetate in 30 ml of dry acetonitrile and 1.7 ml of diisopropylethylamine were added to the mixture, which was then stirred at room temperature overnight. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted with 10% and 20% methanol-ethyl acetate. The fraction containing the desired compound was concentrated by evaporation under reduced pressure to obtain 2.99 g of (2S,4S)-2-[(3S)-3-[2-[2,3-bis(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidin-1-ylcarbonyl]-4-(4-methoxybenzylthio)-1-methylpyrrolidine, as a powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:28][O:29][CH2:30]OCOCCl.OC1C=CC=CC=1C=O>ClCCCl>[CH3:28][O:29][CH2:30][O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: ClCOCOCOCCl
Solvent: O=Cc1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (10 g, 40 mmol) in 1,2-dichloroethane (200 mL) was added N,N-diisopropylethylamine (6.97 mL, 40 mmol) and the solution was stirred for 1 h at room temperature. Chloromethoxymethyl ether (3.77 mL, 50 mmol) was added and the reaction mixture was stirred for 1 h at room temperature and then refluxed for 16 h until no more hydroxybenzaldehyde was detected by TLC (Rf=0.78 for product and 0.70 for starting, material using 1:1 hexanes/EtOAc). The reaction mixture was cooled to room temperature and washed with water. The organic layer was concentrated and the residue applied to a silica gel column and eluted with mixture of pentane/EtOAc. The title compound was isolated in 100% yield as a brown oil.
Reaction SMILES: CO.[OH:3][C:4]1[CH:27]=[C:26]([O:28]COC)[CH:25]=[C:24]([O:32]COC)[C:5]=1[C:6](=[O:23])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]COC)=[C:11]([O:19]COC)[CH:10]=1.Cl.CO>O>[OH:3][C:4]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([OH:32])[C:5]=1[C:6](=[O:23])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:19])[CH:10]=1
Reactant: COCOc1cc(O)c(C(=O)C=Cc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccc(O)c(O)c1)c1c(O)cc(O)cc1O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
Then, 20 ml of methanol was added to 5.19 g of the so-obtained 2'-hydroxy-3,4,4',6'-tetrakis(methoxymethoxy)chalcone, and 40 ml of a hydrochloric acid/methanol reagent was added to the formed suspension and the mixture was stirred at 60° C. for 15 minutes. After the reaction, the reaction liquid was poured into water, and the precipitated crystal was recovered by filtration, washed with water and dried to obtain 2.81 g (yield=87.2%) of a crude crystal. The crude crystal was subjected to the column chromatography (200 g of 240-400 mesh Kieselgel 60; 0.3 kg/cm2 : eluting solvent: hexane/ethyl acetate=2/1, 2700 ml, hexane/ethyl acetate=1/1). Fractions of 50 ml were collected and the 92nd to 149th fractions were combined and concentrated to dryness to obtain 1.06 g (yield=32.9%) of 2',3,4,4',6'-pentahydroxychalcone.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])(=[O:20])=[O:21])[CH:18]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 4-fluoro-2-nitroaniline (1 mmol) in pyridine (3 mL), 5-bromo-2-methoxybenzenesulfonyl chloride (1.2 mmol) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (20 mL). The contents were washed with 10% aqueous HCl (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate to give 223 mg of 5-bromo-N-(4-fluoro-2-nitrophenyl)-2-methoxybenzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][CH3:22])=[CH:6]2.[H-].[Na+].F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH2:20][CH2:21][CH3:22])=[CH:6]2
Reactant: CCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 89 %

Procedure:
6-(Methyloxy)-2-phenyl-3-propyl-1-naphthalenol (97) (0.54 g, 1.86 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.66 g (89%) of the title compound (98) as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J=7.3 Hz, 3H), 1.40-1.55 (m, 2H), 2.53 (t, J=7.7 Hz, 2H), 3.94 (s, 3H), 6.67 (d, J=8.7 Hz, 2H), 7.05 (dd, J1=9.0 Hz, J2=2.5 Hz, 1H), 7.08-7.14 (m, 2H), 7.18 (d, J=2.5 Hz, 1H), 7.19-7.25 (m, 3H), 7.58-7.64 (m, 3H), 7.67 (d, J=9.2 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 397 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:45][O:46][C:47]1[CH:55]=[CH:54][C:50]([CH2:51][O:52][NH2:53])=[CH:49][CH:48]=1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[CH3:45][O:46][C:47]1[CH:55]=[CH:54][C:50]([CH2:51][O:52][NH:53][C:15](=[O:16])[C@H:14]([N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:18]([CH3:19])[CH3:20])=[CH:49][CH:48]=1
Reactant: COc1ccc(CON)cc1
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: COc1ccc(CONC(=O)[C@@H](C(C)C)N(Cc2cccnc2)S(=O)(=O)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride (2.41 g, 5.82 mmol), 1-hydroxybenzotriazole (0.786 g, 5.82 mmol), 4-methyl-morpholine (1.9 mL, 17.46 mmol), and O-(4-methoxybenzyl)hydroxylamine (1.78 g, 11.63 mmol) (prepared according to Pol. J. Chem. 55, 1163-1167 (1981)) are dissolved in methylene chloride (55 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.45 g, 7.57 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (ethyl acetate followed by 5% methanol/ethyl acetate) to give N-(4-methoxybenzyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanamide, m.p. 45°-53° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)NCc2c(C(=O)N(C)C)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
7-Chloro-3-[(4-methoxy-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 4-methoxybenzoic acid. MS calcd. for C27H24ClN3O4 [(M+H)+] 490.2, obds. 490.0.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCc3ccccc3)[nH]c2c1
Temperature: 70 °C

Procedure:
A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (1, 6.14 g, 18.3 mmol), 2-(benzyloxy)phenylboronic acid (5.00 g, 21.9 mmol) and potassium carbonate (5.80 g, 42 mmol) in 450 mL of 1,2-dimethoxyethane/water (4:1) was thoroughly flushed with argon. Then trans-BIS(triphenylphosphine)palladium(II) chloride (0.641 g, 0.91 mmol) was added and the reaction was heated at 70° C. under argon for 12 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethylacetate (AcOEt). Combined organic layers were washed with a saturated solution of NaHCO3 and brine, dried over anhydrous Na2SO4 and filtered. The filtered solution was concentrated under vacuum to give methyl 2-[2-(benzyloxy)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate 2: m/z=440 (M+H)+. Step 2
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13](=O)[CH2:14][S:15][C:16]3[NH:21][CH2:20][CH2:19][CH2:18][N:17]=3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13]3[N:21]4[CH2:20][CH2:19][CH2:18][N:17]=[C:16]4[S:15][CH:14]=3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(CSC1=NCCCN1)C1(c2ccc(Cl)cc2)CCC1
Agent: Br
Solvent: CC(=O)O
Product: Clc1ccc(C2(C3=CSC4=NCCCN34)CCC2)cc1
Temperature: 25 °C

Procedure:
A suspension of 1-[1-(4-chlorophenyl)cyclobutyl]-2-(3,4,5,6-tetrahydropyrimidin-2-ylthio)ethanone hydrobromide (3.4 g; prepared in a similar manner to that described above) in acetic acid (8.5 ml) was heated under reflux for 16 hours, then allowed to cool to ambient temperature. The solvent was removed in vacuo, the residue was triturated with ether (50 ml), and the resulting solid was collected by filtration, washed with ether (50 ml), and dried in vacuo at ambient temperature to give 3-[1-(4-chlorophenyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine hydrobromide as a white solid (3.0 g), m.p. 256° C.
Reaction SMILES: [C:1]([C@:4]1([OH:22])[CH2:13][C:12]2[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[C:6]2([S:21][CH2:20][CH2:19][S:18]2)[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1>[OH:22][C@@:4]1([CH:1]([OH:3])[CH3:2])[CH2:13][C:12]2[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[C:6]2([S:18][CH2:19][CH2:20][S:21]2)[CH2:5]1
Reactant: COc1ccc(OC)c2c1C[C@@](O)(C(C)=O)CC21SCCS1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1C[C@@](O)(C(C)O)CC21SCCS1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.5 %

Procedure:
16.48 g of (S)-3'-acetyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] were suspended in 1450 ml of dry tetrahydrofuran and 3.59 g of sodium borohydride were added to the mixture. The mixture was then stirred at room temperature under nitrogen for 4 hours. The solvent was removed by evaporation and the white residue was cooled to 0° C. 1500 ml of 5% ammonium chloride solution were added and the mixture was stirred at room temperature until the evolution of gas had ceased. The solution was extracted with three 500 ml portions of ethyl acetate and the combined ethyl acetate extracts were washed with 1000 ml of water, dried over magnesium sulphate and evaporated to give 17.65 g of (3'S)-1',2',3',4'-tetrahydro-3'-hydroxy-3'-(1-hydroxyethyl)-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in the form of a colourless gum which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14]3[C:15](=[O:22])[O:16][C:17]([CH:20]=[O:21])([CH3:19])[CH2:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CC(=CC)C.[O-:28]Cl=O.[Na+].[NH4+].[Cl-]>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14]3[C:15](=[O:22])[O:16][C:17]([CH3:19])([C:20]([OH:28])=[O:21])[CH2:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: [O-][Cl+][O-]
Reactant: CC1(C=O)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1(C(=O)O)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To 50 mg (0.16 mmol) of 43 in each of t-BuOH H2O is added 0.84 mL (7.9 mmol) of 2-methyl-but-2-ene, 71 mg (0.79 mmol) of NaClO2 and 76 mg (0.63 mmol) of NaH2PO4. The mixture stirred for 1 h, and then 20 mL of saturated NH4Cl is added. The mixture is extracted three times with 20 mL of EtOAc, and the extract is dried with MgSO4, filtered, and concentrated to provide 46 mg (0.14 mmol) of 44.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:36][CH2:37][CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:17]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]([CH2:36][CH2:37][CH3:38])=[N:10][C:11]=3[CH:16]=2)=[CH:34][CH:33]=1
Reactant: CCCc1nc2cc(N(Cc3ccc(Cl)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccc(Cl)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(4-Chloro-benzyl)-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.72 (m, 2H), 7.48 (m, 2H), 7.31 (m, 4H), 7.18 (d, 1H), 7.08 (d, 1H), 6.72 (dd, 1H), 4.81 (s, 2H), 4.35 (s, 2H), 2.67 (t, 2H), 1.72 (m, 2H), 0.94 (t, 3H). MS calculated for C25H23FClN3O4S—H: 514, observed: 514.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([O:18][CH3:19])[C:12]([O:20][CH3:21])=[CH:11]2.[N:22]([O-])=O.[Na+].C(OCC)(=O)C>Br.O.[Cu]>[CH3:19][O:18][C:13]1[C:12]([O:20][CH3:21])=[CH:11][C:10]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[C:8]1[C:9]=2[N:22]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: COc1cc2ccc(-c3ccccc3N)cc2cc1OC
Reactant: O=N[O-]
Agent: [Cu]
Agent: Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2ccc3c4ccccc4nnc3c2cc1OC
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
6-(2-Aminophenyl)-2,3-dimethoxynaphthalene (5, 70 mg, 0.25 mmol) was dissolved in 48% hydrobromic acid (4.25 mL), cooled in ice-salt bath, and treated dropwise with stirring with sodium nitrite (0.13 g) in water (2.2 mL). Stirring was continued for 0.5 h., and to the cold solution was then added with stirring freshly precipitated copper (0.5 g). The mixture was allowed to rise slowly to room temperature and left overnight. The solid was filtered off and washed with hot chloroform. The chloroform solution was washed with diluted sodium hydroxide solution, then with water, dried (anhydrous Na2SO4) and rotaevaporated to give the crude product. Chromatography on silica gel using 50:50 hexanes:ethyl acetate afforded the title compound (13 mg) in 18% yield; 1H NMR (CDCl3) d 4.11(3H, s), 4.24(3H, s), 7.37(1H, s), 7.89˜7.94 (2H, m), 8.14(1H, d, J=8.9), 8.41(1H, d, J=8.8), 8.61˜8.66(1H, m), 8.75˜8.80(1H, m), 9.24(1H, s); 13C NMR d 56.1, 56.4, 104.0, 107.3, 112.3, 116.5, 118.5, 121.7, 126.7, 128.6, 128.8, 131.1, 131.2, 131.9, 141.5, 146.3, 150.9, 151.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Yield: 73.6 %

Procedure:
A N,N-dimethylformamide solution (2.2 mL) of 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (329 mg, 1 mmol), and tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (277 mg, 1 mmol) is heated at 90° C. for 0.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide and ether to give 423 mg (74%) of the title compound as a yellow solid. MS (ESI) m/z 575.2 (M+H)+1
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][C@@H:9]([CH2:19][O:20][C:21]2[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][C:22]=2[F:30])[O:8][CH2:7]1)(=[O:3])[NH2:2]>C(OCC)(=O)C>[NH2:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:30])[C:21]=1[O:20][CH2:19][C@H:9]1[O:8][CH2:7][C@@H:6]([CH2:5][O:4][C:1](=[O:3])[NH2:2])[N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2c(F)cccc2[N+](=O)[O-])OC[C@H]1COC(N)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](COc2c(N)cccc2F)OC[C@H]1COC(N)=O
Reaction time: 16 h
Yield: 53.1 %

Procedure:
A solution of the product from step 4 (1.4 g, 3.3 mmol) was dissolved in ethyl acetate (50 mL) and the solution was de-gassed with a stream of nitrogen for 10 min. To the degassed solution was added 5% palladium on charcoal (400 mg), and the mixture was stirred under a hydrogen atmosphere at ambient pressure for 16 h. The catalyst was removed by filtration through a celite pad, and the filter cake was washed with CH2Cl2 (200 mL). The filtrate solvents were removed under reduced pressure. The residue was purified on a 12 g SiO2 column using 20-50% EtOAc in hexanes to provide the product (700 mg) as a white solid. LC MS: RT=3.49 min, M+H=400 (6 min gradient).
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=1.[O:16]=[C:17]1[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:35][C:36](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:29]1([C:22]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:20][CH2:19][N:18]([CH2:35][C:36]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=4)[N:14]=3)[C:17]2=[O:16])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)nc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)—N-hydroxy-6-(trifluoromethyl)nicotinimidamide (0.146 g, 0.711 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.200 g, 0.646 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.161 g, 0.840 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 3 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF15-12 column (Analogix®) and the product eluted using a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate over 30 minutes (Flow=30 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 9.44 (d, J=1.9, 1H), 8.56 (ddd, J=0.5, 2.0, 8.1, 1H), 7.95-7.75 (m, 1H), 7.43-7.08 (m, 10H), 4.94 (s, 2H), 3.65 (t, J=6.5, 2H), 2.84-2.57 (m, 2H), 1.93 (dtd, J=3.1, 6.4, 9.4, 2H).